GLP-1R modulating compound

Abstract

To provide methods for the treatment of diseases.SOLUTION: The present disclosure provides GLP-1R agonists, and compositions, methods, and kits thereof. Such compounds are generally useful for treating a GLP-1R mediated disease or condition. The present disclosure relates to compounds that bind to and act as agonists or modulators of the glucagon-like peptide-1 receptor (GLP-1R) and act as agonists or modulators of GLP-1R. The disclosure further relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions by the compounds.SELECTED DRAWING: None

Description

Technical Field

[0001] (Cross - reference to Related Applications) This application claims priority to U.S. Provisional Patent Application No. 62 / 967,289, filed on January 29, 2020. The content of this application is hereby incorporated by reference in its entirety into this specification.

[0002] (Field of the Invention) The present disclosure relates to compounds that bind to and act as agonists or modulators of the glucagon - like peptide - 1 receptor (GLP - 1R), and that act as agonists or modulators of GLP - 1R. The present disclosure further relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions by the compounds.

Background Art

[0003] Glucagon - like peptide - 1 (GLP - 1) is a peptide hormone secreted from enteroendocrine cells in the intestine in response to a meal. GLP - 1 is thought to play a role in the regulation of post - meal blood glucose by directly enhancing meal - induced insulin secretion from pancreatic β - cells, and in promoting satiety by delaying the transport of food through the intestine. GLP - 1 belongs to a family of G - protein - coupled receptors present on the cell membrane and mediates intracellular signaling via the GLP - 1 receptor (GLP - 1R), which can result in the accumulation of the secondary messenger cyclic adenosine monophosphate (cAMP) upon activation. Non - alcoholic steatohepatitis (NASH) may be associated with features of the metabolic syndrome including 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 such as exenatide, liraglutide, and dulaglutide that are approved for the management of type 2 diabetes. Such peptides are primarily administered by subcutaneous injection. Oral GLP-1 agonists are also being investigated for the treatment of type 2 diabetes. Some GLP-1R agonists, such as liraglutide, dulaglutide, and exenatide, are resistant to rapid degradation by dipeptidyl peptidase 4 and have a longer half-life than endogenous GLP-1.

[0005] There is still a need for compounds, such as agonists of GLP-1R, that have desirable therapeutic, metabolic, and / or ease of administration properties in the treatment of metabolic disorders and related diseases, including but not limited to NASH, obesity, and type 2 diabetes. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0006] In one embodiment, the present disclosure provides a compound of formula (I):

[0007] [Chemical formula] (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, heteroaryl, -C(O)N(R 1b )(R 1c ), -C(O)R 1b or -C(O)OR 1c and each of the above alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 Z 1 groups. Ring A is an aromatic ring, and U 1 , U 2 , U 3 is, independently of one another, -C(H)=, -C(Z 1a )=, or -N=, Ring B is C 6~10 aryl or heteroaryl, each of which is optionally substituted with 1 to 4 R 4 s, R 2 is H, 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, heteroaryl, -S-R 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 above alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 4 Z 1 s, X 1 , X 2 , and X 3 are each independently -N=, -C(H)=, or -C(R 8 )=, Y 1 and Y 2 are each -C(R y1 )(R y2 ), -N(R y1 ), -O-, -S-, -S(O)2-, or -C(O)-, W is -C(R 5 )- or -N-, wherein when W is -N, one of Y 1 and Y 2 is -C(R y1 )(Ry2 ) - or -C(O)-, and Y 1 and Y 2 the other of which is -C(R y1 )(R y2 ) -, -C(O)-, or -S(O)2-, R 3 is 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, heteroaryl, -CN, -NO2, -OR 3a , -C(O)R 3a , C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )2, -C(O)NHS(O)2R 3a , -C(O)NR 3a S(O)2R 3b , -C(O)NR 3a S(O)2NR 3b R 3c , -C(O)NR 3a -S(O)(=NR 3b )R 3c -S(O)2R 3a , -S(O)2OR 3a , -S(O)2N(R 3a )(R 3b ), -N(R 3a )S(O)2R 3b , -S(O)2NHC(O)R 3a , -S(O)(=NR 3a )R 3b , -S(O)(=NR 3a )NR 3b , -S(=NR 3a )(=NR 3b )R 3c , -P(O)(OR 3a )(R3b ), -P(O)(OR 3a )(OR 3b ), or -B(OR 3a )(OR 3b ), where alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 R 3d ; each R 3a , R 3b , and R 3c is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 2~8 alkoxyalkyl, -C 1~4 alkyl-N(R 9a )(R 9b ), -C 1~4 alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 alkyl-O-C(O)-C 1~4 alkyl, -C 1~4 alkyl-O-C(O)-O-C 1~4 alkyl, -C 1~4 alkyl-O-C(O)-C 1~4 alkyl-N(R 9a )(R 9b ), -C 1~4 alkyl-C 3~8 cycloalkyl, -C 1~4 alkyl-heterocyclyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, -P(O)(OR 9c )2, -OP(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d)、 -CH2P(O)(R 9c )(OR 9d )、 -OCH2P(O)(R 9c )(OR 9d )、 -C(O)OCH2P(O)(R 9c )(OR 9d )、 -P(O)(N(R 9c )2)2、 -OP(O)(N(R 9c )2)2、 -CH2P(O)(N(R 9c )2)2、 -OCH2P(O)(N(R 9c )2)2、 -C(O)OCH2P(O)(N(R 9c )2)2、 -P(O)(N(R 9c )2)(OR 9d )、 -OP(O)(N(R 9c )2)(OR 9d )、 -CH2P(O)(N(R 9c )2)(OR 9d )、 -OCH2P(O)(N(R 9c )2)(OR 9d )、 -C(O)OCH2P(O)(N(R 9c )2)(OR 9d )、 -P(O)(R 9c )(N(R 9d )2)、 -OP(O)(R 9c )(N(R 9d )2)、 -CH2P(O)(R 9c )(N(R 9d )2)、 -OCH2P(O)(R 9c )(N(R 9d )2)、 or -C(O)OCH2P(O)(R 9c )(N(R 9d )2), wherein said alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b ; each R 4 is independently C 1~9 alkyl, C 1~8 haloalkyl, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -O-R 4a , -C(O)R 4a , -C(O)O-R 4a , -C(O)N(R 4a )(R 4b ), -N(R 4a )(R 4b ), -N(R 4a )2(R 4b ) + , -N(R 4a )-C(O)R 4b , -N(R 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b )(R 4c ), -N(R 4a )S(O)2(R 4b ), -N(R 4a )S(O)2-N(R 4b )(R 4c ), -N(R 4a )S(O)2O(R 4b ), -OC(O)R 4a , -OC(O)OR 4a , -OC(O)-N(R 4a )(R 4b ), -S-R 4a , -S(O)R 4a , -S(O)(NH)R 4a , -S(O)2R 4a , -S(O)2N(R 4a )(R 4b ), -S(O)(NR 4a )R 4b , or -Si(R 4a )3, and the above alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b ; or alternatively, two R 4 groups bonded to adjacent ring atoms combine with the atoms to which they are attached to form a C5~10 forms a cycloalkyl or heterocyclyl, each of which is optionally substituted with 1 to 4 Zs 1b and is R 5 is H, cyclopropyl, or C 1~3 alkyl, and C 1~3 alkyl is optionally substituted with one, two or three groups selected from halogen, -OH, -OCH3, -CN, oxo, and -N(R x1 )(R x2 ), or alternatively, R 5 and R y1 are combined with the atom to which they are attached to form a C 3~10 cycloalkyl or heterocyclyl which is optionally substituted with oxo, R x1 and R x2 are each independently H, C 1~6 alkyl, C 3~10 cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)2N(R 6a1 )(NR 6a2 ), and C 1~6 alkyl, cycloalkyl or heterocyclyl is each optionally substituted with F, -CN, oxo, or C 3~6 cycloalkyl, or alternatively, R x1 and R x2 are combined with the atom to which they are attached to form a heterocyclyl which is optionally substituted with 1 to 4 Rs 6b1 , or V is -C(O)-, -O-, -N(R 6a )-, or -C(R 6b )(R 6c ), and R 6a is H, C 1~6 alkyl, C 3~10 cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)2N(R 6a1 )(NR 6a2) and cycloalkyl or heterocyclyl are each optionally substituted with C 1~6 alkyl, F, or -CN, each R 6b and R 6c is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkoxyalkyl, halogen, C 3~10 cycloalkyl, heterocyclyl, -C 1~6 alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 , or -N(R 6c2 )(R 6c3 ), and the above alkyl, cycloalkyl, or heterocyclyl is each optionally substituted with 1 to 4 R 6b1 s, or R 6b and R 6c combine with the atom to which they are attached to form C 3~10 cycloalkyl or heterocyclyl, and each of them is optionally substituted with 1 to 4 R 6b1 s, or R 6a or R 6c combines with one R 4 group and the atom to which they are attached to form C 5~10 cycloalkyl or heterocyclyl, and each of them is optionally substituted with 1 to 4 R 10 s, each R y1 and R y2 is independently H, halo, C 1~6 alkyl, C 1~6 haloalkyl, and the alkyl and haloalkyl are each optionally substituted with oxo, each R 3d , R 6b1 , and R 10 is independently C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, or -C(O)N(R 2a )(R 2b ) and where heterocyclyl or heteroaryl is optionally substituted with C 1~6 alkyl, C 1~6 haloalkyl, or C 1~6 haloalkoxy, each R 6a1 , R 6a2 , R 6c1 , R 6c2 , and R 6c3 is independently H, C 1~6 alkyl, or C 3~10 cycloalkyl, each R 9a and R 9b is independently H, C 1~6 alkyl, or C 1~6 haloalkyl, each Z 1 is independently C 1~9 alkyl, C 1~8 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R 12a , -C(O)-R 12a , -C(O)O-R 12a , -C(O)-N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a)C(O)-R 12b 、-N(R 12a )C(O)O-R 12b 、-N(R 12a )C(O)N(R 12b )(R 12c )、-N(R 12a )S(O)2(R 12b )、-NR 12a S(O)2N(R 12b )(R 12c )、-NR 12a S(O)2O(R 12b )、-OC(O)R 12a 、-OC(O)OR 12a 、-OC(O)-N(R 12a )(R 12b )、-S-R 12a 、-S(O)R 12a 、-S(O)(NH)R 12a 、-S(O)2R 12a 、-S(O)2N(R 12a )(R 12b )、-S(O)(NR 12a )R 12b 、 or -Si(R 12a )3, and the above alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1a s, and each Z 1a is independently C 1~9 alkyl, C 1~8 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -O-R 12a 、-C( O)R 12a 、-C(O)O-R 12a 、-C(O)N(R 12a )(R 12b)、 -N(R 12a )(R 12b )、 -N(R 12a )2(R 12b ) + 、 -N(R 12a )-C(O)R 12b 、 -N(R 12a )C(O)O(R 12b )、 -N(R 12a )C(O)N(R 12b )(R 12c )、 -N(R 12a )S(O)2(R 12b )、 -N(R 12a )S(O)2-N(R 12b )(R 12c )、 -N(R 12a )S(O)2O(R 12b )、 -OC(O)R 12a 、 -OC(O)OR 12a 、 -OC(O)-N(R 12a )(R 12b )、 -S-R 12a 、 -S(O)R 12a 、 -S(O)(NH)R 12a 、 -S(O)2R 12a 、 -S(O)2N(R 12a )(R 12b )、 -S(O)(NR 12a )R 12b 、 or -Si(R 12a )3, and the above alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b ; each R 8 or Z 1b is independently C 1~9 alkyl, C 1~8 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8(haloalkyl), -O(C 2~6 (alkenyl), -O(C 2~6 (alkynyl), -O(C 3~15 (cycloalkyl), -O(heterocyclyl), -O(C 6~10 (aryl), -O(heteroaryl), -NH(C 1~9 (alkyl), -NH(C 1~8 (haloalkyl), -NH(C 2~6 (alkenyl), -NH(C 2~6 (alkynyl), -NH(C 3~15 (cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 (aryl), -NH(heteroaryl), -N(C 1~9 (alkyl)2, -N(C 1~8 (haloalkyl)2, -N(C 2~6 (alkenyl)2, -N(C 2~6 (alkynyl)2, -N(C 3~15 (cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 (aryl)2, -N(heteroaryl)2, -N(C 1~9 (alkyl)(C 1~8 (haloalkyl), -N(C 1~9 (alkyl)(C 2~6 (alkenyl), -N(C 1~9 (alkyl)(C 2~6 (alkynyl), -N(C 1~9 (alkyl)(C 3~15 (cycloalkyl), -N(C 1~9 (alkyl)(heterocyclyl), -N(C 1~9 (alkyl)(C 6~10 (aryl), -N(C 1~9 (alkyl)(heteroaryl), -C(O)(C 1~9 (alkyl), -C(O)(C 1~8 (haloalkyl), -C(O)(C 2~6 (alkenyl), -C(O)(C 2~6 (alkynyl), -C(O)(C 3~15 (cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 (aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 (alkyl), -C(O)O(C1~8 (haloalkyl), -C(O)O(C 2~6 (alkenyl), -C(O)O(C 2~6 (alkynyl), -C(O)O(C 3~15 (cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 (aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 (alkyl), -C(O)NH(C 1~8 (haloalkyl), -C(O)NH(C 2~6 (alkenyl), -C(O)NH(C 2~6 (alkynyl), -C(O)NH(C 3~15 (cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 (aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 (alkyl)2, -C(O)N(C 1~8 (haloalkyl)2, -C(O)N(C 2~6 (alkenyl)2, -C(O)N(C 2~6 (alkynyl)2, -C(O)N(C 3~15 (cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 (aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1~9 (alkyl), -NHC(O)(C 1~8 (haloalkyl), -NHC(O)(C 2~6 (alkenyl), -NHC(O)(C 2~6 (alkynyl), -NHC(O)(C 3~15 (cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 (aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 (alkyl), -NHC(O)O(C 1~8 (haloalkyl), -NHC(O)O(C 2~6 (alkenyl), -NHC(O)O(C 2~6 (alkynyl), -NHC(O)O(C 3~15 (cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~ 10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(C 1~9 alkyl), -S(C 1~8 haloalkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(heterocyclyl), -S(C 6~10 aryl), -S(heteroaryl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(C 1~8 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)(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(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9(alkyl), or -S(O)2N(C 1~9 is (alkyl)2, In each case, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 3 C 1~9 alkyl, C 1~8 haloalkyl, halogen, -OH, -NH2, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 3~15 cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)2N(C 1~9 is 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, C 1~9 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b and each heteroaryl has 5 to 12 ring members and has 1 to 4 heteroatoms each independently being N, O, or S, each heterocyclyl has 3 to 12 ring members and has 1 to 4 heteroatoms each independently being N, O, or S), or a pharmaceutically acceptable salt thereof.

[0008] The present disclosure further provides pharmaceutical compositions, methods, and uses comprising the compounds of formula (I), or pharmaceutically acceptable salts thereof. For example, the compounds of the present disclosure are generally useful in methods of treating GLP-1R mediated diseases or conditions.

DETAILED DESCRIPTION OF THE INVENTION

[0009] I. Definitions 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 front or end of a chemical group is for convenience to indicate the point of attachment to the parent moiety, and the chemical group can be depicted with or without one or more dashes without losing their ordinary meaning. "C u~v " or "C u ~Cv Prefixes such as "C" indicate that the following group has u to v carbon atoms, where u and v are integers. For example, "C" 1~6 "alkyl" or "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0010] "Alkyl" is a monovalent or divalent straight-chain or branched saturated hydrocarbon radical. For example, an alkyl group has 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 1~4It may have an (alkyl). Examples 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 (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 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)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3), but are not limited thereto. The alkyl group may be unsubstituted or substituted.

[0011] "Alkoxy" refers to an -O-alkyl group, and 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 may be unsubstituted or substituted.

[0012] "Alkoxyalkyl" is an alkoxy group bonded to the alkyl 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. The alkoxyalkyl group can be unsubstituted or substituted.

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

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

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

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

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

[0018] "Cycloalkyl" is a monovalent or divalent single all-carbon ring or all-carbon ring-fused polycyclic system where the ring is a non-aromatic saturated or unsaturated ring in each instance. For example, in some embodiments, the cycloalkyl group has 3 to 12 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Exemplary monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Cycloalkyl also includes a fused polycyclic system having about 7 to 12 carbon atoms (e.g., a ring system containing two rings). The rings of the fused polycyclic system can be connected to each other via fused, spiro, or bridged bonds when 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. The cycloalkyl group can be unsubstituted or substituted.

[0019] "Alkylcycloalkyl" refers to alkyl as defined herein, where one or more hydrogen atoms of the alkyl are independently replaced by a cycloalkyl group, which can be the same or different. The alkyl group and the cycloalkyl group can be any of those described above. In some embodiments, the number of carbon atoms in the alkyl portion and the cycloalkyl portion can be specified separately (e.g., C 1~6 alkyl-C 3~12 cycloalkyl). The alkylcycloalkyl group can be unsubstituted or substituted.

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

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

[0022] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic system having at least one heteroatom (i.e., at least one cyclic (i.e., ring-shaped) heteroatom selected from oxygen, nitrogen, and sulfur) within the ring. Unless otherwise specified, a heterocyclyl group has from 3 to about 20 ring atoms, such as from 3 to 12 ring atoms, such as from 4 to 12 ring atoms, from 4 to 10 ring atoms, or from 3 to 8 ring atoms, or from 3 to 6 ring atoms, or from 3 to 5 ring atoms, or from 4 to 6 ring atoms, or from 4 to 5 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having from about 1 to 6 cyclic carbon atoms and from about 1 to 3 cyclic heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. The rings of a fused polycyclic (e.g., bicyclic heterocyclyl) system can be connected to each other via condensation, spiro, and bridging bonds when permitted by valence requirements. Heterocycles include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinacridine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 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. are included, but not limited thereto. The heterocyclyl group may be unsubstituted or substituted.

[0023] "Alkylheterocyclyl" refers to alkyl as defined herein, and one or more hydrogen atoms of the alkyl are independently replaced by a heterocyclyl group, which may be the same or different. The alkyl group and the heterocyclyl group may be any of the above as long as the alkyl is divalent. In some embodiments, the number of atoms in the alkyl moiety and the heterocyclyl moiety may be specified separately (e.g., C having 1 to 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] "Heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur, and "heteroaryl" also includes a fused polycyclic system having at least one such aromatic ring, which is further described below. Thus, "heteroaryl" includes a single aromatic ring of about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Sulfur atoms and nitrogen atoms may also be in oxidized forms, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also includes a fused polycyclic system (e.g., a ring system containing 2, 3, or 4 rings), and a heteroaryl group as defined above may be fused with one or more rings selected from heteroaryl (e.g., to form 1,8-naphthyridinyl) and aryl (e.g., to form benzimidazolyl or indazolyl) to form a fused polycyclic system. Thus, heteroaryl (a single aromatic ring or a fused polycyclic system) may have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms within the heteroaryl ring. For example, tetrazolyl has 1 carbon atom and 4 nitrogen heteroatoms within the ring. The rings of the fused polycyclic system can be connected to each other via fused bonds when permitted by valence requirements. It should be understood that the individual rings of the fused polycyclic system can be connected to each other in any order. It should be understood that the point of attachment of the heteroaryl or the fused polycyclic system of heteroaryl can be at any suitable atom (e.g., nitrogen) of the heteroaryl or heteroaryl fused polycyclic system containing carbon atoms and heteroatoms. Also, when referring to a particular atom range of heteroaryl (e.g., 5- to 10-membered heteroaryl), the atom range is with respect to the total ring atoms of the heteroaryl and is understood to include carbon atoms and heteroatoms. It should also be understood that the rings of the fused polycyclic system can include aryl rings fused to a heterocyclic ring having saturated or partially unsaturated bonds and having about 1 to 6 cyclic carbon atoms within the ring and about 1 to 3 cyclic heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur (e.g., 3-, 4-, 5-, 6-, or 7-membered rings).For example, 5-membered heteroaryl includes thiazolyl, and 10-membered heteroaryl includes quinolinyl. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolinyl, benzofuranyl, benzimidazolyl, thianaphthylenyl, pyrrolo[2,3-b]pyridinyl, quinazolin-4(3H)-one, triazolyl, and tetrazolyl. The heteroaryl group can be unsubstituted or substituted.

[0025] "Alkylheteroaryl" is alkyl as defined herein, and 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 group and the heteroaryl group can be any of those described above. In some embodiments, the number of atoms in the alkyl portion and the heteroaryl portion are specified separately (e.g., C alkyl-5-10 membered heteroaryl having 1-4 heteroatoms each independently being N, O, or S). The alkylheteroaryl group can be unsubstituted or substituted. 1~6 When used herein, "oxo" refers to =O.

[0026] As used herein, "substituted" means that one or more hydrogen atoms of the group are independently replaced by one or more substituents (e.g., 1, 2, 3, or 4, or more) as indicated.

[0027]

[0028] "The compounds of the present disclosure" include the compounds disclosed herein. For example, the compounds of the present disclosure include the compounds of the examples, the compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If).​

[0029] As used herein, "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, lubricant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent that has been approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock.

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

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

[0032] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to being useful for preparing a pharmaceutical composition suitable for veterinary or human pharmaceutical use and refers to a compound, salt, composition, dosage form, and other substances.

[0033] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as the free base. Pharmaceutically acceptable salts are non-toxic salts of the free base form of a compound that have the desired pharmacological activity. These salts can be derived from inorganic acids, organic acids, or bases. For example, a compound containing basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0034] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from suitable bases such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N(C1-C4 alkyl)4 + and the like. Also included are base addition salts such as sodium or potassium salts.

[0035] Also provided are the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms bonded to a carbon atom may be replaced by deuterium atoms or D, and n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds can enhance resistance to metabolism and, thus, may be useful for increasing the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 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 are replaced by deuterium. In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) contain one or more deuterium atoms.

[0036] Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Substitution with positron-emitting isotopes, for example, 11 C, 18 F, 15 O and 13N may be useful in positron emission topography (PET) studies for examining substrate receptor occupancy. The isotopically labeled compounds of formula (I) are generally prepared by conventional techniques known to those skilled in the art using appropriate isotopically labeled reagents in place of the previously used unlabeled reagents, or by processes similar to those described in the Examples below. It can be prepared by a process similar to that described.

[0037] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more chiral centers and, thus, can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry, or (D)- or (L)- for amino acids. This disclosure is intended to encompass all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using a chiral synthon or chiral reagents or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or, for example, chiral high pressure liquid It includes the resolution of racemic compounds (or racemic compounds of salts or derivatives) using chromatography, HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers and are not otherwise specified, these compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included. When the compounds are represented in their chiral forms, it is understood that the embodiments include, but are not limited to, specifically diastereomerically or enantiomerically enriched forms. When chirality is not specified but present, it is understood that the embodiments are directed to either a specifically diastereomerically or enantiomerically enriched form, or a racemic or scalemic mixture of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0038] As used herein, "stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, including "enantiomers" which refer to two stereoisomers that are mirror images of each other and whose molecules cannot be superimposed on each other.

[0039] As used herein, "tautomers" refer to a proton shift from one atom of a molecule to another atom of the same molecule. In some embodiments, the present disclosure includes tautomers of the compounds.

[0040] As used herein, "solvates" refer to the result of the interaction between 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.

[0041] As used herein, "hydrates" refer to the compounds of the present disclosure that are chemically associated with one or more molecules of water.

[0042] "Prevention" or "preventing" means any treatment of a disease or condition that does not cause the clinical symptoms of the disease or condition. In some embodiments, the compound can be administered to a subject (including humans) at risk or having a family history of a disease or condition.

[0043] As used herein, "prodrug" refers to a derivative of a drug that is converted into the parent drug following some chemical or enzymatic pathways upon administration into the human body. In some embodiments, the prodrug is a biologically inactive derivative of a drug that is converted into a biologically active parent drug following some chemical or enzymatic pathways upon administration into the human body.

[0044] As used herein, "treatment" or "treating" or "treat" refers to an approach for obtaining a beneficial or desired result. For the purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation and / or reduction in the degree of symptoms, and / or prevention of worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or reducing the degree of the disease or condition), b) delaying or halting the onset of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition), and c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, improving the disease state, delaying the progression of the disease, enhancing the quality of life, and / or extending the survival period.

[0045] As used herein, "at-risk individual" refers to an individual at risk of developing the condition to be treated. An "at-risk" individual may or may not have a detectable disease or condition, and may or may not present a detectable disease prior to treatment with the methods described herein. "At-risk" means that the individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing a disease or condition than an individual without these risk factors.

[0046] II. Compounds In some embodiments, the compounds of the disclosure have the formula (I):

[0047] [Chemical Formula] (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, heteroaryl, -C(O)N(R 1b )(R 1c ), -C(O)R 1b , or -C(O)OR 1c and each of the above alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 Z 1 and ring A is an aromatic ring, and U 1 , U 2 , U 3 are each independently -C(H)=, -C(Z 1a )=, or -N= ring B is C 6~10 aryl or heteroaryl, each of which is optionally substituted with 1 to 4 R4 is replaced by R 2 wherein R is H, 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, heteroaryl, -S-R 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 and wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1 ; X 1 , X 2 , and X 3 are each independently -N=, -C(H)=, or -C(R 8 )=; Y 1 and Y 2 are each -C(R y1 )(R y2 )-, -N(R y1 )-, -O-, -S-, -S(O)2-, or -C(O)-; W is -C(R 5 )- or -N-; wherein when W is -N, one of Y 1 and Y 2 is -C(R y1 )(R y2 )- or -C(O)-, and the other of Y 1 and Y 2 is -C(R y1 )(R y2 )-, -C(O)-, or -S(O)2-; R 3 is H, C 1~6 alkyl, C 1~6Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CN, -NO2, -OR 3a , -C(O)R 3a , -C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )2, -C(O)NHS(O)2R 3a , -C(O)NR 3a S(O)2R 3b , -C(O)NR 3a S(O)2NR 3b R 3c , -C(O)NR 3a -S(O)(=NR 3b )R 3c , -S(O)2R 3a , -S(O)2OR 3a , -S(O)2N(R 3a )(R 3b ), -N(R 3a )S(O)2R 3b , -S(O)2NHC(O)R 3a , -S(O)(=NR 3a )R 3b , -S(O)(=NR 3a )NR 3b , -S(=NR 3a )(=NR 3b )R 3c , -P(O)(OR 3a )(R 3b ), -P(O)(OR 3a )(OR 3b ), or -B(OR 3a )(OR 3b ), and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with 1 to 4 R 3dis replaced by, each R 3a , R 3b , and R 3c is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 2~8 alkoxyalkyl, -C 1~4 alkyl-N(R 9a )(R 9b ), -C 1~4 alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 alkyl-O-C(O)-C 1~4 alkyl, -C 1~4 alkyl-O-C(O)-O-C 1~4 alkyl, -C 1~4 alkyl-O-C(O)-C 1~4 alkyl-N(R 9a )(R 9b ), -C 1~4 alkyl-C 3~8 cycloalkyl, -C 1~4 alkyl-heterocyclyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, -P(O)(OR 9c )2, -OP(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -OCH2P(O)(R 9c )(OR 9d ), -C(O)OCH2P(O)(R 9c )(OR 9d ), -P(O)(N(R 9c )2)2, -OP(O)(N(R 9c)2)2, -CH2P(O)(N(R 9c )2)2, -OCH2P(O)(N(R 9c )2)2, -C(O)OCH2P(O)(N(R 9c )2)2, -P(O)(N(R 9c )2)(OR 9d ), -OP(O)(N(R 9c )2)(OR 9d ), -CH2P(O)(N(R 9c )2)(OR 9d ), -OCH2P(O)(N(R 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d ), -OP(O)(R 9c )(N(R 9d ), -CH2P(O)(R 9c )(N(R 9d ), -OCH2P(O)(R 9c )(N(R 9d ), or -C(O)OCH2P(O)(R 9c )(N(R 9d )2), and the above alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b . Each R 4 is independently C 1~9 alkyl, C 1~8 haloalkyl, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -O-R 4a , -C(O)R 4a , -C(O)O-R 4a , -C(O)N(R 4a )(R 4b)、 -N(R 4a )(R 4b )、 -N(R 4 a )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 、 -S-R 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, and the above alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b ; or alternatively, two R 4 groups bonded to adjacent ring atoms are combined with the above atoms to which they are bonded to form a C 5~10 cycloalkyl or heterocyclyl, each of which is optionally substituted with 1 to 4 Z 1b ; R 5 is H, cyclopropyl, or C 1~3 alkyl, provided that C 1~3Alkyl is optionally substituted with one, two or three groups selected from halogen, -OH, -OCH3, -CN, oxo, and -N(R x1 )(R x2 ), or R and R 5 and R y1 are combined with the atom to which they are attached to optionally form a C 3~10 cycloalkyl or heterocyclyl optionally substituted with oxo, R x1 and R x2 are each independently H, C 1~6 alkyl, C 3~10 cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)2N(R 6a1 )(NR 6a2 ), provided that C 1~6 alkyl, cycloalkyl or heterocyclyl is each optionally substituted with F, -CN, oxo, or C 3~6 cycloalkyl, or R and R x1 and R x2 are combined with the atom to which they are attached to optionally form a heterocyclyl substituted with 1 to 4 R 6b1 , V is -C(O)-, -O-, -N(R 6a )-, or -C(R 6b )(R 6c )-, R 6a is H, C 1~6 alkyl, C 3~10 cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)2N(R 6a1 )(NR 6a2 ), where cycloalkyl or heterocyclyl is each optionally substituted with C 1~6 alkyl, F, or -CN, each R 6b and R 6c is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6Alkoxyalkyl, 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 is each optionally substituted with 1 to 4 R 6b1 s, or alternatively, R 6b and R 6c combine with the atom to which they are attached to form a C 3~10 cycloalkyl or heterocyclyl, each of which is optionally substituted with 1 to 4 R 6b1 s, or alternatively, R 6a or R 6c combines with one R 4 group and the atom to which they are attached to form a C 5~10 cycloalkyl or heterocyclyl, each of which is optionally substituted with 1 to 4 R 10 s, and each R y1 and R y2 is independently H, halo, C 1~6 alkyl, C 1~6 haloalkyl, provided that alkyl and haloalkyl are each optionally substituted with oxo, each R 3d , R 6b1 , and R 10 is independently C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~10 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -OH, -CN, -NO2, or -C(O)N(R 2a )(R2b ) and provided that the heterocyclyl or heteroaryl is optionally substituted with C 1~6 alkyl, C 1~6 haloalkyl, or C 1~6 haloal alkoxy, each R 6a1 , R 6a2 , R 6c1 , R 6c2 , and R 6c3 is independently H, C 1~6 alkyl, or C 3~10 cycloalkyl, each R 9a and R 9b is independently H, C 1~6 alkyl, or C 1~6 haloalkyl, each Z 1 is independently C 1~9 alkyl, C 1~8 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R 12a , -C(O)-R 12a , -C(O)O-R 12a , -C(O)-N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ), + , -N(R 12a )C(O)-R 12b , -N(R 12a )C(O)O-R 12b , -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -NR12a S(O)2N(R 12b )(R 12c )、-NR 12a S(O)2O(R 12b )、-OC(O)R 12a 、-OC(O)OR 12a 、-OC(O)-N(R 12a )(R 12b )、-S-R 12a 、-S(O)R 12a 、-S(O)(NH)R 12a 、-S(O)2R 12a 、-S(O)2N(R 12a )(R 12b )、-S(O)(NR 12a )R 12b 、or -Si(R 12a )3, and the above alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1a groups, each Z 1a is independently C 1~9 alkyl, C 1~8 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -O-R 12a 、-C(O)R 12a 、-C(O)O-R 12a 、-C(O)N(R 12a )(R 12b )、-N(R 12a )(R 12b )、-N(R 12a )2(R 12b ) + 、-N(R 12a )-C(O)R 12b 、-N(R 12a )C(O)O(R 12b )、-N(R12a )(O)C(N(R 12b )(R 12c ), -N(R 12a )(O)S(R 12b ), -N(R 12a )(O)S(N(R 12b )(R 12c ), -N(R 12a )(O)S(O)(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -S-R 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )(R 12b , or -Si(R 12a )3, and the above alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b s, each R 8 or Z 1b is independently C 1~9 alkyl, C 1~8 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8(haloalkyl), -NH(C 2~6 (alkenyl), -NH(C 2~6 (alkynyl), -NH(C 3~15 (cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 (aryl), -NH(heteroaryl), -N(C 1~9 (alkyl)2, -N(C 1~8 (haloalkyl)2, -N(C 2~6 (alkenyl)2, -N(C 2~6 (alkynyl)2, -N(C 3~15 (cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 (aryl)2, -N(heteroaryl)2, -N(C 1~9 (alkyl)(C 1~8 (haloalkyl), -N(C 1~9 (alkyl)(C 2~ 6(alkenyl), -N(C 1~9 (alkyl)(C 2~6 (alkynyl), -N(C 1~9 (alkyl)(C 3~15 (cycloalkyl), -N(C 1~9 (alkyl)(heterocyclyl), -N(C 1~9 (alkyl)(C 6~10 (aryl), -N(C 1~9 (alkyl)(heteroaryl), -C(O)(C 1~9 (alkyl), -C(O)(C 1~8 (haloalkyl), -C(O)(C 2~6 (alkenyl), -C(O)(C 2~6 (alkynyl), -C(O)(C 3~15 (cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 (aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 (alkyl), -C(O)O(C 1~8 (haloalkyl), -C(O)O(C 2~6 (alkenyl), -C(O)O(C 2~6 (alkynyl), -C(O)O(C 3~15 (cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10Aryl), -C(O)O(Heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 Alkyl), -C(O)NH(C 1~8 Haloalkyl), -C(O)NH(C 2~6 Alkenyl), -C(O)NH(C 2~6 Alkynyl), -C(O)NH(C 3~15 Cycloalkyl), -C(O)NH(Heterocyclyl), -C(O)NH(C 6~10 Aryl), -C(O)NH(Heteroaryl), -C(O)N(C 1~9 Alkyl)2, -C(O)N(C 1~8 Haloalkyl)2, -C(O)N(C 2~6 Alkenyl)2, -C(O)N(C 2~6 Alkynyl)2, -C(O)N(C 3~15 Cycloalkyl)2, -C(O)N(Heterocyclyl)2, -C(O)N(C 6~10 Aryl)2, -C(O)N(Heteroaryl)2, -NHC(O)(C 1~9 Alkyl), -NHC(O)(C 1~8 Haloalkyl), -NHC(O)(C 2~6 Alkenyl), -NHC(O)(C 2~6 Alkynyl), -NHC(O)(C 3~15 Cycloalkyl), -NHC(O)(Heterocyclyl), -NHC(O)(C 6~10 Aryl), -NHC(O)(Heteroaryl), -NHC(O)O(C 1~9 Alkyl), -NHC(O)O(C 1~8 Haloalkyl), -NHC(O)O(C 2~6 Alkenyl), -NHC(O)O(C 2~6 Alkynyl), -NHC(O)O(C 3~15 Cycloalkyl), -NHC(O)O(Heterocyclyl), -NHC(O)O(C 6~10 Aryl), -NHC(O)O(Heteroaryl), -NHC(O)NH(C 1~9 Alkyl), -NHC(O)NH(C 1~8 Haloalkyl), -NHC(O)NH(C 2~6 Alkenyl), -NHC(O)NH(C 2~6(alkynyl), -NHC(O)NH(C 3~15 (cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10 (aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~9 (alkyl), -N(C 1~9 (alkyl)(S(O)(C 1~9 (alkyl), -S(C 1~9 (alkyl), -S(C 1~8 (haloalkyl), -S(C 2~6 (alkenyl), -S(C 2~6 (alkynyl), -S(C 3~15 (cycloalkyl), -S(heterocyclyl), -S(C 6~10 (aryl), -S(heteroaryl), -S(O)N(C 1~9 (alkyl)2, -S(O)(C 1~9 (alkyl), -S(O)(C 1~8 (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)(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(heteroaryl), -S(O)(NH)(C 1~9 (alkyl), -S(O)2NH(C 1~9 (alkyl), or -S(O)2N(C 1~9 (alkyl)2, and In each case, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 3 C 1~9 alkyl, C 1~8 haloalkyl, halogen, -OH, -NH2, -O(C1~9 (alkyl), -O(C 1~8 (haloalkyl), -O(C 3~15 (cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 (alkyl), -NH(C 1~8 (haloalkyl), -NH(C 3~15 (cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 (alkyl)2, -N(C 3~15 (cyclo (alkyl)2, -NHC(O)(C 1~8 (haloalkyl), -NHC(O)(C 3~15 (cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 (alkyl), -NHC(O)O(C 1~8 (haloalkyl), -NHC(O)O(C 2~6 (alkynyl), -NHC(O)O(C 3~15 (cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 (alkyl), S(O)2(C 1~9 (alkyl), -S(O)2(C 1~8 (haloalkyl), -S(O)2(C 3~15 (cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 (alkyl), -S(O)2NH(C 1~9 (alkyl), or -S(O)2N(C 1~9 (alkyl)2 and is substituted with each R 1b , R 1c , R 2a , R 2b , R 4a , R 4b , R 4c , R 9c , R 9d , R 12a , R 12b , and R12c is, independently, H, C 1~9 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b and each heteroaryl has 5 to 12 ring members and has 1 to 4 heteroatoms each independently being N, O, or S each heterocyclyl has 3 to 12 ring members and has 1 to 4 heteroatoms each independently being N, O, or S), a compound of or another compound of a formula described herein, or a pharmaceutically acceptable salt thereof

[0048] In some embodiments, the compounds of the disclosure are of formula (Ia):

[0049] [Chemical formula] (wherein ring B is C 6~10 aryl or heteroaryl, each of which is optionally substituted with 1 to 4 R 4 and R 2 is H, 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, heteroaryl, -S-R 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 and The above alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1 and is X 1 X 2 and X 3 are each independently -N=, -C(H)=, or -C(R 8 )=, R 3 is H, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~10 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, -CN, -NO2, -OR 3a , -C(O)R 3a , -C(O) OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )2, -C(O)NHS(O)2R 3a , -C(O)NR 3a S(O)2R 3b , -C(O)NR 3a S(O)2NR 3b R 3c , -C(O)NR 3a -S(O)(=NR 3b )R 3c , -S(O)2R 3a , -S(O)2OR 3a , -S(O)2N(R 3a )(R 3b ), -N(R 3a )S(O)2R 3b , -S(O)2NHC(O)R 3a , -S(O)(=NR 3a )R 3b , -S(O)(=NR 3a )NR3b 、 -S(=NR 3a )(=NR 3b )R 3c 、 -P(O)(OR 3a )(R 3b )、 -P(O)(OR 3a )(OR 3b )、 or -B(OR 3a )(OR 3b ) and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with 1 to 4 R 3d s, each R 3a , R 3b , and R 3c are independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 2~8 alkoxyalkyl, -C 1~4 alkyl-N(R 9a )(R 9b ), -C 1~4 alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 alkyl-O-C(O)-C 1~4 alkyl, -C 1~4 alkyl-O-C(O)-O-C 1~4 alkyl, -C 1~4 alkyl-O-C(O)-C 1~4 alkyl-N(R 9a )(R 9b ), -C 1~4 alkyl-C 3~8 cycloalkyl, -C 1~4 alkyl-heterocyclyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, -P(O)(OR 9c )2, -OP(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c) 2, -P(O)(R 9c )(OR 9d )、-OP(O)(R 9c )(OR 9d )、-CH2P(O)(R 9c )(OR 9d )、-OCH2P(O)(R 9c )(OR 9d )、-C(O)OCH2P(O)(R 9c )(OR 9d )、-P(O)(N(R 9c )2)2、-OP(O)(N(R 9c )2)2、-CH2P(O)(N(R 9c )2)2、-OCH2P(O)(N(R 9c )2)2、-C(O)OCH2P(O)(N(R 9c )2)2、-P(O)(N(R 9c )2)(OR 9d )、-OP(O)(N(R 9c )2)(OR 9d )、-CH2P(O)(N(R 9c )2)(OR 9d )、-OCH2P(O)(N(R 9c )2)(OR 9d )、-C(O)OCH2P(O)(N(R 9c )2)(OR 9d )、-P(O)(R 9c )(N(R 9d )2)、-OP(O)(R 9c )(N(R 9d )2)、-CH2P(O)(R 9c )(N(R 9d )2)、-OCH2P(O)(R 9c )(N(R 9d )2)、 or -C(O)OCH2P(O)(R 9c )(N(R 9d )2); wherein said alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b ; each R 4 is independently C 1~9 alkyl, C 1~8 haloalkyl, 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, heteroaryl, oxo, -NO2, -CN, -N3, -O-R 4a , -C(O)R 4a , -C(O)O-R 4a , -C(O)N(R 4a )(R 4b ), -N(R 4a )(R 4b ), -N(R 4a )2(R 4b ) + , -N(R 4a )-C(O)R 4b , -N(R 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b )(R 4c ), -N(R 4a )S(O)2(R 4b ), -N(R 4a )S(O)2-N(R 4b )(R 4c ), -N(R 4a )S(O)2O(R 4b ), -OC(O)R 4a , -OC(O)OR 4a , -OC(O)-N(R 4a )(R 4b ), -S-R 4a , -S(O)R 4a , -S(O)(NH)R 4a , -S(O)2R 4a , -S(O)2N(R 4a )(R 4b ), -S(O)(NR 4a )R 4b , or -Si(R 4a )3, and the above alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b . Alternatively, two Rs attached to adjacent ring atoms 4 groups, in combination with the atoms to which they are attached, form a C cycloalkyl or heterocyclyl, each of which is optionally substituted with 1 to 4 Zs 5~10 and 1b is substituted with R 5 is H, cyclopropyl, or C 1~3 alkyl, provided that the C 1~3 alkyl is optionally substituted with one, two or three groups selected from halogen, -OH, -OCH3, -CN, oxo, and -N(R x1 )(R x2 ) alternatively, R 5 and R y1 in combination with the atoms to which they are attached form an optionally oxo-substituted C 3~10 cycloalkyl or heterocyclyl R x1 and R x2 are each independently H, C 1~6 alkyl, C 3~10 cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)2N(R 6a1 )(NR 6a2 ), provided that the C 1~6 alkyl, cycloalkyl or heterocyclyl is each optionally substituted with F, -CN, oxo, or C 3~6 cycloalkyl alternatively, R x1 and R x2 in combination with the atoms to which they are attached form a heterocyclyl optionally substituted with 1 to 4 Rs 6b1 and V is -C(O)-, -O-, -N(R 6a )-, or -C(R 6b )(R 6c )- R 6a is H, C 1~6 alkyl, C 3~10cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl or heterocyclyl is each optionally substituted with C 1~6 alkyl, F, or -CN, each R 6b and R 6c is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkoxyalkyl, halogen, C 3~10 cycloalkyl, heterocyclyl, -C 1~6 alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 , or -N(R 6c2 )(R 6c3 ), and the alkyl, cycloalkyl, or heterocyclyl is each optionally substituted with 1 to 4 R 6b1 s, or R 6b and R 6c combine with the atom to which they are attached to form a C 3~10 cycloalkyl or heterocyclyl, each of which is optionally substituted with 1 to 4 R 6b1 s, or R 6a or R 6c combines with one R 4 group and the atom to which they are attached to form a C 5~10 cycloalkyl or heterocyclyl, each of which is optionally substituted with 1 to 4 R 10 s, each R y1 and R y2 is independently H, halo, C 1~6 alkyl, C 1~6 haloalkyl, provided that the alkyl and haloalkyl are each optionally substituted with oxo, each R 3d , R 6b1 , and R 10is, independently, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~10 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -OH, -CN, -NO2, or -C(O)N(R 2a )(R 2b ) provided that heterocyclyl or heteroaryl is optionally substituted with C 1~6 alkyl, C 1~6 haloalkyl, or C 1~6 haloalkoxy, each R 6a1 , R 6a2 , R 6c1 , R 6c2 , and R 6c3 is, independently, H, C 1~6 alkyl, or C 3~10 cycloalkyl, each R 9a and R 9b is, independently, H, C 1~6 alkyl, or C 1~6 haloalkyl, each Z 1 is, independently, C 1~9 alkyl, C 1~8 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R 12a , -C(O)-R 12a , -C(O)O-R 12a , -C(O)-N(R 12a )(R 12b ), -N(R 12a )(R12b )、 -N(R 12a )2(R 12b ) + 、 -N(R 12a )C (O)-R 12b 、 -N(R 12a )C(O)O-R 12b 、 -N(R 12a )C(O)N(R 12b )(R 12c )、 -N(R 12a )S(O)2(R 12b )、 -NR 12a S(O)2N(R 12b )(R 12c )、 -NR 12a S(O)2O(R 12b )、 -OC(O)R 12a 、 -OC(O)OR 12a 、 -OC(O)-N(R 12a )(R 12b )、 -S-R 12a 、 -S(O)R 12a 、 -S(O)(NH)R 12a 、 -S(O)2R 12a 、 -S(O)2N(R 12a )(R 12b )、 -S(O)(NR 12a )R 12b 、 or -Si(R 12a )3, and the above alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1a and each Z 1a is independently C 1~9 alkyl, C 1~8 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -O-R 12a, -C(O)R 12a , -C(O)O-R 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b , -N(R 12a )C(O)N(R 12b )(R 12c , -N(R 12a )S(O)2(R 12b , -N(R 12a )S(O)2-N(R 12b )(R 12c , -N(R 12a )S(O)2O(R 12b , -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b , -S-R 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b , -S(O)(NR 12a )R 12b , or -Si(R 12a )3, and the above alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b ; each R 8 or Z 1b is independently C 1~9 alkyl, C 1~8 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl)2, -N(heteroaryl)2, -N(C 1~9 alkyl)(C 1~8 haloalkyl), -N(C 1~9 alkyl)(C 2~6 alkenyl), -N(C 1~9 alkyl)(C 2~6 alkynyl), -N(C 1~9 alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH( C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1~9 alkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6(alkenyl), -NHC(O)O(C 2~6 (alkynyl), -NHC(O)O(C 3~15 (cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~10 (aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 (alkyl), -NHC(O)NH(C 1~8 (haloalkyl), -NHC(O)NH(C 2~6 (alkenyl), -NHC(O)NH(C 2~6 (alkynyl), -NHC(O)NH(C 3~15 (cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10 (aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~9 (alkyl), -N(C 1~9 (alkyl)(S(O)(C 1~9 (alkyl), -S(C 1~9 (alkyl), -S(C 1~8 (haloalkyl), -S(C 2~6 (alkenyl), -S(C 2~6 (alkynyl), -S(C 3~15 (cycloalkyl), -S(heterocyclyl), -S(C 6~10 (aryl), -S(heteroaryl), -S(O)N(C 1~9 (alkyl)2, -S(O)(C 1~9 (alkyl), -S(O)(C 1~8 (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)(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(C6~10 aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)2N(C 1~9 alkyl)2, and in each case, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 C 1~9 alkyl, C 1~8 haloalkyl, halogen, -OH, -NH2, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 3~15 cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9(alkyl), -S(O)2NH(C 1~9 (alkyl), or -S(O)2N(C 1~9 (alkyl)2 and is substituted with each R 1b , R 1c , R 2a , R 2b , R 4a , R 4b , R 4c , R 9c , R 9d , R 12a , R 12b , and R 12c is, independently, H, C 1~9 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, or heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b and is the subscript p is 1, 2, or 3, the subscript q is 0, 1, or 2, each heteroaryl has 5 to 12 ring members and has 1 to 4 heteroatoms each independently being N, O, or S, each heterocyclyl has 3 to 12 ring members and has 1 to 4 heteroatoms each independently being N, O, or S), or a compound of another formula described herein, or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the compounds of the disclosure are of formula (Ib):

[0051]

Chemical Formula

[0052] In some embodiments, the compounds of the disclosure are of formula (Ic):

[0053]

Chemical formula

[0054] In some embodiments, the compounds of the disclosure are of formula (Id):

[0055]

Chemical formula

[0056] In some embodiments, the compounds of the disclosure are of formula (Ie):

[0057] [Chemical formula] (wherein R 2 is H, 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, heteroaryl, -S-R2a 、 -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 and the above alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1 and R 3 is H, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~10 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, -CN, -NO₂, -OR 3a , -C(O)R 3a , -C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )₂, -C(O)NHS(O)₂R 3a , -C(O)NR 3a S(O)₂R 3b , -C(O)NR 3a S(O)₂NR 3b R 3c , -C(O)NR 3a -S(O)(=NR 3b )R 3c , -S(O)₂R 3a , -S(O)₂OR 3a , -S(O)₂N(R 3a )(R 3b ), -N(R 3a )S(O)₂R 3b , -S(O)₂NHC(O)R 3a , -S(O)(=NR 3a )R3b , -S(O)(=NR 3a )NR 3b , -S(=NR 3a )(=NR 3b )R 3c , -P(O)(OR 3a )(R 3b ), -P(O)(OR 3a )(OR 3b ), or -B(OR 3a )(OR 3b ), where alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 R 3d s, each R 3a , R 3b , and R 3c is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 2~8 alkoxyalkyl, -C 1~4 alkyl-N(R 9a )(R 9b ), -C 1~4 alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 alkyl-O-C(O)-C 1~4 alkyl, -C 1~4 alkyl-O-C(O)-O-C 1~4 alkyl, -C 1~4 alkyl-O-C(O)-C 1~4 alkyl-N(R 9a )(R 9b ), -C 1~4 alkyl-C 3~8 cycloalkyl, -C 1~4 alkyl-heterocyclyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, -P(O)(OR 9c )2, -OP(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -OCH2P(O)(OR9c ) 2, -C(O)OCH2P(O)(OR 9c ) 2, -P(O)(R 9c )(OR 9d )、-OP(O)(R 9c )(OR 9d )、-CH2P(O)(R 9c )(OR 9d )、-OCH2P(O)(R 9c )(OR 9d )、-C(O)OCH2P(O)(R 9c )(OR 9d )、-P(O)(N(R 9c )2)2、-OP(O)(N(R 9c )2)2、-CH2P(O)(N(R 9c )2)2、-OCH2P(O)(N(R 9c )2)2、-C(O)OCH2P(O)(N(R 9c )2)2、-P(O)(N(R 9c )2)(OR 9d )、-OP(O)(N(R 9c )2)(OR 9d )、-CH2P(O)(N(R 9c )2)(OR 9d )、-OCH2P(O)(N(R 9c )2)(OR 9d )、-C(O)OCH2P(O) (N(R 9c )2)(OR 9d )、-P(O)(R 9c )(N(R 9d )2)、-OP(O)(R 9c )(N(R 9d )2)、-CH2P(O)(R 9c )(N(R 9d )2)、-OCH2P(O)(R 9c )(N(R 9d )2)、 or -C(O)OCH2P(O)(R 9c )(N(R 9d )2), and the above alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b and each R4 is, independently, C 1~9 alkyl, C 1~8 haloalkyl, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -O-R 4a , -C(O)R 4a , -C(O)O-R 4a , -C(O)N(R 4a )(R 4b ), -N(R 4a )(R 4b ), -N(R 4a )2(R 4b ) + , -N(R 4a )-C(O)R 4b , -N(R 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b )(R 4c ), -N(R 4a )S(O)2(R 4b ), -N(R 4a )S(O)2-N(R 4b )(R 4c ), -N(R 4a )S(O)2O(R 4b ), -OC(O)R 4a , -OC(O)OR 4a , -OC(O)-N(R 4a )(R 4b ), -S-R 4a , -S(O)R 4a , -S(O)(NH)R 4a , -S(O)2R 4a , -S(O)2N(R 4a )(R 4b ), -S(O)(NR 4a )R 4b , or -Si(R 4a )3, and The above alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b and, alternatively, two R 4 groups bonded to adjacent ring atoms combine with the above atoms to which they are attached to form a C 5~10 cycloalkyl or heterocyclyl, each of which is optionally substituted with 1 to 4 Z 1b and, R 5 is H, cyclopropyl, or C 1~3 alkyl, provided that the C 1~3 alkyl is optionally substituted with one, two, or three groups selected from halogen, -OH, -OCH3, -CN, oxo, and -N(R x1 )(R x2 ), alternatively, R 5 and R y1 combine with the atoms to which they are attached to form a C 3~10 cycloalkyl or heterocyclyl optionally substituted with oxo, R x1 and R x2 are each independently H, C 1~6 alkyl, C 3~10 cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)2N(R 6a1 )(NR 6a2 ), and the C 1~6 alkyl, cycloalkyl, or heterocyclyl is each optionally substituted with F, -CN, oxo, or C 3~6 cycloalkyl, alternatively, R x1 and R x2 combine with the atoms to which they are attached to form a heterocyclyl optionally substituted with 1 to 4 R 6b1 , R 6a is H, C 1~6 alkyl, C 3~10Cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl or heterocyclyl is each optionally substituted with C 1~6 alkyl, F, or -CN, each R 6b and R 6c is independently H, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkoxyalkyl, halogen, C 3~10 cycloalkyl, heterocyclyl, -C 1~6 alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 , or -N(R 6c2 )(R 6c3 ), wherein the alkyl, cycloalkyl, or heterocyclyl is each optionally substituted with 1 to 4 R 6b1 s, or R 6b and R 6c combine with the atom to which they are attached to form a C 3~10 cycloalkyl or heterocyclyl, each of which is optionally substituted with 1 to 4 R 6b1 s, or R 6a or R 6c combines with one R 4 group and the atom to which they are attached to form a C 5~10 cycloalkyl or heterocyclyl, each of which is optionally substituted with 1 to 4 R 10 s, each R y1 and R y2 is independently H, halo, C 1~6 alkyl, C 1~6 haloalkyl, provided that the alkyl and haloalkyl are each optionally substituted with oxo, each R 3d , R 6b1 , and R 10is, independently, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~10 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -OH, -CN, -NO2, or -C(O)N(R 2a )(R 2b ) provided that heterocyclyl or heteroaryl is optionally substituted with C 1~6 alkyl, C 1~6 haloalkyl, or C 1~6 haloalkoxy, each R 6a1 , R 6a2 , R 6c1 , R 6c2 , and R 6c3 is, independently, H, C 1~6 alkyl, or C 3~10 cycloalkyl, each R 9a and R 9b is, independently, H, C 1~6 alkyl, or C 1~6 haloalkyl, each Z 1 is, independently, C 1~9 alkyl, C 1~8 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R 12a , -C(O)-R 12a , -C(O)O-R 12a , -C(O)-N(R 12a )(R 12b ), -N(R 12a )(R12b )、 -N(R 12a )2(R 12b ) + 、 -N(R 12a )C(O)-R 12b 、 -N(R 12a )C(O)O-R 12b 、 -N(R 12a )C(O)N(R 12b )(R 12c 、 -N(R 12a )S(O)2(R 12b 、 -NR 12a S(O)2N(R 12b )(R 12c 、 -NR 12a S(O)2O(R 12b 、 -OC(O)R 12a 、 -OC(O)OR 12a 、 -OC(O)-N(R 12a )(R 12b 、 -S-R 12a 、 -S(O)R 12a 、 -S(O)(NH)R 12a 、 -S(O)2R 12a 、 -S(O)2N(R 12a )(R 12b 、 -S(O)(NR 12a )R 12b 、 or -Si(R 12a )3, and the above alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1a and each Z 1a is independently C 1~9 alkyl, C 1~8 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -O-R 12a 、 -C(O)R12a 、 -C(O)O-R 12a 、 -C(O)N(R 12a )(R 12b )、 -N(R 12a )(R 12b )、 -N(R 12a )2(R 12b ) + 、 -N(R 12a )-C(O)R 12b 、 -N(R 12a )C(O)O(R 12b )、 -N(R 12a )C(O)N(R 12b )(R 12c )、 -N(R 12a )S(O)2(R 12b )、 -N(R 12a )S(O)2-N(R 12b )(R 12c )、 -N(R 12a )S(O)2O(R 12b )、 -OC(O)R 12a 、 -OC(O)OR 12a 、 -OC(O)-N(R 12a )(R 12b )、 -S-R 12a 、 -S(O)R 12a 、 -S(O)(NH)R 12a 、 -S(O)2R 12a 、 -S(O)2N(R 12a )(R 12b )、 -S(O)(NR 12a )R 12b 、 or -Si(R 12a )3, and the above alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b s, and each R 8 or Z 1b is independently C 1~9 alkyl, C 1~8 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~15 cycloalkyl, heterocyclyl, C 6~10Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O (C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl)2, -N(heteroaryl)2, -N(C 1~9 alkyl)(C 1~8 haloalkyl), -N(C 1~9 alkyl)(C 2~6 alkenyl), -N(C 1~9 alkyl)(C 2~6 alkynyl), -N(C 1~9 alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1~9 alkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6(alkenyl), -NHC(O)O(C 2~6 (alkynyl), -NHC(O)O(C 3~15 (cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~10 (aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 (alkyl), -NHC(O)NH(C 1~8 (haloalkyl), -NHC(O)NH(C 2~6 (alkenyl), -NHC(O)NH(C 2~6 (alkynyl), -NHC(O)NH(C 3~15 (cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10 (aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~9 (alkyl), -N(C 1~9 (alkyl)(S(O)(C 1~9 (alkyl), -S(C 1~9 (alkyl), -S(C 1~8 (haloalkyl), -S(C 2~6 (alkenyl), -S(C 2~6 (alkynyl), -S(C 3~15 (cycloalkyl), -S(heterocyclyl), -S(C 6~10 (aryl), -S(heteroaryl), -S(O)N(C 1~9 (alkyl)2, -S(O)(C 1~9 (alkyl), -S(O)(C 1~8 (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)(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(C6~10 aryl), -S(O)2(hetero aryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)2N(C 1~9 alkyl)2, and in each case, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 3 C 1~9 alkyl, C 1~8 haloalkyl, halogen, -OH, -NH2, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 3~15 cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9(alkyl), -S(O)2NH(C 1~9 (alkyl), or -S(O)2N(C 1~9 (alkyl)2 and is substituted with each R 1b , R 1c , R 2a , R 2b , R 4a , R 4b , R 4c , R 9c , R 9d , R 12a , R 12b , and R 12c is independently H, C 1~9 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~15 cycloalkyl, heterocyclyl, C 6~10 aryl, or heteroaryl, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 Z 1b and the subscript p is 1, 2, or 3, the subscript q is 0, 1, or 2, the subscript n is 0, 1, 2, or 3, each heteroaryl has 5 to 12 ring members and has 1 to 4 heteroatoms each independently being N, O, or S, each heterocyclyl has 3 to 12 ring members and has 1 to 4 heteroatoms each independently being N, O, or S), a compound of another formula described herein, or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the compounds of the disclosure are of formula (If):

[0059]

Chemical Formula

[0060] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 is, C 1~6 alkyl, C 1~6 haloalkyl, C3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is each optionally substituted with 1 to 4 Z 1 groups.

[0061] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 is C 6~10 Aryl, or heteroaryl, each of which is optionally substituted with 1 to 3 Z 1 groups.

[0062] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R1 is a 6-membered aryl or a 5- or 6-membered heteroaryl, which is substituted with 1, 2, or 3 groups selected from C 1~8 Haloalkyl, halogen, C 1~6 Alkoxy, -CN, and -C(O)-N(R 12a )(R 12b ).

[0063] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 is a 6-membered aryl or a 5- or 6-membered heteroaryl substituted with one or two -Cl, -F, or -CN.

[0064] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharmaceutically acceptable salt thereof, R 5 is hydrogen or methyl. In some embodiments, R 5 is methyl.

[0065] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Y 1 and Y 2At least one of which is -O-. In some embodiments, Y 1 and Y 2 are both -O-.

[0066] In some embodiments, the present disclosure provides a compound having the structure of formula (Ia) or formula (Ib):

[0067]

Chemical formula

[0068] In some embodiments, the present disclosure provides a compound having the structure of formula (Ia):

[0069]

Chemical formula

[0070] In some embodiments, the present disclosure provides a compound having the structure of formula (Ib):

[0071]

Chemical formula

[0072] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, each Z 1a is independently C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~10 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, -OH, -CN, -NO2, -OR 12a , -C(O)N(R 12a )(R 12b ), and each of them is optionally substituted with Z 1b .

[0073] In some embodiments of the compounds of formula (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, ring B is phenyl or a 5- to 6-membered heteroaryl, and phenyl or heteroaryl is optionally substituted with 1 to 4 R 4 . In some embodiments, ring B is

[0074]

Chemical formula

[0075] In some embodiments of the compounds of formula (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, ring B is

[0076]

Chemical formula

[0077] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are of formula (Ic) or formula (Id):

[0078]

Chemical formula

[0079] In embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), and / or (Id), or pharmaceutically acceptable salts thereof, X 1 、X 2 、and X 3 are each independently -CH=, -C(F)=, -C(Cl)=, -C(Br)=, or -C(CN)=.

[0080] In embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), and / or (Id), or pharmaceutically acceptable salts thereof, V is -O-, -NH-, or -CH2-.

[0081] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ie) or formula (If):

[0082]

Chemical formula

[0083]

[0065]

[0066] In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the structure of formula (Ig):

[0084]

Chemical formula

[0085] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, each Z 1 is independently C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~10 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, heterocyclyl-C 1~6 alkyl, heterocyclyl-C 1~6 halo Alkyl, heteroaryl-C 1~6 Alkyl, heteroaryl-C 1~6 Haloalkyl, oxo, -OH, -CN, -NO2, or -C(O)N(R 12a )(R 12b ) and heteroaryl or heterocyclyl are each optionally 1 to 4 halogens, C 1~6 Haloalkyl, C 3~6 Cycloalkyl or 4- to 6-membered heterocyclyl, or -CN.

[0086] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, each Z 1 is independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, halogen, oxo, -OH, -CN, or -NO2, C 3~10 Cycloalkyl, 3- to 12-membered heterocyclyl having 1 to 3 heteroatoms, or 5- to 10-membered heteroaryl having 1 to 3 heteroatoms. In some embodiments, each Z 1 is independently C 1~6 Haloalkyl, C 1~6 Haloalkoxy, halogen, -CN, or 5- to 6-membered heteroaryl having 1 to 3 heteroatoms. In some embodiments, each Z 1 is independently halogen, C 1~6 Haloalkyl, C 1~3 Alkoxy, C 3~10 Cycloalkyl, or -CN.

[0087] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, R 2 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, Heterocyclyl, C 6~10 Aryl, Heteroaryl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 1~6 Alkyl-Heterocyclyl, C 1~6 Alkyl-C 6~10 Aryl, C 1~6 Alkyl-Heteroaryl, C 1~6 Alkyl-C 3~10 Cycloalkyl-C 1~6 Alkyl, C 1~6 Alkyl-Heterocyclyl-C 1~6 Alkyl, -C(O)R 2a , -C(O)OR 2a , -C(O)N(R 2a )(R 2b ), -C(O)NR 2c S(O)2R 2a , -S(O)2R 2a , -S(O)2N(R 2a )(R 2b ), or -S(O)2NR 2c C(O)R 2a wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted with 1 to 4 Z 1b and each Z 1b is independently C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, C 2~6 alkenyl, C 2~6 alkynyl, halogen, C 3~10 cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, heterocyclyl-C 1~6 alkyl, heterocyclyl-C 1~6 haloalkyl, heteroaryl-C 1~6 alkyl, heteroaryl-C 1~6 haloalkyl, oxo, -OH, -CN, -NO2, or -C(O)N(R12a )(R 12b ) is.

[0088] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, R 2 is C 1~6 alkyl, C 3~10 cycloalkyl, heterocyclyl, heteroaryl, C 1~6 alkyl-C 3~10 cycloalkyl, C 1~6 alkyl-heterocyclyl, C 1~6 alkyl-C 3~10 cycloalkyl-C 1~6 alkyl, C 1~6 alkyl-heterocyclyl-C 1~6 alkyl, or C 1~6 alkyl-heteroaryl, and each of them is optionally substituted with 1 to 4 Z 1b . In some embodiments, R 2 is C 1~6 alkyl-C 3~10 cycloalkyl or C 1~6 alkyl-C 3~10 cycloalkyl-C 1~6 alkyl, and each of them is optionally substituted with 1 to 4 Z 1b .

[0089] In some embodiments, R 2 is

[0090]

Chemical formula

[0091] In some embodiments, R 2 is

[0092]

Chemical formula

[0093] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, R 3 is heteroaryl, -C(O)OH, -C(O)OR 3a , -C(O)N(R 3a )S(O)2(R 3b ), -S(O)2NHC(O)R 3a , or -C(O)N(R 3a )S(O)2N(R 3b )(R 3c ), wherein heteroaryl is optionally substituted with 1 to 4 R 3d s. In some embodiments, R 3 is 5- to 6-membered heteroaryl, optionally substituted with 1 to 4 R 3d s. In some embodiments, R 3 is -C(O)OR 3a . In some embodiments, R 3 is -C(O)OH.

[0094] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, each R 4 is independently C 1~6 alkyl, C 1~6 haloalkoxy, C 2~6 alkoxyalkyl, halogen, oxo, -CN, or -OR 4a . In some embodiments, each R 4 is independently C 1~6 alkyl, halogen, oxo, -CN, or -OR 4a . In some embodiments, each R 4 is independently C 1~6 alkyl, halogen, oxo, -OH, or -CN. In some embodiments, each R 4 is independently F, oxo, or -CN.

[0095] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharma- ceutically acceptable salts thereof, R 6a , H, C 1~6 Alkyl, C 3~10 In some embodiments, each R 6b and R 6c However, independently, H, C 1~3 Alkyl, F, Cl, or -CN.

[0096] Compounds of formula (I), (Ic), (Id), (Ie), (If), and / or (Ig) In some embodiments of the compound, or a pharma- ceutically acceptable salt thereof, the subscript n is 0, 1, or 2.

[0097] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharma- ceutically acceptable salts thereof, subscript p is 1 or 2.

[0098] In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharma- ceutically acceptable salt thereof, has the formula:

[0099] [ka]

[0100] [ka]

[0101] [ka]

[0102] [ka]

[0103] In vivo metabolites of the compounds described herein are also disclosed only to the extent that such products are novel and not obvious based on the prior art. Such products can result, for example, mainly from oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound by an enzymatic process. Accordingly, the process includes contacting the compound with a mammal for a period of time sufficient to obtain its metabolite, and includes novel and non-obvious compounds produced by the process. Such products are typically identified by preparing a radioactively labeled (e.g., 14 C or 3 H) compound, administering the compound to an animal such as a rat, mouse, guinea pig, monkey, etc., or a human at a detectible dose (e.g., about 0.5 mg / kg) parenterally, allowing sufficient time (typically about 30 seconds to 30 hours) for metabolism to occur, and isolating the conversion product from urine, blood or other biological samples. Since these products are labeled, they can be easily isolated (others are isolated by the use of antibodies that can bind to epitopes surviving in the metabolite). The metabolite structure is determined in a conventional manner, for example, by MS or NMR analysis. In general, the analysis of metabolites can be carried out in the same manner as conventional drug metabolism studies well known to those skilled in the art. The conversion product can be useful in diagnostic assays for the therapeutic administration of the compound, even if it does not have its own GLP-1R activity, unless it is separately found in vivo.

[0104] Recipes and methods for determining the stability of compounds in surrogate gastrointestinal secretions are known. A compound is defined herein as being stable in the gastrointestinal tract where less than about 50 mole percent of the protecting groups are deprotected in surrogate intestinal or gastric fluids when incubated at 37 °C for 1 hour. Simply, because compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. Prodrugs are typically stable in the digestive system but can be substantially hydrolyzed to the parent drug in the gastrointestinal lumen, liver, lung, or other metabolic organs, or generally intracellularly. As used herein, a prodrug is understood to be a compound that is chemically designed to efficiently release the parent drug after overcoming the biological barriers to oral delivery.

[0105] III. Methods for Preparing Compounds The compounds of the present disclosure can be prepared by any method known in the art. The following exemplary general methods illustrate the routes that can be used to obtain the compounds of the present disclosure.

[0106] [Chemical formula]

[0107] First, a compound of formula 1.3 can be constructed to obtain intermediate 1.2 by reacting intermediate 1.1 with an amine in the presence of a suitable base (e.g., DIPEA, KOtBu, etc.). This intermediate 1.2 can then be converted to intermediate 1.3 using suitable reduction conditions (e.g., H2 and Pd / C, Fe and HCl, etc.).

[0108] [Chemical formula]

[0109] The substituted diol of general structure 2.1 can be reacted with a ketone or aldehyde of general structure 2.2 under reflux in an aprotic solvent such as benzene, toluene, or xylene in the presence of a catalytic amount of a light acid catalyst such as p-toluenesulfonic acid to construct the compound of formula 2.7. In the process of this reaction, water can be removed by azeotropic distillation using a Dean-Stark trap or a molecular sieve. The catechol of formula 2.1 can also be reacted with the bis-halide of formula 2.3 in the presence of an organic base such as pyridine to form the compound of general structure 2.7. Further, an acetal or ketal of acyclic structure (no dotted line) or cyclic structure (dotted line present) 2.4 can be reacted with the catechol of formula 2.1 in the presence of either an acid or a base to obtain the compound of structure 2.7. Similarly, a thioacetal or thioketal of acyclic structure (no dotted line) or cyclic structure (dotted line present) 2.5 can be reacted with the catechol of formula 2.1 in the presence of a mercury salt, a mild oxidizing agent, or an alkylating agent to obtain the compound of structure 2.7. Further, R 1 is an aryl or heteroaryl alkyne of formula 2.6 can be reacted with the catechol of formula 2.1 in the presence of trityltetracarbonyl in an aprotic solvent such as toluene to form the compound of formula 2.7. The reactants are degassed with an inert gas such as argon or nitrogen and stirred at 100 °C.

[0110] [Chemical formula]

[0111] First, under standard amide bond formation conditions (e.g., with HATU and DIPEA etc.), by combining intermediate 3.1 with intermediate 1.3, exemplary compounds of formula (I) such as the compounds of formula (1g) above can be constructed. Intermediate 3.3 can be obtained by treatment with a suitable acid catalyst (e.g., HCl, AcOH etc.). Halogen-metal exchange from -X to -M can be achieved using a suitable reagent (e.g., iPrMgBr etc.), or transition metal coupling using a suitable palladium catalyst and metal source (e.g., B2Pin2, Bu6Sn2 etc.) to obtain intermediate 3.4. Then, this can be coupled to intermediate 2.7 using a suitable palladium catalyst to obtain intermediate 3.5. When R is methyl or ethyl, compound 3.5 can be converted to formula (Ig) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, Me3SnOH etc.). When R is tert-butyl, compound 3.5 can be converted to formula (Ig) in the presence of a protonic acid (e.g., trifluoroacetic acid etc.).

[0112]

Chemical formula

[0113] Exemplary compounds of formula (I) including the compounds of formula (Ig) above can be formed by first converting intermediate 2.7 to a variant of metal-oxidized intermediate 4.1 using a suitable palladium catalyst and metal source (e.g., bis(neopentyl glycolate) diboron, B2Pin2, Bu6Sn2 etc.). Then, this can be coupled to intermediate 3.3 using a suitable palladium catalyst to obtain intermediate 3.5. When R is methyl or ethyl, compound 3.5 can be converted to formula (Ig) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, Me3SnOH etc.). When R is tert-butyl, compound 3.5 can be converted to formula (Ig) in the presence of a protonic acid (e.g., trifluoroacetic acid etc.).

[0114] [Chemistry]

[0115] The compound of formula 5.1 can be obtained by reacting the compound of formula (I) with a sulfonamide under suitable coupling conditions (e.g., EDC and DMAP, etc.).

[0116] [Chemistry]

[0117] First, using a suitable coupling partner and a palladium catalyst, a bond is first formed to the halogen - X of intermediate 6.1 to obtain intermediate 6.2, and then this intermediate 6.2 is converted to compound 6.3 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.), whereby the compound of formula 6.3 can be constructed.

[0118] [Chemistry]

[0119] Protect the alcohol group of intermediate 7.1 (the protecting group Pg can be benzyl or trimethylsilylethoxymethyl) to construct a compound of formula (Ig) and obtain intermediate 7.2. Using a suitable transition metal catalyst (e.g., palladium, etc.), intermediate 7.2 can be cross - linked with an intermediate of type 3.4 to obtain intermediate 7.3. Then, This can be deprotected (e.g., when Pg is benzyl, using a metal catalyst and H2 gas, or when Pg is trimethoxysilylethoxymethyl, using, for example, HCl or TFA) to obtain Intermediate 7.4. Intermediate 7.4 can be reacted with a carbonyl-containing intermediate 2.2 or an alkyne intermediate 2.6 to access Intermediate 3.5 in a manner similar to the procedure described in Scheme 2. This can then be converted to Formula (Ig) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0120]

Chemical formula

[0121] Intermediate 2.7 can first be coupled with Intermediate 8.1 (obtained commercially or by metallation of the corresponding halide) using a suitable palladium catalyst to also construct a compound of Formula (Ig) to obtain Intermediate 8.2. Following conversion to acid 8.3 using standard conditions (e.g., LiOH, LiI, and pyridine, etc.), Intermediate 1.3 can be coupled using standard amide bond formation conditions (e.g., with HATU and DIPEA, etc.) to obtain Intermediate 8.4. This can then be converted to the corresponding benzimidazole 3.5 under the influence of an acid catalyst (e.g., HCl, AcOH, TFA, etc.), and thereafter, it can be converted to Formula (Ig) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0122]

Chemical formula

[0123] First, using a suitable coupling partner and a metal catalyst (e.g., a palladium catalyst, etc.), first bond to the halogen - X of intermediate 9.1 to construct a compound of formula 9.3 to obtain intermediate 9.2, and this intermediate 9.2 can be converted to compound 9.3 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0124] IV. Pharmaceutical Preparations In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient.

[0125] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, as more fully described hereinafter.

[0126] A pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof can be prepared with one or more pharmaceutically acceptable excipients that can be selected according to ordinary conventions. Tablets may contain excipients including lubricants, fillers, binders, etc. Aqueous compositions can be prepared in a sterile form and may generally be isotonic if delivery other than oral administration is intended. In some embodiments, the composition is described in Rowe et al, Handbook It may contain excipients such as those described in Pharmaceutical Excipients, 6th edition, American Pharmacists Association, 2009. Examples of excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, and stearic acid. In some embodiments, the composition is provided as a solid dosage form including a solid oral dosage form.

[0127] The composition is suitable for various routes of administration, including oral administration. The composition may be presented in unit dosage form and may be prepared by any of the methods known in the pharmaceutical art. Such methods include associating the active ingredient (e.g., a compound of the present disclosure or a pharmaceutically acceptable salt thereof) with one or more pharmaceutically acceptable excipients. The composition may be prepared by uniformly and intimately associating the active ingredient with a liquid excipient or a finely divided solid excipient or both, and then shaping the product, if necessary. Techniques and formulations are generally found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0128] The compositions described herein suitable for oral administration may be presented as discrete units (unit dosage forms) including, but not limited to, capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition of the present disclosure is a tablet.

[0129] The pharmaceutical compositions disclosed herein comprise one or more of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable excipients and optionally other therapeutic agents. The pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more excipients including sweetening agents, flavoring agents, coloring agents, and preserving agents to provide a palatable preparation. Tablets are acceptable which contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binding agents such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may or may not be coated and may include known techniques such as microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a long period of time and may be coated by known techniques

[0130] The amount of active ingredient that can be combined with an inert ingredient to produce a dosage form can vary depending on the intended treatment subject and mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain from about 1 to 1000 mg of active substance formulated with a suitable and convenient amount of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable excipients vary from about 5% to about 95% (weight:weight) of the total composition.

[0131] In some embodiments, a composition containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof in a variant form does not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, in one aspect, it is understood that a composition containing a compound of the present disclosure does not contain an agent that affects (e.g., delays, inhibits, or prevents) the metabolism of the compound of the present disclosure or any other active ingredient administered separately, sequentially, or simultaneously with the compound of the present disclosure. In one aspect, it is also understood that none of the methods, kits, articles of manufacture, etc. detailed herein contain an agent that affects (e.g., delays, inhibits, or prevents) the metabolism of the compound of the present disclosure or any other active ingredient administered separately, sequentially, or simultaneously with the compound of the present disclosure.

[0132] In some embodiments, the above pharmaceutical composition is for use in humans or animals.

[0133] The present disclosure further includes the compounds of the present disclosure for administration as a single active ingredient in a pharmaceutically acceptable composition that can be prepared by conventional methods known in the art, for example, by binding or mixing the active ingredient to a pharmaceutically acceptable, therapeutically inert organic and / or inorganic carrier or excipient. In one aspect, the use of the compounds of the present disclosure as a second or other active ingredient having a synergistic effect with other active ingredients in known drugs, or the co-administration of the compounds of the present disclosure with such drugs, is provided herein.

[0134] The compounds of the present disclosure may also be used in the form of prodrugs or other suitably modified forms that release the active ingredient in vivo.

[0135] V. Route of Administration The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route appropriate for the condition being 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). 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.

[0136] The compounds of the present disclosure can be administered to an individual according to an effective dosing regimen over 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 compound is administered daily or on an intermittent schedule over the lifetime of the individual.

[0137] The dosage or frequency of administration of the compounds of the present disclosure can be adjusted over the course of treatment based on the judgment of the administering physician.

[0138] 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.

[0139] 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 from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or for example from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example from about 0.01 mg / kg body weight to about 1 mg / kg body weight per day, or for example from about 0.05 mg / kg body weight to about 0.5 mg / kg body weight per day, or for example from about 0.3 mg to about 30 mg per day, or for example from about 30 mg to about 300 mg per day.

[0140] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compounds of the present disclosure (e.g., 1 mg to 1000 mg of the compound). The therapeutically effective amount can include from about 1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or for example from about 100 mg per dose to about 400 mg per dose, or for example from about 150 mg per dose to about 350 mg per dose, or for example from about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure 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 disclosure 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. Single doses can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In some embodiments, a single dose can be administered once a week. A single dose can also be administered once a month.

[0141] Also included in the present disclosure are kits comprising a compound of the present disclosure, or a mirror image isomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the foregoing. In one embodiment, the kit further includes instructions for use. In one aspect, the kit includes a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, a mixture of stereoisomers, a prodrug, or a deuterated analog, and a label and / or instructions for the use of the compound in the treatment of indications such as the diseases or conditions described herein. In one embodiment, a kit is provided that includes a compound of the present disclosure, or a pharmaceutically 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.

[0142] Also provided herein are articles of manufacture containing a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, a mixture of stereoisomers, a prodrug, or a deuterated analog, in a suitable container. The container can be a vial, a wide-mouth bottle, an ampoule, a filled syringe, and an infusion bag.

[0143] VI. Combination Therapy In some embodiments, a compound of the present disclosure or a pharmaceutically acceptable salt thereof can be combined with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 - 3, or 1 - 4) additional therapeutic agents. In some embodiments, the additional therapeutic agent is an apoptotic 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 combinations thereof.

[0144] In some embodiments, the therapeutic agent or combination of therapeutic agents is an ACE inhibitor, 2-acylglycerol O-acyltransferase 2 (DGAT2) inhibitor, acetaldehyde dehydrogenase inhibitor, Alstrom syndrome protein 1 (ALMS1) / PKC alpha inhibitor, or a combination thereof. Protein interaction inhibitor, apelin receptor agonist, acetyl-CoA carboxylase inhibitor, diacylglycerol O-acyltransferase 2 inhibitor, adenosine A3 receptor agonist, adiponectin receptor agonist, aldehyde dehydrogenase 2 stimulator, AKT protein kinase inhibitor, AMP-activated protein kinase (AMPK), AMP kinase activator, ATP citrate lyase inhibitor, AMP-activated protein kinase stimulator, endothelial nitric oxide synthase stimulator, NAD-dependent deacetylase sirtuin-1 stimulator, adrenergic receptor antagonist, androgen receptor agonist, amylin receptor agonist, angiotensin II AT-1 receptor antagonist, autophagy protein modulator, autotaxin inhibitor, Axl tyrosine kinase receptor inhibitor, Bax protein stimulator, β-catenin inhibitor, bioactive lipid, calcitonin agonist, cannabinoid receptor modulator, caspase inhibitor, caspase-3 stimulator, cathepsin inhibitor, caveolin-1 inhibitor, CCL26 gene inhibitor, CCR2 chemokine antagonist, CCR2 chemokine antagonist, angiotensin II AT-1 receptor antagonist, CCR3 chemokine antagonist, CCR5 chemokine antagonist, CD3 antagonist, chloride channel stimulator, CNR1 inhibitor, connective tissue growth factor ligand inhibitor, cyclin D1 inhibitor, cytochrome P450 7A1 inhibitor, DGAT1 / 2 inhibitor, diacylglycerol O-acyltransferase 1 inhibitor (Diacylglycerol O acyltransferase 1 inhibitor, DGAT1), cytochrome P450 2E1 inhibitor (Cytochrome P450 2E1inhibitor, CYP2E1), CXCR4 chemokine antagonist, dihydroceramide δ4 desaturase inhibitor, dihydroorotate dehydrogenase inhibitor, dipeptidyl peptidase IV inhibitor, endocianlin modulator, eotaxin ligand inhibitor, extracellular matrix protein modulator, farnesoid X receptor agonist, fatty acid synthase inhibitor, FGF1 receptor agonist, fibroblast growth factor (Fibroblast growth factor, FGF-15, FGF-19, FGF-21) ligand, fibroblast activation protein inhibitor, galectin-3 inhibitor, GDNF family receptor α-like agonist, glucagon receptor agonist, glucagon-like peptide 1 agonist, glucocorticoid receptor antagonist, glucose 6-phosphate 1-dehydrogenase inhibitor, G-protein coupled bile acid receptor 1 agonist, G-protein coupled receptor 84 antagonist, Hedgehog (Hh) modulator, hepatitis C virus NS3 protease inhibitor, hepatocyte nuclear factor 4 alpha modulator, HNF4A), hepatocyte growth factor modulator, his tone deacetylase inhibitor, STAT-3 modulator, HMG CoA reductase inhibitor, HSD17B13 gene inhibitor, hydrolase inhibitor, hypoxia-inducible factor-2α inhibitor, IL-10 agonist, IL-17 antagonist, IL-22 agonist, ileal bile acid sodium cotransporter inhibitor, insulin sensitizer, insulin ligand agonist, insulin receptor agonist, integrin modulator, integrin antagonist, integrin α-V / β-1 antagonist, integrin α-V / β-6 antagonist, interleukin-1 receptor-associated kinase 4 (intereukin-1 receptor-associated kinase 4, IRAK4) inhibitor, IL-6 receptor agonist, interleukin 17 ligand inhibitor, Jak2 tyrosine kinase inhibitor, Jun N-terminal kinase-1 inhibitor Pesticide, Kelch-like ECH-associated protein 1 modulator, Ketohexokinase (KHK) inhibitor, Klotho β stimulator, 5-lipoxygenase inhibitor, lipoprotein lipase inhibitor, liver X receptor, LPL gene stimulator, lysophosphatidate-1 receptor antagonist, lysyl oxidase homolog 2 inhibitor, LXR inverse agonist, macrophage mannose receptor 1 modulator, Matrix metalloproteinase (MMP) inhibitor, MEKK-5 protein kinase inhibitor, MCH receptor-1 antagonist, membrane copper amine oxidase (VAP-1) inhibitor, methionine aminopeptidase-2 inhibitor, methyl CpG-binding protein 2 modulator, MicroRNA-132 (miR-132) antagonist, MicroRNA-21 (miR-21) inhibitor, mitochondria uncoupling agent, mixed lineage kinase-3 inhibitor, myelin basic protein stimulator, NACHT LRR PYD domain protein 3 (NACHT LRR PYD domain protein 3, NL RP3) inhibitor, NAD-dependent deacetylase sirtuin stimulator, NADPH oxidase inhibitor (NADPH oxidase inhibitor, NOX), nicotinic acid receptor 1 agonist, P2Y13 purinergic receptor stimulator, nuclear erythroid 2-related factor 2 stimulator, nuclear receptor modulator, P2X7 purinergic receptor modulator, PACAP type I receptor agonist, PDE3 inhibitor, PDE4 inhibitor, PDE5 inhibitor, PDGF receptor β modulator, phenylalanine hydroxylase stimulator, phospholipase C inhibitor, PPARα agonist, PPARδ agonist, PPARγ agonist, peptidyl-prolyl cis-trans isomerase A inhibitor, PPARγ modulator, protease-activated receptor-2 antagonist, protein kinase modulator, PTGS2 gene inhibitor, resistin / CAP1 (adenylyl cyclase associated protein 1. Adenylyl cyclase-related protein 1) Interaction inhibitor, Rho-related protein kinase inhibitor, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitor, sodium glucose transporter-2 inhibitor, SREBP transcription factor inhibitor, STAT-1 inhibitor, stearoyl-CoA desaturase-1 inhibitor, STK25 inhibitor, cytokine signaling-1 stimulator inhibitor, cytokine signaling-3 stimulator inhibitor, telomerase stimulator, TERT gene modulator, TGFβ (TGFB1) ligand inhibitor, TNF antagonist, Transforming growth factor β (TGF-β), Transforming growth factor β-activated kinase 1 (TAK1), thyroid hormone receptor β agonist, TLR-4 antagonist, TLR-9 antagonist, VDR agonist, transglutaminase inhibitor, tyrosine kinase receptor modulator, GPCR modulator, nuclear hormone receptor modulator, WNT modulator, or YAP / TAZ modulator and zonulin inhibitor.

[0145] Non-limiting examples of one or more additional therapeutic agents include the following. - ACE inhibitors such as enalapril, - Aldehyde dehydrogenase inhibitors such as ADX-629, - Acetyl-CoA carboxylase (ACC) inhibitors such as NDI-010976 (filocostat), DRM-01, gemcabene, PF-05175157, QLT-091382 or 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, CGS21680, - Adenosine A3 receptor antagonists such as FM-101, - Adiponectin receptor agonists such as ADP-355, ADP-399, - Adrenergic receptor antagonists such as bromocriptine, VI-0521, - Aldehyde dehydrogenase 2 stimulants such as FP-045, - α-glucosidase inhibitors (e.g., voglibose, acarbose, or miglitol), - Amylin / calcitonin receptor agonists such as KBP-042, KBP-089, - AMP-activated protein kinase stimulants such as PXL-770, 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 stimulants such as NS-0200 (leucine + metformin + sildenafil), - Androgen receptor agonists such as LPCN-1144, LPCN-1148, - Angiotensin II AT-1 receptor antagonists such as irbesartan, - Angiopoietin-related protein-3 inhibitors such as IONIS-ANGPTL3-LRx, - Apelin receptor agonists such as CB-5064, - Anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), - Autophagy protein modulators such as A-2906, - Autotaxin inhibitors such as 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 bemcentinib (BGB-324, R-428), - Bax protein stimulants such as CBL-514, - Bioactive lipids such as DS-102, - Biguanides such as metformin, - Cannabinoid receptor modulators such as namacimab, GWP-42004, REV-200, CRB-4001, SCN-002, - Caspase inhibitors such as emricasan, - Total cathepsin B inhibitors such as VBY-376, - Total cathepsin inhibitors such as VBY-825, - CCL26 gene inhibitors such as KDDF-201410-10, - CCR2 / CCR5 chemokine antagonists such as cenicriviroc, maraviroc, CCX-872, 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 belimumab, - CD3 antagonists such as NI-0401 (foralumab), - Chloride channel stimulants such as cobiprostone and lubiprostone, - Casein kinase-1 (CK1) δ / ε 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, PF-06865571, - Inhibitors of diglyceride acyltransferase 1 (DGAT1), such as GSK-3008356, - Inhibitors of diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 (CYP2E1), such as SNP-610 , CYP2E1), - Inhibitors of dihydroorotate dehydrogenase, such as vidofludimus - Dipeptidyl peptidase IV inhibitors, such as linagliptin, evogliptin, sitagliptin, vildagliptin, saxagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, treagliptin, dutogliptin, or omarigliptin - Eotaxin ligand inhibitors, such as belimumab, CM-101 - Extracellular matrix protein modulators, such as CNX-024 - Farnesoid X receptor (FXR) agonists, such as AGN-242266, AGN-242256, EP-024297, RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, GS-9674, HPG-1860, LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M-480, MET-409, PX20606, EYP-001, TERN-101, TC-100, INT-2228, ZG-5266, or silofexol - 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, FT8225 - Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as NGM-282 - Fibroblast growth factor 21 (FGF-21) ligands, such as BMS-986171, BIO89-100, 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), AKR-001, - FGF receptor agonists / Klotho β stimulators such as BFKB-8488A (RG-7992), - Galectin-3 inhibitors such as GR-MD-02, GB-1107 (Gal-300), GB1211 (Gal-400), - GDNF family receptor α-like agonists such as NGM-395, - Glitazars such as saroglitazar, aleglitazar, muraglitazar, or tesaglitazar, - Glitazones (e.g., pioglitazone, rosiglitazone, balaglitazone, riboglitazone, or lobeglitazone), - Glucagon-like peptide 1 (Glucagon-like peptide 1, GLP-1R) agonists such as ALT-801, AC-3174, liraglutide, cotadutide (MEDI-0382), SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, semaglutide, - Gastric inhibitory polypeptide / glucagon-like peptide-1 (GIP / GLP-1) receptor co-agonists such as tilsepide (LY-3298176), - PEGylated long-acting glucagon-like peptide-1 / glucagon (GLP-1R / GCG) receptor dual agonists such as DD-01, - Glucocorticoid receptor antagonists such as CORT-118335 (millicorilant), - Glucose 6-phosphate 1-dehydrogenase inhibitors such as ST001, ​​- Glucokinase stimulators such as sinoglitin (RO-5305552) - G protein-coupled bile acid receptor 1 (TGR5) agonists such as RDX-009 and INT-777 - GPR40 agonists (FFAR1 / FFA1 agonists, e.g., fasiglifam) - Glucose-dependent insulinotropic peptide (GIP) and their analogs - 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, simvastatin - HSD17B13 gene inhibitors such as ARO-HSD - Hydrolase inhibitors such as ABD-X - Hypoxia-inducible factor-2α inhibitors such as PT-2567 - IL-10 agonists such as peg-ilodecakin - Ileal sodium bile acid cotransporter inhibitors such as odesivabat (A-4250), volixibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, elobixibat (A-3309) - Insulin sensitizers such as KBP-042, MSDC-0602K, MSDC-5514, Px-102, RG-125 (AZD4076), trimidone, VVP-100X, CB-4211, ETI-101 - Insulin ligand / ds insulin receptor agonists such as ORMD-0801 - Insulin or insulin analogs - Integrin antagonists such as IDL-2965, - IL-6 receptor agonists such as KM-2702, - Integrin α-V / β-6 and α-V / β-1 dual 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, - Ketohexokinase (KHK) inhibitors such as PF-06835919, - β Klotho (KLB)-FGF1c agonists such as MK-3655 (NGM-313), - 5-Lipoxygenase inhibitors such as tipepidust (MN-001), DS-102 (AF-102), - Lipoprotein lipase inhibitors such as CAT-2003, - LPL gene stimulants such as alipogene tiparvovec, - Liver X receptor (LXR) inhibitors such as PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, SR-9238, - Lysophosphatidic acid-1 receptor antagonists such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, 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), - Meglitinides such as nateglinide, repaglinide, - Membrane copper amine oxidase (VAP-1) inhibitors such as TERN-201, ​- Inhibitors of MEKK-5 protein kinase (ASK-1), such as CJ-16871, selonsertib (GS-4997), SRT-015, GS-444217, GST-HG-151, etc. - MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158), etc. - Inhibitors of semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1), such as PXS-4728A (BI-1467335), etc. - Sulfonylureas, such as tolbutamide, glibenclamide, glipizide, chlorpropamide, tolazamide, acetohexamide, glycopyramide, glimepiride, or glibendamide, etc. - Inhibitors of methionine aminopeptidase-2, such as ZGN-1061, ZGN-839, ZN-1345, etc. - Methyl CpG-binding protein 2 modulators, such as mercaptamine, etc. - Mineralocorticoid receptor antagonists (MCRA), such as MT-3995 (apararenone), etc. - Mitochondrial uncoupling agents, such as 2,4-dinitrophenol, Mito-99-0053, and HU6, etc. - Mixed lineage kinase-3 inhibitors, such as URMC-099-C, etc. - Myelin basic protein stimulants, such as olesoxime, etc. - Myeloperoxidase inhibitors, such as PF-06667272, AZM-198, etc. - NADPH oxidase inhibitors, such as GKT-831, GenKyoTex, APX-311, the nicotinic acid receptor 1 agonist of setanaxib (e.g., ARI-3037MO), etc. - Inhibitors of NACHT LRR PYD domain protein 3 (NLRP3), such as KDDF-201406-03, NBC-6, IFM-514, JT-194 (JT-349), - Inhibitors of the NFE2L2 gene, such as GeRP-amiR-144, - Nuclear receptor modulators, such as DUR-928 (DV-928), - Modulators of the P2X7 purinergic receptor, such as SGM-1019, - Stimulators of the P2Y13 purinergic receptor, such as CER-209, - PDE 3 / 4 inhibitors, such as ciclesonide (MN-001), - PDE 5 inhibitors, such as sildenafil, MSTM-102, - Modulators of the PDGF receptor β, such as BOT-191, BOT-509, - Peptidyl-prolyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018, NV-556 (NVP-025), - Stimulators of phenylalanine hydroxylase, such as HepaStem, - PPAR agonists, such as ciglitazone, elafibranor (GFT-505), seladelpar (MBX-8025), deuterated pioglitazone R-enantiomer, pioglitazone, DRX-065, saroglitazar, lanifibranor (IVA-337), CHS-131, pemafibrate (K-877), ZSP-0678, - Antagonists of protease-activated receptor-2, such as PZ-235, - Protein kinase modulators, such as CNX-014, - Inhibitors of the PTGS2 gene, such as STP-705, STP-707, - Inhibitors of the resistin / CAP1 (adenylyl cyclase-associated protein 1) interaction, 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, 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, sotagliflozin, empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, and sergliflozin etabonate, - Sodium glucose transporter-1 / 2 (SGLT1 / 2) inhibitors such as licogliflozin bis(prolinate) (LIK-066), - SREBP transcription factor inhibitors such as CAT-2003 and MDV-4463, - Stearoyl-CoA desaturase-1 inhibitors such as alamchol, - Thiazolidinediones such as pioglitazone, rosiglitazone, or lobeglitazone, - Thyroid hormone receptor (THR) β agonists such as ALG-009, ASC-41, CNPT-101101, CNPT-101207 / R292P / MGL-3196 / MGL-3745 / VK-2809, - TLR-2 / TLR-4 antagonists such as VB-201 (CI-201), - TLR-4 antagonists such as JKB-121 and JKB-122; - Tyrosine kinase receptor modulators such as CNX-025 and 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, - Inhibitors of xanthine oxidase / urate anion exchanger 1 (URAT1) such as RLBN-1001, RLBN-1127, and - Zonulin inhibitors such as lorazotide acetate (INN-202).

[0146] In some embodiments, the one or more additional therapeutic agents are A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogene tiparvovec, AMX-342, AN-3015, aramchol, ARI-3037MO, ASP-8232, AZD-2693, belimumab, 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, 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, flurasterone (ST-002), FT-4101, GDD-3898, GH-509, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, HEC-96719, HTD -1801, HSG-4112, HST-202, HST-201, Hydrochlorothiazide, Icosapentate (PRC-4016), Ethyl Icosapentate, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, Ipragliflozin, Irbesartan, Propagermanium, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, Metformin, Sildenafil, LB-700, LC-280126, Linagliptin, Liraglutide, LJN-452 (Tropifexor), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MBX-8025, MDV-4463, Mercaptamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, Namatizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-011, NP-135, NP-160, Norursodeoxycholic Acid, NVP-022, O-304, Obeticholic Acid (OCA), 25HC3S, Olesoxime, PAT-505, PAT-048, PB-4547, peg-Ildecakin, PF-05221304, Pioglitazone, Pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RCYM-001, RDX-009, Remogliflozin Etabonate, RG-125 (AZD4076), RPI-500, Saroglitazar, Semaglutide, SH-2442, Simtuzumab, Solithromycin, Sotagliflozin, Statins (Atorvastatin, Fluvastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin), Symbiotic Agent, TCM-606F, TEV-45478, TQA-3526, TQA-3563, Tipelcast (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, Ursodeoxycholic Acid, VBY-376, VBY-825, VK-2809, Bismodegib, Bolicivabat Potassium Ethanol Adduct Hydrate (SHP-626), VVP-100X, WAV-301, WNT-974,It is selected from XEN-103, XRx-117, ZGN-839, ZG-5216, ZSYM-008, and ZYSM-007.

[0147] In some embodiments, the compounds of the present disclosure include peptide YY or an analog thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, a cannabinoid receptor type 1 (CB1 R) antagonist, a lipase inhibitor (e.g., orlistat), a human insulinotropic peptide (HIP), a melanocortin receptor 4 agonist (e.g., setmelanotide), a melanin-concentrating hormone receptor 1 antagonist, a farnesoid X receptor (FXR) agonist (e.g., obeticholic acid), zonisamide, phentermine (alone or in combination with topiramate), a norepinephrine / dopamine reuptake inhibitor (e.g., bupropion), an opioid receptor antagonist (e.g., naltrexone), a combination of a norepinephrine / dopamine reuptake inhibitor and an opioid receptor antagonist (e.g., a combination of bupropion and naltrexone), a GDF-15 analog, sibutramine, a cholecystokinin agonist, amylin and an analog thereof (e.g., pramlintide), leptin and an analog thereof (e.g., metreleptin), a serotonin agonist (e.g., lorcaserin), a methionine aminopeptidase 2 (MetAP2) inhibitor (e.g., verolanimib or ZGN-1061), phentermine, diethylpropion, benzfetamine, an SGLT2 inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), an SGLTL1 inhibitor, a dual SGLT2 / SGLT1 inhibitor, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, biotin, a MAS receptor modulator, or a glucagon receptor agonist (alone or with another GLP-1 R agonist, e.g., liraglutide, exenatide, dulaglutide, albig (in combination with rutid, lixisenatide, or semaglutide), pharmaceutically acceptable salts of the above specifically named agents, and solvates of those agents and salts, are included, but not limited thereto.

[0148] In some embodiments, the methods and compositions comprise a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a farnesoid X receptor (FXR) agonist. In some embodiments, the FXR agonist is a compound of formula (II) or (III):

[0149]

Chemical formula

[0150] In some embodiments, the methods and compositions comprise a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an ASK1 inhibitor. In some embodiments, the ASK-1 inhibitor is a compound of formula (IV):

[0151]

Chemical formula

[0152] In some embodiments, the methods and compositions comprise a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an acetyl CoA carboxylase (ACC) inhibitor. In certain embodiments, the ACC inhibitor is a compound of formula (V):

[0153] [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the methods and compositions comprise a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a thyroid hormone receptor (THR) β agonist. In certain embodiments, the THRβ agonist is a compound of formula (VI):

[0155] [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.

[0156] VII. Methods of Treatment In some embodiments, the compounds of the present disclosure are useful in methods of treating and / or preventing GLP-1R-mediated diseases or conditions. In some embodiments, a method for treating and / or preventing a GLP-1R-mediated disease or condition comprises administering to a subject in need thereof a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the disease or condition is a liver disease or a related disease or condition, such as liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, compensated hepatic fibrosis, decompensated hepatic fibrosis, hepatocellular carcinoma, primary biliary cirrhosis , primary biliary cholangitis (PBC), or primary sclerosing cholangitis (PSC). In some embodiments, the disease or condition includes a metabolic disease or related disease or condition such as diabetes, obesity, or a cardiometabolic disease.

[0158] GLP-1R agonists are currently being investigated in relation to certain disorders and conditions, including, for example, diabetes. They are DPP4 resistant and have a longer half-life than endogenous GLP-1 GLP-1 analogs have been reported to be associated with weight loss and improved insulin action. Liraglutide, a peptide GLP-1R agonist approved in relation to the treatment of diabetes, has been reported to show a favorable improvement in outcomes in subjects with NASH.

[0159] In some embodiments, the present disclosure relates to the use of a compound of formula (I) or a compound of another formula described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention and / or treatment of a GLP-1R-mediated disease or condition, such as a liver disease or a metabolic disease.For example, some embodiments relate to chronic intrahepatic or certain forms of extrahepatic cholestatic conditions, liver fibrosis, acute intrahepatic cholestatic conditions, obstructive or chronic inflammatory diseases resulting from inappropriate bile composition, gastrointestinal conditions associated with reduced uptake of dietary fat and fat-soluble dietary vitamins, inflammatory bowel disease, lipid and lipoprotein disorders, type II diabetes and clinical complications of type I and type II diabetes, conditions and diseases resulting from chronic fatty and fibrotic degeneration of organs due to forced lipid and specifically triglyceride accumulation and subsequent activation of fibrosis-promoting pathways, obesity and metabolic syndrome (a complex condition of dyslipidemia, diabetes and an abnormally high body mass index), acute myocardial infarction, acute stroke, thrombosis resulting as an endpoint of chronic obstructive atherosclerotic disease, persistent infection by intracellular bacteria or parasitic protozoa, non-malignant hyperproliferative disorders such as colon adenocarcinoma and hepatocellular carcinoma, fatty liver and related syndromes, liver failure or liver dysfunction as a result of chronic liver disease or surgical hepatectomy, cholestatic and fibrotic effects associated with hepatitis B infection, hepatitis C infection and / or alcohol-induced cirrhosis or virus-mediated forms of hepatitis, type I diabetes, prediabetes, idiopathic type 1 diabetes, latent autoimmune diabetes, adult-onset diabetes, juvenile 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 accumulation, obesity, eating disorders, sleep apnea, weight gain, sugar craving, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial dyslipidemia, metabolic acidosis, ketosis, arthritis, left ventricular hypertrophy, Parkinson's disease, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, angina, premenstrual syndrome, thrombosis, atherosclerosis, abnormal glucose metabolism, or restenosis, and provide a compound of formula (I) or other compounds of formulas described herein, or a pharmaceutically acceptable salt thereof, or the use thereof for the treatment and / or prevention of the same.

[0160] In some embodiments, a method of treating and / or preventing non-alcoholic fatty liver disease (NAFLD) comprises administering to a subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0161] The present disclosure also relates to a compound of formula (I) or other compounds of formulas described herein, or a pharmaceutical composition comprising such compounds, for the prevention and post-traumatic treatment of cardiovascular disorders such as acute myocardial infarction, acute stroke, or thrombosis, which occur as endpoints of chronic obstructive atherosclerotic disease. In some embodiments, a method for treating and / or preventing a cardiovascular disorder comprises administering to a subject in need thereof a compound of formula (I) or other compounds of formulas described herein.

[0162] The present disclosure further relates to compounds or pharmaceutical compositions for the treatment and / or prevention of related disorders such as obesity and metabolic syndrome (a complex condition of dyslipidemia, diabetes, and an abnormally high body mass index) that can overcome elevated serum triglycerides, GLP1R-mediated reduction of blood glucose and increase of insulin sensitivity, and GLP1R-mediated weight loss. In some embodiments, a method for treating and / or preventing a metabolic disorder comprises administering to a subject in need thereof a compound of formula (I) or other compounds of formulas described herein.

[0163] In further embodiments, the compounds or pharmaceutical compositions of the present disclosure are useful in preventing and / or treating clinical complications of type I and type II diabetes. Examples of such complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, or peripheral arterial occlusive disease (PAOD). Other clinical complications of diabetes are also encompassed by the present disclosure. In some embodiments, a method for treating and / or preventing complications of type I and type II diabetes comprises administering to a subject in need thereof a compound of formula (I) or other compounds of formulas described herein.

[0164] Furthermore, conditions and diseases resulting from chronic fatty and fibrotic degeneration of organs due to forced lipid and / or triglyceride accumulation and subsequent activation of fibrosis-promoting pathways can also be prevented and / or treated by administering the compounds or pharmaceutical compositions of the present disclosure. Such conditions and diseases can include NASH and chronic cholestatic conditions in the liver, glomerulosclerosis and diabetic nephropathy in the kidney, macular degeneration and diabetic retinopathy in the eye, and neurodegenerative diseases such as Alzheimer's disease in the brain, or neuropathy in the peripheral nervous system. In some embodiments, a method for treating and / or preventing conditions and diseases resulting from chronic fatty and fibrotic degeneration of organs due to forced lipid and / or triglyceride accumulation and subsequent activation of fibrosis-promoting pathways comprises administering a compound of formula (I) to a subject in need thereof. In some embodiments, a method for treating and / or preventing NASH comprises administering a compound of formula (I) or a compound of other formulas described herein to a subject in need thereof.

[0165] There is further provided herein a pharmaceutical composition for use in the treatment of a GLP-1R-mediated disease or condition described herein, comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0166] The present disclosure also describes the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a GLP-1R-mediated disease or condition. The medicament referred to herein can be prepared by conventional processes comprising a combination of a compound according to the present disclosure and a pharmaceutically acceptable carrier.

[0167] There is also disclosed a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of a GLP-1R-mediated disease or condition. There is also disclosed a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the prevention of a GLP-1R-mediated disease or condition.

Examples

[0168] VIII. Examples Numerous general references are available that provide commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (see, for example, Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition, Wiley-Interscience, 2013).

[0169] The compounds described herein can be purified by any of the means known in the art, including chromatographic means such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, such as normal and reverse phases as well as ion exchange resins. For example, the disclosed compounds can be purified via silica gel and / or alumina chromatography. For example, see Introduction to Modern Liquid Chromatography, 2nd ed . , ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979, and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0170] During any of the processes for the preparation of the target compounds, it may be desirable to protect any sensitive or reactive groups on any of the related molecules. This can be accomplished by conventional protecting groups as described in standard treatises such as T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 4th ed., Wiley, New York 2006. The protecting groups can be removed at a convenient subsequent stage using methods known from the art.

[0171] Here, exemplary chemical substances useful in the methods of the embodiments are described by reference to exemplary synthetic schemes for their general preparation herein and the following specific examples. One skilled in the art will recognize that, in order to obtain the various compounds herein, the starting materials can be suitably selected such that the ultimately desired substituents are carried through the reaction scheme, with or without protection as necessary, to obtain the desired product. Alternatively, it may be desirable to use a suitable group that is carried through the reaction scheme and can be appropriately replaced with the ultimately desired substituent. Further, one skilled in the art will recognize that the transformations shown in the following schemes can be carried out in any order that is compatible with the functionality of the pendant groups. Each of the reactions shown in the general scheme can be carried out at a temperature from about 0 °C to the reflux temperature of the organic solvent used.

[0172] The examples provided herein describe the synthesis of the compounds disclosed herein, as well as the intermediates used to prepare the compounds. It should be understood that the individual steps described herein can be combined. It should also be understood that separate batches of the compounds can be combined and then carried forward to the next synthetic step.

[0173] In the following description of the examples, specific embodiments are described. These embodiments are described in sufficient detail to enable one skilled in the art to practice the specific embodiments of the disclosure. Other embodiments can be utilized and logical changes and other changes can be made without departing from the scope of the disclosure. The embodiments also are directed to processes and intermediates useful in preparing the subject compounds or pharmaceutically acceptable salts thereof. Accordingly, the following description is not intended to limit the scope of the disclosure.

[0174] In some embodiments, the present disclosure generally provides a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer was not determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is drawn without indicating the stereochemistry at that particular stereocenter, even if the compound may be substantially enantiomerically or diastereomerically pure.

[0175] Representative syntheses of the compounds of the present disclosure are described in the following schemes and the following examples.

[0176] The compounds detailed in the examples were synthesized according to the general synthetic methods described below. The compounds were named using ChemDraw version 18.1.0.535 (PerkinElmer Informatics, Inc.) unless otherwise indicated.

[0177] Abbreviations Certain abbreviations and acronyms are used in describing the details of the experiments. Most of these are understood by those skilled in the art, but Table 1 includes a list of many of these abbreviations and acronyms.

[0178]

Table 1-1

[0179]

Table 1-2

[0180] A. Synthesis of Intermediates Preparation of Intermediate I-1:

[0181]

Chemical formula

[0182] 4-(Dibromomethyl)-3-fluorobenzonitrile: To a 40 mL vial, 3-fluoro-4-formylbenzonitrile (500 mg, 3.35 mmol), triphenylphosphine (1.76 g, 6.71 mmol), tetrabutylammonium iodide (1.24 g, 3.35 mmol), and 1,2-dibromoethane (7 mL) were added. The solution was heated at 60 °C overnight. LCMS indicated the formation of the product by UV. The mixture was concentrated under reduced pressure and purified by silica chromatography (eluent: EtOAc / hexane) to afford the desired product 4-(dibromomethyl)-3-fluorobenzonitrile, which was used in the next step. 1H NMR (400 MHz, chloroform-d) δ 8.00 (dd, J = 8.1, 7.4 Hz, 1H), 7.58 (ddd, J = 8.2, 1.5, 0.8 Hz, 1H), 7.38 (dd, J = 9.4, 1.6 Hz, 1H), 6.91 (s, 1H).

[0183] 4-(4-Bromobenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile: To a 40 mL vial, 4-(dibromomethyl)-3-fluorobenzonitrile (744 mg, 2.54 mmol) and 3-bromobenzene-1,2-diol (400 mg, 2.12 mmol) were added. The mixture was dissolved in pyridine (2 mL) and the vial was sealed with a Teflon® cap. The solution was heated at 90 °C overnight. LCMS indicated the formation of the product by UV. The mixture was concentrated under reduced pressure and purified by silica column chromatography (eluent: EtOAc / hexane) to afford the desired product I-1. 1H NMR (400 MHz, chloroform-d) δ 7.76 (dd, J = 8.0, 6.8 Hz, 1H), 7.56 (dd, J = 8.1, 1.5 Hz, 1H) .50 (dd, J = 9.3, 1.5 Hz, 1H), 7.33 (s, 1H), 7.06 (dd, J = 7.7, 1.6 Hz, 1H), 6.87 - 6.75 (m, 2H).

[0184] Preparation of Intermediate I-2:

[0185]

Chemical Structure

[0186] 2-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-5-chloropyridine: In a 40 mL vial, 5-chloro-2-ethynylpyridine (1 g, 7.27 mmol), 3-bromobenzene-1,2-diol (1.37 g, 7.27 mmol), and trityltenium dodecacarbonyl (139 mg, 0.218 mmol) were added. The mixture was dissolved in dry toluene (15 mL), and the mixture was degassed with argon for 2 minutes. The vial was sealed with a Teflon® cap. The solution was heated at 100 °C overnight. LCMS indicated the formation of the product by UV. The mixture was cooled and then diluted with EtOAc (30 mL). The mixture was filtered through celite (rinsed with EtOAc), and the filtrate was concentrated under reduced pressure. The crude material was purified by silica chromatography (eluent: EtOAc / hexane) to obtain the desired product I-2. ES / MS: 328.1 (M+H + ). 1H NMR (400 MHz, chloroform-d) δ 8.66 (dd, J = 2.4, 0.7 Hz, 1H), 7.73 (dd, J = 8.4, 2.4 Hz, 1H), 7.63 (dd, J = 8.4, 0.8 Hz, 1H), 6.99 (dd, J = 7.9, 1.4 Hz, 1H), 6.82 - 6.69 (m, 2H), 2.13 (s, 3H).

[0187] Preparation of Intermediate I-3:

[0188]

Chemical Structure

[0189] 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzod[d][1,3]dioxole: To a 250 mL RBF, 1-(4-chloro-2-fluoro-phenyl)ethanone (9.59 g, 55.6 mmol), 3-bromobenzene-1,2-diol (10 g, 52.9 mmol), and p-toluenesulfonic acid monohydrate (500 mg, 2.65 mmol) were added. The mixture was dissolved in dry toluene (50 mL). The solution was refluxed under Dean-Stark conditions for 48 hours. Then, the mixture was cooled and then dry-packed onto silica. The crude material was purified by silica chromatography (eluent: EtOAc / hexane) to obtain the desired product I-3. 1H NMR (400 MHz, chloroform-d) δ 7.57 (t, J = 8.4 Hz, 1H), 7.20 - 7.09 (m, 2H), 6.98 (dd, J = 8.0, 1.4 Hz, 1H), 6.80 - 6.68( m, 2H), 2.13 (s, 3H).

[0190] Preparation of Intermediate I-4:

[0191]

Chemical formula

[0192] 5-Bromo-3a-(4-chlorophenyl)-1,2,3,3a-tetrahydrobenzod[d]pyrrolo[2,1-b]oxazole: To a 40 mL vial, 4-chloro-1-(4-chlorophenyl)butan-1-one (462 mg, 2.13 mmol) and 2-amino-6-bromophenol (400 mg, 2.13 mmol) were added. The mixture was dissolved in pyridine (5 mL). The vial was sealed and stirred at 50 °C for 4 hours and then at 90 °C for 16 hours. The mixture was concentrated under reduced pressure and the crude material was purified by silica chromatography (eluent: EtOAc / hexane) to obtain the desired product I-4. ES / MS: 350.2 (M +)。1H NMR (400 MHz, chloroform-d) δ 7.65~7.56 (m, 2H), 7.38~7.31 (m, 2H), 6.98 (dd, J = 8.1, 1.2 Hz, 1H), 6.78 (dd, J = 7.6, 1.2 Hz, 1H), 6.75~6.65 (m, 1H), 3.62 (ddd, J = 10.7, 8.6, 6.1 Hz, 1H), 3.33 (ddd, J = 10.9, 7.1, 4.3 Hz, 1H), 2.76~2.59 (m, 1H), 2.29 (ddd, J = 13.7, 9.0, 6.7 Hz, 1H), 2.07~1.88 (m, 2H).

[0193] Preparation of Intermediate I-5:

[0194]

Chemical Structure

[0195] 5-Bromo-3a-(4-chlorophenyl)-3,3a-dihydrobenzod]pyrrolo[2,1-b]oxazol-1(2H)-one: To a 100 mL RBF, 4-(4-chlorophenyl)-4-oxobutanoic acid (1.13 g, 5.32 mmol) and 2-amino-6-bromophenol (1 g, 5.32 mmol) were added. The mixture was dissolved in dry toluene (15 mL). The solution was refluxed under Dean-Stark conditions for 48 h. Then, the mixture was cooled and then dry-packed onto silica. The crude material was purified by silica chromatography (eluent: EtOAc / hexane) to give the desired product I-5. ES / MS: 364.2 (M + )。1H NMR (400 MHz, chloroform-d) δ 8.03~7.96 (m, 2H), 7.60 (dd, J = 8.0, 1.0 Hz, 1H), 7.54~7.45 (m, 3H), 7.21 (t, J = 8.0 Hz, 1H), 3.66 (dd, J = 7.7, 6.6 Hz, 2H), 3.45 (t, J = 7.0 Hz, 2H).

[0196] Preparation of Intermediate I-6:

[0197] [Chemistry]

[0198] Methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate: To a solution of methyl 3-fluoro-4-nitrobenzoate (700 mg, 3.52 mmol) in THF (10 mL) and DMF (5 mL) were added diisopropylethylamine (3.1 mL, 17.6 mmol) and 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride (567 mg, 3.87 mmol). The resulting solution was heated at 70 °C for 24 h. Upon completion, the solvent was removed, and the resulting residue was taken up in EtOAc (50 mL), washed with brine (10 mL), concentrated, and carried on to the next step without further purification. Next, methyl 3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (1.0 g, 3.46 mmol) was dissolved in EtOAc:THF (2:1, 15 mL), and then 10% palladium on carbon (368 mg, 0.346 mmol) was added. The resulting suspension was stirred at room temperature for 16 h under a hydrogen balloon. The mixture was filtered through Celite, washed with EtOAc (50 mL), concentrated, and the desired compound I-6 was obtained without further purification. ES / MS: 260.2 (M+H + )

[0199] Preparation of Intermediate I-7

[0200] [Chemistry]

[0201] Methyl 4-amino-3-(2-methoxyethylamino)benzoate: To a solution of methyl 3-fluoro-4-nitrobenzoate (50.0 g, 251 mmol) in THF (400 mL) was added diisopropylethylamine (70.0 mL, 402 mmol) and 2-methoxyethylamine (34.9 mL, 402 mmol). The resulting solution was heated at 55 °C for 6 hours. Upon completion, the solvent was removed, and the resulting residue was taken up in EtOAc (150 mL), washed with brine (30 mL), concentrated, and carried on to the next step without further purification. Next, methyl 3-(2-methoxyethylamino)-4-nitrobenzoate (20.0 g, 78.7 mmol) was dissolved in EtOAc:EtOH (1:1, 140 mL), and then 10% palladium on carbon (5.02 g, 4.72 mmol) was added. The resulting suspension was stirred at room temperature for 16 hours under a hydrogen balloon. The reaction mixture was filtered through Celite, washed with EtOAc (100 mL), concentrated, and the desired compound I-7 was obtained without further purification. ES / MS: 225.2 (M+H + )

[0202] Preparation of Intermediate I-8

[0203]

Chemical formula

[0204] Methyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (I-8): Methyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate was prepared in the same manner as described for I-7, except that 2-methoxyethylamine was replaced with (1-(fluoromethyl)cyclopropyl)methanamine; 2,2,2-trifluoroacetic acid. ES / MS: 253.3 (M+H + )

[0205] Preparation of Intermediate I-9

[0206]

Chemical formula

[0207] Methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (I-9): Methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate was prepared in the same manner as described for I-7, except that methoxyethylamine was replaced with (S)-oxetan-2-ylmethanamine. ES / MS: 237.0 (M+H + )

[0208] Preparation of Intermediate I-10:

[0209] [Chemical formula]

[0210] Ethyl 3,5-difluoro-4-nitrobenzoate: Ethyl 4-amino-3,5-difluorobenzoate (5.00 g, 24.9 mmol) was taken up in acetic acid (50.0 mL). Sulfuric acid (12.1 M, 2.05 mL, 24.9 mmol) and hydrogen peroxide (30% aqueous solution, 46.7 mL, 74.6 mmol) were added sequentially, and the reaction mixture was heated at 100 °C for 1 hour. . Subsequently, the reaction mixture was cooled to room temperature and then slowly poured into 300 mL of ice water with stirring. The mixture was then diluted with EtOAc (200 mL), transferred to a separatory funnel, and the organic phase was collected. The aqueous phase was extracted with 2 × 100 mL of EtOAc, and the combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc / hexane gradient) to give the product.

[0211] (S)-Ethyl 3-fluoro-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate: Ethyl 3,5-difluoro-4-nitrobenzoate (2.50 g, 10.8 mmol) and (S)-oxetan-2-ylmethanamine (989 mg, 11.4 mmol) were taken up in tetrahydrofuran (12.0 mL) and N,N-dimethylformamide (6.0 mL), and N,N-diisopropylethylamine (9.42 mL, 54.1 mmol) was added. The reaction mixture was heated at 50 °C for 16 h. Subsequently, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (0 - 25% EtOAc / hexane) to give the product. ES / MS: 299.2 (M+H + ).

[0212] (S)-Ethyl 4-amino-3-fluoro-5-(((oxetan-2-ylmethyl)amino)benzoate (I-10): (S)-Ethyl 3-fluoro-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate (2.20 g, 7.38 mmol) was taken up in ethanol (10 mL) and tetrahydrofuran (5 mL), and the mixture was sparged with nitrogen for 5 min. Then, palladium on carbon (10 wt% loaded, 785 mg, 0.74 mmol) was added and nitrogen sparging was continued for 5 min. Next, hydrogen was bubbled through the solution for 1 min, and then the reaction mixture was allowed to stand under a balloon of hydrogen for 21 h. Subsequently, the reaction was quenched and the mixture was filtered through celite. The filter was washed with EtOAc (2 × 20 mL) and methanol (2 × 10 mL), and the filtrate was concentrated in vacuo to give (S)-ethyl 4-amino-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate (I-10). ES / MS: 269.2 (M+H +)。1H NMR (400 MHz, chloroform) δ 7.44~7.30 (m, 2H), 5.13 (qd, J = 7.1, 3.4 Hz, 1H), 4.72 (ddd, J = 8.7, 7.4, 6.0 Hz, 1H), 4.62 (dt, J = 9.1, 6.1 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.58~3.30 (m, 2H), 2.76 (dtd, J = 11.4, 8.0, 6.1 Hz, 1H), 2.56 (ddt, J = 11.3, 9.0, 7.1 Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H).

[0213] Preparation of Intermediate I-11:

[0214]

Chemical formula

[0215] Methyl 5-amino-6-(((1-(fluoromethyl)cyclopropyl)methyl)amino)picolinate: To a solution of methyl 6-chloro-5-nitro-pyridine-2-carboxylate (1.5 g, 6.93 mmol) in 10 mL of THF was added N-ethyldiisopropylamine (5.87 mL, 34.6 mmol). Subsequently, [1-(fluoromethyl)cyclopropyl]methanamine; 2,2,2-trifluoroacetic acid (1.5 g, 6.93 mmol) was added at room temperature. The mixture was stirred overnight, diluted with 50 mL of EtOAc, and washed with 20 mL of brine and water. The organic layer was dried and concentrated. The mixture was dissolved in 10 mL of ethanol and 5 mL of water. Iron (2.4 g, 43.2 mmol) and ammonium chloride (3.3 g, 61.8 mmol) were added to the solution. The mixture was heated to 80 °C for 1 hour. The mixture was cooled and filtered through celite. The filtrate was diluted with 50 mL of EtOAc and washed with 20 mL of brine. The organic layer was dried and concentrated to obtain I-11. This was used without further purification. ES / MS: 254.2 (M+H + )。

[0216] Preparation of Intermediate I-12:

[0217] [Chemistry]

[0218] tert-Butyl 2,3-difluoro-4-nitrobenzoate: To a solution of 2,3-difluoro-4-nitrobenzoic acid (1.00 g, 4.92 mmol) in THF (15 mL) were added di-tert-butyl dicarbonate (2.15 g, 9.85 mmol) and 4-dimethylaminopyridine (180 mg, 1.48 mmol), and the resulting solution was stirred at 40 °C for 3 h. Upon completion, the solvent was removed by rotary evaporation, and the resulting residue was diluted with EtOAc (100 mL), washed with water (25 mL) and brine (25 mL), dried over MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography (0 - 50% EtOAc in hexane) to afford the title compound.

[0219] (S)-tert-Butyl 2-fluoro-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate: To a solution of tert-butyl 2,3-difluoro-4-nitrobenzoate (300 mg, 1.16 mmol) in THF (4 mL) were added diisopropylethylamine (0.61 mL, 3.47 mmol) and (S)-oxetan-2-ylmethanamine (0.12 mL, 1.2 mmol). The resulting solution was heated at 60 °C for 4 h. Upon completion, the solvent was removed, and the resulting residue was taken up in EtOAc (50 mL), washed with water (10 mL) and then brine (10 mL), concentrated, and carried on to the next step without further purification. ES / MS: 327.9 (M+H + )

[0220] (S)-4-Amino-2-fluoro-3-((oxetan-2-ylmethyl)amino)benzoic acid tert-butyl: (S)-2-Fluoro-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid tert-butyl (378 mg, 1.16 mmol) was taken up in ethanol (5 mL), and saturated aqueous ammonium chloride solution (1.5 mL) was added. Then, iron powder (323 mg, 5.79 mmol) was added to the reaction mixture, and the reaction was heated to 60 °C. After 3 hours, the mixture was cooled to room temperature and filtered through celite by washing with water (10 mL), MeOH (10 mL), and EtOAc (25 mL), and concentrated in vacuo. EtOAc (50 mL) was added to the resulting mixture. The organic solution was washed with water (25 mL), brine (25 mL), dried over MgSO4, filtered, and concentrated. Product I-12 was used without further purification. ES / MS: 298.0 (M+H + )

[0221] Preparation of Intermediate I-13:

[0222]

Chemical Structure

[0223] 1-(tert-Butyl) 3-methyl 2-(5-bromo-3-fluoropyridin-2-yl) malonate: To a 40 mL vial, tert-butyl methyl malonate (898 mg, 5.16 mmol) and DMF (10 mL) were added. The solution was cooled to 0 °C and NaH (60% in mineral oil, 237 mg, 6.19 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes and gas evolution was observed. Then the reaction was cooled to 0 °C, 5-bromo-2,3-difluoropyridine (1.0 g, 5.16 mmol) was added, and the reaction was stirred overnight. LCMS indicated the formation of the product. The mixture was partitioned between EtOAc (50 mL) and water (20 mL), the organic layer was separated, dried over MgSO4, and concentrated under reduced pressure to obtain 1-(tert-butyl) 3-methyl 2-(5-bromo-3-fluoropyridin-2-yl) malonate, which was carried directly to the next step. ES / MS: 348.5 (M+H + )

[0224] Methyl 2-(5-bromo-3-fluoropyridin-2-yl) acetate: To a 100 mL RBF, 1-(tert-butyl) 3-methyl 2-(5-bromo-3-fluoropyridin-2-yl) malonate (1.4 g, 4.02 mmol) was added, trifluoroacetic acid (10 mL) and CH2Cl2 (10 mL) were added. The mixture was stirred at room temperature overnight. LCMS indicated the formation of the product. The solvent was evaporated under reduced pressure to obtain the product as the TFA salt. ES / MS: 248.3 (M+H + )

[0225] 2-(5-Bromo-3-fluoro-2-pyridyl)acetic acid (I-13): Methyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate (trifluoroacetate) (1.2 g, 3.31 mmol) was added to a 40 mL RBF. Methanol (10 mL) and THF (5 mL) were added, followed by 1 M NaOH (6.63 mL, 6.63 mmol). The reaction mixture was stirred at 70 °C overnight. The mixture was concentrated under reduced pressure, the residue was dissolved in water and acidified with 1 N HCl. The resulting mixture was extracted three times with a mixture of DCM and methanol. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude I-13 was carried on to the next step without further purification.

[0226] ES / MS: 234.159 (M+H + )

[0227] Preparation of Intermediate I-14:

[0228]

Chemical Structure

[0229] Methyl 4-[[2-(4-bromo-2-fluoro-phenyl)acetyl]amino]-3-(2-methoxyethylamino)benzoate: To a solution of 2-(4-bromo-2-fluoro-phenyl)acetic acid (1.00 g, 4.29 mmol) in DMF (20.0 mL) was added methyl 4-amino-3-(2-methoxyethylamino)benzoate (I-7) (1.18 g, 5.28 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1.96 g, 5.15 mmol), followed by N,N-diisopropylethylamine (3.74 mL, 21.5 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was concentrated in vacuo, the residue was taken up in EtOAc and washed with water (once) and brine (once). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was carried on to the next step without further purification. ES / MS m / z: 583.5 (M+H + )

[0230] Methyl 2-[(4-bromo-2-fluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate: Methyl 4-[[2-(4-bromo-2-fluoro-phenyl)acetyl]amino]-3-(2-methoxyethylamino)benzoate (1.89 g, 4.29 mmol), which is the crude product from the previous step, was dissolved in AcOH (40.0 mL), and the reaction mixture was heated at 60 °C for 2 hours. Then, the reaction mixture was concentrated in vacuo, and the crude residue was taken up in DCM and washed with saturated aqueous sodium bicarbonate. The layers were separated, and the aqueous layer was extracted with DCM (twice). The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0 - 100% EtOAc in hexane) to give the title compound. ES / MS m / z: 421.9 (M+H + )。

[0231] Methyl 2-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate: To a vial were added methyl 2-[(4-bromo-2-fluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (200 mg, 0.475 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (145 mg, 0.570 mmol), (1,1’-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (33.6 mg, 0.0475 mmol), and potassium acetate (0.140 g, 1.42 mmol). 1,4-Dioxane (4.80 mL) was added, and the reaction was heated at 100 °C for 24 hours. The reaction mixture was filtered through celite, eluted with DCM, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0 - 100% EtOAc in hexane) to give compound I-14. ES / MS m / z: 469.4 (M+H )。 +)。

[0232] Preparation of Intermediate I-15:

[0233]

Chem.

[0234] 5-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)thiophene-2-carbonitrile (I-15): 5-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)thiophene-2-carbonitrile was prepared by the method described for Intermediate I-2, except that 5-chloro-2-ethynylpyridine was replaced with 5-ethynylthiophene-2-carbonitrile. 1H NMR (400 MHz, chloroform-d) δ 7.54 (d, J = 3.9 Hz, 1H), 7.26 (d, J = 3.9 Hz, 1H), 7.02 (dd, J = 7.2, 2.2 Hz, 1H), 6.84 - 6.74 (m, 2H), 2.16 (s, 3H).

[0235] Preparation of Intermediate I-16:

[0236]

Chem.

[0237] 2-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-1-methyl-1H-benzo[d]imidazole (I-16): 2-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-1-methyl-1H-benzo[d]imidazole was prepared by the method described for Intermediate I-2, except that 5-chloro-2-ethynylpyridine was replaced with 2-ethynyl-1-methyl-1H-benzo[d]imidazole. ES / MS: 346.2 (M + H + )。

[0238] Preparation of Intermediate I-17: Methyl 2-(4-bromo-2,6-difluorophenyl)acetate: To 2-(4-bromo-2,6-difluoro-phenyl)acetic acid (5.00 g, 1.99 mmol) was added 31.9 mL of HCl in methanol (1.25 M, 2 eq). The mixture was heated at 70 °C overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with 0 - 10% EtOAc in hexane to afford methyl 2-(4-bromo-2,6-difluoro-phenyl)acetate. 1H NMR (400 MHz, chloroform-d) δ 7.16 - 7.08 (m, 2H), 3.74 (s, 3H), 3.69 (s, 2H).

[0239] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d] Methyl (1,3-dioxol-4-yl)-2,6-difluorophenyl)acetate: 2-(4-Bromo-2,6-difluoro-phenyl)acetate (2.83 g, 0.0107 mol) was taken up in 1,4-dioxane (30 mL) with potassium propionate (3.59 g, 0.0320 mol), bis(diphenylphosphino)ferrocene)dichloropalladium(II) (1.19 g, 0.00160 mol), and bis(pinacolato)diboron (3.52 g, 0.0139 mol). The mixture was capped and nitrogen gas was injected for 5 minutes. The mixture was then heated at 110 °C for 1 hour. Following this time, the reaction cap was opened and subsequently bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.594 g, 0.0008 mol) and 2 M aqueous sodium bicarbonate solution (10.7 mL, 0.0214 mol) were added. The mixture was stirred at room temperature for 2 minutes and then 4-bromo-2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxole (5.5 g, 0.0160 mol) was added. The mixture was then capped and heated at 95 °C for 3 hours. LCMS indicated complete conversion of the boronate. Subsequently, the mixture was cooled to room temperature, filtered through celite, and concentrated in vacuo. The mixture was loaded directly onto a column and eluted with a slow gradient of 0 - 30% EtOAc in hexanes to afford an oil. LC-MS (ESI) m / z 449.0 (M+H).

[0240] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid (I-17): Methyl 2-[4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-2,6-difluorophenyl]acetate (1.50 g, 0.00334 mol) was taken up in 15 mL of acetonitrile. Then 0.3 M lithium hydroxide solution (0.0167 mol, 16.7 mL) was added and the mixture was heated at 100 °C for 1 hour. LCMS indicated quantitative conversion to the desired starting material. The reaction mixture was acidified to pH 6 by addition of 1.0 M solution of citric acid, followed by addition of water and EtOAc. The mixture was extracted three times with EtOAc, dried over magnesium sulfate and concentrated under reduced pressure to give 2-[4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-2,6-difluorophenyl]acetic acid. 1H NMR (400 MHz, chloroform-d) δ 11.53 (s, 1H), 7.56 (t, J = 8.2 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.25 - 7.11 (m, 2H), 7.06 (dd, J = 7.9, 1.5 Hz, 1H), 6.99 - 6.86 (m, 2H), 3.86 (s, 2H), 2.16 (s, 3H). ES / MS: 436.0 (M + H+).

[0241] Preparation of Intermediate I-18: Methyl 4-amino-3-((2-(methylsulfonyl)ethyl)amino)benzoate: I-18 was prepared in the same manner as described for I-7, except that methoxyethylamine was replaced with 2-(methylsulfonyl)ethan-1-amine. ES / MS: 273.2 (M + H+).

[0242] Preparation of Intermediate I-19: Methyl 4-amino-3-((2-(difluoromethoxy)ethyl)amino)benzoate: I-19 was prepared in the same manner as described for I-7, except that methoxyethylamine was replaced with 2-(difluoromethoxy)ethan-1-amine. ES / MS: 261.2 (M + H+).

[0243] Preparation of Intermediates I-20 and I-21: 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid I-17 as a mixture of two stereoisomers was separated by chiral SFC (OJ-H column containing 5% MeOH cosolvent) to obtain two different stereoisomers.

[0244] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid: ES / MS: 436.1.

[0245] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid: ES / MS: 436.1.

[0246] Preparation of Intermediate I-22: 3-(2-Methoxyethylamino)-4-nitro-benzonitrile: A solution of 3-fluoro-4-nitro-benzonitrile (2 g, 12.04 mmol), 2-methoxyethanamine (1.25 mL, 14.79 mmol), and N,N-diisopropylethylamine (3.2 mL, 18.37 mmol) in DMF was stirred at room temperature for 3 days. The mixture was diluted with EtOAc and washed twice with 5% LiCl and then with brine. The organic extract was dried over sodium sulfate to obtain the title product. ES / MS m / z: 222 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 8.7, 1.7 Hz, 1H), 8.23 (s, 1H), 7.21 (d, J = 1.7 Hz, 1H), 6.89 (dt, J = 8.8, 1.5 Hz, 1H), 3.71 (dd, J = 5.6, 4.8 Hz, 2H), 3.51 (q, J = 5.2 Hz, 2H), 3.45 (d, J = 1.0 Hz, 3H).

[0247] N-(2-Methoxyethyl)-2-nitro-5-(2H-tetrazol-5-yl)aniline: In a 200 mL round-bottom flask, a suspension of 3-(2-methoxyethylamino)-4-nitro-benzonitrile (2.563 g, 11.6 mmol), sodium azide (1.51 g, 23.2 mmol), and ammonium chloride (1.24 g, 23.2 mmol) in DMF (50 mL) was heated at 110 °C overnight. The mixture was diluted with EtOAc and washed three times with 50 mL of 5% LiCl. The aqueous layer was extracted twice with 100 mL of EtOAc. The combined organic extracts were dried over sodium sulfate to afford the title product as an oil. ES / MS m / z: 265.2 (M+H+), 1H NMR (400 MHz, MeOD) δ 8.32 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.35 (dd, J = 8.9, 1.8 Hz, 1H), 3.82~3.69 (m, 2H), 3.66 (t, J = 5.2 Hz, 2H), 3.46 (s, 3H), 3.01 (d, J = 0.5 Hz, 4H).

[0248] N2-(2-Methoxyethyl)-4-(2H-tetrazol-5-yl)benzene-1,2-diamine (I-22): A solution of N-(2-methoxyethyl)-2-nitro-5-(2H-tetrazol-5-yl)aniline (93 mg, 352 μmol) in EtOH (25 mL) was degassed three times with Ar / Vac. To the mixture was added Pd / C (10%, 37.7 mg, 0.0354 mmol), and the mixture was stirred overnight using a hydrogen balloon. The mixture was filtered through a Celite plug and rinsed with EtOAc. The mixture was concentrated to afford the title product, which was used in the subsequent step without further purification. ES / MS m / z: 235.2 (M+H+).

[0249] Preparation of Intermediate I-23 tert-Butyl 2-(6-chloro-2-methoxypyridin-3-yl)acetate: In a 40 mL reaction vial, 3-bromo-6-chloro-2-methoxy-pyridine (1000 mg, 4.50 mmol), Pd2(dba)3 (103 mg, 0.112 mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (130 mg, A mixture of 0.225 mmol was degassed three times with Ar / vac. THF (10 mL) was added and degassed three times with Ar / vac. To this was added bromo(2-tert-butoxy-2-oxo-ethyl)zinc (0.500 M, 13.5 mL, 6.74 mmol), and the mixture was heated at 65 °C for 3 hours. The reaction was diluted with EtOAc and brine. The organic extract was dried over sodium sulfate and purified by flash chromatography (eluent: EtOAc / hexane) to give the title compound. ES / MS m / z: 258.2 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.43 (dt, J = 7.6, 0.7 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 3.97 (s, 3H), 3.48 (s, 2H), 1.46 (s, 9H).

[0250] 2-(6-Chloro-2-methoxypyridin-3-yl)acetic acid: To a solution of tert-butyl 2-(6-chloro-2-methoxy-3-pyridyl)acetate (250 mg, 0.970 mmol) in DCM (5 mL) was added TFA (0.750 mL). The reaction was stirred at room temperature overnight, concentrated to dryness, and used in the next step without further purification. ES / MS m / z: 202.2 (M+H+)

[0251] Methyl 4-(2-(6-chloro-2-methoxypyridin-3-yl)acetamido)-3-((2-methoxyethyl)amino)benzoate: To a solution of 2-(6-chloro-2-methoxy-3-pyridyl)acetic acid (196 mg, 0.972 mmol), methyl 4-amino-3-(2-methoxyethylamino)benzoate (262 mg, 1.17 mmol), and methyl 4-amino-3-(2-methoxyethylamino)benzoate (262 mg, 1.17 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (626 mg, 1.65 mmol) in DMF (4 mL) was added N,N-diisopropylethylamine (0.800 mL, 4.59 mmol). The mixture was stirred overnight at room temperature. The reaction was diluted with EtOAc and washed with 5% LiCl, saturated NaHCO3, and brine. The organic extract was dried over sodium sulfate and concentrated. Assuming complete conversion, the crude residue was carried on to the next procedure without further purification. ES / MS m / z: 408.2 (M+H+).

[0252] Methyl 2-[(4-bromo-2,6-difluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-23): A solution of methyl 4-[[2-(6-chloro-2-methoxy-3-pyridyl)acetyl]amino]-3-(2-methoxyethylamino)benzoate (397 mg, 0.973 mol) and glacial acetic acid (3.5 mL, 61.2 mmol) in DCE (4 mL) was heated at 60 °C for 7 h. The mixture was concentrated and chromatographed (eluent: EtOAc / hexane) to afford the title compound. ES / MS m / z: 390.2 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 1.6, 0.7 Hz, 1H), 7.99 (dd, J = 8.5, 1.6 Hz, 1H), 7.73 (dd, J = 8.5, 0.6 Hz, 1H), 7.46~7.38 (m, 1H), 6.87 (d, J = 7.7 Hz, 1H), 4.39 (t, J = 5.4 Hz, 2H), 4.30~4.25 (m, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 3.65 (t, J = 5.4 Hz, 2H), 3.26 (s, 3H).

[0253] Preparation of Intermediate I-24: 2-Chloro-5,5-dimethoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene: In a 100 mL vial, 3-2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1 g, 5.14 mmol), methanol (10 mL), HCl (2.5 M methanol solution, 2.05 mL, 1.03 mmol), and trimethyl orthoformate (1.69 mL, 12.5 mmol) were added. The solution was heated at 70 °C for 24 hours. Next, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was diluted with diethyl ether (50 mL) and washed with 50% aqueous NaHCO3 (1 × 20 mL). The aqueous layer was back-extracted with diethyl ether (1 × 50 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the desired product, 2-chloro-5,5-dimethoxy-6,7,8,9-tetrahydro-5H-benzo-5H-benzo[7]annulene, which was used in the next step.

[0254] 4-Bromo-2’-chloro-6’,7’,8’,9’-tetrahydrospiro[benzo[d][1,3]dioxole-2,5’-benzo][7]annulene: To a 100 mL vial were added 2-chloro-5,5-dimethoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene (800 mg, 3.32 mmol), 3-bromobenzene-1,2-diol (691 mg, 3.66 mmol), and para-toluenesulfonic acid monohydrate (63 mg, 0.33 mmol). The mixture was dissolved in toluene (10 mL), and the solution was heated to reflux overnight under Dean-Stark conditions. Then, the mixture was cooled and dried over silica, and purified by silica chromatography (eluent: EtOAc / hexane) to give the desired product I-24. 1H NMR (400 MHz, chloroform-d) δ 7.62~7.54 (m, 1H), 7.28 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 6.96 (dd, J = 8.1, 1.3 Hz, 1H), 6.77 (dd, J = 7.8, 1.2 Hz, 1H), 6.71 (t, J = 7.9 Hz, 1H), 3.06 (dt, J = 7.1, 2.3 Hz, 2H), 2.41~2.26 (m, 2H), 2.18~2.05 (m, 2H), 1.87~1.65 (m, 2H).

[0255] Preparation of Intermediate I-25: 4'-Bromo-8-chloro-3,4-dihydro-2H-spiro[benzo[b]oxepin-5,2'-benzod][1,3]dioxole](I-25): 4'-Bromo-8-chloro-3,4-dihydro-2H-spiro[benzo[b]oxepin-5,2'-benzod][1,3]dioxole was prepared in the same manner as described for I-24, except that 3-2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one was replaced with 8-chloro-3,4-dihydrobenzzo[b]oxepin-5(2H)-one. ES / MS: 367.0 (M+H+). 1H NMR (400 MHz, chloroform-d) δ 7.54 (d, J = 8.4 Hz, 1H), 7.16~6.99 (m, 3H), 6.87~6.63 (m, 2H), 4.33 (ddd, J = 12.2, 6.2, 3.9 Hz, 1H), 4.24~4.09 (m, 1H), 2.58~2.36 (m, 2H), 2.31 (ddp, J = 17.8, 9.0, 4.5 Hz, 1H), 2.15 (tq, J = 11.4, 4.2 Hz, 1H).

[0256] Preparation of Intermediate I-26: 4'-Bromo-8-chloro-3,4-dihydro-2H-spiro[benzo[b]oxepin-5,2'-benzod][1,3]dioxole (I-26): 4-Bromo-6'-chloro-3',4'-dihydro-2'H-spiro[benzod][1,3]dioxole-2,1'-naphthalene was prepared in the same manner as described for I-24, except that 3-2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one was replaced with 6-chloro-3,4-dihydronaphthalene-1(2H)-one. ES / MS: 353.1 (M+H+). 1H NMR (400 MHz, chloroform-d) δ 7.51 (d, J = 8.4 Hz, 1H), 7.26~7.19 (m, 2H), 7.04~6.96 (m, 1H), 6.79~6.75 (m, 2H), 2.89 (t, J = 6.3 Hz, 2H), 2.43~2.22 (m, 2H), 2.19~2.06 (m, 2H).

[0257] Preparation of Intermediate I-27: 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-ethylbenzo[d][1,3]dioxole (I-27): 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-ethylbenzo[d][1,3]dioxole was prepared in the same manner as described for I-24, except that 3-2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one was replaced with 1-(4-chloro-2-fluorophenyl)propan-1-one.

[0258] Preparation of Intermediate I-28: 4-Bromo-2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxole (I-28): 4-Bromo-2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxole was prepared in the same manner as described for I-3, except that 1-(4-chloro-2-fluorophenyl)ethan-1-one was replaced with 1-(2-fluoro-4-(trifluoromethyl)phenyl)ethan-1-one. 1H NMR (400 MHz, chloroform-d) δ 7.83 - 7.73 (m, 1H), 7.49 - 7.36 (m, 2H), 7.05 - 6.84 (m, 2H), 6.83 - 6.67 (m, 1H), 2.25 - 2.09 (m, 3H).

[0259] Preparation of Intermediate I-29: 4-Chloro-1-(diethoxyphosphorylmethyl)-2-fluoro-benzene: To a 40 mL vial (vented to air), 1-(bromomethyl)-4-chloro-2-fluoro-benzene (3.3 g, 14.8 mmol) and triethyl phosphite (2.53 mL, 14.8 mmol) were added (gas evolution). The mixture was heated at 100 °C for 3 h. The mixture was cooled and carried directly to the next step.

[0260] (E)-1-Bromo-3-(4-chloro-2-fluorostyryl)-2-fluorobenzene: THF (100 mL) was added to a 250 mL vial containing 4-chloro-1-(diethoxyphosphorylmethyl)-2-fluorobenzene (4 g, 14.3 mmol), and the mixture was cooled to 0 °C. Solid potassium tert-butoxide (2.4 g, 21.4 mmol) was added, and the mixture was stirred at 0 °C for 30 minutes. 3-Bromo-2-fluorobenzaldehyde (2.89 g, 14.3 mmol) was added, and the mixture was stirred at room temperature for 48 hours. The mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NH4Cl solution (1 × 50 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica chromatography (eluent: EtOAc / hexane) to obtain the desired product. 1H NMR (400 MHz, chloroform-d) δ 7.61~7.55 (m, 2H), 7.49 (ddd, J = 8.1, 6.5, 1.6 Hz, 1H), 7.29 (d, J = 6.2 Hz, 2H), 7.17 (ddd, J = 12.3, 10.4, 2.1 Hz, 2H), 7.06 (td, J = 7.9, 1.0 Hz, 1H).

[0261] 1-(3-Bromo-2-fluorophenyl)-2-(4-chloro-2-fluorophenyl)ethane-1,2-diol: To a 100 mL vial containing (E)-1-bromo-3-(4-chloro-2-fluorostyryl)-2-fluorobenzene (1 g, 3.03 mmol) was added tert-butanol (12 mL), water (10 mL), acetone (10 mL), citric acid (50% aqueous solution, 2.3 mL), potassium osmium(IV) oxide dihydrate (5.6 mg, 0.015 mmol), and 4-methylmorpholine N-oxide (390 mg, 3.3 mmol). The solution was stirred at 40 °C overnight. LCMS indicated consumption of the starting material. The mixture was diluted with EtOAc (50 mL), and 2 mL of saturated aqueous NH4Cl was added. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica chromatography (eluent: EtOAc / hexane) to afford the desired product. 1H NMR (400 MHz, chloroform-d) δ 7.57 - 7.38 (m, 3H), 7.24 - 6.89 (m, 3H), 5.16 (s, 2H).

[0262] 1-Bromo-7-chloro-4b,9b-dihydrobenzofuro[3,2-b]benzofuran (I-29): To a 40 mL vial containing 1-(3-bromo-2-fluorophenyl)-2-(4-chloro-2-fluorophenyl)ethane-1,2-diol (100 mg, 0.275 mmol) was added THF (5 mL), and the mixture was cooled to 0 °C under a nitrogen atmosphere. Potassium tert-butoxide (1 M in THF, 0.825 mL, 0.825 mmol) was added, and the mixture was stirred while warming to room temperature over 1 hour. The mixture was quenched with water (2 mL) and diluted with EtOAc (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica chromatography (eluent: EtOAc / hexane) to afford the desired product.

[0263] Preparation of Intermediate I-30 Methyl 5-amino-6-(((1-(cyanomethyl)cyclopropyl)methyl)amino)picolinate (I-30): Methyl 5-amino-6-(((1-(cyanomethyl)cyclopropyl)methyl)amino)picolinate was prepared in the same manner as I-11, except that [1-(fluoromethyl)cyclopropyl]methanamine; 2,2,2-trifluoroacetic acid was replaced with 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride. ES / MS: 261.2 (M+H+).

[0264] Preparation of Intermediates I-31 and I-32: 2-(4-Bromo-2-methyl-1,3-benzodioxol-2-yl)-5-chloropyridine (I-31 and I-32): 2-(4-Bromo-2-methyl-1,3-benzodioxol-2-yl)-5-chloropyridine (I-2) was separated by chiral SFC (AD-H column containing 5% IPA-NH3 co-solvent) to obtain two different stereoisomers.

[0265] Peak 1: 2-(4-Bromo-2-methyl-1,3-benzodioxol-2-yl)-5-chloropyridine (I-31): ES / MS: 328.1 (M+H+). 1H NMR (400 MHz, chloroform-d) δ 8.66 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 8.4, 2.4 Hz, 1H), 7.63 (dd, J = 8.4, 0.7 Hz, 1H), 6.99 (dd, J = 8.0, 1.4 Hz, 1H), 6.81 - 6.70 (m, 2H), 2.13 (s, 3H).

[0266] Peak 2: 2-(4-Bromo-2-methyl-1,3-benzodioxol-2-yl)-5-chloropyridine (I-32): ES / MS: 328.1 (M+H+). 1H NMR (400 MHz, chloroform-d) δ 8.66 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 8.4, 2.4 Hz, 1H), 7.63 (dd, J = 8.4, 0.7 Hz, 1H), 6.99 (dd, J = 8.0, 1.4 Hz, 1H), 6.81 - 6.70 (m, 2H), 2.13 (s, 3H).

[0267] Preparation of Intermediate I-33: Methyl 4-amino-3-(((4-ethyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate: Methyl 4-amino-3-(((4-ethyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate was prepared in the same manner as described for I-6, except that 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride was replaced with (4-ethyl-4H-1,2,4-triazol-3-yl)methanamine. ES / MS: 276.2 (M+H+).

[0268] Preparation of Intermediate I-34: Methyl 4-amino-3-((oxazol-2-ylmethyl)amino)benzoate: 4- Methyl amino-3-(((4-ethyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate was prepared in the same manner as described for I-6, except that 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride was replaced with oxazol-2-ylmethanamine hydrochloride. ES / MS: 248.2 (M+H+).

[0269] Preparation of Intermediates I-35 and I-36: 4-Bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one: To a solution of 4-chloro-2-fluoroaniline (100 g, 0.69 mmol) in acetic acid (1.37 mL) was added methyl 3-bromo-2-(bromomethyl)benzoate (216 mg, 0.70 mmol). The resulting mixture was heated at 100 °C for 18 hours, then cooled to room temperature and concentrated to dryness. The crude material was then purified using SiO2 column chromatography (eluent: EtOAc / hexane) to obtain 4-bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one (I-35). ES / MS m / z: 341.954 (M+H+).

[0270] 4-Bromo-2-(4-chloro-2-fluorophenyl)isoindoline: Borane-tetrahydrofuran complex (1 M in THF, 1 mL, 1 mmol) was added to 4-bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one (36 mg, 0.10 mmol). The resulting solution was stirred at room temperature for 3 days and then diluted with methanol. The mixture was then concentrated to dryness and the crude material was purified by SiO2 column chromatography (eluent: EtOAc / hexane) to give 4-bromo-2-(4-chloro-2-fluorophenyl)isoindoline (I-36). ES / MS m / z: 326.019 (M+H+).

[0271] Preparation of Intermediate I-37: 7-Bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one: Methyl 2-bromo-6-(bromomethyl)benzoate (270 mg, 0.88 mmol) was added to a solution of 4-chloro-2-fluoroaniline (106 g, 0.73 mmol) in acetic acid (1.5 mL). The resulting mixture was heated at 100 °C for 6 hours, then cooled to room temperature and concentrated to dryness. The crude material was then purified by SiO2 column chromatography (eluent: EtOAc / hexane) to give 7-bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one (I-37). ES / MS m / z: 342.074 (M+H+).

[0272] Preparation of Intermediate I-38: 2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-ol: To a solution of benzene-1,2,3-triol (2.5 g, 19.8 mmol) and 1-(4-chloro-2-fluorophenyl)ethan-1-one (3.5 g, 20.3 mmol) in toluene (19.8 mL) was added p-toluenesulfonic acid (190 mg, 1.0 mmol). The resulting mixture was heated to reflux for 2.5 days using a Dean-Stark trap. The resulting mixture was concentrated to dryness, and the crude material was then purified by SiO2 column chromatography (eluent: EtOAc / hexane) to give 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-ol. 1H NMR (400 MHz, CDCl3) δ 7.61 - 7.52 (m, 1H), 7.20 - 7.10 (m, 2H), 6.73 (t, J = 8.1 Hz, 1H), 6.54 - 6.47 (m, 2H), 5.09 (s, 1H), 2.10 (d, J = 1.2 Hz, 3H).

[0273] 2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl trifluoromethanesulfonate: -78 °C (external temperature, acetone / A solution of 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-ol (60 mg, 0.21 mmol) in dichloromethane (2 mL) for a CO2 bath was added with trifluoromethanesulfonic anhydride (1 M in CH2Cl2, 0.24 mL, 0.24 mmol) and triethylamine (0.06 mL, 0.43 mmol). The resulting mixture was stirred at -78 °C for 20 minutes and slowly warmed to room temperature over 40 minutes. The resulting mixture was diluted with CH2Cl2 and washed with aqueous bicarbonate solution. The aqueous layer was back-extracted with CH2Cl2 and concentrated to dryness. The crude material was then purified by SiO2 column chromatography (eluent: EtOAc / hexane) to obtain 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl trifluoromethanesulfonate (I-38). 1H NMR (400 MHz, CDCl3) δ 7.59 (t, J = 8.4 Hz, 1H), 7.18 (ddd, J = 9.6, 6.2, 2.1 Hz, 2H), 6.89~6.84 (m, 2H), 6.81 (dd, J = 6.9, 2.9 Hz, 1H), 2.13 (d, J = 1.1 Hz, 3H).

[0274] Preparation of Intermediate I-39: 4-(1,1-Dimethoxyethyl)-3-fluorobenzonitrile: To a solution of 4-acetyl-3-fluorobenzonitrile (110 mg, 0.67 mmol) and p-toluenesulfonic acid (6 mg, 0.05 mmol) in methanol (0.79 mL) was added trimethyl orthoformate (0.1 mL, 0.91 mmol). The resulting mixture was heated at 50 °C for 24 hours and then cooled to room temperature. The resulting mixture was diluted with diethyl ether and washed with dilute aqueous bicarbonate solution. The aqueous layer was back-extracted, dried over magnesium sulfate, and concentrated to dryness to obtain 4-(1,1-dimethoxyethyl)-3-fluorobenzonitrile. 1H NMR (400 MHz, CDCl3) δ 7.82 (t, J = 7.9 Hz, 1H), 7.47 (dd, J = 8.2, 1.6 Hz, 1H), 7.37 (dd, J = 10.6, 1.6 Hz, 1H), 3.22 (s, 6H), 1.66 (d, J = 0.7 Hz, 3H).

[0275] 4-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile: p-Toluenesulfonic acid (12 mg, 0.06 mmol) was added to a solution of 4-(1,1-dimethoxyethyl)-3-fluorobenzonitrile (141 mg, 0.67 mmol) and 3-bromobenzene-1,2-diol (133 mg, 0.70 mmol) in toluene (1.5 mL). The resulting mixture was heated at 75 °C for 4 days and then concentrated to dryness. The crude material was then purified by SiO2 column chromatography (eluent: EtOAc / hexane) to give 4-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (I-39). 1H NMR (400 MHz, MeOD) δ 7.81 (t, J = 7.7 Hz, 1H), 7.69 (dd, J = 10.6, 1.5 Hz, 1H), 7.63 (dd, J = 8.0, 1.6 Hz, 1H), 7.02 (dd, J = 8.2, 1.2 Hz, 1H), 6.87 (dd, J = 7.8, 1.2 Hz, 1H), 6.80 (t, J = 8.0 Hz, 1H), 2.13 (d, J = 1.1 Hz, 3H).

[0276] Preparation of Intermediate I-40: Methyl 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: Methyl 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared according to the procedure for the preparation of Intermediate I-14, except that 2-(4-bromo-2,5-difluorophenyl)acetic acid was used to replace 2-(4-bromo-2-fluorophenyl)acetic acid. ES / MS m / z: 487.257 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 1.6 Hz, 1H), 8.00 (dt, J = 8.5, 1.4H z, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 9.4, 4.6 Hz, 1H), 6.98 - 6.88 (m, 1H), 4.40 (d, J = 3.2 Hz, 2H), 4.32 (t, J = 5.2 Hz, 2H), 3.97 (d, J = 1.1 Hz, 3H), 3.64 (t, J = 5.2 Hz, 2H), 3.25 (d, J = 1.8 Hz, 3H), 1.36 (s, 12H).

[0277] Preparation of Intermediate I-41: 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2-fluorophenyl)acetic acid: 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxole (500 mg, 1.46 mmol) and ethyl 2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (538 mg, 1.75 mmol) were dissolved in 1,4-dioxane (3.0 mL), and the solution was degassed by bubbling with N2 for 10 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (107 mg, 0.146 mmol) and aqueous NaHCO3 solution (2.0 M, 2.18 mL, 4.37 mmol) were added to the flask, and the mixture was heated at 90 °C for 1 hour. The reaction was cooled to ambient temperature, diluted with EtOAc (5 mL) and water (2 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (5 × 2 mL), the organic layers were combined, washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified through a silica plug to remove residual palladium (50% EtOAc in hexane). ES / MS: 445.0 (M + H+).

[0278] The residue was dissolved in ACN (5.0 mL), and an aqueous LiOH solution (1.0 M, 2 mL) was added. The reaction mixture was heated at 80 °C for 2 hours. The reaction mixture was cooled to ambient temperature and quenched with an HCl aqueous solution (1 M) until it was determined to be weakly acidic using pH test paper. The reaction mixture was diluted with EtOAc (3 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 × 5 mL), the organic layers were combined, washed with brine (3 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and used without further purification. The title product was obtained. ES / MS: 439.0 (M+Na+).

[0279] Preparation of Intermediate I-42: (S)-Methyl 4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoate: (S)-Methyl 4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoate (I-42) was prepared in the same manner as described for Intermediate I-7, except that methoxyethylamine was replaced with [(2S)-tetrahydrofuran-2-yl)methanamine. ES / MS m / z: 251.2 (M+H+).

[0280] B. Compound Examples Procedure 1: Example 1:

[0281]

Chemical Structure

[0282] Methyl 2-(4-bromo-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate: To a solution of 2-(4-bromo-2,6-difluorophenyl)acetic acid (150 mg, 0.58 mmol), methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (I-6) (174 mg, 0.69 mmol), and HATU (177 mg, 0.75 mmol) in DCM (3.0 mL) and DMF (1.5 mL) was added DIPEA (0.50 mL, 2.90 mmol). The reaction mixture was stirred at room temperature for 16 h and then diluted with saturated aqueous ammonium chloride and EtOAc. The aqueous layer was extracted with two additional portions of EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, isolated by vacuum filtration, and concentrated in vacuo. The crude material was taken up in dichloroethane (1.0 mL) and acetic acid (3.0 mL) and stirred at 60 °C for 4 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (eluent: EtOAc / Hex) to afford the desired product. ES / MS: 474.0, 476.0 (M+H + ).

[0283] Methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate: A solution of methyl 2-(4-bromo-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (40.0 mg, 0.084 mmol), bis(pinacolato)diboron (27.8 mg, 0.11 mmol), potassium propionate (28.4 mg, 0.25 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.4 mg, 0.013 mmol) in 1,4-dioxane (1.0 mL) was degassed by bubbling argon through it for 60 seconds and then heated in a sealed tube at 110 °C for 45 minutes. The reaction mixture was cooled and then 2M aqueous sodium carbonate solution (84 μL, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.7 mg, 0.0063 mmol), and 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole (I-3) (29.0 mg, 0.084 mmol) were added. The solution was degassed by bubbling argon through it for 60 seconds and then heated in a sealed tube at 80 °C for 2 hours. The reaction mixture was cooled, filtered through celite (eluent: EtOAc), and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: EtOAc / Hex) to give the desired product. ES / MS: 658.2 (M+H + )

[0284] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 1): To a solution of methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (48.5 mg, 0.074 mmol) in MeCN (0.75 mL) was added 0.3 M aqueous lithium hydroxide solution (0.49 mL, 0.15 mmol). The reaction mixture was heated at 100 °C for 2 minutes in a sealed tube. The cooled reaction mixture was purified by RP-HPLC (eluent: water / MeCN with 0.1% TFA) to give Example 1 of the product as the trifluoroacetate salt. ES / MS: 644.2 (M+H + ). 1H NMR (400 MHz, MeOD) δ 8.56 (dd, J = 1.4, 0.7 Hz, 1H), 8.14 (dd, J = 8.6, 1.4 Hz, 1H), 7.71 (dd, J = 8.5, 0.6 Hz, 1H), 7.64 - 7.53 (m, 3H), 7.31 (dd, J = 10.9, 2.0 Hz, 1H), 7.23 (ddd, J = 8.4, 2.0, 0.8 Hz, 1H), 7.20 (dd, J = 7.8, 1.5 Hz, 1H), 7.03 - 6.93 (m, 2H), 4.76 (s, 2H), 4.73 (s, 2H), 2.64 (s, 2H), 2.12 (d, J = 1.0 Hz, 3H), 1.03 - 0.96 (m, 2H), 0.96 - 0.88 (m, 2H).

[0285] Procedure 2, Example 2 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 2):

[0286]

Chemical Structure

[0287] (S)-4-(2-(4-Bromo-2,6-difluorophenyl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoic acid tert-butyl: To a solution of 2-(4-bromo-2,6-difluoro-phenyl)acetic acid (100 mg, 0.40 mmol) in DMF (2 mL) were added (S)-4-amino-2-fluoro-3-((oxetan-2-ylmethyl)amino)benzoic acid tert-butyl (I-12) (106 mg, 0.36 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (227 mg, 0.60 mmol), followed by N,N-diisopropylethylamine (0.35 mL, 1.99 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then taken up in EtOAc (40 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was carried on to the next treatment without further purification. ES / MS: 529.5 (M+H + ).

[0288] (S)-2-(4-Bromo-2,6-difluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid: The crude product from the previous step, (S)-4-(2-(4-bromo-2,6-difluorophenyl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoic acid tert-butyl (211 mg, 0.40 mmol), was dissolved in AcOH (2 mL) and the reaction mixture was heated to 100 °C for 30 min. The reaction mixture was concentrated in vacuo and the crude residue was taken up in EtOAc (40 mL) and washed with saturated aqueous sodium bicarbonate (4 × 10 mL), followed by water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (0–100% EtOAc in hexanes) to afford the title compound. ES / MS: 511.9 (M+H+ )

[0289] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl: To a vial were added (S)-2-(4-bromo-2,6-difluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (67 mg, 0.13 mmol), potassium propionate (44 mg, 0.39 mmol), bis(pinacolato)diboron (43 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.020 mmol), and dioxane (1.5 mL). The resulting mixture was degassed by bubbling argon under the liquid surface for 1 minute, then the vial was sealed and placed in a heating block at 110 °C for 30 minutes. Upon cooling, the vial was opened and 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole (54 mg, 0.16 mmol) (I-3), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.3 mg, 0.010 mmol), and potassium carbonate (2 M aqueous solution, 0.13 mL, 0.26 mmol) were added to the reaction mixture. The resulting mixture was degassed by bubbling argon under the liquid surface for 1 minute, then the vial was sealed and placed in a heating block at 0 °C for 2 hours. Upon completion, the reaction mixture was cooled to room temperature, poured into water (15 mL), and extracted with EtOAc (2 × 25 mL). The organic layer was washed with brine (10 mL), dried over MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography (20 - 100% EtOAc in hexane) to give the title compound. ES / MS: 695.3 (M+H + )

[0290] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 2): To a solution of tert-butyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (40 mg, 0.057 mmol) in DCM (2 mL) was added 0.25 mL of TFA, and the resulting solution was stirred at 40 °C for 1 h. The reaction mixture was diluted with EtOAc (30 mL), washed with water (3 × 5 mL), concentrated, and purified by RP-HPLC (eluent: water / MeCN 0.1% TFA). The combined fractions were then diluted with EtOAc (50 mL), washed with water (3 × 20 mL), brine (1 × 15 mL), and dried over MgSO4. EtOAc was removed by rotary evaporation, and the crude residue was taken up in acetonitrile (20 mL) and concentrated to dryness twice and then the residue was dissolved in acetonitrile:water (2:1, 20 mL), frozen, and placed on a freeze dryer to obtain Example 2 of the final compound. ES / MS: 639.6 (M+H + ). 1H NMR (400 MHz, DMSO-d6) δ 7.67~7.53 (m, 5H), 7.44~7.35 (m, 2H), 7.31 (dd, J = 8.0, 1.3 Hz, 1H), 7.07 (dd, 7.8, 1.3 Hz, 1H), 7.01 (t, J = 7.9 Hz, 1H), 5.18~5.10 (m, 1Hz), 4.85 (dd, J = 15.6, 7.1 Hz, 1H), 4.69 (dd, J = 15.7, 2.8 Hz, 1H), 4.62~4.51 (m, 2H), 4.49~4.35 (m, 2H), 2.90~2.70 (m, 1H), 2.47~2.37 (m, 1H), 2.12 (s, 3H).

[0291] Procedure 3: Example 3

[0292]

Chemical Structure

[0293] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-N-(cyclopropylsulfonyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxamide (Example 3): A mixture of 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2,6-difluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid (Example 19) (20.0 mg, 0.0328 mmol), cyclopropanesulfonamide (11.9 mg, 0.0985 mmol), 4-(dimethylamino)-pyridine (16.9 mg, 0.138 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (26.4 mg, 0.138 mmol) in DMF (1.00 mL) was treated with N,N-diisopropylethylamine (0.0515 mL, 0.296 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched by addition of 50 μL of TFA, and the crude reaction mixture was purified directly by RP-HPLC (15~76.84%, 0.1% TFA-ACN, 0.1% TFA in water, 15 min gradient ×, column: Gemini 5 uM, NX-C18 110 Angstrom, 250×21.2 mm) to give the title compound of Example 3 as a racemic mixture of trifluoroacetate salts. ES / MS m / z: 712.3 (M+H + ) 11H NMR (400 MHz, methanol-d4) δ 8.41~8.37 (m, 1H), 8.01 (dd, J = 8.6, 1.6 Hz, 1H), 7.76 (dd, J = 8.6, 0.7 Hz, 1H), 7.65~7.54 (m, 3H), 7.34 (dd, J = 11.0, 2.0 Hz, 1H), 7.29~7.24 (m, 1H), 7.21 (dd, J = 7.8, 1.5 Hz, 1H), 7.05~6.95 (m, 2H), 4.85 (s, 3H), 4.78 (t, J = 5.0 Hz, 2H), 4.73 (s, 2H), 3.87 (t, J = 4.9 Hz, 2H), 3.25~3.17 (m, 1H), 2.14 (s, 3H), 1.41~1.28 (m, 2H), 1.23~1.10 (m, 2H).

[0294] Procedure 4: Example 4

[0295]

Chemical formula

[0296] Methyl 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: Into a vial were added methyl 2-(4-bromo-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (prepared in the same manner as the first step of Procedure 1) (60 mg, 0.142 mmol), bis(neopentyl glycolato)diboron (64.3 mg, 0.285 mmol), Pd(dppf)Cl2 (16 mg, 0.0214 mmol), and potassium propionate (48 mg, 0.43 mmol). 1,4-Dioxane (1.0 mL) was added and the mixture was degassed with argon for 30 seconds. The vial was sealed and the mixture was heated at 120 °C for 1 hour. The vial was cooled and LCMS indicated the conversion of the starting aryl bromide to the intermediate boronic acid. Pd(dppf)Cl2 (8 mg, 0.012 mmol) and 4-(4-bromobenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (I-1) (41 mg, 0.128 mmol) were added and then sodium carbonate (2 M aqueous solution, 0.18 mL, 0.356 mmol) was added. The flask was sealed and stirred at 90 °C for 1 hour. LCMS indicated the conversion to the desired product and the flask was cooled to room temperature. The organic layer was transferred directly onto a packed column and the crude material was purified by silica gel chromatography (eluent: EtOAc / hexane) to afford the desired product. ES / MS: 582.4 (M+H + ).

[0297] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: In a 40 mL vial, methyl 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (32.5 mg, 0.0559 mmol) and acetonitrile (1 mL) were added. To the mixture, LiOH H2O (3.3 mg, 0.06 mmol) dissolved in water (0.2 mL) was added, and the mixture was stirred at 55 °C for 3 hours. LCMS indicated the conversion of the starting material to the product. The mixture was acidified with 50% citric acid (0.2 mL), and 2 drops of trifluoroacetic acid were added. The substance was purified by RP-HPLC (eluent: water / MeCN * 0.1% TFA) to obtain Example 4 of the product as the trifluoroacetate salt. ES / MS: 568.5 (M+H + ). 1H NMR (400 MHz, methanol-d4) δ 8.53 (d, J = 1.4 Hz, 1H), 8.20 (dd, J = 8.6, 1.5 Hz, 1H), 7.85 - 7.78 (m, 1H), 7.78 - 7.63 (m, 4H), 7.49 (t, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.23 (d d, J = 8.0, 1.3 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.99 (dd, J = 7.8, 1.2 Hz, 1H), 4.78 (t, J = 5.0 Hz, 2H), 4.73 (s, 2H), 3.85 - 3.73 (m, 2H), 3.30 (s, 3H).

[0298] Procedure 5: Example 5

[0299]

Chemical Structure

[0300] Methyl 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: To a vial were added (bromobenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (I-1) (65 mg, 0.203 mmol), bis(neopentyl glycolato)diboron (60 mg, 0.264 mmol), Pd(dppf)Cl2 (22.6 mg, 0.03 mmol), and potassium propionate (68 mg, 0.609 mmol). 1,4-Dioxane (1.0 mL) was added and the mixture was degassed with argon for 30 seconds. The vial was sealed and the mixture was heated at 120 °C for 30 minutes. The vial was cooled and LCMS indicated the conversion of the starting aryl bromide to the intermediate boronic acid. Pd(dppf)Cl2 (12 mg, 0.018 mmol) and methyl 2-(4-bromo-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (prepared as in the first step of procedure 1) (93 mg, 0.212 mmol) were added, and sodium carbonate (2 M in water, 0.2 mL, 0.406 mmol) was added. The flask was sealed and stirred at 90 °C for 1 hour. LCMS indicated the conversion to the desired product and the flask was cooled to room temperature. The organic layer was transferred directly onto a packed column and the crude material was purified by silica gel chromatography (eluent: EtOAc / hexane) to afford the desired product. ES / MS: 600.3 (M+H + )

[0301] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: Methyl 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (70 mg, 0.117 mmol) was added to a 40 mL vial, and acetonitrile (1 mL) was added. To the mixture was added LiOH H2O (4.2 mg, 0.18 mmol) dissolved in water (0.2 mL), and the mixture was stirred at 55 °C for 5 hours. LCMS indicated the conversion of the starting material to the product. The mixture was acidified with 50% citric acid (0.2 mL), and 2 drops of trifluoroacetic acid were added. The substance was purified by RP-HPLC (eluent : water / MeCN * 0.1% TFA) to obtain Example 5 of the product as the trifluoroacetate salt. ES / MS: 586.291 (M+H + ). 1H NMR (400 MHz, methanol-d4) δ 8.54 (d, J = 1.5 Hz, 1H), 8.21 (dd, J = 8.5, 1.6 Hz, 1H), 7.86 - 7.62 (m, 4H), 7.51 - 7.40 (m, 2H), 7.35 (dd, J = 10.0, 6.2 Hz, 1H), 7.12 - 6.98 (m, 3H), 4.80 (t, J = 5.0 Hz, 2H), 4.74 (s, 2H), 3.83 (t, J = 4.9 Hz, 2H), 3.30 (s, 3H).

[0302] Procedure 6: Example 32

[0303]

Chemical Structure

[0304] Methyl 2-(2-fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: In a vial, 4-bromo-2-phenylbenzo[d][1,3]dioxole (synthesized from benzal bromide in the same manner as I-1) (59 mg, 0.214 mmol), Pd(dppf)Cl2 (23.8 mg, 0.024 mmol), methyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-14) (100 mg, 0.214 mmol), DME (1 mL), and sodium carbonate (2 M aqueous solution, 0.21 mL, 0.427 mmol) were added. The flask was degassed with argon for 30 seconds, sealed, and stirred at 90 °C for 1 hour. LCMS indicated conversion to the desired product, and the flask was cooled to room temperature. The organic layer was transferred directly to a packed column, and the crude material was purified by silica gel chromatography (eluent: EtOAc / hexane) to obtain the desired product. ES / MS: 539.568 (M+H + ).

[0305] 2-(2-Fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: Methyl 2-(2-fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.186 mmol) and acetonitrile (2 mL) were added to a 40 mL vial. To the mixture was added LiOH (11.1 mg, 0.464 mmol) dissolved in water (0.5 mL), and the mixture was stirred at 55 °C for 24 h. LCMS indicated the conversion of the starting material to the product. The mixture was acidified with 50% citric acid (0.2 mL), and 2 drops of trifluoroacetic acid were added. The substance was purified by RP-HPLC (eluent: water / MeCN with 0.1% TFA) to give Example 32 of the product as the trifluoroacetate salt. ES / MS: 525.581 (M+H + ). 1H NMR (400 MHz, methanol-d4) δ 8.55 (s, 1H), 8.23 (dd, J = 8.6, 1.4 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.74 - 7.64 (m, 2H), 7.60 (dd, J = 7.4, 2.4 Hz, 2H), 7.56 - 7.42 (m, 4H), 7.19 (d, J = 8.1 Hz, 1H), 7.13 (s, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 4.81 (t, J = 5.0 Hz, 2H), 4.76 (s, 2H), 3.80 (t, J = 4.9 Hz, 2H), 3.30 (s, 3H).

[0306] Procedure 7: Example 7

[0307]

Chemical Structure

[0308] Methyl 2-(3-bromo-2-hydroxyphenyl)acetate: To a solution of tert-butylamine (940 mg, 12.9 mmol) in PhMe (10 mL) at -30 °C was added dropwise bromine (1.08 g, 6.74 mmol). The solution was stirred at -30 °C for 1 h and then cooled to -78 °C. A solution of methyl 2-(2-hydroxyphenyl)acetate (1.40 g, 8.42 mmol) in DCM (6 mL) was slowly added. The resulting mixture was slowly warmed to room temperature over 16 h with vigorous stirring. H2O (50 mL) and EtOAc (50 mL) were added and the resulting mixture was poured into a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic extracts were then washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane). ES / MS: 245.2 (M+H + ).

[0309] Methyl 2-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)phenyl)acetate: To a solution of methyl 2-(3-bromo-2-hydroxyphenyl)acetate (1.29 g, 5.26 mmol) in DCM (10 mL) at room temperature were added imidazole (720 mg, 10.5 mmol) and tert-butyldimethylsilyl chloride (1.20 g, 7.90 mmol), respectively. The mixture was stirred at room temperature for 1.5 h, then diluted with H2O (50 mL) and DCM (50 mL) and poured into a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (2 × 50 mL). The combined organic extracts were then washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane). 1H NMR (400 MHz, chloroform-d) δ 7.51~7.40 (m, 1H), 7.21~7.14 (m, 1H), 6.85 (t, J = 7.8 Hz, 1H), 3.72 (s, 3H), 3.69 (s, 2H), 1.06 (s, 9H), 0.30 (s, 6H).

[0310] 2-(3-Bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)acetaldehyde: At 0 °C, a solution of methyl 2-(3-bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)acetate (150 mg, 0.417 mmol) in DCM (10 mL) was added dropwise with diisobutylaluminum hydride (1 M solution in hexane) (1.04 mL, 1.04 mmol). The solution was warmed to room temperature over 1 hour with rapid stirring, then quenched with saturated aqueous sodium potassium tartrate (50 mL) and diluted with EtOAc (50 mL). The resulting slurry was filtered through a plug of celite and the cake was washed with EtOAc (50 mL). The filtrate was poured into a separatory funnel and the layers were separated. The aqueous phase was extracted with EtOAc (2 × 50 mL), the combined organics were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo.

[0311] The crude mixture was dissolved in DCM (10 mL). NaHCO3 (76 mg, 1.25 mmol) and Dess-Martin periodinane (270 mg) were added at room temperature. The mixture was stirred at room temperature for 1 hour, then filtered through celite and the cake was washed with DCM (20 mL). The filtrate was concentrated under vacuum and purified by silica gel chromatography (eluent: EtOAc / hexane). 1H NMR (400 MHz, chloroform-d) δ 9.68 (t, J = 2.1 Hz, 1H), 7.51 (dd, J = 8.0, 1.7 Hz, 1H), 7.09 (dd, J = 7.5, 1.7 Hz, 1H), 6.88 (t, J = 7.8 Hz, 1H), 3.71 (d, J = 2.1 Hz, 2H), 1.06 (s, 9H), 0.30 (s, 6H).

[0312] 2-Bromo-6-(2-hydroxy-2-phenylethyl)phenol: To a solution of 2-(3-bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)acetaldehyde (100 mg, 0.30 mmol) in THF (5 mL) was added dropwise phenylmagnesium bromide (1 M solution in THF) (0.46 mL, 0.46 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, then quenched with saturated aqueous NH4Cl solution (10 mL) with rapid stirring and warmed to room temperature. The mixture was poured into a separatory funnel and the layers were separated. The aqueous phase was extracted with EtOAc (2 × 20 mL), the combined organics were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo.

[0313] The crude mixture was redissolved in THF (5 mL). Tetrabutylammonium fluoride (1 M solution in THF) (0.46 mL, 0.46 mmol) was added dropwise at room temperature, and the resulting mixture was stirred for 1 h, then diluted with EtOAc (20 mL) and saturated aqueous NaHCO3 solution (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous phase was extracted with EtOAc (2 × 20 mL), the combined organics were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane). 1H NMR (400 MHz, chloroform-d) δ 9.29 (s, 1H), 7.37~7.26 (m, 5H), 7.25~7.19 (m, 1H), 6.82 (dd, J = 7.5, 1.6 Hz, 1H), 6.62 (t, J = 7.7 Hz, 1H), 5.49 (s, 1H), 5.10 (dd, J = 8.2, 3.1 Hz, 1H), 3.14 (dd, J = 14.4, 8.2 Hz, 1H), 3.02 (dd, J = 14.4, 3.1 Hz, 1H).

[0314] 7-Bromo-2-phenyl-2,3-dihydrobenzofuran: To a solution of 2-bromo-6-(2-hydroxy-2-phenylethyl)phenol (48 mg, 0.164 mmol) in THF (6 mL) at room temperature were added triphenylphosphine (52 mg, 0.20 mmol) and diisopropyl azodicarboxylate (50 mg, 0.25 mmol) respectively. The mixture was stirred at room temperature for 15 minutes and then concentrated under vacuum. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane). 1H NMR (4 00 MHz, chloroform-d) δ 7.51~7.37 (m, 4H), 7.37~7.32 (m, 2H), 7.13 (dt, J = 7.2, 1.1 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 3.96~3.67 (m, 1H), 3.33 (ddt, J = 15.8, 7.9, 1.0 Hz, 1H).

[0315] Methyl 2-(2-fluoro-4-(2-phenyl-2,3-dihydrobenzofuran-7-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: To a 5 mL microwave vial were added methyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-14) (61 mg, 0.13 mmol), 7-bromo-2-phenyl-2,3-dihydrobenzofuran (30 mg, 0.11 mmol), and Pd(dppf)Cl2 (10 mg, 0.0135 mmol). Dioxane (3 mL) and Na2CO3 (1.5 M in H2O) (0.22 mL, 0.33 mmol) were added, and the resulting mixture was purged with argon for 2 minutes. The mixture was heated to 85 °C, stirred for 2 hours, and then cooled to room temperature. After dilution with H2O (20 mL) and EtOAc (20 mL), the mixture was poured into a separatory funnel. The layers were separated, and the aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic extracts were then washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane). ES / MS: 537.20 (M+H + ).

[0316] 2-(2-Fluoro-4-(2-phenyl-2,3-dihydrobenzofuran-7-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: Methyl 2-(2-fluoro-4-(2-phenyl-2,3-dihydrobenzofuran-7-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (43 mg, 0.080 mmol) was dissolved in acetonitrile (0.9 mL), and then LiOH (2 M in H2O) (0.2 mL, 0.40 mmol) was added. The resulting mixture was stirred at 50 °C for 3 hours. The pH of the reaction mixture was adjusted to pH 2 using citric acid (1 M in H2O) (1 mL), and extracted with EtOAc (2 x 10 mL). The combined organics were concentrated and purified by RP-HPLC (eluent: H2O / MeCN 0.1% TFA) to give the product (Example 7) as the trifluoroacetate salt. ES / MS: 523.2 (M+H + ). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 1.5 Hz, 1H), 7.89 (dd, J = 8.5, 1.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.49 - 7.37 (m, 6H), 7.37 - 7.31 (m, 1H), 7.28 (dd, J = 7.3, 1.3 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 5.92 (dd, J = 9.4, 8.1 Hz, 1H), 4.64 (t, J = 5.2 Hz, 2H), 4.51 (s, 2H), 3.75 (dd, J = 15.9, 9.4 Hz, 1H), 3.66 (t, J = 5.0 Hz, 2H), 3.25 - 3.14 (m, 4H).

[0317] Procedure 8: Example 8

[0318]

Chemical Structure

[0319] Methyl 2-(5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)thiophen-2-yl)acetate: In an 8 mL reaction vial, a suspension of methyl 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]acetate (150 mg, 0.532 mmol), 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole I-3 (198 mg, 0.575 mmol), (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (30.1 mg, 0.0425 mmol), and sodium carbonate (2.00 M, 0.550 mL, 1.10 mmol) in dioxane (2 mL) was degassed with argon for 5 minutes. The reaction mixture was heated at 100 °C for 6 hours. The reaction mixture was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate and purified by silica gel chromatography (eluent: EtOAc / hexane). 1H NMR (400 MHz, CDCl3) δ 7.58 (t, J = 8.3 Hz, 1H), 7.48 (d, J = 3.7 Hz, 1H), 7.18 (dd, J = 10.5, 2.0 Hz, 1H), 7.13 (ddd, J = 8.4, 2.0, 0.8 Hz, 1H), 7.09 (dd, J = 8.1, 1.2 Hz, 1H), 6.98 (dd, J = 3.7, 1.0 Hz, 1H), 6.84 (t, J = 7.9 Hz, 1H), 6.75 (dd, J = 7.7, 1.1 Hz, 1H), 3.89 (d, J = 0.9 Hz, 2H), 3.78 (s, 3H), 2.15 (d, J = 1.1 Hz, 3H).

[0320] 2-(5-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)thiophen-2-yl)acetic acid: A solution of methyl 2-[5-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-2-thienyl]acetate (69.0 mg, 0.165 mmol) and lithium hydroxide monohydrate (19.3 mg, 0.461 mmol) in CH3CN (3 mL) and water (1 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and adjusted to about pH 6 with 1N HCl (500 μL). The organic extract was dried over sodium sulfate to afford the desired product. ES / MS: 405.0 (M+).

[0321] Methyl 2-((5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)thiophen-2-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: To a solution of 2-[5-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-2-thienyl]acetic acid (66.7 mg, 0.165 mmol), methyl 4-amino-3-(2-methoxyethylamino)benzoate I-7 (44.3 mg, 0.198 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (106 mg, 0.279 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.135 mL, 0.776 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with 5% LiCl, saturated NaHCO3, and brine. The organic extract was dried over sodium sulfate to give the crude product, which was used in the following step.

[0322] A solution of methyl 4-[[2-[5-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2-thienyl]acetyl]amino]-3-(2-methoxyethylamino)benzoate (101 mg, 0.165 mmol) in AcOH (0.650 mL) and DCE (4 mL) was heated at 60 °C for 18 h. The reaction mixture was concentrated and purified by silica gel chromatography (eluent: EtOAc / hexane). ES / MS: 593.2 (M + ). Multiplet Report 1H NMR (400 MHz, CDCl3) δ 8.11 (t, J = 1.0 Hz, 1H), 8.07~7.96 (m, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.55 (t, J = 8.2 Hz, 1H), 7.46 (d, J = 3.7 Hz, 1H), 7.15 (dd, J = 10.6, 2.0 Hz, 1H), 7.11 (ddd, J = 8.3, 2.0, 0.7 Hz, 1H), 7.03 (dd, J = 8.1, 1.1 Hz, 1H), 6.96 (d, J = 3.6 Hz, 1H), 6.82 (t, J = 7.9 Hz, 1H), 6.74 (dd, J = 7.8, 1.2 Hz, 1H), 4.67 (s, 2H), 4.40 (t, J = 5.3 Hz, 2H), 3.98 (s, 3H), 3.66 (t, J = 5.3 Hz, 2H), 3.29 (s, 3H), 2.13 (d, J = 1.0 Hz, 3H).

[0323] 2-((5-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)thiophen-2-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: A mixture of methyl 2-[[5-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2-thienyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (32.3 mg, 0.0545 mmol) and lithium hydroxide monohydrate (0.300 M, 0.545 mL, 0.163 mmol) in CH3CN (1 mL) placed in a 40 mL reaction vial was heated at 90 °C for 15 minutes. The mixture was diluted with EtOAc and water and neutralized with 0.160 mL of 1 M citric acid. The organic extract was dried over sodium sulfate and purified by RP-HPLC (eluent: H2O / MeCN 0.1% TFA) to obtain the product (Example 8) as the trifluoroacetate salt. ES / MS: 593.2 (M + ). Multiplex report 1H NMR (400 MHz, DMSO) δ 12.83 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.51 (d, J = 3.7 Hz, 1H), 7.35 (dd, J = 8.4, 2.1 Hz, 1H), 7.18 - 7.12 (m, 1H), 7.11 (d, J = 3.7 Hz, 1H), 6.94 - 6.79 (m, 2H), 4.64 (s, 2H), 4.56 (t, J = 5.0 Hz, 2H), 3.61 (t, J = 5.1 Hz, 2H), 3.19 (s, 3H), 2.10 (s, 3H).

[0324] Procedure 9: Example 9 and Example 13

[0325]

Chemical Structure

[0326] 1-((1-(2-Amino-2-oxoethyl)cyclopropyl)methyl)-2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-4-fluoro-1H-benzo[d]imidazole-6-carboxylic acid (Example 9) and 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-4-fluoro-1H-benzo[d]imidazole-6-carboxylic acid (Example 13): To a solution of ethyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (synthesized in the same manner as in Procedure 1) (70 mg, 0.1 mmol) in MeCN (1 mL) was added 0.3 M aqueous lithium hydroxide (0.49 mL, 0.15 mmol). The reaction mixture was heated at 70 °C for 2 h in a sealed tube. The cooled reaction mixture was purified by RP-HPLC (eluent: water / MeCN with 0.1% TFA) to give the products of Example 9 and Example 13 as trifluoroacetate salts.

[0327] Example 9: ES / MS m / z: 680.0 (M+H + )。1H NMR (400 MHz, methanol-d4) δ 8.24 (d, J = 1.2 Hz, 1H), 7.70~7.55 (m, 2H), 7.51 (d, J = 9.0 Hz, 2H), 7.33 (dd, J = 10.9, 2.0 Hz, 1H), 7.27~7.14 (m, 2H), 7.07~6.87 (m, 2H), 4.69 (s, 2H), 4.57 (s, 2H), 2.26 (s, 2H), 2.13 (d, J = 1.0 Hz, 3H), 0.96~0.80 (m, 1H).

[0328] Example 13: ES / MS m / z: 662.2 (M+H +)。1H NMR (400 MHz, methanol-d4) δ 8.24 (d, J = 1.2 Hz, 1H), 7.73 - 7.57 (m, 2H), 7.57 - 7.46 (m, 2H), 7.32 (dd, J = 10.9, 2.0 Hz, 1H), 7.28 - 7.15 (m, 2H), 7.06 - 6.81 (m, 2H), 4.66 (s, 2H), 4.55 (s, 2H), 2.61 (s, 2H), 2.13 (d, J = 1.0 Hz, 3H), 0.98 - 0.79 (m, 4H).

[0329] Procedure 10: Example 10 and Example 17

[0330]

Chemical Structure

[0331] 2-(4-(2-(2-Carboxyethyl)-2-(4-chlorophenyl)-2,3-dihydrobenzo[d]oxazol-7-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 1 0) and 2-(4-(3a-(4-chlorophenyl)-1-oxo-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazol-5-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 17): To a solution of methyl 2-(4-(3a-(4-chlorophenyl)-1-oxo-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazol-5-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (synthesized in the same manner as in Procedure 1) (112 mg, 0.174 mmol) in MeCN (1 mL) was added lithium hydroxide monohydrate (11 mg, 0.26 mmol) dissolved in water (0.5 mL). The reaction mixture was heated in a sealed tube at 100 °C for 3 minutes. The cooled reaction mixture was purified by RP-HPLC (eluent: water / MeCN with 0.1% TFA) to obtain the products of Example 10 and Example 17 as trifluoroacetate salts.

[0332] Example 10: ES / MS m / z: 648.2 (M + )。1H NMR (400 MHz, methanol-d4) δ 8.54 (t, J = 1.0 Hz, 1H), 8.21 (dd, J = 8.6, 1.4 Hz, 1H), 8.08 - 8.00 (m, 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.41 - 7.33 (m, 2H), 7.33 - 7.21 (m, 2H), 7.00 (t, J = 7.8 Hz, 1H), 4.85 - 4.81 (m, 2H), 4.78 (s, 2H), 3.88 - 3.81 (m, 2H), 3.47 (t, J = 6.4 Hz, 2H), 3.32 (s, 3H), 2.94 (t, J = 6.4 Hz, 2H).

[0333] Example 17: ES / MS m / z: 630.2 (M + )。1H NMR (400 MHz, methanol-d4) δ 8.58 (s, 1H), 8.28 - 8.22 (m, 1H), 8.12 - 8.01 (m, 2H), 7.78 (d, J = 8.6 Hz, 1H), 7.71 (t, J = 8.6 Hz, 4H), 7.59 - 7.44 (m, 3H), 4.86 - 4.83 (m, 4H), 3.87 (t, J = 4.9 Hz, 2H), 3.74 (t, J = 6.6 Hz, 2H), 3.46 (t, J = 6.5 Hz, 2H), 3.32 (s, 3H).

[0334] Procedure 11: 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Examples 33 and 34):

[0335]

Chemical Structure

[0336] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 4 obtained in the same manner as described in Procedure 4), as a mixture of two stereoisomers, was separated by chiral SFC (CELL-2 column containing 30% EtOH-TFA co-solvent) to obtain two different stereoisomers.

[0337] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 33): ES / MS m / z: 568.4 (M+H + )。1H NMR (400 MHz, methanol-d4) δ 8.41 (s, 1H), 8.13 - 8.06 (m, 1H), 7.84 - 7.77 (m, 1H), 7.77 - 7.59 (m, 5H), 7.43 (d, J = 14.0 Hz, 2H), 7.25 - 7.17 (m, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.97 (dd, J = 7.6, 1.1 Hz, 1H), 4.67 (t, J = 5.0 Hz, 2H), 4.62 (s, 2H), 3.75 (t, J = 4.9 Hz, 2H), 3.28 (s, 3H).

[0338] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 34). ES / MS: 568.4 (M+H +)。1H NMR (400 MHz, methanol-d4) δ 8.41 (s, 1H), 8.11 (dd, J = 8.6, 1.5 Hz, 1H), 7.80 (t, J = 7.5 Hz, 1H), 7.77 - 7.57 (m, 5H), 7.43 (d, J = 12.3 Hz, 2H), 7.22 (dd, J = 8.0, 1.2 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.97 (dd, J = 7.8, 1.2 Hz, 1H), 4.67 (t, J = 5.0 Hz, 2H), 4.63 (s, 2H), 3.75 (t, J = 5.0 Hz, 2H), 3.28 (s, 3H).

[0339] Step 12: 2-(2-Fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Examples 35 and 36):

[0340]

Chemical Structure

[0341] 2-(2-Fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(2-Fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid as a mixture of two stereoisomers (Example 32 obtained in the same manner as described in Step 6) was separated by chiral SFC (AD-H column containing 30% MeOH co-solvent) to obtain two different stereoisomers.

[0342] 2-(2-Fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 35): ES / MS: 525.3 (M + H +)。1H NMR (400 MHz, methanol-d4) δ 8.52~8.48 (m, 1H), 8.19 (dd, J = 8.6, 1.4 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.72~7.64 (m, 2H), 7.64~7.56 (m, 2H), 7.52~7.42 (m, 4H), 7.19 (dd, J = 8.1, 1.2 Hz, 1H), 7.13 (s, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.93 (dd, J = 7.7, 1.2 Hz, 1H), 4.76 (t, J = 5.0 Hz, 2H), 4.71 (s, 2H), 3.79 (t, J = 4.9 Hz, 2H), 3.29 (s, 3H).

[0343] 2-(2-Fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 36): ES / MS: 525.3 (M + H + )。1H NMR (400 MHz, methanol-d4) δ 8.50 (t, J = 1.0 Hz, 1H), 8.18 (dd, J = 8.6, 1.4 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.71~7.64 (m, 2H), 7.63~7.57 (m, 2H), 7.51~7.40 (m, 4H), 7.19 (dd, J = 8.1, 1.2 Hz, 1H), 7.13 (s, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.93 (dd, J = 7.7, 1.2 Hz, 1H), 4.76 (t, J = 5.0 Hz, 2H), 4.71 (s, 2H), 3.78 (t, J = 4.9 Hz, 2H), 3.29 (s, 3H).

[0344] Procedure 13: 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Examples 37 and 38):

[0345]

Chemical Structure

[0346] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 5 obtained in the same manner as described in Procedure 5), as a mixture of two stereoisomers, was separated by chiral SFC (AD-H column containing 40% MeOH co-solvent) to obtain two different stereoisomers.

[0347] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 37): ES / MS m / z: 586.2 (M+H + ). 1H NMR (400 MHz, methanol-d4) δ 8.59~8.34 (m, 1H), 8.21~8.02 (m, 1H), 7.93~7.53 (m, 4H), 7.41 (d, J = 8.8 Hz, 2H), 7.37~7.21 (m, 1H), 7.15~6.89 (m, 3H), 4.79~4.71 (m, 2H), 4.67 (s, 2H), 3.86~3.73 (m, 2H), 3.28 (s, 3H).

[0348] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 38): ES / MS m / z: 586.2 (M+H + ). 1H NMR (400 MHz, methanol-d4) δ 8.45 (s, 1H), 8.14 (dd, J = 8.4, 1.5 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.76~7.70 (m, 2H), 7.67 (dd, J = 8. 0, 1.6 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.28 (dd, J = 10.1, 6.2 Hz, 1H), 7.12 - 6.97 (m, 3H), 4.73 (t, J = 5.0 Hz, 2H), 4.66 (s, 2H), 3.79 (t, J = 4.9 Hz, 2H), 3.29 (s, 3H).

[0349] Step 14: 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Examples 39 and 40):

[0350]

Chemical Structure

[0351] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid as a mixture of two stereoisomers (Example 31 obtained in the same manner as described in Step 1) was separated by chiral SFC (CELL-2 column containing 45% MeOH co-solvent) to obtain two different stereoisomers.

[0352] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 39): ES / MS m / z: 586.2 (M + H +)。1H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 8.18 (dd, J = 8.6, 1.6 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.78 - 7.64 (m, 3H), 7.49 - 7.40 (m, 2H), 7.31 (dd, J = 10.1, 6.2 Hz, 1H), 7.10 - 6.98 (m, 3H), 4.77 (t, J = 5.0 Hz, 2H), 4.70 (s, 2H), 3.81 (t, J = 5.0 Hz, 2H), 3.30 (s, 3H).

[0353] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 40): ES / MS m / z: 586.2 (M+H + )。1H NMR (400 MHz, methanol-d4) δ 8.47 (s, 1H), 8.16 (dd, J = 8.5, 1.5 Hz, 1H), 7.82 (t, J = 7.4 Hz, 1H), 7.77 - 7.64 (m, 3H), 7.48 - 7.39 (m, 2H), 7.30 (dd, J = 10.0, 6.0 Hz, 1H), 7.10 - 6.98 (m, 3H), 4.75 (t, J = 5.1 Hz, 2H), 4.68 (s, 2H), 3.81 (t, J = 5.1 Hz, 2H), 3.29 (s, 3H).

[0354] Procedure 15: 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 41 and Example 42):

[0355]

Chemical Structure

[0356] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 30 obtained in the same manner as described in Procedure 1), as a mixture of two stereoisomers, was separated by chiral SFC (IG column containing 50% MeOH co-solvent) to obtain two different stereoisomers.

[0357] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 41): ES / MS m / z: 598.1 (M+H + )。1H NMR (400 MHz, methanol-d4) δ 8.44 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.82 (t, J = 7.4 Hz, 1H), 7.72 (dd, J = 24.1, 9.1 Hz, 3H), 7.55 (d, J = 8.9 Hz, 2H), 7.49 (s, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.12 - 6.98 (m, 2H), 5.31 - 5.21 (m, 1H), 4.93 - 4.61 (m, 5H), 4.54 - 4.44 (m, 1H), 2.84 (t, J = 9.4 Hz, 1H), 2.61 - 2.47 (m, 1H).

[0358] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 42): ES / MS m / z: 598.2 (M+H +)。1H NMR (400 MHz, methanol-d4) δ 8.47 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.77 - 7.67 (m, 3H), 7.55 (d, J = 8.9 Hz, 2H), 7.48 (s, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.11 - 6.98 (m, 2H), 5.26 (qd, J = 7.3, 2.4 Hz, 1H), 4.84 - 4.62 (m, 5H), 4.50 (dt, J = 9.1, 6.0 Hz, 1H), 2.85 (dq, J = 14.6, 7.7 Hz, 1H), 2.64 - 2.50 (m, 1H).

[0359] Step 16: 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Examples 43 and 44):

[0360]

Chem.

[0361] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid as a mixture of two stereoisomers (Example 28 obtained in the same manner as described in Step 1) was separated by chiral SFC (AZ-H column containing 25% IPA-NH3 co-solvent) to obtain two different stereoisomers.

[0362] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 43): ES / MS m / z: 621.3 (M + )。1H NMR (400 MHz, methanol-d4) δ 8.32 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.62 (t, J = 8.3 Hz, 1H), 7.32 (ddd, J = 19.8, 10.5, 4.0 Hz, 2H), 7.26 - 7.10 (m, 2H), 7.03 - 6.86 (m, 3H), 5.24 - 5.12 (m, 1H), 4.74 (dd, J = 15.7, 6.9 Hz, 1H), 4.69 - 4.56 (m, 3H), 4.55 - 4.40 (m, 2H), 2.79 (dq, J = 16.7, 7.8, 5.9 Hz, 1H), 2.58 - 2.41 (m, 1H), 2.06 (s, 3H).

[0363] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 44): ES / MS m / z: 621.4 (M + )。1H NMR (400 MHz, methanol-d4) δ 8.31 (dd, J = 1.5, 0.7 Hz, 1H), 7.99 (dd, J = 8.5, 1.5 Hz, 1H), 7.67 (dd, J = 8.5, 0.6 Hz, 1H), 7.61 (t, J = 8.3 Hz, 1H), 7.40 - 7.26 (m, 2H), 7.26 - 7.15 (m, 2H), 7.02 - 6.87 (m, 3H), 5.19 (qd, J = 7.0, 2.6 Hz, 1H), 4.78 - 4.39 (m, 7H), 2.80 (dtd, J = 11.4, 8.2, 6.1 Hz, 1H), 2.49 (ddt, J = 11.4, 9.2, 7.2 Hz, 1H), 2.06 (d, J = 1.1 Hz, 3H).

[0364] Procedure 17: 2-(4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Examples 45 and 46):

[0365]

Chem.

[0366] 2-(4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 29 obtained in the same manner as described in Procedure 1) as a mixture of two stereoisomers was separated by chiral SFC (AD-H column containing 35% MeOH-DEA co-solvent) to obtain two different stereoisomers.

[0367] 2-(4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 45): ES / MS m / z: 604.2 (M +)。1H NMR (400 MHz, methanol-d4) δ 8.63 (dd, J = 2.4, 0.7 Hz, 1H), 8.52 (t, J = 1.0 Hz, 1H), 8.17 (dd, J = 8.6, 1.4 Hz, 1H), 7.92 (dd, J = 8.5, 2.4 Hz, 1H), 7.76 (dd, J = 8.6, 0.7 Hz, 1H), 7.71 (dd, J = 8.5, 0.7 Hz, 1H), 7.44 (dd, J = 10.0, 6.0 Hz, 1H), 7.33 (dd, J = 10.0, 6.2 Hz, 1H), 7.04~6.92 (m, 3H), 5.25 (qd, J = 7.4, 2.4 Hz, 1H), 4.99~4.64 (m, 5H), 4.52 (dt, J = 9.1, 5.9 Hz, 1H), 2.95~2.77 (m, 1H), 2.63~2.44 (m, 1H), 2.07 (s, 3H).

[0368] 2-(4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 46): ES / MS m / z: 604.2 (M + )。1H NMR (400 MHz, methanol-d4) δ 8.63 (dd, J = 2.5, 0.7 Hz, 1H), 8.54~8.46 (m, 1H), 8.15 (dd, J = 8.5, 1.4 Hz, 1H), 7.92 (dd, J = 8.5, 2.4 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 8.5, 0.7 Hz, 1H), 7.43 (dd, J = 10.0, 6.0 Hz, 1H), 7.31 (dd, J = 10.0, 6.1 Hz, 1H), 7.04~6.93 (m, 3H), 5.23 (dd, J = 8.1, 5.8 Hz, 1H), 4.86~4.64 (m, 5H), 4.51 (dt, J = 9.2, 6.0 Hz, 1H), 2.93~2.76 (m, 1H), 2.64~2.44 (m, 1H), 2.07 (s, 3H).

[0369] Procedure 18: 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Examples 47 and 48):

[0370] [Chemical formula]

[0371] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 22 obtained in the same manner as described in Procedure 1) as a mixture of two stereoisomers was separated by chiral SFC (AD-H column containing 25% IPA-NH3 co-solvent) to obtain two different stereoisomers.

[0372] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 47): ES / MS m / z: 621.2 (M +)。1H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 8.26 (d, J = 1.6 Hz, 1H), 7.78 (dd, J = 8.4, 1.6 Hz, 1H), 7.67 - 7.47 (m, 5H), 7.39 (dd, J = 8.4, 2.1 Hz, 1H), 7.31 (dd, J = 7.9, 1.4 Hz, 1H), 7.10 - 6.95 (m, 2H), 5.12 (qd, J = 6.9, 2.7 Hz, 1H), 4.81 (dd, J = 15.6, 6.8 Hz, 1H), 4.68 (dd, J = 15.6, 2.7 Hz, 1H), 4.61 - 4.39 (m, 3H), 4.35 (dt, J = 9.1, 5.9 Hz, 1H), 2.82 - 2.71 (m, 1H), 2.44 - 2.36 (m, 1H), 2.12 (s, 3H).

[0373] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 48): ES / MS m / z: 621.2 (M + )。1H NMR (400 MHz, DMSO) δ 12.77 (s, 1H), 8.25 (d, J = 1.6 Hz, 1H), 7.77 (dd, J = 8.4, 1.6 Hz, 1H), 7.69 - 7.50 (m, 5H), 7.39 (dd, J = 8.4, 2.1 Hz, 1H), 7.31 (dd, J = 7.9, 1.4 Hz, 1H), 7.16 - 6.93 (m, 2H), 5.12 (tt, J = 6.9, 3.3 Hz, 1H), 4.80 (dd, J = 15.7, 6.8 Hz, 1H), 4.67 (dd, J = 15.6, 2.7 Hz, 1H), 4.60 - 4.39 (m, 3H), 4.35 (dt, J = 9.0, 5.9 Hz, 1H), 2.78 - 2.71 (m, 1H), 2.45 - 2.35 (m, 1H), 2.12 (s, 3H).

[0374] Procedure 19: 2-(4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Examples 49 and 50):

[0375] [Chem.]

[0376] 2-(4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 27 obtained in the same manner as described in Procedure 1), as a mixture of two stereoisomers, was separated by chiral SFC (AD-H column containing 35% EtOH co-solvent) to obtain two different stereoisomers.

[0377] 2-(4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 49): ES / MS m / z: 604.2 (M +)。1H NMR (400 MHz, DMSO) δ 12.81 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 1.5 Hz, 1H), 8.04 (dd, J = 8.5, 2.5 Hz, 1H), 7.78 (dd, J = 8.5, 1.6 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.57 (dd, J = 10.5, 8.5 Hz, 4H), 7.29 (dd, J = 7.4, 1.9 Hz, 1H), 7.22 - 6.91 (m, 3H), 5.11 (tt, J = 7.1, 3.7 Hz, 1H), 4.81 (dd, J = 15.6, 6.8 Hz, 1H), 4.68 (dd, J = 15.5, 2.7 Hz, 1H), 4.60 - 4.38 (m, 4H), 4.35 (dt, J = 9.1, 5.9 Hz, 1H), 2.74 (dq, J = 11.1, 7.6 Hz, 1H), 2.45 - 2.35 (m, 1H), 2.12 (s, 4H).

[0378] 2-(4-(2-(5-Chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 50): ES / MS m / z: 604.2 (M + )。1H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 1.5 Hz, 1H), 8.04 (dd, J = 8.5, 2.5 Hz, 1H), 7.78 (dd, J = 8.5, 1.6 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.56 (t, J = 8.9 Hz, 4H), 7.29 (dd, J = 7.4, 2.0 Hz, 1H), 7.16 - 6.92 (m, 2H), 5.12 (qd, J = 6.9, 2.7 Hz, 1H), 4.81 (dd, J = 15.6, 6.8 Hz, 1H), 4.67 (dd, J = 15.6, 2.7 Hz, 1H), 4.61 - 4.40 (m, 4H), 4.35 (dt, J = 9.0, 5.9 Hz, 1H), 2.97 - 2.62 (m, 1H), 2.39 (ddt, J = 11.3, 9.1, 6.9 Hz, 1H), 2.12 (s, 4H).

[0379] Procedure 20: Example 82 Methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate: 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl) -2,6-difluorophenyl)acetic acid I-17 (113 mg, 0.144 mmol), methyl 4-amino-3-((2-(methylsulfonyl)ethyl)amino)benzoate I-18 (46.5 mg, 0.154 mmol), and o-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (49 mg, 0.116 mmol) in DMF (3 mL) was treated with N,N-diisopropylethylamine (0.085 mL, 0.776 mmol). The mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with 5% LiCl, saturated NaHCO3, and brine. The organic extract was dried over sodium sulfate to afford the crude product. Acetic acid was then added to the intermediate and the mixture was heated at 80 °C for 4 h. When the reaction was complete, the compound was purified by silica gel chromatography and used in the next step. ES / MS: 672.2 (M+H+).

[0380] 2-[[4-[2-(4-Chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2,6-difluoro-phenyl]methyl]-3-(2-methylsulfonylethyl)benzimidazole-5-carboxylic acid (Example 82): A solution of methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (40.0 mg, 0.05 mmol) and lithium hydroxide monohydrate aqueous solution (0.3 M, 4.2 mg, 0.17 mmol) in CH3CN (1 mL) was stirred at 100 °C for 5 minutes. Upon completion, the reaction mixture was diluted with EtOAc and adjusted to about pH 6 with 1 N HCl. The organic extract was dried over sodium sulfate, filtered, concentrated, and purified by RP-HPLC (eluent: water / MeCN with 0.1% TFA) to give the desired product. ES / MS: 658.2. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 1.5 Hz, 1H), 7.95 - 7.86 (m, 2H), 7.83 - 7.71 (m, 4H), 7.61 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 7.6, 1.7 Hz, 1H), 7.38 (dd, J = 11.6, 6.1 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.65 (t, J = 75.3 Hz, 1H), 5.61 (s, 2H), 4.72 (t, J = 5.1 Hz, 2H), 4.44 (s, 2H), 4.21 (t, J = 5.1 Hz, 2H).

[0381] Procedure 21: Example 84 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)-N-(2-((2-methoxyethyl)amino)-4-(2H-tetrazol-5-yl)phenyl)acetamide: To a solution of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid (I-17, 61.0 mg, 0.140 mmol), N2-(2-methoxyethyl)-4-(2H-tetrazol-5-yl)benzene-1,2-diamine (I-22, 35.7 mg, 0.152 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (79.2 mg, 0.208 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.133 mL, 0.766 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with 5% LiCl solution and brine. The aqueous phase was extracted twice with EtOAc and the combined organic extracts were dried over sodium sulfate. The crude residue was used in the next step without purification. ES / MS m / z: 651.2 (M+)

[0382] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-6-(2H-tetrazol-5-yl)-1H-benzo[d]imidazole (Example 84): To a solution of 2-(4-(2-(4-chloro-2-fluoro (Phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)-N-(2-((2-methoxyethyl)amino)-4-(2H-tetrazol-5-yl)phenyl)acetamide (91.3 mg, 0.140 mmol) and glacial acetic acid (0.521 mL, 9.12 mmol) were heated at 60 °C overnight. The reaction was concentrated to dryness and purified by RP-HPLC (eluent: MeCN / H2O) to give the product as the trifluoroacetate salt. ES / MS: 633.2 (M+H+), 1H NMR (400 MHz, DMSO) δ 8.32 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 8.4, 1.6 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.67~7.53 (m, 4H), 7.39 (dd, J = 8.4, 2.1 Hz, 1H), 7.32 (dd, J = 8.0, 1.4 Hz, 1H), 7.10~6.98 (m, 2H), 4.65 (d, J = 5.3 Hz, 2H), 4.47 (d, J = 6.9 Hz, 2H), 3.77 (t, J = 5.1 Hz, 2H), 3.26 (s, 3H), 2.13 (s, 3H).

[0383] Procedure 22: Example 85 Methyl 2-((6-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2-methoxypyridin-3-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: In a 20 mL reaction vial, a suspension of 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxole (Intermediate I-3, 100 mg, 0.291 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (32.4 mg, 0.0437 mmol), potassium propionate (97.9 mg, 0.873 mmol), and bis(pinacolato)diboron (86.1 mg, 0.339 mmol) in dioxane (3 mL) was degassed with argon for 5 minutes. The reaction was sealed and heated at 120 °C for 50 minutes. After cooling the reaction to room temperature, sodium carbonate (2.00 M, 0.291 mL, 0.582 mmol) was added. The mixture was stirred at room temperature for 2 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.0 mg, 0.0202 mmol) and methyl 2-[(6-chloro-2-methoxy-3-pyridyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (Intermediate I-23, 113 mg, 0.291 mmol) were added. The reaction mixture was degassed with argon for 5 minutes and then heated at 90 °C overnight. The reaction mixture was diluted with EtOAc and washed with brine and saturated sodium bicarbonate solution. The organic extract was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash chromatography (20 - 40% EtOAc in hexane) to give the desired product.ES / MS m / z: 618.0 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 1.5 Hz, 1H), 8.00 (dd, J = 8.5, 1.6 Hz, 1H), 7.81 (dd, J = 8.1, 1.3 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.61 - 7.48 (m, 2H), 7.14 (dd, J = 10.6, 2.0 Hz, 1H), 7.11 - 7.02 (m, 1H), 6.94 (t, J = 7.9 Hz, 1H), 6.86 (dd, J = 7.7, 1.3 Hz, 1H), 4.41 (t, J = 5.5 Hz, 2H), 4.37 (s, 2H), 4.10 (s, 3H), 3.98 (s, 3H), 3.64 (t, J = 5.5 Hz, 2H), 3.26 (s, 3H), 2.12 (d, J = 1.1 Hz, 3H).

[0384] 2 - ((6 - (2 - (4 - chloro - 2 - fluorophenyl) - 2 - methylbenzo[d][1,3]dioxol - 4 - yl) - 2 - methoxypyridin - 3 - yl)methyl) - 1 - (2 - methoxyethyl) - 1H - benzimidazole - 6 - carboxylic acid (Example 85): Methyl 2 - [[6 - [2 - (4 - chloro - 2 - fluorophenyl) - 2 - methyl - 1,3 - benzodioxol - 4 - yl] - 2 - methoxy - 3 - pyridyl]methyl] - 3 - (2 - methoxyethyl)benzimidazole - 5 - carboxylate (64.4 mg, 0.104 mmol) in CH3CN (1.5 mL) placed in a 40 mL reaction vial A suspension with lithium hydroxide monohydrate (0.300 M, 1.05 mL, 0.316 mmol) was heated at 90 °C for 12 minutes. The reaction mixture was diluted with EtOAc and brine. 0.350 mL of 1 M citric acid was added. The organic extract was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by RP-HPLC (eluent: MeCN / H2O) to obtain the title product. ES / MS m / z: 604.2 (M+H+), 1H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.58 (dd, J = 11.1, 2.0 Hz, 1H), 7.36 (dd, J = 8.4, 2.1 Hz, 1H), 7.07 - 6.95 (m, 2H), 4.65 (d, J = 5.4 Hz, 2H), 4.41 (s, 2H), 3.96 (s, 3H), 3.69 (t, J = 5.1 Hz, 2H), 3.21 (s, 3H), 2.12 (s, 3H).

[0385] Procedure 23: Example 86 2-((6-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 86): A solution of 2-[[6-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2-methoxy-3-pyridy...

Claims

1. Structure: 【Chemical 1】 A compound having the following or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to Claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

3. The pharmaceutical composition according to Claim 2, further comprising one or more additional therapeutic agents.

4. The pharmaceutical composition according to Claim 2 or 3 for use in the treatment of a glucagon-like peptide 1 receptor (GLP-1R)-mediated disease or condition.

5. A composition for treating a GLP-1R-mediated disease or condition, comprising the compound according to Claim 1 or a pharmaceutically acceptable salt thereof.

6. The composition according to Claim 5, wherein the disease or condition includes a liver disease.

7. The composition according to Claim 6, wherein the disease or condition includes liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, compensated liver fibrosis, decompensated liver fibrosis, hepatocellular carcinoma, primary biliary cirrhosis (PBC), or primary sclerosing cholangitis (PSC).

8. The composition according to Claim 7, wherein the disease or condition includes non-alcoholic fatty liver disease (NAFLD).

9. The composition according to Claim 7, wherein the disease or condition includes non-alcoholic steatohepatitis (NASH).

10. The composition according to Claim 5, wherein the disease or the condition includes a metabolic disease. **Claim 11** The composition according to claim 10, wherein the disease or condition is type 1 diabetes, type 2 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 accumulation, obesity, eating disorder, sleep apnea syndrome, weight gain, sugar craving, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial dyslipidemia, metabolic acidosis, ketosis, arthritis, left ventricular hypertrophy, Parkinson's disease, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, angina pectoris, premenstrual syndrome, thrombosis, atherosclerosis, glucose metabolism disorder, or vascular restenosis. **Claim 12** The composition according to any one of claims 5 to 11, wherein the composition is administered in combination with an additional therapeutic agent. **Claim 13** The pharmaceutical composition according to claim 3 or the composition according to claim 12, wherein the additional therapeutic agent comprises an apoptosis signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fish oil, an acetyl-CoA carboxylase (ACC) inhibitor, or a TGFβ antagonist. **Claim 14** A method for manufacturing a pharmaceutical for the treatment of a human in need of treatment for a GLP-1R-mediated disease or condition, characterized in that the compound according to claim 1 or a pharmaceutically acceptable salt thereof is used. **Claim 15** Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for manufacturing a pharmaceutical for treating a GLP-1R-mediated disease or condition. **Claim 16** A composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment of a human in need of treatment for a GLP-1R-mediated disease or condition.

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