Carboxy-benzimidazole glp-1r modulating compounds

Abstract

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 disorder in a human.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 177,778, filed April 21, 2021, and U.S. Provisional Application No. 63 / 286,475, filed December 6, 2021, which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] This disclosure relates to compounds that bind to the glucagon-like peptide-1 receptor (GLP-1R) and act as its agonists or modulators, as well as compounds that act as agonists or modulators of GLP-1R. This disclosure also relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions. Background Technology

[0004] Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by enteroendocrine cells in the gut in response to diet. GLP-1 is thought to play a role in postprandial blood glucose regulation by directly increasing diet-induced insulin secretion from pancreatic β-cells and by promoting satiety through delaying food transport through the intestines. GLP-1 mediates intracellular signaling via the GLP-1 receptor (GLP-1R), a member of the G protein-coupled receptor family located on the cell membrane, which, upon activation, leads to the accumulation of the second messenger cyclic adenosine monophosphate (cAMP). Nonalcoholic steatohepatitis (NASH) is associated with features of metabolic syndrome, including obesity, type 2 diabetes, insulin resistance, and cardiovascular disease.

[0005] GLP-1R agonists are currently being investigated in conjunction with diabetes, obesity, and NASH. GLP-1R agonists include peptides already approved for the treatment of type 2 diabetes, such as exenatide, liraglutide, and dulaglutide. These peptides are primarily administered via subcutaneous injection. Oral GLP-1 agonists are also being investigated for the treatment of type 2 diabetes. Some GLP-1R agonists, such as liraglutide, dulaglutide, and exenatide, are resistant to rapid degradation by dipeptidyl peptidase 4, resulting in a longer half-life for GLP-1 agonists than for endogenous GLP-1.

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

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

[0008]

[0009] Or its pharmaceutically acceptable salt, wherein

[0010] R 1 for

[0011] i)C 6-10 aryl or 6-membered heteroaryl, each of which is optionally divided by one to four R 4 Replace; or

[0012] ii) A 6-membered heteroaryl group, wherein the heteroaryl group is fused with a 5- or 6-membered ring having zero to three heteroatoms, each independently N, O, or S, to form a fused ring system, wherein the fused ring system is optionally separated by one to four R atoms. 5 replace;

[0013] Ring A is

[0014] These groups are each optionally surrounded by one to three R groups. A Replace, each R A Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -OH, -CN, or -N(R) 10a (R) 10b );

[0015] Ring B is

[0016] (i)C 6-10 aryl or heteroaryl, each optionally surrounded by one to four R B Replace, each R B Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 10a -C(O)R 10a -C(O)OR 10a -N(R) 10a (R) 10b ), N(R 10a )2(R 10b ) + -N(R) 10a)C(O)-R 10b -N(R) 10a )C(O)OR 10b -N(R) 10a )C(O)N(R 10b (R) 10c ), -N(R 10a )S(O)2(R 10b -NR 10a S(O)2N(R 10b (R) 10c -NR 10a S(O)₂O(R) 10b -OC(O)R 10a -OC(O)OR 10a -OC(O)-N(R) 10a (R) 10b ), -SR 10a -S(O)R 10a -S(O)(NH)R 10a -S(O)2R 10a -S(O)2N(R) 10a (R) 10b ), -S(O)(NR 10a )R 10b or -Si(R) 10a )3; or

[0017] (ii)C 6-10 An aryl or heteroaryl group, each fused with a 5- or 6-membered ring having zero to four heteroatoms, each independently N, O, or S, to form a fused ring system, wherein the fused ring system is optionally separated by one to five R atoms. B Replace, each R B Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 10a -C(O)R 10a -C(O)OR 10a -N(R) 10a (R) 10b ), N(R 10a )2(R 10b ) + -N(R) 10a)C(O)-R 10b -N(R) 10a )C(O)OR 10b -N(R) 10a )C(O)N(R 10b (R) 10c ), -N(R 10a )S(O)2(R 10b -NR 10a S(O)2N(R 10b (R) 10c -NR 10a S(O)₂O(R) 10b -OC(O)R 10a -OC(O)OR 10a -OC(O)-N(R) 10a (R) 10b ), -SR 10a -S(O)R 10a -S(O)(NH)R 10a -S(O)2R 10a -S(O)2N(R) 10a (R) 10b ), -S(O)(NR 10a )R 10b or -Si(R) 10a 3;

[0018] V is -C(R) 11a (R) 11b )-;

[0019] X 1 X 2 and X 3 Each is independently -C(H) = or -C(R) 8 = ;

[0020] R 2 for

[0021] i)C 3-10 Cycloalkyl or heterocyclic group, wherein each cycloalkyl or heterocyclic group is optionally surrounded by one to four Z groups. 1 Replace, where each Z 1 Independently for C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, oxo groups, -OH, -CN, C 1-6 Alkyl-CN, -C(O)R 10a-C(O)OR 10a -C(O)NH2, -C(O)NH(C 1-9 alkyl), -N(R) 10a (R) 10b ), -N(R 10a )C(O)OR 10b -N(R) 10a )C(O)-R 10b -S(O)2R 10a -S(O)2(C 1-9 alkyl), -OC 3-6 cycloalkyl or heteroaryl,

[0022] Each of the -OC 3-6 cycloalkyl or heteroaryl groups are optionally separated by one to four Z groups. 1a Group substitution, each Z 1a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; or

[0023] (ii) in

[0024] R 2a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-CN, -C 3-6 cycloalkyl or heteroaryl,

[0025] Each alkyl, cycloalkyl, or heteroaryl group is optionally divided by one to four independently C2 groups. 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl or C 1-6 Group substitution of halogenated alkoxy groups; R 2b For H, C 1-3 Alkyl, C 1-3 Haloalkyl; and R 2c For H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0026] R 3 -C(O)OR 3a ;

[0027] Where R 3a For H, C 1-4 Alkyl-N(R)9a (R) 9b -C 1-4 Alkyl-N(R) 9a )C(O)-OC 1-4 Alkyl-OP(O)(OR) 9c 2. C 1-4 Alkyl-C(O)N(R) 9a (R) 9b -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-OP(O)(OR) 9c )2、-CH2CH(N(R 9a )2)C(O)OR 9b -P(O)(OR) 9c )2、-OP(O)(OR 9c )2、-CH2P(O)(OR 9c )2、-CH2OP(O)(OR 9c )2、-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)(OR9d ), -OP(O)(N(R) 9c )2)(OR 9d -CH2P(O)(N(R) 9c )2)(OR 9d ), -OCH2P(O)(N(R) 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R) 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -OP(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), -OCH2P(O)(R 9c )(N(R 9d )2), -C(O)OCH2P(O)(R 9c )(N(R 9d )2) or C 1-6 alkyl-heterocyclic groups

[0028] Each alkyl or heterocyclic group is optionally substituted with one to four halogens;

[0029] Each R 4 Independently for C 1-6 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 10a -C(O)R 10a -C(O)OR 10a -N(R) 10a (R) 10b ), -N(R 10a )2(R 10b ) + -N(R) 10a )-C(O)R 10b -N(R) 10a )C(O)O(R 10b ), -N(R 10a )C(O)N(R 10b (R) 10c ), -N(R 10a)S(O)2(R 10b ), -N(R 10a )S(O)2-N(R 10b (R) 10c ), -N(R 10a )S(O)2O(R 10b -OC(O)R 10a -OC(O)OR 10a -OC(O)-N(R) 10a (R10) b -S-R10 a -S(O)R 10a -S(O)(NH)R 10a -S(O)2R 10a -S(O)2N(R) 10a (R) 10b ), -S(O)(NR 10a )R 10b or -Si(R) 10a )3,

[0030] Each alkyl, haloalkyl, alkenyl, or aryl group is optionally surrounded by one to four R groups. 5 Replace, and

[0031] Each cycloalkyl, heterocyclic, or heteroaryl group is optionally surrounded by one to four R groups. 12 replace;

[0032] Each R 5 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 10a -C(O)-R 10a -C(O)OR 10a C(O)-N(R) 10a (R) 10b ), -N(R 10a (R) 10b ), -N(R 10a )2(R 10b ) + -N(RR) 10a )C(O)-R 10b -N(R)10a )C(O)OR 10b -N(R) 10a )C(O)N(R 10b (R) 10c ), -N(R 10a )S(O)2(R 10b -NR 10a S(O)2N(R 10b (R) 10c -NR 10a S(O)₂O(R) 10b -OC(O)R 10a -OC(O)OR 10a -OC(O)-N(R) 10a (R) 10b ), -SR 10a -S(O)R 10a -S(O)(NH)R 10a -S(O)2R 10a -S(O)2N(R) 10a (R) 10b ), -S(O)(NR 10a )R 10b or -Si(R) 10a )3,

[0033] Each of the following groups is an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, or a heterocyclic group.

[0034] Aryl or heteroaryl groups are optionally separated by one to four R groups. 6 replace;

[0035] Each R 6 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 10a -C(O)-R 10a -C(O)OR 10a -C(O)-N(R) 10a (R) 10b ), -N(R 10a (R) 10b ), -N(R10a )C(O)-R 10b -N(R) 10a )C(O)OR 10b -N(R) 10a )C(O)N(R 10b (R) 10c ), -N(R 10a )S(O)2(R 10b -NR 10a S(O)2N(R 10b (R) 10c -NR 10a S(O)₂O(R) 10b -OC(O)R 10a -OC(O)OR 10a -OC(O)-N(R) 10a (R) 10b ), -SR 10a -S(O)R 10a -S(O)(NH)R 10a -S(O)2R 10a -S(O)2N(R) 10a (R) 10b ), -S(O)(NR 10a )R 10b or -Si(R) 10a )3,

[0036] Each alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one to four R groups. 7 replace;

[0037] Each R 7 and R 8 Independently for C 1-9 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C) 1-9 alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -C(O)(C 3-15 cycloalkyl), -C(O)(heterocyclic), -C(O)(C 6-10 aryl), -C(O)(heteroaryl), -C(O)O(C 1-9 Alkyl), -C(O)O(C 1-8 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6alkenyl), -C(O)NH(C 2-6 ynyl group), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH (heterocyclic), -C(O)NH (C 6-10 aryl), -C(O)NH (heteroaryl), -C(O)N(C 1-9 Alkyl)2、-C(O)N(C 1-8 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 2, -C(O)N(C) 3-15 Cycloalkyl)2, -C(O)N(heterocyclic)2, -C(O)N(C 6-10 aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2,

[0038] Each alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally bounded by one to three Cs. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -CO2H, -O(C) 1-9 alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2-substituted;

[0039] Each alkyl or heterocyclic group is optionally substituted with one to four halogens;

[0040] Each R 9a and R 9b H and C independently 1-6 Alkyl or C 1-6 Halogenated alkyl, or R 9a and R 9b Together they form a 6-membered heterocyclic group;

[0041] Each R 9c R 9d R 10a R 10b and R 10c H and C independently 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally surrounded by one to four R groups. 6 replace;

[0042] Each R 11a and R 11b Independently -H, C 1-6 Alkyl, oxo, or halogen;

[0043] Each R 12 C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C2-6 Alkyne, halogen, oxo group, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C) 1-9 alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -C(O)(C 3-15 cycloalkyl), -C(O)(heterocyclic), -C(O)(C 6-10 aryl), -C(O)(heteroaryl), -C(O)O(C 1-9 Alkyl), -C(O)O(C 1-8 Halogenated alkyl groups), -C(O)O(C 2-6alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH (heterocyclic), -C(O)NH (C 6-10 aryl), -C(O)NH (heteroaryl), -C(O)N(C 1-9 Alkyl)2、-C(O)N(C 1-8 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 2, -C(O)N(C) 3-15 Cycloalkyl)2, -C(O)N(heterocyclic)2, -C(O)N(C 6-10 aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2,

[0044] Each alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally bounded by one to three carbon atoms. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -CO2H, -O(C) 1-9 alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2-substituted,

[0045] Each alkyl or heterocyclic group is optionally substituted with one to four halogens;

[0046] Each heterocyclic group has three to twelve ring members and one to four heteroatoms, each independently N, O, or S; and

[0047] Each heteroaryl group has five to twelve ring members and one to four heteroatoms that are independently N, O or S.

[0048] This disclosure also provides pharmaceutical compositions, methods, and uses of compounds comprising formula (I) or pharmaceutically acceptable salts thereof. This disclosure further provides pharmaceutical compositions, methods, and uses of compounds comprising formula (IA-1) or pharmaceutically acceptable salts thereof. For example, the compounds of this disclosure are commonly used in methods for treating GLP-1R-mediated diseases or conditions. Attached Figure Description

[0049] Figure 1 A graph depicting plasma concentration in cynomolgus monkeys as a function of time.

[0050] Figure 2A graph depicting plasma concentration in cynomolgus monkeys as a function of time. Detailed Implementation

[0051] I. Definition

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes at the beginning or end of chemical groups are for the purpose of indicating the point of connection with the parent part; chemical groups may be depicted without one or more dashes without losing their ordinary meaning. Prefixes such as "C" u-v "or "C u -C v "Indicates that the following groups have u to v carbon atoms, where u and v are integers. For example, "C 1-6 "alkyl" or "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0053] "Alkyl" is a monovalent or divalent straight-chain or branched saturated hydrocarbon radical. For example, an alkyl group can have 1 to 10 carbon atoms (i.e., C64 ... 1-10 Alkyl group or 1 to 8 carbon atoms (i.e., C46) 1-8 Alkyl group or 1 to 6 carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 1-6 Alkyl group or 1 to 4 carbon atoms (i.e., C46) 1-4Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), and 2-butyl (s-Bu, sec-butyl, -CH(CH3)). CH2CH3), 2-methyl-2-propyl (t-Bu, tert-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 (-CH2C) H2CH(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(CH 3) 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). The alkyl group can be unsubstituted or substituted.

[0054] "Alkoxy" refers to the -O-alkyl group, where alkyl is as defined above. For example, C 1-4 An alkoxy group is a -O-alkyl group having one to four carbon atoms. Alkoxy groups can be unsubstituted or substituted.

[0055] "Alkoxyalkyl" is an alkoxy group attached to an alkyl group as defined above, such that the alkyl group is divalent. For example, C 2-6 Alkoxyalkyl groups include -CH2-OMe, -CH2-O-iPr, -CH2-CH2-OMe, -CH2-CH2-O-CH2-CH3, and -CH2-CH2-O-tBu. The alkoxyalkyl group can be unsubstituted or substituted.

[0056] "Hydroxyalkyl" is a hydroxyl group attached to an alkyl group as defined above, such that the alkyl group is divalent. For example, C 1-6 Hydroxyalkyl groups include -CH2-OH and -CH2-CH2-OH. The hydroxyalkyl group can be unsubstituted or substituted.

[0057] "Alkenyl" is a monovalent or divalent straight-chain or branched hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C2, C3, C4, C5, C6, C6, C7, C8, C9 ... 2-8 Alkenyl) or 2 to 6 carbon atoms (i.e., C) 2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3. Alkenyl groups can be unsubstituted or substituted.

[0058] "Alynyl" is a monovalent or divalent straight-chain or branched hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl group can have 2 to 8 carbon atoms (i.e., C64 ... 2-8 (alkynyl group) or 2 to 6 carbon atoms (i.e., C10, C20, C30, C40, C50, C6 ... 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C46) 2-4 (Alynyl group). Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), and -CH2-C≡C-CH3. The alkynyl group can be unsubstituted or substituted.

[0059] "Halogens" refer to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0060] "Haloalkyl" is an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted with a halogen (which may be the same or different), such that the alkyl group is divalent. The alkyl group and the halogen may be any of those described above. In some embodiments, the haloalkyl group defines the number of carbon atoms in the alkyl moiety, for example, C... 1-4 Alkyl halogens include CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH2CH3, and C(CH3)2(CF2H). The alkyl halogen group can be unsubstituted or substituted.

[0061] "Haloalkoxy" is an alkoxy group as defined herein, wherein one or more hydrogen atoms of the alkyl group in the alkoxy group are independently substituted by a halogen (which may be the same or different), such that the alkyl group is divalent. The alkoxy group and the halogen may be any of those described above. In some embodiments, the haloalkoxy group defines the number of carbon atoms in the alkyl moiety, for example, C... 1-4 Haloalkoxy groups include OCF3, OCH2F, OCH2CF3, OCH2CH2CF3, OCCl2CH2CH2CH3, and OC(CH3)2(CF2H). The haloalkoxy group can be unsubstituted or substituted.

[0062] "Cycloalkyl" is a monovalent or divalent single all-carbon ring or a polyfused all-carbon ring system, wherein the ring is, in each instance, a non-aromatic saturated or unsaturated ring. For example, in some embodiments, the cycloalkyl group has 3 to 12 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Exemplary monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Cycloalkyl also includes polyfused ring systems having about 7 to 12 carbon atoms (e.g., ring systems comprising 2 rings). When valence requirements permit, these rings in the polyfused ring system may be interconnected by fusion, spirocyclic, or bridging bonds. Exemplary polycyclic cycloalkyl groups include octahydrocyclopentadiene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, and spiro[2.5]octane. The cycloalkyl groups may be unsubstituted or substituted.

[0063] "alkylcycloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted by a cycloalkyl group (which may be the same or different). The alkyl group and the cycloalkyl group may be any of those described above. In some embodiments, the number of carbon atoms in the alkyl and cycloalkyl moieties may be specified separately, for example, C... 1-6 Alkyl-C 3-12 Cycloalkyl. The alkylcycloalkyl group can be unsubstituted or substituted.

[0064] As used herein, “aryl” refers to a monovalent or divalent single all-carbon aromatic ring or a polyfused all-carbon ring system, wherein the ring is aromatic. For example, in some embodiments, the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl groups include phenyl radicals. Aryl groups also include polyfused ring systems having about 9 to 20 carbon atoms (e.g., ring systems comprising 2, 3, or 4 rings), wherein multiple rings are aromatic. When valence requirements permit, these rings in a polyfused ring system may be interconnected by fusion, spirocyclic, or bridging bonds. It should also be understood that when referring to a range of atomic aryl groups (e.g., 6-10 aryl groups), the atomic range is the total number of ring atoms in the aryl group. For example, a 6-membered aryl group would include a phenyl group, and a 10-membered aryl group would include a naphthyl group. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, etc. The aryl group can be unsubstituted or substituted.

[0065] "alkylaryl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted by an aryl group (which may be the same or different). The alkyl group and the aryl group may be any of those described above, such that the alkyl group is divalent. In some embodiments, the alkylaryl group has 7 to 24 carbon atoms, 7 to 16 carbon atoms, 7 to 13 carbon atoms, or 7 to 11 carbon atoms. The alkylaryl group defined by the number of carbon atoms refers to the total number of carbon atoms present in the combined constitutive alkyl and aryl groups. For example, C7 alkylaryl refers to benzyl, while C7 alkylaryl refers to Benzyl. 11 Alkyl aryl groups include 1-methylnaphthyl and n-pentylphenyl. In some embodiments, the number of carbon atoms in the alkyl and aryl moieties can be specified separately, for example, C... 1-6 Alkyl-C 6-10 Aryl. Non-limiting examples of alkyl aryl groups include, but are not limited to, benzyl, 2,2-dimethylphenyl, n-pentylphenyl, 1-methylnaphthyl, 2-ethylnaphthyl, etc. Alkyl aryl groups may be unsubstituted or substituted.

[0066] As used herein, "heterocyclic group" or "heterocyclic" or "heterocyclic alkyl" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic system having at least one heteroatom (i.e., at least one cyclic heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclic group has 3 to about 20 cyclic atoms, for example, 3 to 12 cyclic atoms, for example, 4 to 12 cyclic atoms, 4 to 10 cyclic atoms, or 3 to 8 cyclic atoms, or 3 to 6 cyclic atoms, or 3 to 5 cyclic atoms, or 4 to 6 cyclic atoms, or 4 to 5 cyclic atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3, 4, 5, 6, or 7-membered ring) having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms selected from oxygen, nitrogen, and sulfur. When valence requirements permit, these rings in the polyfused ring system can be interconnected by fusion, spirocyclic linkages, or bridging bonds. Heterocyclic rings include, but are not limited to, aziridine, imidazoline, morpholine, ethylene oxide (epoxide), oxacyclobutane, thiobutane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinine ring, 2-oxa-6-azaspiro[3.3]hept-6-yl, 6-oxa-1-azaspiro[3.3]hept-1-yl, 2- Thiophene-6-azaspiro[3.3]hept-6-yl, 2,6-diazaspiro[3.3]hept-2-yl, 2-azabicyclo[3.1.0]hex-2-yl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]hept-2-yl, 4-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl, etc. The heterocyclic group can be unsubstituted or substituted.

[0067] "alkyl heterocyclic group" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted by a heterocyclic group (which may be the same or different). The alkyl group and the heterocyclic group can be any of those described above, such that the alkyl group is divalent. In some embodiments, the number of atoms in the alkyl and heterocyclic moieties may be specified separately, for example, having one to three heteroatoms, each independently N, O, or S. 1-6 Alkyl-3 to 12-membered heterocyclic groups. The alkyl heterocyclic group can be unsubstituted or substituted.

[0068] "Heteroaryl" refers to a monoaryl aromatic ring having at least one atom other than carbon, wherein the atom is selected from oxygen, nitrogen, and sulfur; "heteroaryl" also includes polyfused ring systems having at least one such aromatic ring, which will be further described below. Thus, "heteroaryl" includes a monoaryl aromatic ring having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also be present in oxidized forms, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes polyfused ring systems (e.g., ring systems comprising 2, 3, or 4 rings), wherein a heteroaryl group as defined above is fused with one or more rings selected from heteroaryls (to form, for example, 1,8-naphthidyl) and fused with an aryl group (to form, for example, benzimidazolyl or indazolyl), thereby forming a polyfused ring system. Therefore, a heteroaryl group (monoaromatic ring or polyfused ring system) may have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms within the heteroaryl ring. For example, a tetrazolium group has 1 carbon atom and 4 nitrogen heteroatoms within the ring. These rings of the polyfused ring system may be interconnected by fusion, spirocyclic, or bridging bonds, where valence requirements permit. It should be understood that the individual rings of the polyfused ring system may be connected relative to each other in any order. It should be understood that the connection points of the heteroaryl group or the polyfused ring system may be located on any suitable atom of the heteroaryl group or the polyfused ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when referring to a certain atomic range of mono-heteroaryl groups (e.g., 5- to 10-membered heteroaryl groups), the atomic range is the total number of ring atoms of the heteroaryl group and includes carbon atoms and heteroatoms. It should also be understood that these rings in the polyfused ring system may include aryl rings (e.g., 3, 4, 5, 6, or 7-membered rings) fused with heterocycles having saturated or partially unsaturated bonds, having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms selected from oxygen, nitrogen, and sulfur. For example, 5-membered heteroaryl groups include thiazolyl groups, and 10-membered heteroaryl groups include quinolinyl groups. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiophene, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzooxazolyl, indazole, quinoxolinyl, quinazolinyl, benzofuranyl, benzimidazolyl, thiophene, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. The heteroaryl group may be unsubstituted or substituted.

[0069] "alkylheteroaryl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted by a heteroaryl group (which may be the same or different), such that the alkyl group is divalent. The alkyl group and the heteroaryl group can be any of those described above. In some embodiments, the number of atoms in the alkyl and heteroaryl moieties are specified separately, for example, C having one to four heteroatoms, each independently N, O, or S. 1-6 Alkyl-5 to 10-membered heteroaryl groups. The alkyl heteroaryl groups can be unsubstituted or substituted.

[0070] As used in this article, "oxo" refers to =O.

[0071] As used herein, “substitution” means that one or more hydrogen atoms in the group are independently replaced by one or more substituents (e.g., 1, 2, 3 or 4 or more), as indicated.

[0072] "Compounds of this disclosure" includes compounds disclosed herein, such as compounds of formula (I), including the compounds of the examples. In some embodiments, "compounds of this disclosure" includes compounds of formula (I).

[0073] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for acceptable use in humans or livestock.

[0074] As used herein, "therapeutic effective amount" or "effective amount" means an amount capable of effectively evoking the desired biological or medical response, including amounts of such a treatment sufficient to affect the disease when administered to a subject. Effective amounts will vary depending on the compound being treated, the disease and its severity, and factors such as age and weight. Effective amounts may include a range of amounts. As understood in the art, an effective amount may be one or more doses; that is, a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. Effective amounts may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered if, in combination with one or more other agents, a desired or beneficial outcome can be achieved or attained. The appropriate dose of any co-administered compound may optionally be reduced due to the combined effects of the compounds (e.g., additive or synergistic effects).

[0075] As used herein, “co-administration” means administering a unit dose of the compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents, for example, administering the compound disclosed herein within seconds, minutes, or hours after administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents after several hours (e.g., 1 hour to 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein after several hours (e.g., 1 hour to 12 hours). Co-administration of the compound disclosed herein with one or more additional therapeutic agents generally means administering the compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of each agent is present in the subject.

[0076] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other substances that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0077] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of compounds in their free base form, possessing the desired pharmacological activity of a free base. These salts can be derived from inorganic acids, organic acids, or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propargylates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, etc. Alkyne-1,4-diacidate, hexyne-1,6-diacidate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methanesulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in *Remington: The Science and Practice of Pharmacy*, 21st edition, Lippincott, Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0078] 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⁺). Base addition salts, such as sodium or potassium salts, are also included.

[0079] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein one to n hydrogen atoms bonded to a carbon atom may be substituted with a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds can increase resistance to metabolism and are therefore used to increase the half-life of compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to mammals. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., Vol. 5, No. 12, pp. 524-527, 1984. Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been substituted with deuterium.

[0080] Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Using positron-emitting isotopes such as 11 C 18 F, 15 O and 13 Substitution of N can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared using conventional techniques known to those skilled in the art, or by methods similar to those described in the examples listed below, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0081] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)- or (D)- or (L)- for amino acids. This disclosure is intended to include all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise stated, the compounds are intended to include E and Z geometric isomers. Similarly, all tautomers are also intended to be included. When a compound is represented in its chiral form, it should be understood that the embodiments cover, but are not limited to, specific diastereomeric or enantiomerically enriched forms. When chirality is not specified but is present, it should be understood that the embodiments relate to specific diastereomeric or enantiomerically enriched forms; or racemic or non-racemic mixtures of such compounds. As used herein, a “non-racemic mixture” is a mixture of stereoisomers in a ratio not equal to 1:1.

[0082] As used herein, a "stereoisomer" refers to a compound consisting of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This disclosure envisions various stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0083] As used herein, "tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. In some embodiments, this disclosure includes tautomers of the compounds.

[0084] As used herein, "solvent" refers to the result of the interaction between the solvent and the compound. Solvents of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0085] As used herein, “hydrate” means a compound of this disclosure that is chemically associated with one or more water molecules.

[0086] "Prevention" or "preventing" means any treatment that prevents the development of clinical symptoms of a disease or condition. In some implementations, the compound may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0087] As used herein, a "prodrug" is a derivative of a drug that, when administered to the human body, is converted into the parent drug via some chemical or enzymatic pathway. In some implementations, a "prodrug" is a non-biologically active derivative of a drug that, when administered to the human body, is converted into the biologically active parent drug via some chemical or enzymatic pathway.

[0088] As used herein, “treatment” or “treat” or “treating” refers to a method for achieving a beneficial or desired outcome. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, the reduction of symptoms and / or the lessening of the severity of symptoms and / or the prevention of the worsening of symptoms associated with a disease or condition. In one embodiment, “treatment” or “treating” includes one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition, and / or lessening the severity of a disease or condition); b) slowing or preventing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition); and c) alleviating a disease or condition, such as causing the disappearance of clinical symptoms, improving disease status, delaying disease progression, improving quality of life, and / or prolonging survival. As used herein, “individual at risk” means an individual at risk of developing a condition requiring treatment. Individuals “at risk” may or may not have a detectable disease or condition, and may or may not show a detectable disease prior to the treatment described herein. “At risk” means that an individual has one or more so-called risk factors that are associated with the development of a disease or condition and are measurable parameters known in the art. Individuals with one or more of these risk factors are more likely to develop a disease or condition than individuals without these risk factors.

[0089] II.Compounds

[0090] In one embodiment, this disclosure provides a compound of formula (I):

[0091]

[0092] Or its pharmaceutically acceptable salt, wherein

[0093] R 1 for

[0094] i)C 6-10 aryl or 6-membered heteroaryl, each of which is optionally divided by one to four R 4 Replace; or

[0095] ii) A 6-membered heteroaryl group, wherein the heteroaryl group is fused with a 5- or 6-membered ring having zero to three heteroatoms, each independently N, O, or S, to form a fused ring system, wherein the fused ring system is optionally separated by one to four R atoms. 5 replace;

[0096] Ring A is

[0097] These groups are each optionally surrounded by one to three R groups. A Replace, each R A Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -OH, -CN, or -N(R) 10a (R) 10b );

[0098] Ring B is

[0099] (i)C 6-10 aryl or heteroaryl, each optionally surrounded by one to four R B Replace, each R B Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 10a -C(O)R 10a -C(O)OR 10a -N(R) 10a (R) 10b ), N(R 10a )2(R 10b ) + -N(R) 10a )C(O)-R 10b -N(R) 10a )C(O)OR 10b -N(R) 10a )C(O)N(R 10b (R) 10c ), -N(R 10a )S(O)2(R 10b -NR 10a S(O)2N(R 10b (R)10c -NR 10a S(O)₂O(R) 10b -OC(O)R 10a -OC(O)OR 10a -OC(O)-N(R) 10a (R) 10b ), -SR 10a -S(O)R 10a -S(O)(NH)R 10a -S(O)2R 10a -S(O)2N(R) 10a (R) 10b ), -S(O)(NR 10a )R 10b or -Si(R) 10a )3; or

[0100] (ii)C 6-10 An aryl or heteroaryl group, each fused with a 5- or 6-membered ring having zero to four heteroatoms, each independently N, O, or S, to form a fused ring system, wherein the fused ring system is optionally separated by one to five R atoms. B Replace, each R B Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 10a -C(O)R 10a -C(O)OR 10a -N(R) 10a (R) 10b ), N(R 10a )2(R 10b ) + -N(R) 10a )C(O)-R 10b -N(R) 10a )C(O)OR 10b -N(R) 10a )C(O)N(R 10b (R) 10c ), -N(R 10a )S(O)2(R 10b -NR 10a S(O)2N(R 10b (R)10c -NR 10a S(O)₂O(R) 10b -OC(O)R 10a -OC(O)OR 10a -OC(O)-N(R) 10a (R) 10b ), -SR 10a -S(O)R 10a -S(O)(NH)R 10a -S(O)2R 10a -S(O)2N(R) 10a (R) 10b ), -S(O)(NR 10a )R 10b or -Si(R) 10a 3;

[0101] V is -C(R) 11a (R) 11b )-;

[0102] X 1 X 2 and X 3 Each is independently -C(H) = or -C(R) 8 = ;

[0103] R 2 for

[0104] i)C 3-10 Cycloalkyl or heterocyclic group, wherein each cycloalkyl or heterocyclic group is optionally surrounded by one to four Z groups. 1 Replace, where each Z 1 Independently for C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, oxo groups, -OH, -CN, C 1-6 Alkyl-CN, -C(O)R 10a -C(O)OR 10a -C(O)NH2, -C(O)NH(C 1-9 alkyl), -N(R) 10a (R) 10b ), -N(R 10a )C(O)OR 10b -N(R) 10a )C(O)-R 10b -S(O)2R 10a -S(O)2(C1-9 alkyl), -OC 3-6 cycloalkyl or heteroaryl,

[0105] Each of the -OC 3-6 cycloalkyl or heteroaryl groups are optionally separated by one to four Z groups. 1a Group substitution, each Z 1a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; or

[0106] (ii) in

[0107] R 2a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-CN, -C 3-6 cycloalkyl or heteroaryl,

[0108] Each alkyl, cycloalkyl, or heteroaryl group is optionally divided by one to four independently C2 groups. 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl or C 1-6 Group substitution of halogenated alkoxy groups;

[0109] R 2b For H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups; and

[0110] R 2c For H, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0111] R 3 -C(O)OR 3a ;

[0112] Where R 3a For H, C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-N(R) 9a )C(O)-OC 1-4 Alkyl-OP(O)(OR) 9c 2. C 1-4 Alkyl-C(O)N(R) 9a)(R 9b )、 -C 1-4 alkyl - 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 - O - C(O) - C 1-4 alkyl - OP(O)(OR 9c )2、 - CH2CH(N(R 9a )2)C(O)OR 9b 、 - P(O)(OR 9c )2、 - OP(O)(OR 9c )2、 - CH2P(O)(OR 9c )2、 - CH2OP(O)(OR 9c )2、 - OCH2P(O)(OR 9c )2、C(O)OCH2P(O)(OR 9c )2、 - P(O)(R 9c )(OR 9d )、 - OP(O)(R 9c )(OR 9d )、 - CH2P(O)(R 9c )(OR 9d )、 - OCH2P(O)(R 9c )(OR 9d )、 - C(O)OCH2P(O)(R 9c )(OR 9d )、 - P(O)(N(R 9c )2)2、 - OP(O)(N(R 9c )2)2、 - CH2P(O)(N(R 9c )2)2、 - OCH2P(O)(N(R 9c )2)2、 - C(O)OCH2P(O)(N(R 9c )2)2、 - P(O)(N(R 9c )2)(OR 9d )、 - OP(O)(N(R 9c )2)(OR 9d )、 - CH2P(O)(N(R 9c )2)(OR 9d )、 - OCH2P(O)(N(R 9c )2)(OR 9d), -C(O)OCH2P(O)(N(R) 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -OP(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), -OCH2P(O)(R 9c )(N(R 9d )2), -C(O)OCH2P(O)(R 9c )(N(R 9d )2) or C 1-6 alkyl-heterocyclic groups

[0113] Each alkyl or heterocyclic group is optionally substituted with one to four halogens;

[0114] Each R 4 Independently for C 1-6 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 10a -C(O)R 10a -C(O)OR 10a -N(R) 10a (R) 10b ), -N(R 10a )2(R 10b ) + -N(R) 10a )-C(O)R 10b -N(R) 10a )C(O)O(R 10b ), -N(R 10a )C(O)N(R 10b (R) 10c ), -N(R 10a )S(O)2(R 10b ), -N(R 10a )S(O)2-N(R 10b (R) 10c ), -N(R 10a )S(O)2O(R 10b -OC(O)R 10a -OC(O)OR10a -OC(O)-N(R) 10a (R10) b -S-R10 a -S(O)R 10a -S(O)(NH)R 10a -S(O)2R 10a -S(O)2N(R) 10a (R) 10b ), -S(O)(NR 10a )R 10b or -Si(R) 10a )3,

[0115] Each alkyl, haloalkyl, alkenyl, or aryl group is optionally surrounded by one to four R groups. 5 Replace, and

[0116] Each cycloalkyl, heterocyclic, or heteroaryl group is optionally surrounded by one to four R groups. 12 replace;

[0117] Each R 5 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 10a -C(O)-R 10a -C(O)OR 10a C(O)-N(R) 10a (R) 10b ), -N(R 10a (R) 10b ), -N(R 10a )2(R 10b ) + -N(RR) 10a )C(O)-R 10b -N(R) 10a )C(O)OR 10b -N(R) 10a )C(O)N(R 10b (R) 10c ), -N(R 10a )S(O)2(R 10b -NR 10a S(O)2N(R10b (R) 10c -NR 10a S(O)₂O(R) 10b -OC(O)R 10a -OC(O)OR 10a -OC(O)-N(R) 10a (R) 10b ), -SR 10a -S(O)R 10a -S(O)(NH)R 10a -S(O)2R 10a -S(O)2N(R) 10a (R) 10b ), -S(O)(NR 10a )R 10b or -Si(R) 10a )3,

[0118] Each of the following groups is an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, or a heterocyclic group.

[0119] Aryl or heteroaryl groups are optionally separated by one to four R groups. 6 replace;

[0120] Each R 6 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 10a -C(O)-R 10a -C(O)OR 10a -C(O)-N(R) 10a (R) 10b ), -N(R 10a (R) 10b ), -N(R 10a )C(O)-R 10b -N(R) 10a )C(O)OR 10b -N(R) 10a )C(O)N(R 10b (R) 10c ), -N(R 10a )S(O)2(R10b -NR 10a S(O)2N(R 10b (R) 10c -NR 10a S(O)₂O(R) 10b -OC(O)R 10a -OC(O)OR 10a -OC(O)-N(R) 10a (R) 10b ), -SR 10a -S(O)R 10a -S(O)(NH)R 10a -S(O)2R 10a -S(O)2N(R) 10a (R) 10b ), -S(O)(NR 10a )R 10b or -Si(R) 10a )3,

[0121] Each of the following groups is an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, or a heterocyclic group.

[0122] Aryl or heteroaryl groups are optionally separated by one to four R groups. 7 replace;

[0123] Each R 7 and R 8 Independently for C 1-9 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C) 1-9 alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -C(O)(C 3-15 cycloalkyl), -C(O)(heterocyclic), -C(O)(C 6-10 aryl), -C(O)(heteroaryl), -C(O)O(C 1-9 Alkyl), -C(O)O(C 1-8 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH (heterocyclic), -C(O)NH (C 6-10 aryl), -C(O)NH (heteroaryl), -C(O)N(C 1-9 Alkyl)2、-C(O)N(C1-8 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 2, -C(O)N(C) 3-15 Cycloalkyl)2, -C(O)N(heterocyclic)2, -C(O)N(C 6-10 aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2,

[0124] Each alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally bounded by one to three Cs. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -CO2H, -O(C) 1-9 alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2-substituted,

[0125] Each alkyl or heterocyclic group is optionally substituted with one to four halogens;

[0126] Each R 9a and R 9b H and C independently 1-6 Alkyl or C 1-6 Halogenated alkyl, or R 9a and R 9b Together they form a 6-membered heterocyclic group;

[0127] Each R 9c R 9d R 10a R 10b and R 10c H and C independently 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally surrounded by one to four R groups. 6 replace;

[0128] Each R 11a and R 11b Independently -H, C 1-6 Alkyl, oxo, or halogen;

[0129] Each R 12 C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, oxo group, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C) 1-9 alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -C(O)(C 3-15 cycloalkyl), -C(O)(heterocyclic), -C(O)(C 6-10 aryl), -C(O)(heteroaryl), -C(O)O(C 1-9 Alkyl), -C(O)O(C 1-8 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH (heterocyclic), -C(O)NH (C 6-10 aryl), -C(O)NH (heteroaryl), -C(O)N(C 1-9 Alkyl)2、-C(O)N(C 1-8 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 2, -C(O)N(C) 3-15 Cycloalkyl)2, -C(O)N(heterocyclic)2, -C(O)N(C 6-10 aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2,

[0130] Each alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally bounded by one to three carbon atoms. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -CO2H, -O(C) 1-9 alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2-substituted,

[0131] Each alkyl or heterocyclic group is optionally substituted with one to four halogens;

[0132] Each heterocyclic group has three to twelve ring members and one to four heteroatoms, each independently N, O, or S; and

[0133] Each heteroaryl group has five to twelve ring members and one to four heteroatoms that are independently N, O or S.

[0134] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 C 6-10 aryl or 6-membered heteroaryl, each of which is optionally divided by one to four R 4 replace.

[0135] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 It is a phenyl or a 6-membered heteroaryl group, each of which is optionally surrounded by one to four R groups. 4 Substitution. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 for

[0136] It is arbitrarily divided by one to four R 4 replace.

[0137] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 It is a 6-membered heteroaryl group, each of which is optionally divided by one to four R groups. 4 Substitution. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 for

[0138] It is arbitrarily divided by one to four R 4 replace.

[0139] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 By three Rs 4 Substitution. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 By two R 4 Substitution. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 It can be an R 4 replace.

[0140] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 It is a 6-membered heteroaryl group, wherein the heteroaryl group is fused with a 5- or 6-membered ring having zero to three heteroatoms, each independently N, O, or S, to form a fused ring system, wherein the fused ring system is optionally separated by one to four R atoms. 5 replace.

[0141] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, ring A is

[0142] These groups are each optionally surrounded by one to three R groups. A replace.

[0143] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, ring A is

[0144] It is optionally divided by one to three R A replace.

[0145] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, ring A is

[0146] These groups are each optionally surrounded by one to three R groups. A replace.

[0147] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, ring A is It is optionally divided by one to three R A Substitution. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, ring A is... It is optionally controlled by one or two R A Substitution. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, ring A is... It is arbitrarily controlled by an R A replace.

[0148] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, ring A is It is optionally divided by one to three R A Substitution. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, ring A is... It is optionally controlled by one or two R A Substitution. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, ring A is... It is arbitrarily controlled by an R A replace.

[0149] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R A Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, -OH, -CN, or -N(R) 10a (R) 10b ).

[0150] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, ring B is C. 6-10 aryl or heteroaryl, each optionally surrounded by one to four R B replace.

[0151] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring B is a phenyl or a 5- to 6-membered heteroaryl group, wherein the phenyl or heteroaryl group is optionally surrounded by one to four R groups. B replace.

[0152] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, ring B is

[0153] It is optionally divided by one to four R B replace.

[0154] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, ring B is It is arbitrarily divided by one to four R B Substitution. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, ring B may be replaced by three R... B Substitution. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, ring B may be replaced by two R... B Substitution. In some embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, ring B may be replaced by an R B replace.

[0155] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, ring B is a phenyl or a 5- to 6-membered heteroaryl group, each of which is fused with a 5- or 6-membered ring having zero to four heteroatoms, each independently N, O, or S, to form a fused ring system, wherein the fused ring system is optionally separated by one to five R groups. B replace.

[0156] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, ring B is

[0157] It is optionally divided by one to five R B replace.

[0158] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, each R B Independently for C 1-9 Alkyl, C 1-8 Halogenated alkyl, halogen, heteroaryl, oxo, or -N(R) 10a (R) 10b ).

[0159] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, V is CH2-, -C(O)-, -C(F)2-, -CH(F)- or -CH(CH3)-.

[0160] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, X 1 X 2 and X 3 Each is independently -CH=, -C(Br)=, -C(C≡CCH2CH2CH3)= or -C(C≡CC(CH3)(CH3)(CH2(OH)))=. In some embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, X 1 X 2 and X 3Each can be independently -CH=, -C(F)=, -C(Cl)=, -C(Br)=, or -C(CN)=. In some implementations, X 1 X 2 and X 3 Each is independently -CH= or -C(F)=. In some implementations, X 1 X 2 and X 3 In this context, both are represented by -CH=, and one by -C(F)=. In some implementations, X 1 Let -C(F) = , and X 2 and X 3 Each is -CH=. In some implementations, X 2 Let -C(F) = , and X 1 and X 3 Each is -CH=. In some implementations, X 1 and X 2 Each is -CH=, and X 3 For -C(F) = . In some implementations, X 1 X 2 and X 3 Each is -CH=. In some implementations, X 1 X 2 and X 3 Each is independently -CH= or -C(Cl)=. In some implementations, X 1 X 2 and X 3 Both are -CH=, and one is -C(Cl)=. In some implementations, X 1 Let -C(Cl) = , and X 2 and X 3 Each is -CH=. In some implementations, X 2 Let -C(Cl) = , and X 1 and X 3 Each is -CH=. In some implementations, X 1 and X 2 Each is -CH=, and X 3 For -C(Cl) = . In some implementations, X 1 X 2 and X 3 Each is -CH=.

[0161] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 C 3-10 Cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by one to four Z groups. 1replace.

[0162] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 for

[0163] These groups are each optionally divided by one to four Z groups. 1 replace.

[0164] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 for

[0165] These groups are each optionally divided by one to four Z groups. 1 replace.

[0166] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 for These groups are each optionally divided by one to four Z groups. 1 Substitution. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 2 for In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 for In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 for

[0167] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 for

[0168]

[0169] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 for

[0170] in

[0171] R 2a C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0172] R 2b For H or C 1-3 alkyl;

[0173] R 2c For H or C 1-3Alkyl; or

[0174] Alternatively, R 2b and R 2c They can combine to form a ring.

[0175] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 for

[0176] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 for

[0177] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, each Z 1 Independently for C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, halogen, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, oxo groups, -OH, -CN, C 1-6 Alkyl-CN, -C(O)R 10a -C(O)OR 10a -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -N(R) 10a (R) 10b ), -N(R 10a )C(O)OR 10b -N(R) 10a )C(O)-R 10b -S(O)2R 10a -S(O)2(C 1-9 alkyl).

[0178] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, each Z 1 Independently for C 1-6 Alkyl, C 1-6 Alkoxy groups, halogens, oxo groups, -C(O)R 10a -C(O)OR 10a -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -N(R) 10a (R) 10b ), -N(R 10a )C(O)OR 10b -N(R) 10a )C(O)-R 10b-S(O)2R 10a or -S(O)2(C 1-9 alkyl).

[0179] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, each Z 1 Independently for C 1-6 Alkyl, C 1-6 Alkoxy, halogen or C 1-6 Halogenated alkyl groups.

[0180] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, each Z 1 Independently methyl, ethyl, or propyl. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, each Z 1 Independently methyl or ethyl. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, each Z 1 It is methyl on its own.

[0181] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 3 It is -C(O)OH.

[0182] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 4 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 10a -C(O)R 10a -C(O)OR 10 R 10a -N(R) 10a (R) 10b ), -N(R 10a )2(R 10b ) + -N(R) 10a )-C(O)R 10b -N(R) 10a )S(O)2-N(R 10b (R) 10c ), -S(O)R 10a or -S(O)(NR) 10a )R 10b -S(O)2R 10a .

[0183] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 4 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, halogen, C 3-10 cycloalkyl, heteroaryl, or -C(O)R 10a .

[0184] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 4 Independently -F, -Cl, -CN, C 1-9 Alkyl, C 3-10 cycloalkyl, heteroaryl, or -C(O)R 10a In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 4 Independently -F, -Cl, -CN, or heteroaryl. In some embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, each R 4 Independently -F, -Cl, or -CN. In some embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, each R 4 Independently -F, -Cl, or heteroaryl. In some embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, each R 4 The heteroaryl group is pyrrole, imidazole, triazole, or thiazole. In some embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, each R 4 The heteroaryl group is an imidazole or a triazole. In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 4 The heteroaryl group is a triazole.

[0185] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 5 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 Cycloalkyl, heterocyclic, heteroaryl, C 6-10 aryl, heteroaryl, oxo, -N3, -CN, -OR 10a -C(O)-R 10a -C(O)OR 10aC(O)-N(R) 10a (R) 10b ), -N(R 10a (R) 10b ), -N(R 10a )2(R 10b ) + -N(R) 10a R 10b )C(O)-R 10b -N(R) 10a )C(O)OR 10b -N(R) 10a )C(O)N(R 10b (R) 10c ), -OC(O)-N(R) 10a (R) 10b ).

[0186] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 5 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, halogen, C 3-15 Cycloalkyl, heteroaryl, or -CN.

[0187] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 6 Independently for C 1-9 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-8 Halogenated alkyl groups, halogens, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, -O(C 1-9 alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 ynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 Aryl) or -NH (heteroaryl).

[0188] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 6 Independently for C 1-9 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-8 Haloalkyl, C 3-15 Cycloalkyl or halogen.

[0189] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 7 Independently for C 1-9 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 1-8 Halogenated alkyl groups, oxo groups, -OH, -CN, -NH2, or halogens.

[0190] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R 7 C 2-6 Alkoxyalkyl.

[0191] In some implementations, compounds of formula (II) are provided:

[0192]

[0193] Or its pharmaceutically acceptable salt, wherein

[0194] R 1 For optional use by R 4 Substituted phenyl or 6-membered heteroaryl;

[0195] X 1 -C(H) = or -C(R) 8 = ;

[0196] X 4 -C(H) = , -C(R) 8 ) = or N;

[0197] Each R 4 Independently halogenated or -CN;

[0198] Each R B Independently for C 1-9 Alkyl, C 1-8 Halogenated alkyl groups or halogens;

[0199] Each R 8 Independently H or halogen; and

[0200] n can be 0, 1, 2, or 3.

[0201] In some embodiments, the compound of formula (I) is the compound of formula (II).

[0202] In some embodiments of the compound of formula (II) or its pharmaceutically acceptable salt, R 1 It is a phenyl group that has been substituted with halogen or -CN.

[0203] In some embodiments of the compound of formula (II) or its pharmaceutically acceptable salt, R 1 For those substituted with halogen or -CN

[0204] In some embodiments of the compound of formula (II) or its pharmaceutically acceptable salt, R 1 for

[0205]

[0206] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R B It is methyl, ethyl, F, or Cl. In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R B It is methyl or F. In some embodiments, the embodiment, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R B It is F.

[0207] In some embodiments of the compound of formula (II) or its pharmaceutically acceptable salt, R 8 It can be F or Cl.

[0208] In some implementations, compounds of formula (III) are provided:

[0209]

[0210] Or its pharmaceutically acceptable salt, wherein

[0211] X 1 -C(H) = or -C(R) 8 = ;

[0212] X 4 -C(H) = , -C(R) 8 ) = or N;

[0213] X 5 -C(H) = or N;

[0214] Each R B Independently for C 1-9 Alkyl, C 1-8 Halogenated alkyl groups or halogens;

[0215] Each R 4 It can be pyrrole, imidazole, triazole, or thiazole independently;

[0216] Each R 8 Halogens are independent of each other;

[0217] m is 0 or 1; and

[0218] n can be 0, 1, 2, or 3.

[0219] In some embodiments, the compound of formula (I) is the compound of formula (III).

[0220] In some embodiments of the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R B It is methyl, ethyl, F, or Cl. In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R B It is methyl or F. In some embodiments, the embodiment, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R B It is F.

[0221] In some embodiments, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 4 It is an imidazole or a triazole. In some embodiments, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 4 It is a triazole.

[0222] In some embodiments, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 4 for

[0223]

[0224] In some embodiments, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 4 for

[0225]

[0226] In some embodiments of the compound of formula (II) or its pharmaceutically acceptable salt, R 8 It can be F or Cl.

[0227] In some embodiments, the compounds of formula (I), formula (II) or formula (III) or their pharmaceutically acceptable salts have the structures of the compounds in Table 2.

[0228] This document also discloses in vivo metabolites of the compounds described herein, which are novel and unobservable relative to the prior art. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the applied compound, primarily due to enzymatic processes. Therefore, methods including the generation of novel and unobservable compounds by means of exposing the compound to a mammal for a period sufficient to produce its metabolites are employed. Such products are typically identified by: the preparation of radiolabels (e.g., 14 C or 3 For compounds of type H), the radiolabeled compound is administered parenterally to animals, such as rats, mice, guinea pigs, monkeys, or humans, at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism (typically about 30 seconds to 30 hours), and its metabolites are isolated from urine, blood, or other biological samples. These products can be readily separated due to labeling (other products are separated by using antibodies capable of binding to viable epitopes in the metabolites). The metabolite structures are determined in a conventional manner, such as by MS or NMR analysis. Typically, the analysis of metabolites can be performed in the same manner as routine drug metabolism studies well known to those skilled in the art. The metabolites can be used for diagnostic determination of the therapeutic dose of the compound, provided they are not otherwise detected in vivo, even if they themselves do not possess GLP-1R activity.

[0229] Formulations and methods for determining the stability of compounds in alternative gastrointestinal secretions are known. Compounds are defined herein as stable in the gastrointestinal tract, wherein less than about 50 mol% of the protecting group is deprotected in alternative intestinal or gastric juices after incubation at 37°C for 1 hour. The fact that compounds are stable in the gastrointestinal tract does not mean they cannot be hydrolyzed in vivo. Prodrugs are generally stable in the digestive system but can be hydrolyzed substantially to the parent drug in the digestive lumen, liver, lungs, or other metabolic organs, or generally intracellularly. As used herein, a prodrug is understood to be a compound chemically engineered to efficiently release the parent drug after overcoming the biological barriers of oral delivery.

[0230] III. Methods for preparing compounds

[0231] The compounds disclosed herein can be prepared by any method known in the art. The following exemplary general methods illustrate a route that can be used to obtain the compounds disclosed herein.

[0232] Option 1

[0233]

[0234] Intermediate 1.3 can be assembled by reacting an amine with intermediate 1.1 (where X is a halogen and R is an alkyl, alkylaryl, or aryl group) in the presence of a suitable base (e.g., DIPEA, KOtBu, etc.) to give intermediate 1.2. Intermediate 1.2 can be converted into intermediate 1.3 using suitable reducing conditions (e.g., H2 and Pd / C, Fe and HCl, etc.).

[0235] Option 2

[0236]

[0237] Compounds of formula (I) having the structure of a compound of formula 2.9 can be assembled as follows: first, intermediate 2.1 (where X) is assembled by metal-mediated cross-coupling using a suitable base (e.g., DIPEA, KOtBu, etc.) or a suitable palladium catalyst. 21 and X 22 Intermediate 2.2 (where Y = O, NH, or S) is coupled with a leaving group, such as a halogen (e.g., Cl or Br), to give intermediate 2.3 (Scheme 2). Intermediate 2.4 (where M = Li, MgBr, MgCl, or MgI, commercially available or obtained by metallization of the corresponding halide) can be combined with intermediate 2.3 using a suitable palladium catalyst to produce intermediate 2.5. After conversion to acidic intermediate 2.6 using standard conditions (e.g., LiOH, LiI, and pyridine), intermediate 1.3 can be added using standard amide bond forming conditions (e.g., DIPEA and HATU) to give intermediate 2.7, which can then be converted to the corresponding benzimidazole intermediate 2.8 under the influence of an acid catalyst (e.g., HCl, AcOH, etc.) or a dehydrating agent (e.g., POCl3, Tf2O / triphenylphosphine oxide). This intermediate can be converted to a compound of formula (I) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0238] Although Scheme 2 above uses intermediate 2.1 as a dihalopyridine for illustration, any dihalogenated A-ring starting material can be used to obtain similar compounds of formula (I).

[0239] Option 3

[0240]

[0241] In some embodiments, compounds of formula (I) having the structure of compounds of formula 2.9 can be assembled as follows: first, intermediate 3.1 (where X31 is Cl, Br, or I) is combined with intermediate 1.3 (where R = alkyl, alkylaryl, or aryl) under standard amide bond forming conditions (e.g., DIPEA and HATU, etc.) (Scheme 3). Intermediate 3.3 is obtained by treatment with a suitable acid catalyst (e.g., HCl, AcOH, etc.) or a dehydrating agent (e.g., POCl3, Tf2O / triphenylphosphine oxide, etc.). Halogen metal exchange from -X31 to -M can be achieved by transition metal coupling using suitable reagents (e.g., iPrMgBr, etc.) or using suitable palladium catalysts and metal sources (e.g., B2Pin2, Bu6Sn2, etc.) to obtain intermediate 2.8, which can be converted to compounds of formula (I) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0242] Option 4

[0243]

[0244] In some embodiments, the compound of formula 2.9 can be formed by first converting intermediate 2.3 into a metallized variant intermediate 4.1 using a suitable palladium catalyst and a metal source (e.g., B2Pin2, Bu6Sn2, etc.) (Scheme 4). Intermediate 4.1 can be coupled with intermediate 3.3 using a suitable palladium catalyst to generate intermediate 2.8, and then intermediate 2.8 can be converted into the compound of formula (I) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0245] Option 5

[0246]

[0247] Compounds of formula (IA-1) and / or formula (I) having the structure of a compound of formula 5.3 can be assembled as follows: first, a suitable coupling coupler and a palladium catalyst are coupled to the halogen-X of intermediate 5.1 (where X is Cl, Br or I) to produce intermediate 5.2, which can be converted into a compound of formula 5.3 using standard ester hydrolysis conditions (e.g., LiOH, LiI and pyridine, etc.) (Scheme 5).

[0248] Option 6

[0249]

[0250] Compounds of formula (I) having the structure of a compound of formula 6.1 can be obtained by reacting intermediate 2.9 with a sulfonamide under suitable coupling conditions (e.g., EDCI and DMAP, etc.) (Scheme 6).

[0251] Option 7

[0252]

[0253] Compounds of formula (I) having the structure of compounds of formula 7.3 can be assembled as follows: first, halogen-X of intermediate 7.1 is coupled to intermediate 7.2 using a suitable coupling coupler and a palladium catalyst, and intermediate 7.2 can be converted into compounds of formula 7.3 (scheme 7) using standard ester hydrolysis conditions (e.g., LiOH, LiI and pyridine).

[0254] Option 8

[0255]

[0256] Compounds of formula (I) having the structure of compounds of formula 2.9 can be assembled as follows: First, intermediate 3.4 is cross-coupled with intermediate 2.1 using a suitable transition metal catalyst (e.g., palladium, etc.) (Scheme 8). Then, intermediate 2.8 is coupled to a heteroatom-containing intermediate 2.2 (where Y = O, N, or S) via metal-mediated cross-coupling using a suitable base (e.g., DIPEA, KOtBu, etc.) or a suitable palladium catalyst to obtain intermediate 2.8. Intermediate 2.8 can be converted to compounds of formula (I) having the structure of compounds of formula 2.9 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0257] Option 9

[0258]

[0259] Compounds of formula (I) having the structure of a compound of formula 2.9 can be assembled as follows: First, intermediate 3.4 is cross-coupled with intermediate 9.1 using a suitable transition metal catalyst (e.g., palladium, etc.) (Scheme 9). Then, the benzyl ether is removed by reduction using H2 and a suitable catalyst (Pd / C, etc.) to obtain intermediate 9.2. Then, a suitable base (K2CO3, Cs2CO3, Ag2CO3, etc.) is used to remove the benzyl ether from intermediate 9.3 (where X... 91 Intermediate 9.2 can be alkylated with a suitable electrophilic reagent (which may be represented by -Cl, -Br, I, or -OTs). Intermediate 2.8 can be converted into a compound of formula (I) having the structure of the compound of formula 2.9 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine).

[0260] Option 10

[0261]

[0262] Compounds of formula (I) having the structure of a compound of formula 10.4 can be assembled as follows: first, intermediate 9.2 is alkylated with a type 10.1 intermediate using a suitable base (K2CO3, Cs2CO3, Ag2CO3, etc.), wherein X 101 and X 102 Each can be independently -Cl, -Br, -I, -OTs, or -OTf, and Y 1 Y 2 Y 3 and Y 4 Each is independently -CH= or -N=. Intermediate 10.2 is then converted to intermediate 10.3 using a suitable transition metal catalyst (e.g., palladium, etc.). Intermediate 10.3 can be converted to a compound of formula (I) having the structure of a compound of formula 10.4 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0263] IV. Pharmaceutical Preparations

[0264] In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound of the disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0265] In some embodiments of this disclosure, the pharmaceutical composition comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, as more fully described below.

[0266] Pharmaceutical compositions comprising the compounds disclosed herein or their pharmaceutically acceptable salts may be prepared using one or more pharmaceutically acceptable excipients, which may be selected according to conventional practice. Tablets may contain excipients, including gliding agents, fillers, binders, etc. Aqueous compositions may be prepared aseptically and are typically isotonic when intended for delivery by means other than oral administration. In some embodiments, the composition may contain excipients such as those described in Rowe et al., “Handbook of Pharmaceutical Excipients,” 6th edition, American Pharmacists Association, 2009. Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. In some embodiments, the composition is provided as a solid dosage form, including solid oral dosage forms.

[0267] The compositions comprise those suitable for various routes of administration, including oral administration. The compositions may be present in unit dosage forms and may be prepared by any of the methods well known in the pharmaceutical field. Such methods include the step of associating an active ingredient (e.g., a compound of this disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients. The compositions may be prepared by homogeneously and tightly associating the active ingredient with a liquid excipient or a finely divided solid excipient, or both, and then, if desired, shaping the product. Techniques and formulations are generally available in “Remington: The Science and Practice of Pharmacy,” 21st edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0268] The compositions described herein suitable for oral administration may exist as discrete units (unit dosage forms), including but not limited to capsules, sachets, or tablets each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition disclosed herein is a tablet.

[0269] The pharmaceutical compositions disclosed herein comprise one or more of the compounds disclosed herein or pharmaceutically acceptable salts thereof, as well as pharmaceutically acceptable excipients and optional other therapeutic agents. Pharmaceutical compositions containing an active ingredient may be in any form suitable for the intended method of administration. For example, when intended for oral use, they may be prepared as tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Tablets containing an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for manufacturing tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, polyvinylpyrrolidone, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or can be coated using known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

[0270] The amount of active ingredient that can be combined with an inactive ingredient to produce a dosage form can vary depending on the intended treatment subjects and the mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain about 1 mg to 1000 mg of the active material, formulated together with an appropriate and convenient amount of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient comprises about 5% to about 95% (by weight) of the total composition.

[0271] In some embodiments, in one variation, compositions comprising the compounds of this disclosure or pharmaceutically acceptable salts thereof do not contain agents that affect the metabolic rate of the active ingredient. Therefore, it should be understood that, in one aspect, compositions comprising the compounds of this disclosure do not contain agents that would affect (e.g., slow down, inhibit, or block) the metabolism of the compounds of this disclosure or any other active ingredient applied separately, sequentially, or simultaneously with the compounds of this disclosure. It should also be understood that any of the methods, kits, articles, etc., detailed in one aspect herein do not contain agents that would affect (e.g., slow down, inhibit, or block) the metabolism of the compounds of this disclosure or any other active ingredient applied separately, sequentially, or simultaneously with the compounds of this disclosure.

[0272] In some embodiments, the above-described pharmaceutical composition is used in humans or animals.

[0273] This disclosure also includes compounds of the disclosure applied as a single active ingredient in a pharmaceutically acceptable composition, the active ingredient being prepared by conventional methods known in the art, for example by binding the active ingredient to a pharmaceutically acceptable, therapeutically inert organic and / or inorganic carrier or excipient, or by mixing the active ingredient with them.

[0274] In one aspect, this document provides for the use of the compounds of this disclosure as a second or other active ingredient that has a synergistic effect with other active ingredients in known pharmaceutical products, or for the administration of the compounds of this disclosure together with such pharmaceutical products.

[0275] The compounds disclosed herein can also be used as prodrugs or other suitable modified forms that release the active ingredient in vivo.

[0276] V. Route of application

[0277] The compounds disclosed herein (also referred to herein as the active ingredients) may be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratumoral, intrathecal, intrathecal, and epidural). It should be understood that preferred routes may vary depending on, for example, the recipient's condition. An advantage of some of the compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0278] The compounds disclosed herein may be administered to an individual for the required period of time or duration according to an effective dosing regimen, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one variant, the compounds are administered on a daily or intermittent schedule throughout the individual's life.

[0279] The dosage or frequency of administration of the disclosed compounds may be adjusted during treatment based on the judgment of the physician administering the medication.

[0280] The compound can be applied in an effective amount to an individual (e.g., a human). In some embodiments, the compound is applied once daily.

[0281] The compound may be administered by any available route and method, such as by oral or parenteral (e.g., intravenous) administration. Therapeutic amounts of the compound may include 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 such as from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or such as from about 0.3 mg to about 30 mg per day, or such as from about 30 mg to about 300 mg per day.

[0282] The compounds disclosed herein may be combined with one or more additional therapeutic agents at any dose of the disclosed compounds (e.g., 1 mg to 1000 mg of the compound). Therapeuticly effective doses may include about 1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose to about 500 mg / dose, or such as about 100 mg / dose to about 400 mg / dose, or such as about 150 mg / dose to about 350 mg / dose, or such as about 200 mg / dose to about 300 mg / dose. Other therapeutically effective doses of the compounds disclosed herein are about 100 mg / dose, about 125 mg / dose, about 150 mg / dose, about 175 mg / dose, about 200 mg / dose, about 225 mg / dose, about 250 mg / dose, about 275 mg / dose, about 300 mg / dose, about 325 mg / dose, about 350 mg / dose, about 375 mg / dose, about 400 mg / dose, about 425 mg / dose, about 450 mg / dose, about 475 mg / dose, or about 500 mg / dose. Other therapeutically effective amounts of the compounds disclosed herein are about 100 mg / dose, or about 125 mg / dose, about 150 mg / dose, about 175 mg / dose, about 200 mg / dose, about 225 mg / dose, about 250 mg / dose, about 275 mg / dose, about 300 mg / dose, about 350 mg / dose, about 400 mg / dose, about 450 mg / dose, or about 500 mg / dose. A single dose may be administered hourly, daily, or weekly. For example, a single dose may be administered every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, or 16 hours, or every 24 hours. A single dose may also be administered every 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days, or every 7 days. A single dose may also be administered every 1 week, 2 weeks, 3 weeks, or every 4 weeks. In some embodiments, a single dose may be administered weekly. A single dose may also be administered monthly.

[0283] This disclosure also includes kits comprising compounds of the present disclosure, or enantiomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing any of the foregoing. In one embodiment, the kit further includes instructions for use. In one aspect, the kit comprises a label and / or instructions for use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, and a compound described herein for a therapeutic indication (such as the disease or condition described herein). In one embodiment, kits are provided comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0284] This document also provides articles in suitable containers, including compounds of the present disclosure, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof. Containers may be vials, wide-mouth bottles, ampoules, pre-loaded syringes, and intravenous bags.

[0285] VI. Combination therapy

[0286] In some embodiments, the compounds of this disclosure or pharmaceutically acceptable salts thereof may be combined with therapeutically effective amounts of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) adjunctive therapeutic agents. In some embodiments, the adjunctive therapeutic agents include apoptosis signal-regulated kinase-1 (ASK-1) inhibitors, farnesol X receptor (FXR) agonists, peroxisome proliferator-activated receptor α (PPARα) agonists, fish oil, acetyl-CoA carboxylase (ACC) inhibitors, TGFβ antagonists, LPAR antagonists, SGLT2 inhibitors, Tpl2 inhibitors, GLP-1 agonists, or combinations thereof.

[0287] The beneficial effects of the combination may be to increase the efficacy of the components and / or reduce their side effects, as the dosage of the component can be reduced to decrease its side effects while benefiting from the enhanced efficacy of the compounds disclosed herein.

[0288] In some implementations, the therapeutic agent or combination of therapeutic agents includes ACE inhibitors, 2-acylglycerol O-acyltransferase 2 (DGAT2) inhibitors, aldehyde dehydrogenase inhibitors, acetyl-CoA carboxylase inhibitors, adrenergic receptor agonists, Alstrom syndrome protein 1 (ALMS1) / PKCα protein interaction inhibitors, apralin peptide receptor agonists, diacylglycerol O-acyltransferase 2 inhibitors, adenosine A3 receptor agonists, adenosine A3 receptor antagonists, adiponectin receptor agonists, aldehyde dehydrogenase 2 stimulators, AKT protein kinase inhibitors, AMP-activated protein kinase (AMPK), AMP kinase activators, ATP citrate lyase inhibitors, AMP-activated protein kinase stimulators, endothelial nitric oxide synthase stimulators, NAD-dependent deacetylase Sirtuin-1 stimulators, adrenergic receptor antagonists, androgen receptor agonists, pancreatic amyloid peptide receptor agonists, and angiotensin II. AT-1 receptor antagonists, apical membrane sodium-dependent bile acid transport inhibitors, autophagy protein modulators, autocrine motor factor inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, β-catenin inhibitors, bioactive lipids, calcitonin agonists, cannabinoid receptor modulators, caspase inhibitors, caspase-3 stimulators, cathepsin inhibitors, caveolin 1 inhibitors, CCK receptor antagonists, CCL26 gene inhibitors, CCR2 chemokine antagonists, angiotensin II AT-1 receptor antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, CDGSH iron-sulfur domain protein modulators, chitosanase inhibitors, chloride channel stimulators, chitosan trisaccharidase 1 inhibitors, CNR1 inhibitors, connective tissue growth factor ligand inhibitors, COT protein kinase inhibitors, cyclin D1 inhibitors, cytochrome P450. 7A1 inhibitors, cytochrome P450 reductase inhibitors, DGAT1 / 2 inhibitors, diacylglycerol O-acyltransferase 1 inhibitors (DGAT1), cytochrome P450CYP2E1 inhibitors, CXCR3 chemokine antagonists, CXCR4 chemokine antagonists, dihydroceramide δ4 desaturase inhibitors, dihydroorotate dehydrogenase inhibitors, dipeptidyl peptidase IV inhibitors, endothelial sialic acid protein modulators, eosinophil activation chemokine ligand inhibitors, extracellular matrix protein modulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligands, fibroblast activation protein inhibitors, free fatty acid receptor 1 agonists, and galactolectin-3 inhibitors. GDNF family receptor alpha-like agonists, glucagon receptor agonists, glucagon-like peptide-1 agonists, glucocorticoid receptor antagonists, glucose-6-phosphate 1-dehydrogenase inhibitors, G protein-coupled bile acid receptor 1 agonists, G protein-coupled receptor-119 agonists, G protein-coupled receptor 84 antagonists, hedgehog (Hh) modulators, hepatitis C virus NS3 protease inhibitors, hepatocyte nuclear factor 4α modulators (HNF4A), hepatocyte growth factor modulators, histone deacetylase inhibitors, STAT-3 modulators, HMG coenzyme A reductase inhibitors, HSD17B13 gene inhibitors, 5-HT 2α receptor antagonists, hydrolase inhibitors, hypoxia-inducible factor-2α inhibitors, IL-10 agonists, IL-17 antagonists, IL-22 agonists, ileal bile acid sodium cotransporter inhibitors, insulin sensitizers, insulin ligand agonists, insulin receptor agonists, integrin modulators, integrin antagonists, integrin α-V / β-1 antagonists, integrin α-V / β-6 antagonists, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, IL-6 receptor agonists, interleukin-17 ligand inhibitors, Jak2 tyrosine kinase inhibitors, Jun N-terminal kinase-1 inhibitors, Kelch-like ECH-associated protein 1 modulators, ketohexokinase (KHK) inhibitors, Klothoβ stimulants, leukotriene A4 hydrolase inhibitors, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptor, LPL gene stimulants, lysophosphatidic acid-1 receptor antagonists, lysyl oxidase homologue 2 inhibitors, LXR anti-agonists, macrophage mannose receptor 1 modulators, matrix metalloproteinase (MMP) inhibitors, MEKK-5 protein kinase inhibitors, MCH receptor-1 antagonists, membrane copper amine oxidase (VAP-1) inhibitors, methionine aminopeptidase-2 inhibitors, methyl CpG binding protein 2 modulators, microRNA-132 (miR-132) antagonists, microRNA-21 (miR-21) inhibitors, mitochondrial uncoupling agents, mixed lineage kinase 3 inhibitors, motile sperm domain protein 2 inhibitors, myelin basic protein stimulants, NACHT LRRPYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase Sirtuin stimulants, NADPH oxidase inhibitors (NOX), NFE2L2 gene inhibitors, nicotinic acid receptor 1 agonists, opioid receptor μ antagonists, P2Y13 purine receptor stimulants, nucleoerythrocyte 2-associated factor 2 stimulants, nuclear receptor modulators, nuclear transport modulators of transcription factors, P2X7 purine receptor modulators, PACAP type I receptor agonists, PDE3 inhibitors, PDE4 inhibitors, PDE 5. Inhibitors, PDGF receptor β modulators, phenylalanine hydroxylase stimulators, phospholipase C inhibitors, phosphodiesterase inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, peptidylprolyl cis-trans isomerase A inhibitors, PNPLA3 gene inhibitors, PPARγ modulators, protease-activated receptor-2 antagonists, protein kinase modulators, protein NOV homologue modulators, PTGS2 gene inhibitors, renin inhibitors, resistin / CAP1 (adenylate cyclase-associated protein 1) interaction inhibitors, Rho-associated protein kinase inhibitors, RNA polymerase inhibitors, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter-2 inhibitors, sphingolipid δ4 desaturase DES1 inhibitors, SREBP transcription factor inhibitors. Agents, STAT-1 inhibitors, stearoyl-CoA desaturase-1 inhibitors, STK25 inhibitors, cytokine signaling inhibitor-1 stimulators, cytokine signaling inhibitor-3 stimulators, taste receptor type 2 agonists, telomerase stimulators, TERT gene regulators, TGFβ (TGFB1) ligand inhibitors, TNF antagonists, transforming growth factor β (TGF-β), transforming growth factor β activated kinase 1 (TAK1), thyroid hormone receptor β agonists, TLR-4 antagonists, transglutaminase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, TLR-9 antagonists, VDR agonists, vitamin D3 receptor modulators, WNT modulators, YAP / TAZ modulators, or ligand inhibitors, and combinations thereof.

[0289] Non-limiting examples of one or more additional therapeutic agents include:

[0290] -ACE inhibitors, such as enalapril;

[0291] - Acetaldehyde dehydrogenase inhibitors, such as ADX-629;

[0292] - Acetyl-CoA carboxylase (ACC) inhibitors, such as NDI-010976 (firsocostat), DRM-01, gecarbene, GS-834356, PF-05175157, QLT-091382, PF-05221304.

[0293] - Acetyl-CoA carboxylase / diacylglycerol O acyltransferase 2 inhibitors, such as PF-07055341;

[0294] - Adenosine receptor agonists, such as CF-102 (namodenoson), CF-101 (piclidenoson), CF-502, and CGS21680;

[0295] -Adenosine A3 receptor antagonists, such as FM-101;

[0296] -Adiponectin receptor agonists, such as ADP-355, ADP-399, and ALY668-SR;

[0297] -Adrenergic receptor antagonists, such as bromoergot, phenylbutyramine, and VI-0521;

[0298] - Acetaldehyde dehydrogenase 2 stimulators, such as FP-045;

[0299] -Amylin / calcitonin receptor agonists, such as KBP-042 and KBP-089;

[0300] -AMP-activated protein kinase stimulants, such as C-455, PXL-770, and O-304;

[0301] -AMP kinase activators / ATP citrate lyase inhibitors, such as bepidelic acid (ETC-1002, ESP-55016);

[0302] -AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase Sirtuin-1 stimulators, such as NS-0200 (leucine + metformin + sildenafil);

[0303] -Androgen receptor agonists, such as LPCN-1144, LPCN-1148, and testosterone prodrugs;

[0304] -Angiotensin II AT-1 receptor antagonists, such as irbesartan;

[0305] - Angiopoietin-associated protein-3 inhibitors, such as vupanorsen (IONIS-ANGPTL3-LRx);

[0306] - Apalin peptide receptor agonists, such as CB-5064 and MBT-2;

[0307] -Aperture membrane sodium-dependent bile acid transport inhibitors, such as A-3907;

[0308] - Autophagy protein regulators, such as A-2906 and GM-90194;

[0309] - Inhibitors of autocrine motor factors (exonucleic acid pyrophosphatase / phosphodiesterase 2 (NPP2 or ENPP2)), such as FP10.47, PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, TJC-0265, TJC-0316, AM-063, BBT-877;

[0310] -Axl tyrosine kinase receptor inhibitors, such as besentinib (BGB-324, R-428);

[0311] -Bax protein stimulants, such as CBL-514;

[0312] -Bioactive lipids, such as DS-102;

[0313] - Cannabinoid receptor modulators, such as namacizumab, GWP-42004, REV-200, CRB-4001, INV-101, SCN-002;

[0314] - Cysteine ​​protease inhibitors, such as enricazone;

[0315] -Pan cathepsin B inhibitors, such as VBY-376;

[0316] -Pan cathepsin inhibitors, such as VBY-825;

[0317] -CCK receptor antagonists, such as propargylamine;

[0318] - CCL26 gene inhibitors, such as mosedipimod and KDDF-201410-10;

[0319] -CCR2 / CCR5 chemokine antagonists, such as BMS-687681, sinivirol, maraviro, CCX-872, leronlimab, WXSH-0213;

[0320] - CCR2 / CCR5 chemokine antagonists and FXR agonists, such as LJC-242 (zopifexoline + linagliptin (cenivriviroc));

[0321] -CCR2 chemokine antagonists, such as propargyl germanium;

[0322] -CCR2 chemokine / angiotensin II AT-1 receptor antagonists, such as DMX-200 and DMX-250;

[0323] -CCR3 chemokine antagonists, such as bertilimab;

[0324] -CD3 antagonists, such as NI-0401 (formeluzumab);

[0325] -CDGSH iron-sulfur domain protein regulators, such as EYP-002;

[0326] - Chitosan polysaccharide inhibitors, such as OATD-01;

[0327] - Chitotriosidase 1 inhibitors, such as OAT-2068;

[0328] - Chloride channel stimulants, such as coprostaglandin and lubiprostaglandin;

[0329] - Casein kinase-1 (CK1) δ / ε inhibitors, such as PF-05006739;

[0330] - Connective tissue growth factor ligand inhibitors, such as PBI-4050;

[0331] -COT protein kinase inhibitors, such as GS-4875 and GS-5290;

[0332] -CXCR4 chemokine antagonists, such as AD-214;

[0333] - Cytochrome P450 reductase inhibitors, such as SNP-630;

[0334] - Diglyceride acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx and PF-06865571;

[0335] - Diglyceride acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356;

[0336] - Diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 inhibitor (CYP2E1), such as SNP-610;

[0337] - Dihydroorotate dehydrogenase inhibitors, such as vidofluradimo;

[0338] - Dipeptidyl peptidase IV inhibitors, such as linagliptin or etagliptin;

[0339] - Inhibitors of eosinophil activation chemokine ligands, such as bertilimab and CM-101;

[0340] - Extracellular matrix protein modulators, such as CNX-024;

[0341] - Farnesoid X receptor (FXR) agonists, such as AGN-242266, AGN-242256, ASC-42, EDP-297 (EP-024297), RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, cilofexor Tromethamine (GS-9674), HPG-1860, IOT-022, LMB-763, Obeticholic Acid, Px-102, Px-103, M790, M780, M450, M-480, MET-409, MET-642, PX20606, SYHA-1805, Viloribumab (EYP-001), TERN-101, TC-100, INT-2228, TQA-3526, ZG-5266, HPD-001, Alentherol;

[0342] - Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767;

[0343] - Fatty acid synthase inhibitors, such as TVB-2640 and FT-8225;

[0344] - Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as odavmin (NGM-282);

[0345] - Fibroblast growth factor 21 (FGF-21) ligand modulators, such as AP-025, BMS-986171, B-1654, BIO89-100, BOS-580, pebefamine (BMS-986036), B-1344, NN-9499;

[0346] - Fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists, such as YH-25723 (YH-25724; YH-22241) and iluxivmin (AKR-001);

[0347] -FGF receptor agonists / Klothoβ stimulators, such as BFKB-8488A (RG-7992);

[0348] - Free fatty acid receptor 1 agonists, such as SCO-267;

[0349] -Galactolectin-3 inhibitors, such as belapectin (GR-MD-02), GB-1107 (Gal-300), GB-1211 (Gal-400), and IMT-001;

[0350] -GDNF family receptor alpha-like agonists, such as NGM-395;

[0351] - Glucagon-like peptide-1 receptor (GLP1R) agonists, such as ALT-801, AC-3174, liraglutide, cotodextrin (MEDI-0382), SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, PF-06882961, and smegglutide;

[0352] - Glucagon-like peptide-1 receptor agonists; gastric acid regulator ligands; glucagon receptor agonists, such as enopedus peptide;

[0353] - Glucagon / glucagon-like peptide-1 (GIP / GLP-1) receptor co-agonists, such as telposide (LY-3298176);

[0354] - Pegylated long-acting glucagon-like peptide-1 / glucagon (GLP-1R / GCGR) receptor dual agonists, such as DD-01;

[0355] - Glucagon / GLP1 receptor agonists, such as BI-456906 and NN-6177;

[0356] - Glucocorticoid receptor antagonists, such as CORT-118335 (Milicorice);

[0357] - Glucose 6-phosphate 1-dehydrogenase inhibitors, such as ST001;

[0358] - Glucokinase stimulants, such as doggliatin and sinogliatin (RO-5305552);

[0359] -G protein-coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009, INT-777, and HY-209;

[0360] -G protein-coupled receptor 84 antagonists, such as PBI-4547;

[0361] -G protein-coupled receptor-119 agonists, such as DA-1241;

[0362] - Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201;

[0363] - Hedgehog protein TGFβ ligand inhibitors, such as Oxy-210;

[0364] -Histone deacetylase inhibitors / STAT-3 regulators, such as SFX-01;

[0365] -HMG coenzyme A reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin;

[0366] -HSD17B13 gene inhibitors, such as ALN-HSD and ARO-HSD;

[0367] - Hydrolytic enzyme inhibitors, such as ABD-X;

[0368] - Hypoxia-inducible factor-2α inhibitors, such as PT-2567;

[0369] -IL-10 agonists, such as pegylated interleukin;

[0370] - Inhibitors of sodium ileoside cotransporter, such as ovacitabine (A-4250), vocitabine potassium ethanol hydrate (SHP-262), GSK2330672, CJ-14199, and elocitabine (A-3309).

[0371] - Insulin sensitizers, such as KBP-042, azemiglitazone potassium (MSDC-0602K), ION-224, MSDC-5514, Px-102, RG-125 (AZD4076), torimidone, VVP-100X, CB-4211, ETI-101;

[0372] -Insulin ligands / ds insulin receptor agonists, such as ORMD-0801;

[0373] -Integrin antagonists, such as IDL-2965;

[0374] -IL-6 receptor agonists, such as KM-2702;

[0375] - Dual inhibitors of integrin α-V / β-6 and α-V / β-1, such as PLN-74809;

[0376] - Interleukin-17 ligand inhibitors, such as nittazimab;

[0377] -Jak1 / 2 tyrosine kinase inhibitors, such as baricitinib;

[0378] -Jun N-terminal kinase-1 inhibitors, such as CC-90001;

[0379] -Kelch-like ECH-associated protein 1 regulators, such as α-cyclodextrin-stabilized sulforaphane;

[0380] - Ketohexokinase (KHK) inhibitors, such as PF-06835919, LY-3478045, and LY-3522348;

[0381] -βKlotho(KLB)-FGF1c agonists, such as MK-3655(NGM-313);

[0382] - Leukotriene A4 hydrolase inhibitors, such as LYS-006;

[0383] -5-lipoxygenase inhibitors, such as tylucast (MN-001), acetylpetroleum (DS-102, (AF-102));

[0384] - Lipoprotein lipase inhibitors, such as CAT-2003;

[0385] -LPL gene stimulants, such as aliprine;

[0386] - Hepatic receptor X (LXR) inhibitors, such as PX-665, PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, SR-9238;

[0387] - Lysophosphatidylcholine-1 receptor antagonists, such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, KI-16198;

[0388] - Lysyl oxidase homologue 2 inhibitors, such as sintuzumab, PXS-5382A (PXS-5338);

[0389] - Macrophage mannose receptor 1 modulators, such as temannoxetine-Cy3 (Tc99m temannoxetine);

[0390] - Matrix metalloproteinase inhibitors, such as ALS-L1023;

[0391] - Inhibitors of membrane copper amine oxidase (VAP-1), such as TERN-201 and TT-01025;

[0392] -MEKK-5 protein kinase (ASK-1) inhibitors, such as CJ-16871, CS-17919, selosenoside (GS-4997), SRT-015, GS-444217, GST-HG-151, TERN-301;

[0393] -MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158);

[0394] -Inhibitors of aminourea-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1), such as PXS-4728A (BI-1467335);

[0395] -Methionine aminopeptidase-2 inhibitors, such as ZGN-1061, ZGN-839, and ZN-1345;

[0396] β-methylCpG-binding protein 2 regulators, such as mercaptoethylamine;

[0397] - Mineralocorticoid receptor antagonists (MCRAs), such as MT-3995 (aparidone);

[0398] - Mitochondrial uncoupling agents, such as 2,4-dinitrophenol, HU6, Mito-99-0053;

[0399] - Mixed lineage kinase-3 inhibitors, such as URMC-099-C;

[0400] - Inhibitors of active sperm domain protein 2, such as VB-601;

[0401] - Myelin basic protein stimulants, such as orlisoxi;

[0402] - Green peroxidase inhibitors, such as PF-06667272 and AZM-198;

[0403] - NADPH oxidase inhibitors, such as GKT-831, GenKyoTex, APX-311, and celtanazine;

[0404] - Nicotinic acid receptor 1 agonists, such as ARI-3037MO;

[0405] -NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514, JT-194 (JT-349);

[0406] -NFE2L2 gene inhibitors, such as GeRP-amiR-144;

[0407] - Nuclear transport of transcription factor regulators such as AMTX-100;

[0408] - Nuclear receptor modulators, such as DUR-928 (DV-928);

[0409] -Opioid receptor μ antagonists, such as methylnaltrexone;

[0410] -P2X7 purine receptor modulators, such as SGM-1019;

[0411] -P2Y13 purine receptor stimulators, such as CER-209;

[0412] -PDE 3 / 4 inhibitors, such as tylucast (MN-001);

[0413] -PDE 5 inhibitors, such as sildenafil and MSTM-102;

[0414] -PDGF receptor β modulators, such as BOT-191 and BOT-509;

[0415] - Peptidyl prolyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018, and NV-556 (NVP-025);

[0416] -Phenylanase hydroxylase stimulants, such as HepaStem;

[0417] - Phosphodiesterase inhibitors, such as ZSP-1601;

[0418] - PNPLA3 gene inhibitors, such as AZD-2693;

[0419] -PPAR agonists, such as selafinranor, elafinranor (GFT-505), seladelpar lysine (MBX-8025), deuterated pioglitazone R-enantiomer, pioglitazone, PXL-065 (DRX-065), salrogleeza, ranirino (IVA-337), CHS-131, pemafidate (K-877), ZG-0588, ZSP-0678, ZSYM-008;

[0420] -Protein-activating receptor-2 antagonists, such as PZ-235;

[0421] - Protein kinase modulators, such as CNX-014;

[0422] - Protein NOV homologue regulators, such as BLR-200;

[0423] -PTGS2 gene inhibitors, such as STP-705 and STP-707;

[0424] - Renin inhibitors, such as PRO-20;

[0425] - Inhibitors of the resistin / CAP1 (adenylate cyclase-associated protein 1) interaction, such as DWJ-211;

[0426] -Rev protein modulators, such as ABX-464;

[0427] -Rho-associated protein kinase (ROCK) inhibitors, such as REDX-10178 (REDX-10325), KD-025, RXC-007, and TDI-01;

[0428] -RNA polymerase inhibitors, such as rifaximin;

[0429] -S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891;

[0430] - Sodium glucose transporter-2 (SGLT2) inhibitors, such as etagliflozin, regaggliflozin etopolate, etagliflozin, dapagliflozin, toggliflozin, and soggliflozin;

[0431] - Sodium glucose transporter-1 / 2 (SGLT 1 / 2) inhibitors, such as licogliflozinbis (prolinate) (LIK-066);

[0432] -SREBP transcription factor inhibitors, such as CAT-2003, HPN-01, MDV-4463;

[0433] - Stearoyl-CoA desaturase-1 inhibitors, such as eicosanoylaminocholanoic acid;

[0434] - Type 2 taste receptor agonists, such as ARD-101;

[0435] - Thyroid hormone receptor beta agonists, such as ALG-009, ASC-41, CNPT-101101; CNPT-101207, CS-27186, KY-41111, Remetidine (MGL-3196), MGL-3745, TERN-501, VK-2809, HP-515;

[0436] -TLR-2 / TLR-4 antagonists, such as VB-201 (CI-201);

[0437] -TLR-4 antagonists, such as JKB-121, JKB-122, and naltrexone;

[0438] - Tyrosine kinase receptor modulators, such as CNX-025 and GFE-2137 (recycled nitrozonide);

[0439] -TLR-9 antagonists, such as GNKS-356 and AVO-101;

[0440] -TNF antagonists, such as ALF-421;

[0441] -GPCR modulators, such as CNX-023;

[0442] - Nuclear hormone receptor modulators, such as Px-102;

[0443] -VDR agonists, such as CK-15;

[0444] - Xanthine oxidase inhibitors, such as ACQT-1127;

[0445] - Xanthine oxidase / uric acid anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001, RLBN-1127; or

[0446] - Linalool inhibitors, such as larizoline acetate (INN-202).

[0447] In certain specific embodiments, the one or more adjunctive therapeutic agents are selected from A-4250, AC-3174, acetylsalicylic acid, AK-20, aripiprazole, AMX-342, AN-3015, anti-CXCR3 antibody, anti-TAGE antibody, eicosanoylaminocholanic acid, ARI-3037MO, ASP-8232, AXA-1125, bertilimab, anhydrous betaine, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, budesonide, BX-003, CAT-2003, sinivirol, CBW-511, CER-209, C F-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, Cobiprostone, Colesvelam, Dabigatran Mesylate, Dapagliflozin, DCR-LIV1, Deuterated Pioglitazone R-enantiomer, 2,4-Dinitrophenol, DRX-065, DS-102, DUR-928, Edaravone (TTYP-01), EDP-305, elafibranor (GFT-505), Enricacin, Enalapril, Egliflozin, Egliflozin, F-351, Fluasterone (ST-002), FT-4101, GDD-3898, GH-509, GKT-83 1. GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, GS-4875, GS-5290, HEC-96719, HTD-1801, HS-10356, HSG-4112, HST-202, HST-201, HU-6, Hydrochlorothiazide, Icobut (PRC-4016), Ethyl eicosapentaenoic acid, IMM-124-E, INT-767, INV-240, ION-455, IONIS-DGAT2Rx, Epagliflozin, Irbesartan, Propadegerm, IVA-337, J2H-1702, JKB-121, KB- GE-001, KBLP-004, KBLP-009, KBP-042, KD-025, M790, M780, M450, Metformin, Sildenafil, LB-700, LC-280126, Linagliptin, Liraglutide, (LJN-452) Zopifexofylline, LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MB-N-008, MBX-8025, MDV-4463, Mercaptoethylamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, Namacizumab, NC-101, NDI-010976ND-L02-s0201(BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-011, NP-135, NP-160, Norursodeoxycholic acid, NV-422, NVP-022, O-304, Obeticholic acid (OCA), 25HC3S, Orlistat, PAT-505, PAT-048, Polyethylene glycol-modified interleukin, Pioglitazone, Pirfenidone, PRI-724 PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, PZH-2109, RCYM-001, RDX-009, Repaglinide Esophanic Acid, RG-125 (AZD4076), RP-005, RPI-500, S-723595, Sarogliniza, SBP-301, Smegglutide, SH-2442, SHC-028, SHC-023, Simtuzumab, Solomon's Sebum Rheumatoidin, Sorafenib, Stardine (Atorvastatin, Fluvastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin), TCM-606F, TEV-45478, TQA-3526, TQA-3563, Tipelukast (MN-001), TLY-012, TRX-318, TVB-2640, TXR-611, TXR-612, TS-20004, UD-009, UN-03, Ursodeoxycholic acid, Vitamin B Y-376, VBY-825, VK-2809, Vimodil, Vocibart potassium ethoxide hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, WXSH-0038, WXSH-0078, XEN-103, XRx-117, XTYW-003, XW-003, XW-004, XZP-5610, ZGN-839, ZG-5216, ZSYM-008 or ZYSM-007.

[0448] In some embodiments, the compounds of this disclosure are combined with one or more therapeutic agents selected from anti-obesity agents, including but not limited to peptide YY or analogues thereof, neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 agonists, NPYR5 antagonists, cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors (e.g., orlistat), human insulin peptide (HIP), melanocortin receptor 4 agonists (e.g., sermelatide), melanin condensing hormone receptor 1 antagonists, farnesoid X receptor (FXR) agonists (e.g., obeticholic acid), apoptosis signal-regulated kinase (ASK-1) inhibitors, zonisamide, phentermine (alone or in combination with topiramate), norepinephrine / dopamine reuptake inhibitors (e.g., bupropion), opioid receptor antagonists (e.g., naltrexone), norepinephrine / Combinations of dopamine reuptake inhibitors and opioid receptor antagonists (e.g., bupropion and naltrexone), GDF-15 analogs, sibutramine, cholecystokinin agonists, amylin and its analogs (e.g., pramlintide), leptin and its analogs (e.g., metroleptin), serotonergic agents (e.g., lorcaserin), methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranil or ZGN-1061), benzomorpholine, diethylamine acetone, benzphenamine, SG LT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ioggliflozin, tolagliflozin, seragliflozin ecaponicate, repaggliflozin ecaponicate, or etagliflozin), SGLT2 / SGLT1 inhibitors, dual SGLT2 / SGLT1 inhibitors, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, biotin, MAS receptor modulators, or glucagon receptor agonists (alone or in combination with another GLP-1R agonist, e.g., liraglutide, exenatide, etc.). Laglutide, abiglutide, lixilatide, or semaglutide), insulin sensitizers such as thiazolidinediones (TZDs), peroxisome proliferator-activated receptor α (PPARα) agonists, fish oil, acetyl-CoA carboxylase (ACC) inhibitors, transforming growth factor β (TGFβ) antagonists, GDNF family receptor α-like (GFRAL) agonists, melanocortin-4 receptor (MC4R) agonists, including pharmaceutically acceptable salts of the specifically named reagents and pharmaceutically acceptable solvates of said reagents and salts.

[0449] VII. Treatment Methods

[0450] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in methods for treating and / or preventing GLP-1R-mediated diseases or conditions. In some embodiments, methods for treating and / or preventing GLP-1R-mediated diseases or conditions include administering a pharmaceutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof to a subject in need. In some embodiments, the disclosed compound has desired properties, including, for example, favorable pharmacokinetic properties, physicochemical properties such as hepatic uptake properties and / or bile salt export pump (BSEP) inhibitory properties. In one embodiment, the disclosed compound has desired pharmacokinetic properties such as prolonged exposure time and / or higher oral bioavailability. In one embodiment, the disclosed compound has desired hepatic uptake properties such as reduced transporter-mediated hepatic uptake. In one embodiment, the disclosed compound exhibits desired BSEP inhibitory activity.

[0451] In some implementations, the disease or condition includes liver disease or related diseases or conditions, such as liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, compensated liver fibrosis, decompensated liver fibrosis, hepatocellular carcinoma, primary biliary cirrhosis (PBC), or primary sclerosing cholangitis (PSC). In some implementations, the disease or condition includes metabolic disease or related diseases or conditions, such as diabetes, obesity, or cardiovascular metabolic disease.

[0452] GLP-1R agonists are currently being investigated in conjunction with certain diseases and conditions, including, for example, diabetes. GLP-1 analogs that are DPP4 resistant and have a longer half-life than endogenous GLP-1 have been reported to be associated with weight loss and improved insulin action. Liraglutide (a peptide GLP-1R agonist approved for use in the treatment of diabetes) has been reported to show beneficial improvements in NASH subjects.

[0453] In some embodiments, this disclosure relates to the use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention and / or treatment of GLP-1R-mediated diseases or conditions, such as liver diseases or metabolic diseases. For example, some embodiments provide compounds of formula (I) or pharmaceutically acceptable salts thereof, or their use for the treatment and / or prevention of chronic intrahepatic or some forms of extrahepatic cholestasis, liver fibrosis, acute intrahepatic cholestasis, obstructive or chronic inflammatory conditions caused by improper bile composition, gastrointestinal conditions with reduced dietary fat intake and fat-soluble dietary vitamins, inflammatory bowel disease, lipid and lipoprotein diseases, type II diabetes and clinical complications of type I and type II diabetes, and the accumulation of lipids and, in particular, triglycerides due to forced lipids. The following are symptoms and diseases caused by the activation of subsequent pro-fibrotic pathways leading to chronic fatty degeneration and fibrotic degeneration of organs: obesity and metabolic syndrome (a syndrome of dyslipidemia, diabetes, and abnormally high body mass index); acute myocardial infarction; acute stroke; thrombosis as an endpoint of chronic obstructive atherosclerosis; persistent infections caused by intracellular bacteria or parasitic protozoa; non-malignant hyperproliferative diseases; malignant hyperproliferative diseases (e.g., colonic adenocarcinoma and hepatocellular carcinoma); hepatic steatosis and related syndromes; and liver failure or liver damage as a result of chronic liver disease or surgical hepatectomy. Functional impairment, hepatitis B infection, hepatitis C infection and / or cholestasis and fibrosis associated with alcohol-induced cirrhosis or viral hepatitis, type 1 diabetes, prediabetes, idiopathic type 1 diabetes, occult autoimmune diabetes, adolescent-onset adult-onset diabetes, early-onset diabetes, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, Obesity, eating disorders, sleep apnea, weight gain, glucose cravings, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, left ventricular hypertrophy, Parkinson's disease, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, angina pectoris, premenstrual syndrome, thrombosis, atherosclerosis, impaired glucose metabolism, or restenosis.

[0454] In some embodiments, methods for treating and / or preventing non-alcoholic fatty liver disease (NAFLD) include administering the compound of this disclosure or a pharmaceutically acceptable salt thereof to a subject in need.

[0455] This disclosure also relates to compounds of formula (I) or pharmaceutical compositions comprising said compounds for the preventive and post-traumatic treatment of cardiovascular diseases, such as acute myocardial infarction, acute stroke, or thrombosis that occurs as an endpoint of chronic obstructive atherosclerosis. In some embodiments, a method of treating and / or preventing cardiovascular disease includes administering a compound of formula (I) to a subject in need.

[0456] This disclosure also relates to compounds or pharmaceutical compositions for the treatment and / or prevention of obesity and related diseases, such as metabolic syndrome (a syndrome of dyslipidemia, diabetes, and abnormally high body mass index), which can be overcome by GLP-1R-mediated reduction of serum triglycerides, blood glucose, and insulin sensitivity, as well as GLP-1R-mediated weight loss. In some embodiments, a method of treating and / or preventing metabolic diseases includes administering a compound of formula (I) to a subject in need.

[0457] In another embodiment, the compounds or pharmaceutical compositions of this disclosure may be used to prevent and / or treat clinical complications of type 1 and type 2 diabetes. Examples of such complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, or peripheral artery occlusive disease (PAOD). This disclosure also covers other clinical complications of diabetes. In some embodiments, a method of treating and / or preventing complications of type 1 and type 2 diabetes includes administering a compound of formula (I) to a subject in need.

[0458] Furthermore, the use of the compounds or pharmaceutical compositions disclosed herein can also prevent and / or treat conditions and diseases resulting from chronic fatty degeneration and fibrotic degeneration of organs due to forced accumulation of lipids and / or triglycerides and subsequent activation of profibrotic pathways. Such conditions and diseases may include NASH and chronic cholestasis in the liver, glomerulosclerosis and diabetic nephropathy in the kidneys, macular degeneration and diabetic retinopathy in the eyes, and neurodegenerative diseases such as Alzheimer's disease in the brain or diabetic neuropathy in the peripheral nervous system. In some embodiments, a method for treating and / or preventing conditions and diseases resulting from chronic fatty degeneration and fibrotic degeneration of organs due to forced accumulation of lipids and / or triglycerides and subsequent activation of profibrotic pathways comprises administering a compound of formula (I) to a subject in need. In some embodiments, a method for treating and / or preventing conditions and diseases resulting from chronic fatty degeneration and fibrotic degeneration of organs due to forced accumulation of lipids and / or triglycerides and subsequent activation of profibrotic pathways comprises administering a compound of formula (I) to a subject in need. In some embodiments, methods for treating and / or preventing NASH include administering a compound of formula (I) to a subject in need.

[0459] This document also provides a pharmaceutical composition for treating the GLP-1R-mediated diseases or conditions described herein, the pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0460] This disclosure also describes the use of a medicament for treating GLP-1R-mediated diseases or conditions, the medicament comprising a compound of this disclosure or a pharmaceutically acceptable salt thereof. The medicaments mentioned herein can be prepared by conventional methods, including combinations of compounds according to this disclosure and pharmaceutically acceptable carriers.

[0461] The present disclosure also discloses compounds or pharmaceutically acceptable salts thereof for the treatment of GLP-1R-mediated diseases or conditions. The present disclosure also discloses compounds or pharmaceutically acceptable salts thereof for the prevention of GLP-1R-mediated diseases or conditions.

[0462] VIII. Examples

[0463] Numerous general references are available that provide commonly known chemical synthesis schemes and conditions that can be used to synthesize the disclosed compounds (see, for example, Smith, “March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure”, 7th edition, Wiley-Interscience, 2013).

[0464] The compounds described herein can be purified by any method known in the art, including chromatographic methods such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, rapid column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal and reversed-phase phases, as well as ion exchange resins. For example, the compounds disclosed in this invention can be purified by silica gel and / or alumina chromatography. See, for example, “Introduction to Modern Liquid Chromatography,” 2nd edition, edited by L.S. Nyder and J.J. Kirkland, John Wiley and Sons, 1979; and “Thin Layer Chromatography,” edited by E. Stahl, Springer-Verlag, New York, 1969.

[0465] In any method for preparing the subject compound, it may be necessary to protect any sensitive or reactive groups on any molecules in the relevant molecule. This can be achieved by means of conventional protecting groups as described in standard works such as TW Greene and PGM Uts, “Protective Groups in Organic Synthesis,” 4th edition, Wiley, New York, 2006. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0466] Exemplary chemical entities that can be used to implement the methods will now be described with reference to the general preparation described herein and the illustrative synthetic schemes of specific examples below. Those skilled in the art will recognize that, in order to obtain the various compounds described herein, starting materials may be suitably selected such that the desired product is produced by carrying the final desired substituent through a reaction scheme, whether carried out or not, as appropriate. Alternatively, it may be necessary to use a suitable group at the position of the final desired substituent, which may be carried out by the reaction scheme and, as appropriate, replaced with the desired substituent. Furthermore, those skilled in the art will recognize that the transformations shown in the following schemes can be performed in any order compatible with the functionality of the side groups. Each reaction depicted in the general scheme can be operated at a temperature from about 0°C to the reflux temperature of the organic solvent used.

[0467] The examples provided herein describe the synthesis of the compounds disclosed herein and the intermediates used to prepare these compounds. It should be understood that the various steps described herein can be combined. It should also be understood that individual batches of the compounds can be combined and then proceeded to the next synthetic step.

[0468] Specific embodiments are described in the following description of examples. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of this disclosure. Other embodiments may be utilized, and logical and other changes may be made without departing from the scope of this disclosure. The embodiments also relate to methods and intermediates for preparing the subject compounds or pharmaceutically acceptable salts thereof. Therefore, the following description is not intended to limit the scope of this disclosure.

[0469] In some embodiments, this disclosure typically provides a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer is not determined in all cases. When the stereochemistry of a specific stereocenter in the enantiomer or diastereomer is not determined, the compound is drawn without any stereochemistry showing at that specific stereocenter, even if the compound may be substantially enantiomerically pure or diastereomerically pure.

[0470] Representative syntheses of the compounds disclosed herein are described in the following schemes and examples.

[0471] The compounds detailed in the examples were synthesized according to the general synthetic methods described below. Unless otherwise specified, the compounds were named using ChemDraw version 18.1.0.535 (PerkinElmer Informatics, Inc.).

[0472] abbreviation

[0473] Certain abbreviations and acronyms are used to describe experimental details. Although most of these abbreviations and acronyms are understandable to those skilled in the art, Table 1 contains a list of many of these abbreviations and acronyms.

[0474] Table 1: List of Abbreviations and Acronyms

[0475]

[0476]

[0477]

[0478] A. Synthesis of intermediates

[0479] Preparation of intermediate I-1 :

[0480]

[0481] Methyl 4-amino-3-(2-methoxyethylamino)benzoate (I-1) To a solution of methyl 3-fluoro-4-nitrobenzoate (50.0 g, 251 mmol) in THF (400 mL), diisopropylethylamine (70.0 mL, 402 mmol) and 2-methoxyethylamine (34.9 mL, 402 mmol) were added. The resulting solution was heated to 55 °C for 6 hours. After completion, the solvent was removed, and the resulting residue was dissolved in EtOAc (150 mL), washed with brine (30 mL), concentrated, and allowed to proceed without further purification. Then, methyl 3-(2-methoxyethylamino)-4-nitrobenzoate (20.0 g, 78.7 mmol) was dissolved in EtOAc:EtOH (1:1, 140 mL), and then 10% carbon-supported palladium (5.02 g, 4.72 mmol) was added. The resulting suspension was stirred for 16 hours at room temperature under a hydrogen balloon. The mixture was filtered through a Celite filter, washed with EtOAc (100 mL), and concentrated to obtain the desired compound without further purification: ES / MS: 225.2 (M+H). + ).

[0482] Preparation of intermediate I-2 :

[0483]

[0484] 4-{[2-(4-bromo-2-fluoro-phenyl)acetyl]amino}-3-(2-methoxyethylamino)benzoate methyl ester 4-Amino-3-(2-methoxyethylamino)benzoate (1.18 g, 5.28 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.96 g, 5.15 mmol) were added to a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (1.00 g, 4.29 mmol) in DMF (20.0 mL), followed by N,N-diisopropylethylamine (3.74 mL, 21.5 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, and the residue was dissolved in EtOAc and washed with water (1×) and brine (1×). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. Assuming complete conversion, the crude residue could be further purified without further purification: ES / MS m / z: 441.2 (M+H) + ).

[0485] 2-[(4-bromo-2-fluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid methyl ester (I-2)The crude product from the previous step, methyl 4-{[2-(4-bromo-2-fluoro-phenyl)acetyl]amino}-3-(2-methoxyethylamino)benzoate (1.89 g, 4.29 mmol), was dissolved in AcOH (40.0 mL), and the mixture was heated to 60 °C and held for 2 hours. The mixture was concentrated under vacuum, and the crude residue was dissolved in DCM and washed with saturated sodium bicarbonate aqueous solution. The layers were separated, and the aqueous layer was extracted with DCM (2×). The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by column chromatography (0%–100% EtOAc / hexane) to give the title compound: ES / MS m / z: 421.9 (M+H + ).

[0486] Preparation of intermediate I-3 :

[0487]

[0488] 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (I-3) 3-Fluoro-4-(hydroxymethyl)benzonitrile (2 g, 13.2 mmol) was added to 100 mL of dry RBF. The substance was dissolved in anhydrous THF (20 mL) at 0 °C under a nitrogen atmosphere. Sodium hydride (60% dispersion in mineral oil, 0.507 g, 13.2 mmol) was added in one step, and the mixture was stirred at 0 °C under N2 for 30 minutes. Then 2,6-dibromopyridine (3.13 g, 13.2 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (100 mL) and water (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (eluent: EtOAc / hexane) to give intermediate I-6: ES / MS: 307.058 (M+H). + ); 1 ¹H NMR (400MHz, chloroform-d) δ 7.72–7.63 (m, 1H), 7.52–7.46 (m, 2H), 7.41 (dd, J = 9.2, 1.5 Hz, 1H), 7.14 (dd, J = 7.5, 0.7 Hz, 1H), 6.79 (dd, J = 8.2, 0.7 Hz, 1H), 5.50 (t, J = 0.9 Hz, 2H).

[0489] Preparation of intermediate I-4 :

[0490]

[0491] (S)-4-amino-3-((oxetane-2-ylmethyl)amino)methyl benzoate (I-4)Following the procedure for intermediate I-1, methyl (S)-4-amino-3-((oxetane-2-ylmethyl)amino)benzoate was prepared by replacing 2-methoxyethylamine with (S)-oxetane-2-ylmethylamine. ES / MS: 237.2 (M+H) + ).

[0492] Intermediate I-5

[0493]

[0494] Ethyl 3,5-difluoro-4-nitrobenzoate Ethyl 4-amino-3,5-difluorobenzoate (5.00 g, 24.9 mmol) was dissolved in acetic acid (50.0 mL), followed by the addition of sulfuric acid (12.1 M, 2.05 mL, 24.9 mmol) and hydrogen peroxide (30% aqueous solution, 46.7 mL, 74.6 mmol). The mixture was heated to 100 °C for 1 hour. The mixture was then cooled to room temperature and slowly poured into 300 mL of ice water while rotating. The mixture was then diluted with EtOAc (200 mL), transferred to a separatory funnel, and the organic phase was collected. The aqueous phase was extracted with EtOAc (2 × 100 mL), and the combined organic matter was dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography (elution: EtOAc / hexane gradient) to obtain the product.

[0495] Ethyl (S)-3-fluoro-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate Ethyl 3,5-difluoro-4-nitrobenzoate (2.50 g, 10.8 mmol) and (S)-oxetane-2-ylmethylamine (989 mg, 11.4 mol) were dissolved in tetrahydrofuran (12.0 mL) and N,N-dimethylformamide (6.0 mL), and N,N-diisopropylethylamine (9.42 mL, 54.1 mmol) was added. The mixture was heated to 50 °C for 16 hours. Subsequently, the mixture was concentrated under vacuum, and the residue was purified by column chromatography (elution: 0%-25% EtOAc / hexane) to give the product. ES / MS: 299.2 (M+H) + ).

[0496] (S)-4-amino-3-fluoro-5-((oxetanebut-2-ylmethyl)amino)ethyl benzoate (I-5)Ethyl (S)-3-fluoro-4-nitro-5-((oxetanebut-2-ylmethyl)amino)benzoate (2.20 g, 7.38 mmol) was dissolved in ethanol (10 mL) and tetrahydrofuran (5 mL), and the mixture was bubbled under nitrogen for 5 min. Then, carbon-supported palladium (10 wt%, 785 mg, 0.74 mmol) was added and bubbling continued for 5 min. Hydrogen was then bubbled through the solution for one minute, and the mixture was placed in a hydrogen atmosphere balloon for 21 h. Afterward, the reaction was stopped, and the mixture was filtered through a Celite filter. The filter was washed with EtOAc (2 × 20 mL) and methanol (2 × 10 mL), and the filtrate was concentrated under vacuum to give ethyl (S)-4-amino-3-fluoro-5-((oxetanebut-2-ylmethyl)amino)benzoate (I-5). ES / MS: 269.2 (M+H) + ); 1 ¹H NMR (400MHz, chloroform) δ 7.44–7.30 (m, 2H), 5.13 (qd, J = 7.1, 3.4 Hz, 1H), 4.72 (ddd, J = 8.7, 7.4, 6.0 Hz, 1H), 4.62 (dt, J = 9.1, 6.1 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.58–3.30 (m, 2H), 2.76 (dtd, J = 11.4, 8.0, 6.1 Hz, 1H), 2.56 (ddt, J = 11.3, 9.0, 7.1 Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H).

[0497] Preparation of intermediate I-6 :

[0498]

[0499] 3-((2-methoxyethyl)amino)-4-nitrobenzene tert-butyl ester 10 g (41.5 mmol) of tert-butyl 3-fluoro-4-nitrobenzoate was added to 500 mL of RBF. The substance was dissolved in THF (150 mL), and 2-methoxyethylamine (7.2 mL, 82.9 mmol) and N,N-diisopropylethylamine (21.7 mL, 124 mmol) were added. The mixture was stirred overnight at 50 °C. The mixture was then concentrated to remove most of the THF, and the crude substance was dissolved in EtOAc (400 mL). The organic matter was washed with 50% NH4Cl (2 × 100 mL) and brine (1 × 50 mL). The organic matter was then dried over MgSO4, filtered, and concentrated under reduced pressure. The crude substance could be further purified without further purification: ES / MS: 297.1 (M+H) + ); 1¹H NMR (400 MHz, chloroform-d) δ 8.21 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.20 (dd, J = 8.9, 1.7 Hz, 1H), 3.72 (dd, J = 5.8, 4.8 Hz, 2H), 3.57 (q, J = 5.2 Hz, 2H), 3.46 (s, 3H), 1.62 (s, 9H).

[0500] 4-Amino-3-((2-methoxyethyl)amino)tert-butyl benzoate (I-6) Add tert-butyl 3-((2-methoxyethyl)amino)-4-nitrobenzoate (13 g, 43.9 mmol), ethanol (100 mL), and EtOAc (50 mL) to 1 L RBF. Stir the mixture and sonicate until all substances are dissolved. Bubble nitrogen through the mixture for 5 minutes, then add carbon-supported palladium (10 wt%, 2.33 g, 2.19 mmol). Bubble hydrogen through the mixture for 5 minutes and stir overnight under a hydrogen balloon. Then bubble nitrogen through the flask for 10 minutes, and then filter the mixture through a Celite filter to remove the catalyst. Concentrate the filtrate under reduced pressure, and it is ready for use without further purification: ES / MS: 267.2 (M+H). + ).

[0501] Preparation of intermediate I-7 :

[0502]

[0503] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)methyl acetate A suspension of methyl 2-(4-bromo-2,5-difluorophenyl)acetate (10.5 g, 39.6 mmol), bis(neopentylethylene glycol)diboron (17.9 g, 79.2 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride; PdCl2(dppf) (2.94 g, 3.96 mmol) and potassium propionate (15.6 g, 139 mmol) in dioxane (50 mL) was degassed with Ar for 20 minutes. The mixture was sealed and heated at 100 °C for 2 hours. Sodium carbonate (2.0 M, 39.6 mL, 79.2 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Add [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride; PdCl2 (dppf) (1.47 g, 1.98 mmol) and I-3 (14 g, 45.6 mmol), degas the mixture with Ar for 10 min, then seal and heat at 100 °C for 1 h. Dilute the mixture with EtOAc and wash with brine. Dry the organic extract with sodium sulfate and separate by chromatography (eluent: EtOAc / hexane) to give the title product: ES / MS: 413.2 (M+H) + ).

[0504] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetic acid (I-7) A solution of methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetate (12.5 g, 30.3 mmol) and lithium hydroxide (0.2 M, 19.7 mL, 39.4 mmol) in CH3CN (50 mL) was heated at 50 °C for 2 hours. The mixture was acidified to pH 6-7 with 1 N hydrochloride. The precipitate was filtered through a filter funnel. The solid was washed with water and dried overnight to give the product: ES / MS: 399.2 (M+H) + ); 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.83–7.77 (m, 1H), 7.78–7.65 (m, 2H), 7.64–7.59 (m, 2H), 7.58–7.51 (m, 1H), 7.26–7.14 (m, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.63 (s, 2H), 3.73 (d, J = 1.2 Hz, 2H).

[0505] Preparation of intermediate I-8 :

[0506]

[0507] (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid Methyl ester (I-8) Following the procedure for intermediate I-2, (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester was prepared by replacing I-1 with I-4 and 2-(4-bromo-2,5-difluorophenyl)acetic acid instead of 2-(4-bromo-2-fluorophenyl)acetic acid. ES / MS: 451.0, 453.0 (M+H) + ).

[0508] Preparation of intermediate I-9 :

[0509]

[0510] (S)-2-(4-(6-(benzyloxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetane-2-ylmethyl)- 1H-Benzo[d]imidazol-6-carboxylic acid methyl esterMethyl (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (I-8) (450 mg, 0.997 mmol), Pd(dppf)Cl2 (74.0 mg, 0.100 mmol), potassium propionate (336 mg, 2.99 mmol), and bis(pinacol)diboron (304 mg, 2.99 mmol) were dissolved in 1,4-dioxane (4.00 mL), and the mixture was bubbled with argon for 5 minutes. The mixture was then heated to 110 °C for 1 hour. After this, complete conversion to the intermediate borate ester was observed. The mixture was cooled to room temperature, and an aqueous solution of sodium carbonate (2.0 M, 0.997 mL, 1.99 mmol) was added. The mixture was stirred for 5 minutes, then 2-(benzyloxy)-6-bromopyridine (290 mg, 1.10 mmol) and Pd(dppf)Cl2 (37.0 mg, 0.050 mmol) were added, and the mixture was heated to 90 °C for 1 hour. The mixture was then directly loaded onto SiO2 for purification by normal-phase chromatography (elution buffer: EtOAc / CH2Cl2 gradient) to obtain the desired product. ES / MS: 556.2 (M+H) + )

[0511] (S)-2-(2,5-Difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetane-2-ylmethyl)-1H-benzyl [d]imidazolium-6-carboxylic acid methyl ester (I-9) Methyl (S)-2-(4-(6-(benzyloxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (426.0 mg, 0.767 mmol) was dissolved in ethanol (6.0 mL) and tetrahydrofuran (3.0 mL), and the solution was bubbled with nitrogen for 5 minutes. Pd / C (408 mg, 0.383 mmol) was added, and nitrogen was bubbled through the suspension for another 5 minutes. Then hydrogen was bubbled through the solution for 5 minutes, and the mixture was placed under a hydrogen atmosphere balloon. The mixture was stirred at room temperature for 30 minutes. After that, the suspension was filtered through Celite and washed with EtOAc (3 × 10 mL). The filtrate was concentrated under vacuum to give (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-9). ES / MS: 466.2 (M+H) + )

[0512] Preparation of intermediate I-10 :

[0513]

[0514] 2-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl]-3- (2-Methoxyethyl)benzimidazole-5-carboxylic acid methyl ester (I-10)Add methyl 2-[(4-bromo-2-fluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-2) (200 mg, 0.475 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentanane (145 mg, 0.570 mmol), (1,1'-bis(diphenylphosphine)ferrocene)-palladium(II) dichloride (33.6 mg, 0.0475 mmol), and potassium acetate (0.140 g, 1.42 mmol) to a vial. Then, add 4.80 mL of 1,4-dioxane and heat the mixture to 100 °C for 24 hours. Filter the mixture through a Celite filter, elute with DCM, and concentrate the filtrate under vacuum. The crude residue was purified by column chromatography (0-100% EtOAc / hexane) to obtain methyl 2-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid (I-10). ES / MS m / z: 469.4 (M+H) + )

[0515] Preparation of intermediate I-11 :

[0516]

[0517] 2-(2,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzyl)-1-(2- Methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester (I-11) Following the method described for intermediate I-10, 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester was prepared by replacing 2-(4-bromo-2,5-difluorophenyl)acetic acid with 2-(4-bromo-2-fluorophenyl)acetic acid and replacing methyl 4-amino-3-((2-methoxyethyl)amino)benzoate with tert-butyl 4-amino-3-(2-methoxyethyl)amino)benzoate (I-6). ES / MS: 529.3 (M+H) + ); 1 HNMR (400MHz, DMSO-d) 6)δ8.13(s,1H),7.74(dd,J=8.4,1.6Hz,1H),7.56(d,J=8.4Hz,1H),7.33(dd,J=9.3,4.6Hz,1H),7.17(dd,J=9.1 ,5.5Hz,1H),4.54(t,J=5.1Hz,2H),4.39(s,2H),3.65(t,J=5.1Hz,2H),3.20(s,3H),1.57(s,9H),1.31(s,12H).

[0518] Preparation of intermediate I-12 :

[0519]

[0520] 2-[[4-(6-chloropyridin-2-yl)-2,5-difluorophenyl]methyl]-3-(2-methoxyethyl)-1,3-benzodimethyl tert-butyl azole-5-carboxylate (I-12) 2-[[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl]-3-(2-methoxyethyl)-1,3-benzodiazole-5-carboxylic acid tert-butyl ester (I-11) (30.0 g, 56.7 mmol, 1.00 equivalent) and 2-bromo-6-chloropyridine (14.2 g, 73.8 mmol, 1.30 equivalent) were dissolved in 1,4-dioxane (600 mL) and H₂O (60 mL). Pd(dppf)Cl₂ (4.15 g, 5.68 mmol, 0.1 equivalent) and K₂CO₃ (15.7 g, 114 mmol, 2.0 equivalent) were added dropwise to this solution. The resulting solution was heated to 90 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (2 / 1) to give 2-[[4-(6-chloropyridin-2-yl)-2,5-difluorophenyl]methyl]-3-(2-methoxyethyl)-1,3-benzodiazole-5-carboxylic acid tert-butyl ester (I-12). ES / MS: 513.8 (M+H) + ); 1 H NMR (400MHz, DMSO-d) 6 )δ8.14(s,1H),8.02(t,J=7.9Hz,1H),7.87(d,J=7.7Hz,1H),7.78 -7.69(m,2H),7.59(d,J=8.2Hz,2H),7.41(dd,J=11.4,6.0Hz,1H),4.58(t, J=5.1Hz,2H),4.44(s,2H),3.68(t,J=5.1Hz,2H),3.22(s,3H),1.58(s,9H).

[0521] Preparation of intermediate I-13 :

[0522]

[0523] (S)-4-(2-(4-bromo-2-fluorophenyl)acetamido)-3-fluoro-5-((oxetane-2-ylmethyl)amino)benzene Ethyl formate A solution of I-5 (500 mg, 1.86 mmol) and 2-(4-bromo-2-fluorophenyl)acetic acid (521 mg, 2.24 mmol) in MeCN (9.0 mL) was cooled to 0 °C, and 1-methylimidazole (765 mg, 0.74 mL, 9.32 mmol) was added, followed by N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (732 mg, 2.61 mmol). The mixture was heated to RT and stirred for 30 minutes. The crude mixture was concentrated under vacuum and then partitioned between water and EtOAc. The organic layer was separated and washed with a separate portion of water, followed by washing with brine. The separated organic layer was dried over sodium sulfate, separated by vacuum filtration, concentrated under vacuum, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to obtain (S)-4-(2-(4-bromo-2-fluorophenyl)acetamido)-3-fluoro-5-((oxetane-2-ylmethyl)amino)benzoate. ES / MS: 483.0, 485.0 [M+H] + .

[0524] (S)-2-(4-bromo-2-fluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid Ethyl acetate (I-13) Acetic acid (1.88 mL, 32.9 mmol) was added to a solution of (S)-4-(2-(4-bromo-2-fluorophenyl)acetamyl)-3-fluoro-5-((oxetane-2-ylmethyl)amino)benzoate (530 mg, 1.10 mmol) in DCE (12.0 mL). The mixture was heated to 60 °C for 12 hours. The mixture was concentrated and partitioned between EtOAc and a saturated aqueous sodium bicarbonate solution. The organic layer was separated and dried over sodium sulfate, separated by vacuum filtration, concentrated under vacuum, and purified by silica gel column chromatography (elution: EtOAc / hexane) to give (S)-2-(4-bromo-2-fluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid ethyl ester (I-13). ES / MS: 465.0, 467.0 [M+H] + .

[0525] Preparation of intermediate I-14 :

[0526]

[0527] (S)-2-(4-bromo-2,5-difluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol- Ethyl 6-carboxylate (I-14)Following the method described for intermediate I-13, (S)-2-(4-bromo-2,5-difluorophenyl)acetic acid was used instead of 2-(4-bromo-2-fluorophenyl)acetic acid to prepare (S)-2-(4-bromo-2,5-difluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid ethyl ester. ES / MS: 483.0, 485.0 (M+H) + ).

[0528] Preparation of intermediate I-15 :

[0529]

[0530] (S)-2-(2,5-Difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-fluoro-1-(oxetane-2-ylmethyl)- 1H-Benzo[d]imidazolium-6-carboxylic acid ethyl ester (I-15) Following the method described for intermediate I-9, (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-fluoro-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid ethyl ester was prepared by replacing I-8 with I-14. ES / MS: 498.2 (M+H) + ).

[0531] Preparation of intermediate I-16 :

[0532]

[0533] (S)-2-(4-(6-chloropyridin-2-yl)-2,5-difluorobenzyl)-1-(oxecyclobut-2-ylmethyl)-1H-benzo[ [d]Imidazole-6-carboxylic acid methyl ester (I-16) Following the method described for intermediate I-12, (S)-2-(4-(6-chloropyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester was prepared by replacing I-6 with I-4. ES / MS: 484.0 (M+H) + ).

[0534] Preparation of intermediate 17 :

[0535]

[0536] 2-(2,5-Difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazol- 6-Tertiary butyl carboxylate (I-17)2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester was prepared using 2-(4-bromo-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester (prepared using 2-(4-bromo-2,5-difluorophenyl)acetic acid instead of 2-(4-bromo-2-fluorophenyl)acetic acid, as described for intermediate I-9) and I-6 instead of I-1. ES / MS: 496.9 (M+H) + ).

[0537] Preparation of intermediate I-18 :

[0538]

[0539] 2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl) 1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester (I-18) Add 4-bromo-1-(bromomethyl)-2-fluorobenzene (406 mg, 1.5 mmol) and silver carbonate (835 mg, 3 mmol) to a solution of 2-[[2,5-difluoro-4-(6-hydroxy-2-pyridyl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid tert-butyl ester (I-17) (500 mg, 1.0 mmol) in toluene (5 mL). Stir the solution at 70 °C for 8 hours, cool, and filter. The solution was concentrated and purified by silica gel column chromatography (elution buffer: EtOAc / hexane) to give 2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester (I-18): ES / MS: 683.2, 684.1 (M+H) + ).

[0540] Preparation of intermediate I-19 :

[0541]

[0542] (S)-2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxoheterocyclic) Butylated 2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-19) Following the description for intermediate I-18, (S)-2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester was prepared by replacing I-17 with I-9. ES / MS: 652.3 (M+H) + ).

[0543] Preparation of intermediate I-20 :

[0544]

[0545] (S)-2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-fluoro-1-(oxy) Heterocyclic butyl-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid ethyl ester (I-20) Following the description for intermediate I-18, (S)-2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-fluoro-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid ethyl ester was prepared by replacing I-17 with I-15. ES / MS: 684.2 (M+H) + ).

[0546] Preparation of intermediate I-21 :

[0547]

[0548] (S)-2-(4-(6-((5-bromothiazo-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxoheterocyclic) Butylated-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-21) Cesium carbonate (560 mg, 1.72 mmol) and 5-bromo-2-(bromomethyl)thiazole (290 mg, 1.13 mmol) were added to a solution of (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-9) (500 mg, 1.07 mmol) in acetonitrile (15 mL), and the resulting mixture was stirred at 50 °C for 1 hour. After completion, the crude mixture was filtered through a Celite filter and washed with DCM. The filtrate was concentrated, and the crude residue was purified by silica gel column chromatography (elution: EtOAc / hexane) to give (S)-2-(4-(6-((5-bromothiazol-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-21). ES / MS: 643.0 (M+H) + ).

[0549] Preparation of intermediate I-22 :

[0550]

[0551] (S)-2-(4-(6-((5-bromothiazo-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-fluoro-1- (oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (I-22) Following the method described for intermediate I-21, (S)-2-(4-(6-((5-bromothiazol-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-fluoro-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid ethyl ester was prepared by replacing I-17 with I-15. ES / MS: 673.0 (M+H) + ).

[0552] Preparation of intermediate I-23 :

[0553]

[0554] (S)-2-(4-(6-((6-chloro-4-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1- (oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-23) Following the method described for intermediate I-19, (S)-2-(4-(6-((6-chloro-4-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester was prepared by replacing 4-bromo-1-(bromomethyl)-2-fluorobenzyl with 5-(bromomethyl)-2-chloro-4-fluoropyridine. ES / MS: 609.2 (M+H) + ).

[0555] Preparation of intermediate I-24 :

[0556]

[0557] (S)-2-(4-(6-((6-bromo-4-chloropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1- (oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-24) Following the method described for intermediate I-19, (S)-2-(4-(6-((6-bromo-4-chloropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester was prepared by replacing 4-bromo-1-(bromomethyl)-2-fluorobenzyl with 2-bromo-5-(bromomethyl)-4-chloropyridine. ES / MS: 654.0, 656.0 (M+H) + ).

[0558] Preparation of intermediate I-25 :

[0559]

[0560] 4-Amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)methyl benzoate (I-25)Following the method described for intermediate I-1, methyl 4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate was prepared by replacing 2-methoxyethylamine with (±)-4,4-dimethyltetrahydrofuran-3-amine as follows: Under argon, DIPEA (17.2 mL, 98.9 mmol) was added to a solution of methyl 3-fluoro-4-nitro-benzoate (3.94 g, 19.8 mmol) and 4,4-dimethyltetrahydrofuran-3-amine hydrochloride (3.00 g, 19.8 mmol) in 40 mL of 2-methyltetrahydrofuran. The resulting solution was refluxed at 80 °C for 3 days. The mixture was concentrated under vacuum and partitioned between EtOAc and water. The aqueous phase was extracted with additional EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The resulting residue was redissolved under argon in EtOH (52 mL) and tetrahydrofuran (26 mL), followed by 10% carbon-supported palladium (2.1 g, 1.98 mmol). The mixture was circulated between argon and vacuum, then placed under hydrogen atmosphere and stirred at room temperature for 18 hours. The mixture was filtered through a Celite filter and concentrated under vacuum. The crude product was purified by silica gel rapid column chromatography (EtOAc / hexane gradient) to give methyl 4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate (intermediate I-25). ES / MS: 265.2 (M+H) + ).

[0561] Preparation of intermediate I-26 :

[0562]

[0563] (R)-4-amino-3-((2-methoxypropyl)amino)tert-butyl benzoate (I-26) Following the method described for intermediate I-6, (R)-4-amino-3-((2-methoxypropyl)amino)tert-butyl benzoate was prepared by replacing 2-methoxyethylamine with (R)-2-methoxypropyl-1-amine. ES / MS: 281.1 (M+H) + ).

[0564] Preparation of intermediate I-27 :

[0565]

[0566] methyl 5-(((6-bromopyridin-2-yl)oxy)methyl)pyridinecarboxylateTo a solution of 6-bromopyridin-2-ol (3.00 g, 17 mmol) in acetonitrile (100 mL), silver carbonate (10.2 g, 37 mmol) and methyl 5-(bromomethyl)pyridin-2-carboxylic acid (5.00 g, 22 mmol) were added, and the resulting mixture was heated to 60 °C for 3 hours. After completion, the mixture was filtered through a Celite filter, concentrated, and purified by silica gel column chromatography (elution: EtOAc / hexane) to obtain the desired product. ES / MS: 325.2 (M+H) + ).

[0567] 5-(((6-bromopyridin-2-yl)oxy)methyl)pyridinecarboxylic acid (I-27) A solution of lithium hydroxide (2.17 g, 51.7 mmol) in water (25 mL) was added to a solution of methyl 5-(((6-bromopyridin-2-yl)oxy)methyl)pyridinecarboxylate (5.57 g, 17 mmol) in acetonitrile (75 mL), and the mixture was stirred at room temperature for 1 hour. The pH was adjusted to approximately 6 with 1 N HCl, and the mixture was then diluted with EtOAc (200 mL) and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give 5-(((6-bromopyridin-2-yl)oxy)methyl)pyridinecarboxylic acid (I-27), which required no further purification. ES / MS: 309.1 (M+H + ).

[0568] Preparation of intermediate I-28 :

[0569]

[0570] 5-(((6-bromopyridin-2-yl)oxy)methyl)-N-(1-cyanocyclopropyl)pyridinecarboxamide (I-28) To a solution of 5-(((6-bromopyridin-2-yl)oxy)methyl)pyridinecarboxylic acid (I-27) (5.32 g, 17 mmol) in DMF (80 mL), 1-aminocyclopropanecarboxynitrile hydrochloride (3.14 g, 26 mmol), HATU (9.62 g, 25 mmol), and diisopropylethylamine (12 mL, 69 mmol) were added sequentially. The resulting solution was stirred at room temperature for 30 minutes. After completion, the mixture was diluted with EtOAc (250 mL), washed with water (2 × 50 mL) and brine (1 × 40 mL), dried over MgSO4, filtered, and concentrated to give 5-(((6-bromopyridin-2-yl)oxy)methyl)-N-(1-cyanocyclopropyl)pyridinecarboxamide (I-28), which required no further purification. ES / MS: 375.1 (M+H + ).

[0571] The following intermediates shall be synthesized in a manner similar to that described for intermediate I-28:

[0572]

[0573] Preparation of intermediates I-29 and I-30 :

[0574]

[0575] 4-Amino-3-(((3aS,6aR)-hexahydrofurano[2,3-b]furan-3-yl)amino)tert-butyl benzoate (I- 29 and I-30) :

[0576] 3-(((3aS,6aR)-hexahydrofurano[2,3-b]furan-3-yl)amino)-4-nitrobenzoate tert-butyl ester A solution of tert-butyl 3-fluoro-4-nitrobenzoate (0.150 g, 0.622 mmol), (3aS,6aR)-2,3,3a,4,5,6a-hexahydrofurano[2,3-b]furan-4-amine (0.0984 g, 0.762 mmol), and N-ethyl-N-isopropyl-propyl-2-amine (0.325 mL, 1.87 mmol) in NMP (4 mL) was heated overnight at 90 °C. The mixture was diluted with EtOAc and washed with 5% LiCl and brine. The organic extract was dried over sodium sulfate and purified by rapid chromatography (eluent: EtOAc / hexane) to give tert-butyl 3-(((3aS,6aR)-hexahydrofurano[2,3-b]furan-3-yl)amino)-4-nitrobenzoate as an inseparable mixture of the two compounds. ES / MS: 351.0 (M+H) + ).

[0577] 4-Amino-3-(((3aS,6aR)-hexahydrofurano[2,3-b]furan-3-yl)amino)tert-butyl benzoate (I- 29 and I-30) The mixture was degassed by circulating a solution of 3-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofurano[2,3-b]furan-4-yl]amino]-4-nitrobenzoate tert-butyl ester (156 mg, 0.445 mmol) in EtOH (15 mL) three times between argon and vacuum. Pd / C (10.0%, 47.4 mg, 0.0445 mmol) was added to the solution, and the solution was degassed once by circulating the mixture between argon and vacuum, and stirred overnight at room temperature using a hydrogen balloon. The mixture was filtered through a diatomaceous earth stopper and washed with EtOAc. Concentration and purification by rapid chromatography (elution buffer: 30% to 40% EtOAc / hexane) yielded two different isomers (I-29 and I-) of tert-butyl benzoate, 4-amino-3-(((3aS,6aR)-hexahydrofurano[2,3-b]furan-3-yl)amino)benzoate.

[0578] Isomer 1 (less polar, eluted first), I-29

[0579] ES / MS: 321.0 (M+H) +¹H NMR (400MHz, chloroform-d) δ 7.45 (dd, J = 8.1, 1.8 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 5.87 (d, J = 5.1 Hz, 1H), 4.32–4.06 (m, 2H), 4.05–3.81 (m, 2H), 3.66 (t, J = 8.7 Hz, 1H), 3.24 (tt, J = 8.7, 4.2 Hz, 1H), 2.03–1.90 (m, 1H), 1.90–1.79 (m, 1H), 1.60 (s, 9H).

[0580] Isomer 2 (more polar, eluted second), I-30

[0581] ES / MS: 321.0 (M+H) + ).1H NMR (400MHz, chloroform-d) δ7.45(dd,J=8.1,1.8Hz,1H),7.38(d,J=1.8Hz,1H),6.75(d,J=8.0Hz,1H),5.87(d,J=5.1Hz,1H),4. 34-4.05(m,2H),4.02-3.82(m,2H),3.67(t,J=8.6Hz,1H),3.24(tt,J=8.6,4.2Hz,1H),2.02-1.81(m,2H),1.60(s,9H).

[0582] Preparation of intermediate I-31 :

[0583]

[0584] 4-Methylbenzenesulfonic acid (5-bromo-3-fluoropyridin-2-yl) methyl ester (I-31) (5-Bromo-3-fluoro-2-pyridyl)methanol (200 mg, 0.97 mmol), p-toluenesulfonic anhydride (350 mg, 1.1 mmol), diisopropylethylamine (0.34 mL, 1.9 mmol), and DCM (10 mL) were combined and stirred at ambient temperature for 16 hours. After completion, the mixture was washed with saturated NaHCO3 aqueous solution (5 mL) and brine (5 mL), dried over MgSO4, filtered, and concentrated to obtain methyl 4-methylbenzenesulfonic acid (5-bromo-3-fluoropyridyl-2-yl) ester (I-31), which can be used without further purification.

[0585] ES / MS

[0586] The following intermediates were prepared in accordance with the manner described for intermediate I-31:

[0587]

[0588] Preparation of intermediate I-32 :

[0589]

[0590] 4-Methylbenzenesulfonic acid (5-chloropyrazine-2-yl) methyl ester (I-32) : 4-methylbenzenesulfonic acid (5-chloropyrazine-2-yl) methyl ester was prepared by replacing (5-bromo-3-fluoro-2-pyridyl) methanol with (5-chloropyrazine-2-yl) methanol in the manner described for intermediate I-31.

[0591] Preparation of intermediate I-33 :

[0592]

[0593] 2-[[4-[6-[(5-bromo-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]- 3-(2-Methoxyethyl)benzimidazole-5-carboxylic acid tert-butyl ester (I-33) Cs₂CO₃ (400 mg, 1.20 mmol) was added to a solution of 2-[[2,5-difluoro-4-(6-hydroxy-2-pyridyl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid tert-butyl ester (I-17) (400 mg, 0.80 mmol) and 4-methylbenzenesulfonic acid (5-bromo-3-fluoro-2-pyridyl)methyl ester (I-31) (350 mg, 0.97 mmol) in 15 mL of acetonitrile. The solution was then heated to 50 °C for 30 minutes. The solution was cooled to room temperature, filtered, and then concentrated. The crude substance was purified by silica gel column chromatography (elution buffer: EtOAc / hexane) to obtain 2-[[4-[6-[(5-bromo-3-fluoro-2-pyridinyl)methoxy]-2-pyridinyl]-2,5-difluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid tert-butyl ester (I-33): product. ES / MS: 686.0 (M+H) + ).

[0594] Preparation of intermediate I-34 :

[0595]

[0596] 2-[[4-[6-[(5-chloropyrazin-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-(2- Methoxyethyl)benzimidazole-5-carboxylic acid tert-butyl ester (I-34) Following the description for intermediate I-33, 2-[[4-[6-[(5-chloropyrazin-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid tert-butyl ester was prepared by replacing I-32 with I-31. ES / MS: 566.0 (M+H) + ).

[0597] Preparation of intermediate I-35 :

[0598]

[0599] 4-Fluoro-5-(hydroxymethyl)thiophene-2-carboxynitrile The (5-bromo-3-fluoro-2-thienyl)methanol (220 mg, 1.04 mmol), zinc cyanide (182 mg, 1.55 mmol), zinc powder (3 mg, 0.05 mmol), and Pd(PPh3)4 (300 mg, 0.26 mmol) in DMF (10 mL) were degassed by purging with argon for 1 minute, sealed, and heated to 100 °C for 20 hours. Afterward, the mixture was poured into H2O (10 mL) and extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (5 mL), dried over MgSO4, filtered, concentrated, and purified by rapid chromatography (eluent: EtOAc / hexane) to give 4-fluoro-5-(hydroxymethyl)thien-2-carboxynitrile. ES / MS: 158.2 (M+1).

[0600] 5-(bromomethyl)-4-fluoro-thiophene-2-carboxynitrile (I-35) Carbon tetrabromide (111 mg, 0.34 mmol) was added to a solution of DCM (3 mL) containing 4-fluoro-5-(hydroxymethyl)thiophene-2-carboxynitrile (48 mg, 0.31 mmol) and triphenylphosphine (88 mg, 0.34 mmol). The mixture was stirred at room temperature for 30 minutes. After stirring, the mixture was concentrated and purified by rapid chromatography (elution: EtOAc / hexane) to give 5-(bromomethyl)-4-fluoro-thiophene-2-carboxynitrile (I-35). ES / MS: 221.2 (M+1).

[0601] Preparation of intermediate I-36 :

[0602]

[0603] [5-(difluoromethyl)thiazolyl-2-yl]methanolOxaloyl chloride (2.0 M DCM solution, 0.65 mL, 1.3 mmol) was added to a solution of sodium [5-(difluoromethyl)thiazol-2-carbonyl]oxy (200 mg, 1.08 mmol) in DCM (5 mL) at room temperature. After stirring at room temperature for 1 hour, MeOH (1 mL) was added, and the mixture was stirred for another 30 minutes. Then, it was poured into H2O (10 mL) and extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (5 mL), dried over MgSO4, filtered, and concentrated. The residue was redissolved in THF (5 mL) and cooled to 0 °C. Diisobutylaluminum hydride (1.0 M DCM solution, 3.3 mL, 3.3 mmol) was added, and the mixture was warmed to room temperature and stirred for 1 hour. After completion, the reaction system was quenched with 2 M NaOH (0.4 mL) and H2O (0.4 mL) and diluted with EtOAc (10 mL). The mixture was then filtered through a Celite stopper. The organic layers were combined, washed with brine (5 mL), dried over MgSO4, filtered, concentrated, and purified by rapid chromatography (eluent: EtOAc / hexane) to obtain the desired product. ES / MS: 166.2 (M+1).

[0604] 2-(bromomethyl)-5-(difluoromethyl)thiazole (I-36) Carbon tetrabromide (190 mg, 0.56 mmol) was added to [5-(difluoromethyl)thiazol-2-yl]methanol (88 mg, 0.53 mmol) and triphenylphosphine (150 mg, 0.56 mmol) in DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. After completion, the mixture was concentrated and purified by rapid chromatography (elution: EtOAc / hexane) to give I-36. ES / MS: 229.2 (M+1).

[0605] Preparation of intermediate I-37 :

[0606]

[0607] [5-(2,2-difluoroethoxy)thiazolyl-2-yl]methanolA suspension of methyl 5-hydroxythiazol-2-carboxylate (200 mg, 1.3 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (300 mg, 1.4 mmol), and cesium carbonate (610 mg, 1.9 mmol) in MeCN (5 mL) was stirred at room temperature for 16 hours. Afterward, the mixture was filtered through a Celite stopper and concentrated. The residue was redissolved in THF (5 mL) and cooled to 0 °C. Diisobutylaluminum hydride (1.0 M DCM solution, 2.8 mL, 2.8 mmol) was added, and the mixture was warmed to room temperature and stirred for 1 hour. Afterward, the reaction system was quenched with 2 M NaOH (0.4 mL) and H₂O (0.4 mL) and diluted with EtOAc (10 mL). The mixture was then filtered through a Celite stopper. The organic layers were combined, washed with brine (5 mL), dried over MgSO4, filtered, concentrated, and purified by rapid chromatography (eluent: EtOAc / hexane) to obtain the desired product.

[0608] 2-(bromomethyl)-5-(2,2-difluoroethoxy)thiazole (I-37) Carbon tetrabromide (160 mg, 0.48 mmol) was added to [5-(2,2-difluoroethoxy)thiazol-2-yl]methanol (91 mg, 0.47 mmol) and triphenylphosphine (125 mg, 0.48 mmol) in DCM (5 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. After completion, the mixture was concentrated and purified by rapid chromatography (elution buffer: EtOAc / hexane) to give I-37. ES / MS: 258.2 (M+1).

[0609] Preparation of intermediate I-38 :

[0610]

[0611] 2-(bromomethyl)-5-(2,2,2-trifluoroethoxy)thiazole (I-38) 2-(bromomethyl)-5-(2,2,2-trifluoroethoxy)thiazole was prepared by replacing 2,2,2-trifluoroethyl trifluoromethanesulfonate with 2,2-difluoroethyl trifluoromethanesulfonate, as described for intermediate I-37. ES / MS: 277.2 (M+1).

[0612] Preparation of intermediate I-39 :

[0613]

[0614] (S)-2-(4-(6-((5-bromothiophen-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxoheterocyclic) Butylated 2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-39)Following the method described for intermediate I-19, (S)-2-(4-(6-((5-bromothiophene-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester was prepared by replacing 2-bromo-5-(bromomethyl)thiophene with 5-(bromomethyl)-2-chloro-4-fluoropyridine. ES / MS: 642.0 (M+H) + ).

[0615] Preparation of intermediate I-40 :

[0616]

[0617] (S)-2-(4-(6-((5-bromo-3-fluorothiophen-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1- (oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-40) Following the method described for intermediate I-19, (S)-2-(4-(6-((5-bromo-3-fluorothiophene-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester was prepared by replacing 5-bromo-2-(bromomethyl)-3-fluorothiophene with 5-(bromomethyl)-2-chloro-4-fluoropyridine. ES / MS: 660.0 (M+H) + ).

[0618] Preparation of intermediate I-41 :

[0619]

[0620] 2-[[4-[6-[(5-bromo-1,3,4-thiadiazol-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl [[(2S)-oxetanebut-2-yl]methyl]benzimidazole-5-carboxylic acid methyl ester (I-41) Following the method described for intermediate I-19, methyl 2-[[4-[6-[(5-bromo-1,3,4-thiadiazole-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetanebut-2-yl]methyl]benzimidazole-5-carboxylic acid was prepared by replacing 2-bromo-5-(bromomethyl)-1,3,4-thiadiazole-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetanebut-2-yl]methyl]benzimidazole-5-carboxylic acid with 5-(bromomethyl)-2-chloro-4-fluoropyridine. ES / MS: 660.0 (M+H) + ).

[0621] Preparation of intermediate I-42 :

[0622]

[0623] Thiazolo[5,4-b]pyridin-2-ylmethanolThiazolo[5,4-b]pyridine-2-carboxylic acid methyl ester (100 mg, 0.52 mmol) in THF (5 mL) was cooled to 0 °C. Diisobutylaluminum hydride (1.0 M DCM solution, 1.5 mL, 1.5 mmol) was added, and the mixture was warmed to room temperature and stirred for 1 hour. After completion, the reaction mixture was quenched with 2 M NaOH (0.4 mL), H₂O (0.4 mL), and diluted with EtOAc (10 mL). The mixture was then filtered through a Celite stopper. The organic layers were combined, washed with brine (5 mL), dried over MgSO₄, filtered, concentrated, and purified by rapid chromatography (eluent: EtOAc / hexane) to give the title product. ES / MS: 167.2 (M+1).

[0624] 4-Methylbenzenesulfonic acid thiazo[5,4-b]pyridin-2-ylmethyl ester (I-42) Toluene-4-sulfonyl chloride (46 mg, 0.24 mmol) was added to a solution of thiazo[5,4-b]pyridin-2-ylmethanol (40 mg, 0.24 mmol) and triethylamine (0.07 mL, 0.5 mmol) in DCM (5 mL) at room temperature. The mixture was stirred at room temperature for 20 hours. After completion, the mixture was concentrated and purified by rapid chromatography (elution buffer: EtOAc / hexane) to give the title product. ES / MS: 321.2 (M+1).

[0625] Preparation of intermediate I-43 :

[0626]

[0627] 2-Bromo-6-[(1-Methylimidazol-4-yl)methoxy]pyridine (I-43) Cs₂CO₃ (338 mg, 1.04 mmol) was added to a solution of 2-bromo-6-fluoropyridine (90.7 mg, 0.52 mmol) and (1-methylimidazol-4-yl)methanol (75.1 mg, 0.67 mmol) in 2.0 mL of acetonitrile. The solution was then heated to 50 °C for 30 minutes. The solution was cooled to room temperature, filtered, and then concentrated. The crude substance was purified by normal-phase chromatography (1%–12% DCM / MeOH). The fractions containing the product were combined and concentrated to give the title product. ES / MS m / z: 268.0, 270.2 (M+H) + ).

[0628] The following intermediates shall be synthesized in accordance with the manner described for intermediate I-43:

[0629]

[0630] Preparation of intermediate I-44 :

[0631]

[0632] 2-Bromo-6-[[1-(difluoromethyl)-2-methylimidazol-4-yl]methoxy]pyridine (I-44) The intermediate was prepared using [1-(difluoromethyl)-2-methylimidazol-4-yl]methanol instead of (1-methylimidazol-4-yl)methanol, as described for intermediate I-43. ES / MS m / z: 318.2 (M+H) + ).

[0633] Preparation of intermediate I-45 :

[0634]

[0635] 2-[(7-bromo-1,3-dihydroisobenzofuran-4-yl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid Methyl ester (I-45) The intermediate was prepared in the manner described for intermediate I-13, using 2-(7-bromo-1,3-dihydroisobenzofuran-4-yl)acetic acid instead of (2-(4-bromo-2-fluorophenyl)acetic acid. ES / MS m / z: 447.1 (M+H) + ).

[0636] Preparation of intermediate I-46 :

[0637]

[0638] (3R,4R)-3-(2-amino-5-methoxycarbonyl-aniline)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (I- 46) The intermediate was prepared in the manner described for intermediate I-6, using (3R,4R)-3-amino-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester instead of 2-methoxyethylamine. ES / MS m / z: 418.4 (M+Na) + ).

[0639] Preparation of intermediate I-47 :

[0640]

[0641] N-tert-butoxycarbonyl-N-(6-chloro-2-methylthio-pyrimidin-4-yl)carbamate tert-butyl ester A solution of methylthioalkyl-pyrimidin-4-amine (1 g, 5.7 mmol), tert-butoxycarbonyl-tert-butyl carbonate (2.61 g, 12 mmol), ethyl diisopropylamine (3 mL, 17.1 mmol), and 4-dimethylaminopyridine (140 mg, 1.14 mmol) in 20 mL of DCM was stirred overnight. The mixture was washed with H2O and brine. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by column chromatography (0%–50% EtOAc / hexane) to give the title compound: ES / MS m / z: 375.2 (M+H+).

[0642] N-tert-butoxycarbonyl-N-[6-chloro-2-[(4-cyano-2-fluoro-phenyl)methoxy]pyrimidin-4-yl]carbamic acid tert-butyl ester (I-47)A solution of N-tert-butoxycarbonyl-N-(6-chloro-2-methylthioalkylpyrimidin-4-yl)carbamate tert-butyl ester (0.5 g, 1.33 mmol) and 3-chloroperoxybenzoic acid (0.6 g, 2.7 mmol, 77%) in 5 mL of DCM was stirred overnight. The mixture was washed with H2O and brine. The solvent was removed and the resulting residue was dried under vacuum. The crude product was dissolved in 3 mL of DMF; 3-fluoro-4-(hydroxymethyl)benzonitrile (220 mg, 1.46 mmol) and potassium carbonate (366 mg, 2.65 mmol) were added to this solution, and the mixture was allowed to stand at room temperature for 2 hours. After 2 hours, the resulting solution was diluted with EtOAc (50 mL) and washed with H2O. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by column chromatography (0%-50% EtOAc / hexane) to give the title compound: ES / MS m / z: 479.1 (M+H+).

[0643] Preparation of intermediate I-48 :

[0644]

[0645] 2-[(2,6-dichloro-4-pyridinyl)oxymethoxy]ethyl-trimethyl-silane A solution of 2,6-dichloropyridin-4-ol (1 g, 6.1 mmol), 2-(chloromethoxy)ethyl-trimethylsilane (1.07 g, 6.4 mmol), and bis(trimethylsilyl)aminolithium (6.4 mL, 6.4 mmol) in 10 mL THF was stirred overnight. The solution was washed with H2O and brine. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by column chromatography (0%–50% EtOAc / hexane) to give the title compound: ES / MS m / z: 294.1 (M+H+).

[0646] 4-[(6-chloro-4-hydroxy-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (I-48)3-Fluoro-4-(hydroxymethyl)benzonitrile (0.77 g, 5.1 mmol) and potassium carbonate (0.94 g, 6.8 mmol) were added to a solution of 2-[(2,6-dichloro-4-pyridinyl)oxymethoxy]ethyl-trimethylsilane (1.0 g, 3.4 mmol) dissolved in 5 mL of DMF. The solution was heated to 120 °C for 6 hours. After heating, the solution was diluted with EtOAc (50 mL) and washed with H2O. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude product was dissolved in 2 mL of THF. Tetrabutylammonium fluoride (4.0 mL, 4 mmol) was added to the resulting solution. The mixture was stirred for 3 hours. The solvent was removed, and the resulting residue was purified by column chromatography (0%–80% EtOAc / hexane) to give the title compound: ES / MS m / z: 279.2 (M+H+).

[0647] Preparation of intermediate I-49 :

[0648]

[0649] 4-[[6-chloro-4-(difluoromethyl)-2-pyridyl]oxymethyl]-3-fluorobenzonitrile (I-49) A solution of 2,6-dichloro-4-(difluoromethyl)pyridine (927 mg, 4.68 mmol) was dissolved in 10 mL of DMF. 3-fluoro-4-(hydroxymethyl)benzonitrile (708 mg, 4.68 mmol) and potassium carbonate (971 mg, 7 mmol) were added to this solution. The mixture was heated to 60 °C overnight, diluted with EtOAc (50 mL), and washed with water. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The solvent was removed, and the resulting residue was purified by column chromatography (0%–60% EtOAc / hexane) to give the title compound: ES / MS m / z: 313.1 (M+H+).

[0650] Preparation of intermediate I-50 :

[0651]

[0652] 6-(4-Cyclopropyltriazol-1-yl)pyridine-3-carboxylic acid methyl esterA suspension of methyl 6-chloropyridine-3-carboxylate (300 mg, 1.75 mmol) and sodium azide (227 mg, 3.5 mmol) in THF was heated to 60 °C for 5 hours. Afterward, the mixture was diluted with EtOAc and washed with saturated sodium bicarbonate solution (20 mL) and brine. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. A solution of ethynylcyclopropane (145 mg, 2.2 mmol) in tert-butanol (5 mL) was added to the crude residue. A solution of sodium ascorbate (0.19 mmol, 38 mg) in water (2.5 mL) and a solution of copper sulfate pentahydrate (0.19 mmol, 48 mg) in H₂O (2.5 mL) were added sequentially to the resulting mixture. The mixture was stirred at room temperature for 18 hours. Afterward, the mixture was diluted with 5 mL of 1 M NH₄OH aqueous solution and extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (0%-100% EtOAc / hexane) using silica gel to give the title compound: ES / MS m / z: 245.2 (M+H+).

[0653] 4-Methylbenzenesulfonic acid [6-(4-cyclopropyltriazol-1-yl)-3-pyridyl]methyl ester (I-50) To a solution of methyl 6-(4-cyclopropyltriazol-1-yl)pyridine-3-carboxylic acid (300 mg, 1.23 mmol) in 2 mL of THF, 0.92 mL of lithium borohydride in THF was added. The resulting solution was stirred for 8 hours, then diluted with 50 mL of EtOAc and washed with H2O and brine. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting crude product was dissolved in 5 mL of DCM. Next, p-toluenesulfonyl 4-methylbenzenesulfonate (365 mg, 1.12 mmol) and ethyl diisopropylamine (0.37 mL, 2.13 mmol) were added to this solution. The mixture was stirred overnight. After completion, the resulting solution was diluted with 20 mL of DCM and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by rapid chromatography (0%-100% EtOAc / hexane) using silica gel to give the title compound: ES / MS m / z: 371.2 (M+H+).

[0654] Preparation of intermediate I-51 :

[0655]

[0656] 6-(3-Cyclopropyl-1,2,4-triazol-1-yl)pyridine-3-carboxylic acid methyl esterA suspension of methyl 6-chloropyridine-3-carboxylate (300 mg, 1.75 mmol), 3-cyclopropyl-1H-1,2,4-triazole (191 mg, 1.75 mmol), and potassium carbonate (483 mg, 3.5 mmol) in THF was heated to reflux for 8 hours. The solution was then diluted with EtOAc and washed with saturated sodium bicarbonate solution (20 mL) and brine. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by rapid chromatography (0%–100% EtOAc / hexane) using silica gel to give the title compound: ES / MS m / z: 245.2 (M+H+).

[0657] 4-Methylbenzenesulfonic acid [6-(3-cyclopropyl-1,2,4-triazol-1-yl)-3-pyridyl]methyl ester (I-51) Add 0.92 mL of a solution of 2N lithium borohydride in THF to a solution of methyl 6-(3-cyclopropyl-1,2,4-triazol-1-yl)pyridine-3-carboxylic acid (300 mg, 1.23 mmol) in 2 mL THF. Stir the solution overnight, dilute with 50 mL EtOAc, and wash with water and brine. Wash the combined organic extracts with brine, dry over Na2SO4, and concentrate under reduced pressure. Dissolve the crude product in 5 mL DCM, and add 4-methylbenzenesulfonyl chloride (241 mg, 1.26 mmol) and triethylamine (0.34 mL, 2.4 mmol). Stir the mixture overnight, dilute with 20 mL DCM, and wash with water and brine. Dry the organic layer over sodium sulfate, filter, and concentrate the filtrate under vacuum. The crude residue was purified by rapid chromatography (0%-100% EtOAc / hexane) using silica gel to obtain I-51: ES / MS m / z: 371.1 (M+H+).

[0658] Preparation of intermediate I-52 :

[0659]

[0660] 4-Methylbenzenesulfonic acid [2-fluoro-4-(2-trimethylsilylethynyl)phenyl]methyl ester(2-fluoro-4-iodo-phenyl)methanol (2 g, 7.94 mmol), ethynyl(trimethyl)silane (1.17 g, 11.9 mmol), copper iodide (75.6 mg, 0.4 mmol), bis(triphenylphosphine)palladium chloride (280 mg, 0.4 mmol), and triethylamine (3.3 mL, 23.8 mmol) were suspended in THF (15 mL). The mixture was degassed with nitrogen and stirred at room temperature for 16 hours. The mixture was then filtered through Celite and washed three times with 20 mL of DCM. The solvent was removed, and the resulting crude product was dried under vacuum. The crude product was then dissolved in 20 mL of DCM, followed by the addition of p-toluenesulfonyl 4-methylbenzenesulfonate (2.58 g, 7.92 mmol) and ethyl diisopropylamine (2.76 mL, 15.8 mmol). The mixture was stirred for 5 hours and examined by LC / MS. The mixture was then diluted with 20 mL of DCM and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by rapid chromatography (0%–50% EtOAc / hexane) using silica gel to give the title compound: ES / MS m / z: 377.1 (M+H+).

[0661] 2-[[4-[6-[(4-ethynyl-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]- 3-[[(2S)-oxetanebut-2-yl]methyl]benzimidazole-5-carboxylic acid methyl ester (I-52) Potassium carbonate (742 mg, 5.37 mmol) was added to a solution of 2-[[2,5-difluoro-4-(6-hydroxy-2-pyridyl)phenyl]methyl]-3-[[(2S)-oxetanebut-2-yl]methyl]benzimidazole-5-carboxylic acid methyl ester (500 mg, 1.07 mmol) and 4-methylbenzenesulfonic acid [2-fluoro-4-(2-trimethylsilylethynyl)phenyl]methyl ester (420 mg, 1.12 mmol) in 5 mL of DMF, and the mixture was stirred for 3 hours. Subsequently, 50 mL of water was added to the solution, and the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude product was dissolved in MeOH (20 mL), and potassium carbonate (51.6 mg, 0.37 mmol) was added to this solution. After 2 hours, the solution was filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by rapid chromatography (0%-80% EtOAc / hexane) using silica gel to give I-52. ES / MS m / z: 598.2 (M+H+).

[0662] Preparation of intermediate I-53 :

[0663]

[0664] N-(1-Cyanocyclopropyl)-4-methoxy-5-methylpyridine-2-carboxamideN,N-diisopropylethylamine (2.14 mL, 12.3 mmol) was added to a solution of 4-methoxy-5-methyl-pyridine-2-carboxylic acid hydrochloride (500 mg, 2.46 mmol), 1-aminocyclopropanecarboxynitrile hydrochloride (349 mg, 2.95 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (1373 mg, 3.61 mmol) in DMF (10 mL). The mixture was stirred overnight at RT. Subsequently, the mixture was diluted with EtOAc and washed with 5% LiCl, saturated NaHCO3, and brine. The organic extract was dried over sodium sulfate and purified by rapid chromatography (eluent: EtOAc / hexane) to give the title compound.

[0665] 5-(bromomethyl)-N-(1-cyanocyclopropyl)-4-methoxy-pyridine-2-carboxamide N-bromosuccinimide (403 mg, 2.26 mmol) was added to a suspension of N-(1-cyanocyclopropyl)-4-methoxy-5-methylpyridine-2-carboxamide (400 mg, 1.73 mmol) in CCl4 (10 mL), followed by benzoyl peroxide (45.1 mg, 0.186 mmol). The resulting solution was heated at 90 °C for 1 hour. After heating, the mixture was cooled to room temperature, diluted with 5 mL of hexane, and the suspension was filtered. The filtrate was concentrated and purified by rapid chromatography (elution: EtOAc / hexane) to give the title compound. ES / MS: 310, 312 (M+H) + ).

[0666] 5-[(6-bromo-2-pyridyl)oxymethyl]-N-(1-cyanocyclopropyl)-4-methoxy-pyridin-2-carboxamide (Intermediate I-53) A suspension of 5-(bromomethyl)-N-(1-cyanocyclopropyl)-4-methoxy-pyridine-2-carboxamide (112 mg, 0.36 mmol), 6-bromopyridine-2-ol (50 mg, 0.29 mmol), and silver carbonate (169 mg, 0.61 mmol) in CH3CN (5 mL) was heated overnight at 50 °C. Afterward, the mixture was diluted with EtOAc and filtered through Celite glass buffer. The mixture was partitioned, and the organic phase was washed once more with brine. The resulting crude product was dried over sodium sulfate, concentrated, and purified by rapid chromatography (eluent: EtOAc / hexane) to give I-53. ES / MS: 403, 405 (M+H) + ).

[0667] Preparation of intermediate I-54 :

[0668]

[0669] 3-(bromomethyl)-1-cyclopropylpyrazole (I-54)Carbon tetrabromide (0.541 g, 0.00163 mol) was added at 0 °C to a solution of (1-cyclopropylpyrazole-3-yl)methanol (0.188 g, 1.36 mmol) and (polymer-bound 4-diphenylphosphine) (78.7%, 0.542 g, 0.00163 mol) in DCM (10 mL). The mixture was gradually warmed to room temperature and stirred overnight. The resulting suspension was filtered, the filtrate was diluted with DCM, and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by rapid chromatography (eluent: EtOAc / hexane) to give I-54. ES / MS: 201.2, 203.2 (M+H) + ).

[0670] The following intermediates were prepared in accordance with the method described for intermediate I-54:

[0671]

[0672] Preparation of intermediate I-55 :

[0673]

[0674] [1-(oxecyclobut-3-yl)pyrazol-3-yl]methanol Diisobutylaluminum hydride (2.40 mL, 2.40 mmol / L DCM solution) was added to a solution of methyl 1-(oxetanebut-3-yl)pyrazole-3-carboxylate (175 mg, 0.961 mmol) in THF (5 mL) at 0 °C and stirred for 1 hour. The mixture was then diluted with 5 mL of Et₂O and cooled to 0 °C. Next, 0.100 mL of water, 0.100 mL of 15% NaOH, and 0.240 mL of water were added. The solution was warmed to room temperature and stirred for 15 minutes. Then, MgSO₄ was added and the solution was stirred for another 15 minutes, followed by filtration to obtain the title product, which can be proceeded to the next step without further purification. ES / MS: 155.2 (M+H) + ).

[0675] 3-(bromomethyl)-1-(oxetanebut-3-yl)-pyrazole (I-55)Carbon tetrabromide (0.281 g, 0.000848 mol) was added at 0 °C to a solution of [1-(oxetane-3-yl)pyrazol-3-yl]methanol (0.109 g, 0.707 mmol) and (polymer-bound 4-diphenylphosphine phenyl polymer) (78.7%, 0.282 g, 0.000848 mol) in DCM (10 mL). The mixture was gradually warmed to room temperature and stirred overnight. The resulting suspension was filtered, the filtrate was diluted with DCM, and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by rapid chromatography (eluent: Et2O / hexane) to give I-55. ES / MS: 217.2, 219.2 (M+H) + ).

[0676] Preparation of intermediate I-56 :

[0677]

[0678] 1-(4-pyridyl)pyrazole-3-carboxylic acid methyl ester In a 40 mL glass vial, a mixture of methyl 1H-pyrazole-3-carboxylate (472 mg, 3.74 mmol), 4-fluoropyridine hydrochloride (500 mg, 3.74 mmol), and potassium carbonate (1358 mg, 9.83 mmol) in NMP (10 mL) was heated at 120 °C for 48 hours. The mixture was then diluted with EtOAc and washed with 5% LiCl (2×) and brine. The organic extract was dried over sodium sulfate, concentrated, and purified by rapid chromatography (eluent: EtOAc / hexane) to give the title compound. ES / MS: 204.2 (M+H) + ).

[0679] [1-(4-pyridyl)pyrazole-3-yl]methanol (I-56) Diisobutylaluminum hydride (1.30 mL, 1.30 mmol in 1.0 M DCM solution) was added to a solution of methyl 1-(4-pyridyl)pyrazole-3-carboxylate (106 mg, 0.520 mmol) in THF (5 mL) at 0 °C. The solution was stirred for 1 hour. The mixture was then diluted with 5 mL of Et₂O and cooled to 0 °C. After cooling, 0.05 mL of water, 0.05 mL of 15% NaOH, and 0.130 mL of water were added to the solution. The solution was then warmed to room temperature and stirred for 15 minutes, followed by the addition of MgSO₄. The solution was stirred for another 15 minutes and then filtered. The crude product was purified by rapid chromatography (elution: EtOAc / hexane) to give I-56. ES / MS: 176.2 (M+H) + ).

[0680] Preparation of intermediate I-57 :

[0681]

[0682] [1-(trifluoromethyl)pyrazole-3-yl]methanol At 0°C, lithium aluminum hydride (2.0 M THF solution) (2.00 mmol / L, 980 mL, 1.96 mmol) was added to a solution of 1-(trifluoromethyl)pyrazole-3-carboxylic acid (321 mg, 1.78 mmol) in 10 mL of THF. The solution was gradually warmed to room temperature and stirred for 1 hour. Afterward, the solution was diluted with Et₂O and cooled to 0°C. After cooling, 0.075 mL of water, 0.075 mL of 15% NaOH aqueous solution, and 0.225 mL of water were added to the solution, and the mixture was warmed to room temperature and stirred for another 15 minutes. After stirring for another 15 minutes, MgSO₄ was added, and the solution was stirred for another 15 minutes. The mixture was then filtered to obtain the title product, which could be proceeded to the next step without further purification. ES / MS: 167.2 (M+H) + ).

[0683] 3-(bromomethyl)-1-(trifluoromethyl)pyrazole (I-57) Carbon tetrabromide (0.465 g, 0.00140 mol) was added at 0 °C to a solution of [1-(trifluoromethyl)pyrazol-3-yl]methanol (0.194 g, 1.17 mmol) and (polymer-bound 4-diphenylphosphine) (78.7%, 0.465 g, 0.00140 mol) in DCM (10 mL). The mixture was gradually warmed to room temperature and stirred overnight. The resulting suspension was filtered, the filtrate was diluted with DCM, and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by rapid chromatography (eluent: Et₂O / hexane) to give I-57. ES / MS: 230.2 (M+H) + ).

[0684] Preparation of intermediate I-58 :

[0685]

[0686] 3-(trifluoromethyl)isothiazol-5-carboxylic acid methyl ester At 0 °C, thionyl chloride (0.125 mL, 1.69 mmol) was added to a solution of 3-(trifluoromethyl)isothiazol-5-carboxylic acid (303 mg, 1.54 mmol) in MeOH (3 mL). The resulting solution was gradually warmed to room temperature and stirred overnight. Subsequently, more thionyl chloride (0.125 mL, 1.69 mmol) was added and stirred for 9 hours. After this time, the mixture was concentrated and purified by rapid chromatography (elution buffer: EtOAc / hexane) to give the title compound. ¹H NMR (400 MHz, chloroform-d) δ 8.01 (s, 1H), 4.01 (s, 3H).

[0687] [3-(trifluoromethyl)isothiazo-5-yl]methanol Diisobutylaluminum hydride (1.61 mL, 1.61 mmol in 1.0 M DCM solution) was added to a solution of methyl 3-(trifluoromethyl)isothiazol-5-carboxylate (136 mg, 0.644 mmol) in THF (5 mL) at 0 °C. The resulting solution was stirred for 3 hours. After this time, the mixture was diluted with 5 mL of Et₂O and cooled to 0 °C. Once the mixture had cooled, 0.064 mL of water, 0.064 mL of 15% NaOH, and 0.161 mL of water were added, and the solution was warmed to room temperature and stirred for 15 minutes. Subsequently, MgSO₄ was added and the solution was stirred for another 15 minutes, followed by filtration. The crude product was purified by rapid chromatography (elution buffer: EtOAc / hexane) to give the title compound. ES / MS: 184.2 (M+H) + ).

[0688] 5-(bromomethyl)-3-(trifluoromethyl)isothiazol (I-58) Carbon tetrabromide (185 mg, 0.557 mmol) was added to a solution of [3-(trifluoromethyl)isothiazolyl-5-yl]methanol (85 mg, 0.464 mmol) and (polymer-bound 4-diphenylphosphine) (78.7%, 185 mg, 0.557 mol) in DCM (10 mL) at 0 °C. The mixture was gradually warmed to room temperature and stirred overnight. The resulting suspension was filtered, the filtrate was diluted with DCM, and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by rapid chromatography (eluent: Et₂O / hexane) to give I₂-58. ¹H NMR (400 MHz, chloroform-d) δ 7.49 (d, J = 0.8 Hz, 1H), 4.72 (d, J = 0.8 Hz, 2H).

[0689] Preparation of intermediate I-59 :

[0690]

[0691] Methyl 4-nitro-3-(spiro[2,2]pentan-2-ylamino)benzoate A solution of methyl 3-fluoro-4-nitrobenzoate (0.205 g, 1.03 mmol), spiro[2,2]pentane-2-amine hydrochloride (0.151 g, 1.26 mmol), and N,N-diisopropylethylamine (0.538 mL, 3.09 mmol) in NMP (3 mL) was heated at 90 °C for 12 hours. The mixture was then diluted with EtOAc and washed with 5% LiCl, brine, and water. The organic extract was dried over sodium sulfate, concentrated, and purified by rapid chromatography (eluent: EtOAc / hexane) to give the title compound. ES / MS: 263.2 (M+H) +); 1H NMR (400MHz, chloroform-d) δ 8.22 (d, J = 8.8Hz, 1H), 8.06 (s, 1H), 7.79 (d, J = 1.8Hz, 1H), 7.29 (dd, J = 8.9, 1.8Hz, 1H), 3.98 (s, 3H), 3.01 (dd, J = 6.3, 3.1Hz, 1H), 1.54-1.42 (m, 1H), 1.14 (ddd, J = 9.0, 5.5, 4.1Hz, 1H), 1.06-0.98 (m, 2H), 0.95 (td, J = 8.5, 4.7Hz, 2H).

[0692] Methyl 4-amino-3-(spiro[2.2]pentan-2-ylamino)benzoate (I-59) The mixture was degassed by circulating a solution of methyl 4-nitro-3-(spiro[2,2]pentan-2-ylamino)benzoate (101 mg, 0.4385 mmol) in EtOAc (8 mL) three times between argon and vacuum. Platinum (1%), carbon-supported vanadium (2%) (50%–70% wetting) were added to the mixture, and I-59 was used for the next step without further purification. ES / MS: 233.2 (M+H) + );

[0693] Preparation of intermediates I-60 and I-61 :

[0694]

[0695] 3-[(6-bromo-2-pyridyl)oxymethyl]pyrazole-1-carboxylic acid tert-butyl ester A suspension of tert-butyl 3-(bromomethyl)pyrazole-1-carboxylic acid (946 mg, 3.6 mmol), 6-bromopyridin-2-ol (500 mg, 2.9 mmol), and silver carbonate (1694 mg, 6.1 mmol) in CH3CN (15 mL) was heated at 50 °C for 15 hours. Subsequently, 335 mg of 6-bromopyridin-2-ol and 5 mL of CH3CN were added, and the solution was heated at 50 °C for 5 hours. After this time, 500 mg of 6-bromopyridin-2-ol was added, and heating continued for 2 hours. The mixture was then diluted with EtOAc and brine. The mixture was filtered through a Celite stopper. The mixture was partitioned, and the organic phase was washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by rapid chromatography (eluent: EtOAc / hexane) to give the title compound. ES / MS: 298,300 (M+H) + ).

[0696] 2-Bromo-6-(1H-pyrazol-3-ylmethoxy)pyridineA solution of 3-[(6-bromo-2-pyridinyl)oxymethyl]pyrazole-1-carboxylic acid tert-butyl ester (456 mg, 1.3 mmol) and TFA (0.49 mL, 6.4 mmol) in DCM (5 mL) was stirred overnight at room temperature. The solution was then diluted with DCM, washed with saturated sodium bicarbonate solution, dried over sodium sulfate, concentrated, and allowed to proceed to the next step without further purification. ES / MS: 254, 256 (M+H) + ).

[0697] 2-[3-[(6-bromo-2-pyridinyl)oxymethyl]pyrazol-1-yl]acetonitrile (I-60) and 2-[5-[(6-bromo-2-pyridinyl)oxymethyl]pyrazol-1-yl]acetonitrile (I-60) [Pyridyl)oxymethyl]pyrazol-1-yl]acetonitrile (I-61) 2-Chloroacetonitrile (0.0314 mL, 0.498 mmol) was added to a suspension of 2-bromo-6-(1H-pyrazol-3-ylmethoxy)pyridine (0.115 g, 0.453 mmol) and cesium carbonate (0.177 g, 0.543 mmol) in DMF (3 mL). The solution was stirred overnight at room temperature. Subsequently, the solution was warmed to 40 °C for 2 hours, diluted with EtOAc, and washed with 5% LiCl (2×) and brine. The organic extract was dried over sodium sulfate, concentrated, and purified by rapid chromatography (eluent: EtOAc / hexane) to give I-60 and I-61.

[0698] 2-[3-[(6-bromo-2-pyridyl)oxymethyl]pyrazol-1-yl]acetonitrile (I-60) ES / MS: 293.2, 295.1 (M+H) + ); 1H NMR (400MHz, chloroform-d) δ 7.55 (d, J = 2.4Hz, 1H), 7.45 (dd, J = 8.2, 7.5Hz, 1H), 7.11 (dd, J = 7.5, 0.7Hz, 1H), 6.76 (dd, J = 8.2, 0.7Hz, 1H), 6.52 (d, J = 2.4Hz, 1H), 5.39 (s, 2H), 5.10 (s, 2H).

[0699] 2-[5-[(6-bromo-2-pyridyl)oxymethyl]pyrazol-1-yl]acetonitrile (I-61) ES / MS: 293.2, 295.0 (M+H) + ); 1H NMR (400MHz, chloroform-d) δ7.57 (d, J=1.9Hz, 1H), 7.50 (dd, J=8.2, 7.5Hz, 1H), 7.15 (d, J= 7.4Hz, 1H), 6.80 (d, J = 8.1Hz, 1H), 6.48 (d, J = 1.9Hz, 1H), 5.47 (s, 2H), 5.35 (s, 2H).

[0700] Preparation of intermediate I-62 :

[0701]

[0702] 1-(1-Methylpyrazol-4-yl)pyrazol-3-carboxylic acid ethyl ester In a 40 mL glass vial, a mixture of ethyl 1H-pyrazole-3-carboxylate (1000 mg, 7.14 mmol), 4-iodo-1-methylpyrazole (1484 mg, 7.14 mmol), cesium carbonate (5812 mg, 17.8 mmol), copper oxide (I) (60.0 mg, 0.419 mmol), and salicylaldehyde oxime (120 mg, 0.875 mmol) in DMF (20 mL) was heated at 110 °C for 48 hours. The mixture was then diluted with EtOAc and washed with 5% LiCl, saturated sodium bicarbonate, and brine. The organic extract was dried over sodium sulfate and purified by rapid chromatography (eluent: EtOAc / hexane) to give the title compound. ES / MS: 221.2 (M+H) + ).

[0703] [1-(1-methylpyrazol-4-yl)pyrazol-3-yl]methanol Diisobutylaluminum hydride (1.0 M DCM solution, 3.26 mL, 3.26 mmol) was added to a solution of ethyl 1-(1-methylpyrazol-4-yl)pyrazol-3-carboxylate (287 mg, 1.30 mmol) in THF (6 mL) at 0 °C. The resulting solution was stirred for 1 hour while being gradually warmed to room temperature. The solution was then diluted with Et₂O and cooled to 0 °C. After cooling, 0.130 mL of water, 0.130 mL of 15% NaOH aqueous solution, and 0.326 mL of water were added to the solution, and the resulting solution was warmed to room temperature. After warming, the solution was stirred for 15 minutes, then MgSO₄ was added and the solution was stirred for another 15 minutes, followed by filtration. The filtrate was concentrated and purified by rapid chromatography (elution: EtOAc / hexane) to give the title compound. ES / MS: 179.2 (M+H) + ).

[0704] 3-(bromomethyl)-1-(1-methylpyrazol-4-yl)pyrazole (I-62) Carbon tetrabromide (303 mg, 0.914 mmol) was added to a solution of [1-(1-methylpyrazol-4-yl)pyrazol-3-yl]methanol (136 mg, 0.762 mmol) and (polymer-bound 4-diphenylphosphoalkylphenyl) (78.7%, 303 mg, 0.914 mmol) in DCM (10 mL) at 0 °C. The mixture was gradually warmed to room temperature and stirred overnight. The resulting suspension was filtered, the filtrate was diluted with DCM, and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by rapid chromatography (eluent: Et2O / hexane) to give I-62. ES / MS: 241.2, 243.2 (M+H) +); 1H NMR (400MHz, chloroform-d) δ 7.71 (s, 1H), 7.69 (d, J = 0.8 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 4.56 (s, 2H), 3.96 (s, 3H).

[0705] The following intermediates were prepared in accordance with the method described for intermediate I-62. :

[0706]

[0707] Preparation of intermediate I-63 :

[0708]

[0709] 2-(bromomethyl)thiazolyl-5-carboxynitrile (I-63) N-bromosuccinimide (375 mg, 2.11 mmol) was added to a solution of 2-methylthiazolyl-5-carboxynitrile (200 mg, 1.61 mmol) in CCl4 (8 mL), followed by benzoyl peroxide (42.0 mg, 0.173 mmol). The solution was heated at 90 °C for 9 hours. Afterward, the mixture was cooled to room temperature and 5 mL of hexane was added. The suspension was filtered, the filtrate was concentrated, and purified by rapid chromatography (elution: EtOAc / hexane) to give I-63. ES / MS: 203.0, 205.2 (M+H) + ); 1H NMR (400MHz, chloroform-d) δ 8.23 ​​(s, 1H), 4.74 (s, 2H).

[0710] The following intermediates were prepared in accordance with the manner described for intermediate I-63. :

[0711]

[0712] Preparation of intermediate I-64 :

[0713]

[0714] 3-(bromomethyl)-5-methoxy-1-methyl-1H-pyrazole (I-64)While stirring at room temperature, CBr4 (7.2 g, 21 mmol, 2.0 equivalent) and triphenylphosphine (5.7 g, 21 mmol, 2.0 equivalent) were added to a solution of (5-methoxy-1-methyl-1H-pyrazole-3-yl)methanol (1.42 g, 10 mmol, 1.0 equivalent) in DCM (15 mL). The mixture was stirred for another 16 hours. After completion, the mixture was diluted with water (150 mL), extracted with DCM (3 × 150 mL), washed with brine (50 mL), dried over Na2SO4 and concentrated to obtain a crude product. The crude product was purified by column chromatography (0% to 2% MeOH-DCM) to obtain 3-(bromomethyl)-5-methoxy-1-methyl-1H-pyrazole (I-64).

[0715] The following intermediates were prepared in accordance with the method described for intermediate I-64. :

[0716]

[0717] Preparation of intermediate I-65 :

[0718]

[0719] (5,5-Difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol (I-65) 5,5-Difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (105 mg, 0.56 mmol) was dissolved in THF (3 mL) and stirred at 0 °C for 5 minutes. Then, 1 M borane (3.4 mL) solution was added dropwise to the mixture over 30 minutes at 0 °C. The ice bath was removed, and stirring continued at room temperature for 7 hours. Afterward, the mixture was cooled in an ice bath and treated with 3 M HCl (5 mL). The solution was heated at 50 °C for 1 hour. After the heating time, the solution was washed with EtOAc (2×), the aqueous layer was cooled in an ice bath, and neutralized with 3 M NaOH. The solution was extracted with EtOAc (3×), the combined organic layers were washed with brine, dried (Na2SO4) and concentrated under vacuum to obtain (5,5-difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol (I-65).

[0720] Preparation of intermediate I-66 :

[0721]

[0722] 2-[[4-[6-[(5-bromopyrimidin-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3- [[(2S)-oxetanebut-2-yl]methyl]benzimidazole-5-carboxylic acid methyl ester (I-66)Methyl 2-[[4-[6-[(5-bromopyrimidin-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetanebut-2-yl]methyl]benzimidazole-5-carboxylic acid was prepared in the manner described for intermediate I-21, yielding I-66. ES / MS: 637.4 (M+H+).

[0723] Preparation of intermediate I-67 :

[0724]

[0725] 2-[[4-[6-[(5-chloropyrazin-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3- [[(2S)-oxetanebut-2-yl]methyl]benzimidazole-5-carboxylic acid methyl ester (I-67) Methyl 2-[[4-[6-[(5-chloropyrazin-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetanebut-2-yl]methyl]benzimidazole-5-carboxylic acid was prepared in the manner described for intermediate I-21, yielding I-67. ES / MS: 593 (M+H+).

[0726] Preparation of intermediate I-68 :

[0727]

[0728] 3-Bromo-5-((4,4-dimethyltetrahydrofuran-3-yl)amino-4-nitrobenzene methyl ester Methyl 3-bromo-5-fluoro-4-nitrobenzoate (0.5 g, 1.8 mmol) was dissolved in a 100 mL round-bottom flask containing 10 mL of DMF. Next, 4,4-dimethyltetrahydrofuran-3-amine hydrochloride (0.46 g, 3 mmol) and N,N-diisopropylethylamine (0.63 mL, 3.6 mmol) were added to this solution. The mixture was stirred overnight at 50 °C. The mixture was then concentrated to remove most of the THF, and the crude material was dissolved in EtOAc (40 mL). The organic matter was washed with 50% NH4Cl (2 × 10 mL) and brine (1 × 50 mL). The organic matter was then dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was allowed to proceed without further purification: ES / MS: 374.2 (M+H+).

[0729] Methyl 4-amino-3-bromo-5-[(4,4-dimethyltetrahydrofuran-3-yl)amino]benzoate (I-68) Add methyl 3-bromo-5-((4,4-dimethyltetrahydrofuran-3-yl)amino-4-nitrobenzene (0.58 g, 1.6 mmol), iron (0.43 g, 7.8 mmol), and acetic acid (10 mL) to a 100 mL round-bottom flask. Stir the mixture and heat at 100 °C for 1 hour. Afterward, filter the mixture through a Celite filter to remove the catalyst. Concentrate the filtrate under reduced pressure to give I-68, which can be used without further purification: ES / MS: 344.2 (M+H+).

[0730] Preparation of intermediate I-69 :

[0731]

[0732] 3-Bromo-4-[[2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl] Methyl acetyl]amino]-5-[(4,4-dimethyltetrahydrofuran-3-yl)amino]benzoate 1-Methylimidazole (239 mg, 0.23 mL, 2.9 mmol) was added to a solution of I-68 (200 mg, 0.58 mmol) and I-7 (180 mg, 0.45 mmol) cooled to 0 °C in MeCN (5 mL), followed by N,N,N',N'-tetramethylchloromantadin hexafluorophosphate (204 mg, 0.73 mmol). The mixture was warmed to room temperature and stirred for 30 minutes. After 30 minutes, the crude mixture was concentrated under vacuum and then partitioned between water and EtOAc. The organic layer was separated and washed with a separate portion of water, followed by washing with brine. The separated organic layer was dried over sodium sulfate, separated by vacuum filtration, concentrated under vacuum, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to obtain the desired product. ES / MS: 724.4 [M+H]+.

[0733] 7-Bromo-2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl Methyl 3-(4,4-dimethyltetrahydrofuran-3-yl)benzimidazole-5-carboxylate (I-69) A solution of methyl 3-bromo-4-[[2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetyl]amino]-5-[(4,4-dimethyltetrahydrofuran-3-yl)amino]benzoate (100 mg, 0.14 mmol) in acetic acid (2 mL) was heated to 80 °C for 5 days. The mixture was concentrated and partitioned between EtOAc and a saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, separated by vacuum filtration, concentrated under vacuum, and purified by silica gel column chromatography (elution: EtOAc / hexane) to give I-69. ES / MS: 706.5 [M+H] + .

[0734] Preparation of intermediate I-70 :

[0735]

[0736] 2-(5-bromo-3-fluoropyridin-2-yl)methyl acetatetert-butyl methylmalonate was added dropwise to a suspension of NaH (60% mineral oil solution, 1.3 g, 34 mmol) in DMF (20 mL) at 5 °C, and the suspension was stirred for 5 minutes. Then, 5-bromo-2,3-difluoropyridine was added dropwise, and the resulting suspension was heated to 60 °C and stirred overnight at this temperature. Subsequently, NH4Cl was added, and the mixture was extracted with ether. The organic phase was washed with brine and concentrated. The residue was redissolved in DCM (10 mL). Then, TFA (10 mL) was added, and the resulting solution was heated to 40 °C and stirred for 5 hours. After the time was up, the mixture was concentrated and purified by rapid chromatography (EtOAc / hexane) to give the title product: ES / MS: 248.2 (M+H) + ).

[0737] 5-Bromo-3-fluoro-2-(2-methoxy-2-oxoethyl)pyridine 1-oxide MCPBA (3.51 g, 16 mmol) was added to a solution of methyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate (2.68 g, 11 mmol) in DCM (30 mL) at 0 °C. The resulting solution was warmed to room temperature and stirred overnight. The mixture was then diluted with hexane (20 mL) and filtered. The filtrate was concentrated and purified by rapid chromatography (EtOAc / hexane) to give the title product: ES / MS: 265.2 (M+H). + ).

[0738] 2-(6-amino-5-bromo-3-fluoropyridin-2-yl)methyl acetate Over a period of 1.5 hours, p-toluenesulfonic anhydride (1.5 g) was added to a solution of 5-bromo-3-fluoro-2-(2-methoxy-2-oxoethyl)pyridine 1-oxide (1.24 g, 4.7 mmol), saccharin (6.3 g, 34 mmol), and DIPEA (6.5 mL, 38 mmol) in chloroform (5 mL). The resulting solution was stirred at room temperature for 2 hours. Subsequently, an additional amount of p-toluenesulfonic anhydride (1.3 g) was added and the mixture was stirred for 1 hour. After one hour, an additional amount of p-toluenesulfonic anhydride (2.0 g) was added and the mixture was stirred over the end of the hour. The reaction mixture was quenched with Na₂CO₃ and filtered. The phases were separated, and the aqueous phase was extracted with DCM. The combined organic compounds were washed with 10% citric acid, dried, filtered, concentrated, and purified by rapid chromatography (EtOAc / hexane). The resulting product was suspended in 2M H₂SO₄ (4 mL) and stirred at 90 °C for 18 hours, then heated to reflux and stirred for 24 hours. The mixture was filtered, and the filtrate was washed with CHCl₃. The aqueous phase was alkalized with NaOH to approximately pH 7 and filtered. The filtrate was acidified to approximately pH 5 and extracted with CHCl₃ (3×). The organic matter was dried and concentrated to give the title product: ES / MS: 249.0 (M+H₂SO₄). + ). 1¹H NMR (400MHz, chloroform-d) δ 7.59 (d, J = 7.7Hz, 1H), 5.05 (s, 2H), 3.80 (d, J = 2.2Hz, 2H). 19 FNMR (376MHz, chloroform-d) δ -137.76 (d, J = 7.5Hz).

[0739] 2-(6-amino-5-bromo-3-fluoropyridin-2-yl)acetic acid The title intermediate was prepared in the manner described for intermediate I-7 (step 2), using methyl 2-(6-amino-5-bromo-3-fluoropyridin-2-yl)acetate instead of methyl 2-(4-(6-(((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetate.

[0740] 2-((6-amino-5-bromo-3-fluoropyridin-2-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazol- 6-Tertiary butyl carboxylate The title compound was prepared in the manner described for intermediate I-2, using 2-(6-amino-5-bromo-3-fluoropyridin-2-yl)acetic acid instead of 2-(4-bromo-2-fluoro-phenyl)acetic acid, and using tert-butyl 4-amino-3-((2-methoxyethyl)amino)benzoate instead of methyl 4-amino-3-(2-methoxyethylamino)benzoate. ES / MS: 481.1 (M+H) + ). 1 HNMR (400MHz, chloroform-d) δ8.07(d,J=1.5Hz,1H),7.94(d,J=8.6Hz,1H),7.78(d,J=8.5Hz,1H),7.51(d ,J=7.8Hz,1H),4.79(s,2H),4.57-4.39(m,4H),3.70(t,J=5.3Hz,2H),3.30(s,3H),1.65(s,9H).

[0741] 2-((2'-amino-6-((4-cyano-2-fluorobenzyl)oxy)-5'-fluoro-[2,3'-bipyridine]-6'-yl)methyl 1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester (I-70) Following the method described for intermediate I-7, in step 1, dichlorobis(di-tert-butylphenylphosphine)palladium(II) was used instead of Pd(dppf)Cl2, and 2-((6-amino-5-bromo-3-fluoropyridin-2-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester was used instead of methyl 2-(4-bromo-2,5-difluorophenyl)acetate to prepare I-70. ES / MS: 627.5 (M+H) + ).

[0742] Preparation of intermediate I-71 :

[0743]

[0744] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl) 1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester (I-71)The title compound was prepared using intermediates I-6 and I-7, following the method described for intermediate I-2. ES / MS: 629.5 (M+H) + ).

[0745] Preparation of intermediate I-72 :

[0746]

[0747] 4-Amino-3-iodo-5-((2-methoxyethyl)amino)benzoate methyl benzoate The title compound was prepared in the manner described for intermediate I-1. Reduction was carried out by stirring iron (603 mg, 10.8 mmol), acetic acid (12.0 mL, 1.8 mmol), and crude methyl 3-iodo-5-(2-methoxyethylamino)-4-nitrobenzoate (821 mg, 2.16 mmol) in methanol (5.0 mL) under reflux for 1 hour. The mixture was diluted with DCM, filtered, and the organic matter was dried, filtered, and concentrated to give the crude product.

[0748] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-iodo-1-(2-methyl) methyl 1H-benzo[d]imidazolium-6-carboxylic acid (O-ethyl)-1H-benzo[d]imidazolium-6-carboxylic acid The title compound was prepared using methyl 4-amino-3-iodo-5-((2-methoxyethyl)amino)benzoate and intermediate I-7, as described for intermediate I-13.

[0749] 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-7- Iodine-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid (I-72) In an 8 mL glass vial, a solution of methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-7-iodo-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid (105 mg, 0.15 mmol) and lithium hydroxide monohydrate (25 mg, 0.59 mmol) in THF / water (2:1, 3 mL) was heated at 70 °C until complete (15 min). After mixing, trifluoroacetic anhydride (0.3 mL) was added, and the solution was directly purified by RP-HPLC (elution buffer: MeCN / H2O) to give I-72. ES / MS: 699.1

[0750] Preparation of intermediate I-73 :

[0751]

[0752] (R)-2-(4-(6-((5-bromothiazo-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxy) tert-butyl 6-carboxylic acid (I-73)-(1H-benzo[d]imidazolium-6-carboxylic acid)(R)-2-(4-(6-((5-bromothiazol-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxypropyl)-1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester was prepared by replacing I-4 with I-26, following the method described for intermediate I-21. ES / MS: 686.8 (M+H) + ).

[0753] Preparation of intermediate I-74 :

[0754]

[0755] (1-Methylthiopheno[2,3-c]pyrazol-5-yl)methanol CDI (249 mg, 1.54 mmol) was added to a solution of 1-methylthiopheno[2,3-c]pyrazole-5-carboxylic acid (140 mg, 0.77 mmol) in THF (6 mL), and the resulting slurry was stirred at ambient temperature for 2 hours. Subsequently, NaBH4 (145 mg, 3.84 mmol) was added in portions, and the mixture was stirred overnight. After completion, MeOH (2 mL) was added, and the crude mixture was directly concentrated. The crude residue was purified by silica gel column chromatography (elution: EtOAc / hexane) to obtain the desired product. ES / MS: 169.1 (M+H) + ).

[0756] 5-[(6-bromo-2-pyridyl)oxymethyl]-1-methyl-thieno[2,3-c]pyrazole (I-74) To a solution of 2-bromo-6-fluoropyridine (122 mg, 0.69 mmol) in acetonitrile (2 mL), (1-methylthieno[2,3-c]pyrazol-5-yl)methanol (106 mg, 0.63 mmol) and cesium carbonate (411 mg, 1.26 mmol) were added, and the resulting mixture was stirred at 80 °C for 2 hours. Afterward, the mixture was diluted with EtOAc (25 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give I-74. ES / MS: 326.1 (M+H) + ).

[0757] Preparation of intermediate I-75 :

[0758]

[0759] 2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)- 1H-Benzo[d]imidazolium-6-carboxylic acid methyl ester (I-75)Following the method described for intermediate I-19, methyl 2-(4-(6-(((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid was prepared by replacing I-96 with I-2. ES / MS: 623.3 (M+H) + ).

[0760] Preparation of intermediate I-76 :

[0761]

[0762] 2-(4-(6-((6-chloro-4-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(4,4- Methyl dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazolium-6-carboxylate (I-76) Following the description for intermediate I-23, methyl 2-(4-(6-((6-chloro-4-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazolium-6-carboxylate was prepared by replacing I-4 with I-25. ES / MS: 638.0 (M+H) + ).

[0763] Preparation of intermediate I-77 :

[0764]

[0765] 2-Bromo-6-(1H-pyrazol-3-ylmethoxy)pyridine (I-77) Cesium carbonate (482 mg, 1.5 mmol) and tert-butyl 3-(bromomethyl)pyrazole-1-carboxylic acid (378 mg, 1.4 mmol) were added to a solution of 6-bromopyridin-2-ol (180 mg, 1.0 mmol) in acetonitrile (4 mL). The mixture was then heated to 65 °C for 30 min. After heating, the mixture was filtered through a Celite filter, concentrated, and purified by silica gel column chromatography (elution: EtOAc / hexane) to obtain the desired product. The obtained tert-butyl 3-[(6-bromo-2-pyridinyl)oxymethyl]pyrazole-1-carboxylic acid (343 mg, 0.97 mmol) was dissolved in DCM (4.4 mL) and TFA (1.1 mL) and stirred at ambient temperature for 2 h. After completion, the mixture was diluted with EtOAc (25 mL), washed with saturated NaHCO3 aqueous solution until gas escape stopped, dried over MgSO4, filtered and concentrated to obtain I-77, which can be used without further purification. ES / MS: 254.2, 256.2 (M+H + ).

[0766] Preparation of intermediate I-78 :

[0767]

[0768] (S)-2-(4-(6-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl Methyl 1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (I-78) Following the method described for intermediate I-21, (S)-2-(4-(6-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester was prepared by replacing 5-bromo-2-(bromomethyl)thiazole with 5-bromo-3-(bromomethyl)-1H-pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester. ES / MS: 638.0, 640.0 (M+H) + ).

[0769] Preparation of intermediate I-79 :

[0770]

[0771] 2-[5-(hydroxymethyl)-2-methylpyrazol-3-yl]acetonitrile Sodium cyanide (241 mg, 4.83 mmol) was added to a solution of methyl 5-(bromomethyl)-1-methylpyrazole-3-carboxylic acid (750 mg, 3.22 mmol) in DMF (9.5 mL) and water (1.2 mL), and the resulting mixture was stirred at room temperature for 3.5 hours. After completion, the mixture was diluted with EtOAc (50 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to obtain the desired product. The methyl 5-(cyanomethyl)-1-methylpyrazole-3-carboxylic acid (328 mg, 1.83 mmol) thus obtained was dissolved in THF (10 mL), and lithium borohydride (2.0 M THF solution, 1.83 mL, 3.66 mmol) was added at 0 °C. The mixture was warmed to room temperature and stirred for 6 hours. At this point, additional lithium borohydride (2.0 M THF solution, 1.83 mL, 3.66 mmol) was added, and the mixture was stirred for 2 hours. Afterward, the reaction system was quenched by adding water (5 mL), diluted with EtOAc (50 mL), and the layers were separated. The organic layer was dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to obtain the desired product.

[0772] 2-[5-(bromomethyl)-2-methylpyrazol-3-yl]acetonitrile (I-79)2-[5-(hydroxymethyl)-2-methylpyrazol-3-yl]acetonitrile (100 mg, 0.662 mmol) was dissolved in dichloromethane (2.65 mL), and triphenylphosphine (0.208 g, 0.794 mmol) was added, followed by carbon tetrabromide (0.263 g, 0.794 mmol). The mixture was stirred at room temperature for 5 minutes, at which point the reaction system was quenched by adding water (5 mL), diluted with EtOAc (25 mL), and the layers were separated. The organic layer was dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (elution: EtOAc / hexane) to give I-79. ES / MS: 214.0, 216.0 (M+H) + ).

[0773] Preparation of intermediates I-80 and I-81 (Method 1) :

[0774]

[0775] 4-Amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)methyl benzoate (I-80, I-81) Methyl 4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate, which is a mixture of two stereoisomers, was separated by a chiral SFC (SFC IB column containing EtOH as a cosolvent) to obtain two different stereoisomers.

[0776] (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate, isomer 1 (I-80) The earlier eluted isomer of two isomers separated by chiral SFC (4.6 mm × 100 mm 5 μm IB column, 10% EtOH / CO2). ES / MS: 265.2 (M+H) + ).

[0777] (R)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate, isomer 2 (I-81) The later eluted isomer of two isomers separated by chiral SFC (4.6 mm × 100 mm 5 μm IB column, 10% EtOH / CO2). ES / MS: 265.2 (M+H) + ).

[0778] Preparation of intermediate I-80 (Method 2) :

[0779] 4-Amino-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]methyl benzoate isomer 2 (I-80)A solution of methyl 3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]-4-nitrobenzoate (intermediate I-100, 17.8 g, 60.5 mmol) in EtOAc (380 mL) was purged with argon and then degassed three times under vacuum. Carbon-supported palladium (10.0%, 6.07 g, 5.70 mmol) was added. The mixture was purged with argon and then degassed three times under vacuum, and stirred at room temperature under a hydrogen atmosphere until complete. The suspension was filtered through a Celite stopper and washed with EtOAc. The mixture was concentrated to give methyl 4-amino-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate, which could be used for subsequent steps without further purification. ES / MS:265.0(M+H+).1H NMR (400MHz, chloroform-d) δ7.49(dd,J=8.0,1.8Hz,1H),7.35(d,J=1.8Hz,1H),6.73(d,J=8.1Hz,1H),4.36(dd,J=9.1, 6.4Hz,1H),3.89(s,3H),3.76(t,J=5.9Hz,1H),3.72-3.63(m,2H),3.63-3.59(m,1H),1.22(s,3H),1.15(s,3H).

[0780] Preparation of intermediates I-82 and I-83 (Method 1) :

[0781]

[0782] 2-(4-bromo-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazol-6-carboxylic acid Methyl esters (I-82, I-83) Following the description for intermediate I-8, I-82 and I-83 were prepared by replacing I-4 with I-80 (for intermediate I-82) and I-81 (for intermediate I-83), respectively.

[0783] (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazol- 6-Carboxylic acid methyl ester isomer 1 (intermediate I-82) ES / MS: 479.0, 481.0 (M+H) + ).

[0784] (R)-2-(4-bromo-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazol- 6-Carboxylic acid methyl ester isomer 2 (intermediate I-83) ES / MS: 479.0, 481.0 (M+H) + ).

[0785] Preparation of intermediate I-82 (Method 2) :

[0786] 2-[(4-bromo-2,5-difluoro-phenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole Methyl azole-5-carboxylate (intermediate I-82)N,N-diisopropylethylamine (10.2 mL, 58.4 mmol) was added to a solution of 2-(4-bromo-2,5-difluorophenyl)acetic acid (3301 mg, 13.2 mmol), methyl 4-amino-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate (intermediate I-80, 3.16 g, 12.0 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (6360 mg, 16.7 mmol) in DMF (20 mL) and CH3CN (20 mL). The solution was stirred overnight at room temperature. Then, 0.2 equivalents of 2-(4-bromo-2,5-difluoro-phenyl)acetic acid (600 mg, 2.39 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (930 mg, 2.39 mmol) were added to the mixture, and stirring was continued until complete conversion to the product. The crude mixture was diluted with 200 mL of EtOAc and washed with saturated NH4Cl (200 mL), 5% LiCl (100 mL), saturated NaHCO3 (100 mL), and brine (100 mL). The organic extract was dried over sodium sulfate to give methyl 4-[[2-(4-bromo-2,5-difluoro-phenyl)acetyl]amino]-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate.

[0787] A solution of methyl 4-[[2-(4-bromo-2,5-difluoro-phenyl)acetyl]amino]-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate (5.96 g, 12.0 mmol) in AcOH (60 mL) was heated to 180 °C for 90 min in a microwave reactor. The mixture was concentrated, diluted with EtOAc, and washed with saturated NaHCO3 and brine. The mixture was dried over sodium sulfate and purified by silica gel column chromatography (elution: EtOAc / hexane) to give methyl 2-[(4-bromo-2,5-difluoro-phenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylic acid (intermediate I-82). ES / MS: 478.6, 480.6 (M+H) +).1H NMR (400MHz, chloroform-d) δ8.55(s,1H),8.02(dd,J=8.5,1.5Hz,1H),7.78(d,J=8.5Hz,1H),7.37(dd,J=8.7,5.6Hz,1H),7.12(dd,J=8.4,6.3H z,1H),4.59(d,J=10.5Hz,2H),4.40(dd,J=11.1,7.3Hz,1H),4.31(s,2H),3.97(s,4H),3.80(d,J=8.8Hz,1H),1.35(s,3H),0.67(s,3H).

[0788] Preparation of intermediate I-84 :

[0789]

[0790] 2-[(6-bromo-2-pyridyl)oxymethyl]thiazolyl-5-carboxylonitrile (I-84) To a solution of 6-bromopyridin-2-ol (500 mg, 2.9 mmol) in acetonitrile (10 mL), 2-(bromomethyl)thiazolyl-5-carboxynitrile (I-63) (584 mg, 2.9 mmol) and cesium carbonate (1.34 g, 4.1 mmol) were added, and the mixture was stirred at 65 °C for 1 hour. After completion, the mixture was filtered through a Celite filter, concentrated, and purified by silica gel column chromatography (elution: EtOAc / hexane) to give I-84. ES / MS: 296.0, 298.0 (M+H) + ).

[0791] Preparation of intermediate I-85 :

[0792]

[0793] 2-[[4-[6-[(6-chloro-4-methoxy-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl Methyl benzimidazole-5-carboxylic acid ester (I-85) Following the method described for intermediate I-23, methyl 2-[[4-[6-[(6-chloro-4-methoxy-3-pyridinyl)methoxy]-2-pyridinyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetanebut-2-yl]methyl]benzimidazole-5-carboxylic acid was prepared by replacing 5-(bromomethyl)-2-chloro-4-fluoropyridinyl with 5-(bromomethyl)-2-chloro-4-fluoropyridinyl. ES / MS: 621.2 (M+H) + ).

[0794] Preparation of intermediate I-86 :

[0795]

[0796] 5-(bromomethyl)-4-methoxy-N-methylpyridinecarboxamide (I-86)5-(bromomethyl)-4-methoxy-N-methylpyridine amide was prepared by replacing 1-aminocyclopropane-1-carboxynitrile with methylamine HCl, following the method described for intermediate I-53. ES / MS: 259.2, 261.2 (M+H) + ).

[0797] Preparation of intermediate I-87 :

[0798]

[0799] 5-(bromomethyl)-4-chloro-N-methylpyridinecarboxamide (I-87) 5-(bromomethyl)-4-chloro-N-methylpyridinecarboxamide was prepared by replacing 1-aminocyclopropane-1-carboxynitrile with methylamine HCl and 4-chloro-5-methylpyridinecarboxylic acid with 4-methoxy-5-methylpyridinecarboxylic acid, following the method described for intermediate I-53. ES / MS: 263.0, 265.0 (M+H) + ).

[0800] Preparation of intermediate I-88 :

[0801]

[0802] 2-[[2,5-Difluoro-4-[6-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2- [I-]phenyl]methoxy]-2-pyridyl]phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid tert-butyl ester (I- 88) To a solution of 2-[[4-[6-[(4-bromo-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid tert-butyl ester (300 mg, 0.44 mmol) in 1,4-dioxane (20 mL), bis(pinacol)diboron (179 mg, 0.70 mmol), Pd(dppf)Cl2 (33 mg, 0.044 mmol), and potassium propionate (148 mg, 1.3 mmol) were added. Argon gas was bubbled through the mixture for 1 minute, and then the reaction vessel was sealed and heated to 110 °C in a microwave reactor for 45 minutes. After completion, the mixture was directly concentrated and purified by silica gel column chromatography (elution: EtOAc / hexane) to give I-88. ES / MS: 730.8 (M+H) + ).

[0803] Preparation of intermediate I-89 :

[0804]

[0805] (3S,4R)-4-(5-methoxycarbonyl-2-nitro-aniline)tetrahydrofuran-3-carboxylic acidDiisopropylethylamine (3.1 mL, 17.6 mmol) was added to a solution of methyl 3-fluoro-4-nitrobenzoate (700 mg, 3.52 mmol) and (3S,4R)-4-aminotetrahydrofuran-3-carboxylic acid hydrochloride (648 mg, 17.6 mmol) in DMF (2.5 mL) and THF (5 mL), and the resulting solution was heated to 70 °C for 3 days. After completion, the mixture was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated to obtain the desired product, which could be used without further purification. ES / MS: 311.2 (M+H + ).

[0806] 3-[[(3R,4S)-4-(methylcarbamoyl)tetrahydrofuran-3-yl]amino]-4-nitrobenzoate methyl ester Dissolve (3S,4R)-4-(5-methoxycarbonyl-2-nitro-aniline)tetrahydrofuran-3-carboxylic acid (370 mg, 0.00119 mol), 1-hydroxybenzotriazole hydrate (0.192 g, 0.00125 mol), and methylamine (2000 mmol / L THF solution, 1.19 mL, 0.00239 mol) in tetrahydrofuran (8.00 mL), then add triethylamine (0.151 g, 0.00149 mol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.251 g, 0.00131 mol). Stir the mixture overnight at RT. After completion, the mixture was diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated to obtain the desired product, which could be used without further purification. ES / MS: 324.2 (M+H) + ).

[0807] 4-Amino-3-[[(3R,4S)-4-(methylcarbamoyl)tetrahydrofuran-3-yl]amino]methyl benzoate (I- 89) To a solution of methyl 3-[[(3R,4S)-4-(methylcarbamoyl)tetrahydrofuran-3-yl]amino]-4-nitrobenzoate (168 mg, 0.52 mmol) in EtOH (2 mL) and THF (1 mL), carbon-supported palladium (10%, 111 mg, 0.10 mmol) was added. The mixture was then purged with H2 gas and stirred at 1 atm H2 for 1 hour. After completion, the mixture was filtered through a Celite filter, concentrated, and the crude residue I-89 was usable without further purification. ES / MS: 294.2 (M+H) + ).

[0808] Preparation of intermediate I-90 :

[0809]

[0810] 4-Amino-3-(((3R,4S)-4-(dimethylcarbamoyl)tetrahydrofuran-3-yl)amino)methyl benzoate (I-90) Methyl 4-amino-3-(((3R,4S)-4-(dimethylcarbamoyl)tetrahydrofuran-3-yl)amino)benzoate was prepared by replacing methylamine with dimethylamine, as described for intermediate I-89. ES / MS: 308.2 (M+H) + ).

[0811] Preparation of intermediate I-91 :

[0812]

[0813] 4-Bromo-1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]pyrazole To a solution of 4-bromo-1H-pyrazole (100 mg, 0.68 mmol) in 2-Me tetrahydrofuran (2 mL), bis(trimethylsilyl)aminopotassium (204 mg, 1.0 mmol) and 1-[2-(2-bromoethoxy)ethoxy]-2-methoxy-ethane (309 mg, 1.4 mmol) were added and the mixture was heated to 50 °C for 2 hours. After completion, the mixture was diluted with EtOAc (25 mL), washed with water (5 mL) and brine (5 mL), dried over MgSO4, filtered, and concentrated to obtain the desired product, which was ready for use without further purification. ES / MS: 293.3 (M+H) + ).

[0814] 1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Heterocyclopentane-2-yl)pyrazole (I-91) Following the manner described for intermediate I-88, 4-bromo-1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]pyrazole was converted to 1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazole (I-91). ES / MS: 341.1 (M+H) + ).

[0815] Preparation of intermediate I-92 :

[0816]

[0817] 2-(4-(6-((6-chloropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl) 1H-benzo[d]imidazolium-6-tert-butyl ester (I-92) Following the method described for intermediate I-18, 2-(4-(6-((6-chloropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-tert-butyl ester was prepared by replacing 4-bromo-1-(bromomethyl)-2-fluorobenzyl with 5-(bromomethyl)-2-chloropyridine. ES / MS: 621.2 (M+H) + ).

[0818] Preparation of intermediate I-93 :

[0819]

[0820] (S)-2-(4-(6-((6-bromo-4-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1- (Oxycyclobut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-93) Following the method described for intermediate I-19, (S)-2-(4-(6-((6-bromo-4-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester was prepared by replacing 4-bromo-1-(bromomethyl)-2-fluorobenzyl with 2-bromo-5-(bromomethyl)-4-fluoropyridinium. ES / MS: 654.0, 656.0 (M+H) + ).

[0821] Preparation of intermediate I-94 :

[0822]

[0823] 4-[(4-bromopyrimidin-2-yl)oxymethyl]-3-fluorobenzonitrile (I-94) 4-Bromo-2-chloropyrimidine (1.7 g, 8.8 mmol), 3-fluoro-4-(hydroxymethyl)benzonitrile (1.46 g, 9.7 mmol), potassium hydroxide (542 mg, 9.7 mmol), 18-crown-6 (116 mg, 0.44 mmol), and toluene (20 mL) were combined and heated to 110 °C for 2 hours. After completion, the mixture was diluted with EtOAc (100 mL), washed with water (25 mL), washed with brine (25 mL), dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (elution: EtOAc / hexane) to give I-94. ES / MS: 309.2 (M+H) + ).

[0824] Preparation of intermediate I-95 :

[0825]

[0826] 2-(4-(6-chloropyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazol-6- Methyl carboxylate (I-95) Following the method described for intermediate I-12, (S)-2-(4-(6-chloropyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetanebut-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester was prepared by replacing I-6 with I-1. ES / MS: 472.8 (M+H) + ).

[0827] Preparation of intermediate I-96 :

[0828]

[0829] 2-(4-Bromo-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I- 96) Following the method described for intermediate I-2, methyl 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid was prepared by replacing 2-(4-bromo-2,5-difluorophenyl)acetic acid with 2-(4-bromo-2,5-difluorophenyl)acetic acid. ES / MS: 439.8 (M+H) + ).

[0830] Preparation of intermediate I-97 :

[0831]

[0832] (5-chloro-1-methylpyrazol-3-yl)methanol 5-Chloro-1-methylpyrazol-3-carboxylic acid (700 mg, 4.36 mmol) was dissolved in THF (20.0 mL), and 1,1'-carbonyldiimidazole (1.41 g, 8.72 mmol) was added. The mixture was stirred at room temperature for 2 hours. After stirring, the mixture was cooled to 0 °C, and a solution of sodium borohydride (0.825 g, 21.8 mmol) in water (3.30 mL) was slowly added. The mixture was then warmed to room temperature over 40 minutes. After stirring, methanol (5 mL) was added, and the mixture was directly concentrated and purified by rapid chromatography (elution: EtOAc / hexane) to obtain the desired product.

[0833] 3-(bromomethyl)-5-chloro-1-methylpyrazole (I-97) (5-Chloro-1-methylpyrazol-3-yl)methanol (550 mg, 3.75 mmol) was dissolved in DCM (25.0 mL), and polymer-bound (4-diphenylphosphine) (78.7%, 1.50 g, 0.00450 mol) was added. The mixture was cooled to 0 °C, and then carbon tetrabromide (1.49 g, 0.00450 mol) was added in a single batch. The mixture was stirred at room temperature for 16 hours. After completion, the mixture was filtered, concentrated, and purified by rapid chromatography (elution buffer: EtOAc / hexane) to give I-97. ES / MS: 209.0, 211.0 (M+H) + ).

[0834] The following intermediates were prepared in accordance with the method described for intermediate I-97. :

[0835]

[0836] Preparation of intermediate I-98 :

[0837]

[0838] 5-(hydroxymethyl)-N-methylpyridine-2-carboxamide 5-(hydroxymethyl)pyridine-2-carboxylic acid (400 mg, 2.61 mmol), methylamine hydrochloride (194 mg, 2.87 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (1192 mg, 3.14 mmol) were dissolved in DMF (5.00 mL). N,N-diisopropylethylamine (2.27 mL, 13.1 mmol) was added, and the mixture was stirred for 30 minutes. After stirring, the mixture was diluted with EtOAc (50 mL), washed with water (10 mL), washed with brine (10 mL), dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (elution: MeOH / EtOAc / hexane) to obtain the desired product. ES / MS: 167.2 (M+H) + ).

[0839] 5-(bromomethyl)-N-methylpyridine-2-carboxamide (I-98) 5-(hydroxymethyl)-N-methylpyridine-2-carboxamide (106 mg, 0.638 mmol) and triphenylphosphine (0.167 g, 0.638 mmol) were dissolved in dichloromethane (2.60 mL) and carbon tetrabromide (0.212 g, 0.638 mmol) was added. The mixture was stirred for 15 minutes. After completion, the mixture was filtered, concentrated, and purified by rapid chromatography (elution buffer: EtOAc / hexane) to give I-98. ES / MS: 229.0 (M+H) + ).

[0840] The following intermediates were prepared in accordance with the method described for intermediate I-98. :

[0841]

[0842] Preparation of intermediate I-99 :

[0843]

[0844] (R)-4,4-Dimethyl-2-oxotetrahydrofuran-3-yltrifluoromethanesulfonate (I-99-1)(D)-(-)-pantolactone (4.20 g, 32.3 mmol, 1.0 equivalent) was added to a round-bottom flask. Anhydrous dichloromethane (20 mL) and pyridine (3.39 mL, 42.0 mmol, 1.30 equivalent) were added, and the resulting solution was cooled to -78 °C. A solution of trifluoromethanesulfonic anhydride (5.96 mL, 35.4 mmol, 1.10 equivalent) in dichloromethane (100 mL) was slowly added to the mixture through a feeding funnel while stirring at -78 °C. After addition, the mixture was kept at -78 °C with stirring for 30 minutes, and then the cooling bath was removed. The mixture was kept at room temperature with stirring for another 3 hours. The solvent was removed under vacuum, and the residue was dissolved in diethyl ether (200 mL) and washed with 10% sodium bicarbonate aqueous solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yltrifluoromethanesulfonate. ¹H NMR (500 MHz, CDCl₃) δ = 5.10 (s, ¹H), 4.13 (d, J = 9.5 Hz, ¹H), 4.07 (d, J = 9.5 Hz, ¹H), 1.28 (s, ³H), 1.18 (s, ³H).

[0845] (S)-3-Azide-4,4-Dimethyldihydrofuran-2(3H)-one (I-99-2) Add tetrabutylammonium azide (10.5 g, 36.8 mmol, 1.15 equivalents) to a round-bottom flask. Add anhydrous toluene (50 mL) and cool the resulting solution to 0 °C. Slowly add a solution of trifluoromethanesulfonic acid (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl ester (8.40 g, 32 mmol, 1.0 equivalents) in toluene (50 mL) prepared above through a feeding funnel at 0 °C. Keep the mixture at 0 °C for 30 minutes, then remove the cooling bath and stir the mixture at room temperature for 4 hours. Dilute the mixture with diethyl ether (200 mL) and wash with 10% sodium bicarbonate aqueous solution (200 mL) and brine (100 mL). Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate under vacuum to give 3-azido-4,4-dimethyldihydrofuran-2(3H)-one. The crude substance was immediately used for the next step without purification.

[0846] 3-Azide-4,4-Dimethyltetrahydrofuran-2-ol (I-99-3)3-Azide-4,4-dimethyldihydrofuran-2(3H)-one (4.16 g, 26.8 mmol) was dissolved in dichloromethane (40 mL) and cooled to -78 °C. Then, diisobutylaluminum hydride (1.0 M toluene solution) (32.2 mL, 32.2 mmol, 1.2 mmol) was slowly added at the same temperature. The mixture was stirred at -78 °C for 2 hours until no starting material remained. The reaction was quenched by adding a saturated solution of potassium sodium tartrate (100 mL). The mixture was extracted with dichloromethane (3 × 50 mL). The organic extract was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel) to give 3-azido-4,4-dimethyltetrahydrofuran-2-ol. 1H NMR (400MHz, CDCl3) δ = 5.58-5.29 (m, 1H), 3.93-3.76 (m, 2H), 3.66-3.50 (m, 2H), 1.19-1.08 (m, 6H).

[0847] 4-Azide-3,3-dimethyltetrahydrofuran (I-99-4) 3-Azide-4,4-dimethyltetrahydrofuran-2-ol was dissolved in dichloromethane (80 mL), cooled to -78 °C, and then BF3·Et2O (3.6 mL, 28.7 mmol, 1.5 equivalents) was slowly added, followed by triethylsilane (6.1 mL, 2.0 mmol) at the same temperature. The mixture was stirred at 0 °C for 4 hours until no starting material remained. Water (100 mL) was then added to the mixture. The resulting phase was separated, and the aqueous phase was extracted with dichloromethane (2 × 50 mL). The organic extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel) to give (S)-4-azido-3,3-dimethyltetrahydrofuran. 1H NMR (400MHz, CDCl3)=4.17 (dd, J=6.1, 9.8Hz, 1H), 3.77 (dd, J=3.9, 9.8Hz, 1H), 3.65 (dd, J=3.9, 6.1Hz, 1H), 3.58-3.50 (m, 2H), 1.13 (d, J=6.1Hz, 6H).

[0848] 4,4-Dimethyltetrahydrofuran-3-amine (I-99)10% carbon-supported palladium (2.14 g, 2.0 mmol, 0.15 equivalent) was added to 1.89 g (13.4 mmol) of 4-azido-3,3-dimethyltetrahydrofuran dissolved in ethyl acetate (50 mL). The mixture was stirred at room temperature under 1 atm hydrogen for 16 hours and then filtered through a Celite stopper. The solution was acidified in methanol (5.0 mL) with 4 M HCl and then concentrated under vacuum to give 4,4-dimethyltetrahydrofuran-3-amine hydrochloride. ¹H NMR (400 MHz, CDCl₃) = 4.09–4.05 (m, 1H), 3.72–3.68 (m, 1H), 3.59–3.56 (m, 1H), 3.44–3.42 (m, 1H), 3.35 (m, 1H), 1.07 (s, 6H).

[0849] Preparation of intermediate I-100 :

[0850]

[0851] 3-[[(S)-4,4-dimethyltetrahydrofuran-3-yl]amino]-4-nitrobenzoate (I-100) N,N-diisopropylethylamine (65.6 mL, 377 mmol) was added to a suspension of methyl 3-fluoro-4-nitrobenzoate (15.0 g, 75.3 mmol) and 4,4-dimethyltetrahydrofuran-3-amine hydrochloride (intermediate I-99, 12.6 g, 82.9 mmol) in THF (100 mL) and DMF (50 mL). The resulting solution was heated overnight at 80 °C. The crude mixture was diluted with EtOAc (300 mL) and washed with 5% LiCl (250 mL) and brine (250 mL). The organic extract was dried over sodium sulfate and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give methyl 3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]-4-nitrobenzoate, the structure of which was confirmed by X-ray crystallography. ¹H NMR (400MHz, chloroform-d) δ 8.24 (d, J = 8.8Hz, 2H), 7.57 (d, J = 1.6Hz, 1H), 7.27 (dd, J = 8.9, 1.7Hz, 1H), 4.41 (dd, J = 9.2, 6.8Hz, 1H), 4.02 (s, 1H), 3.97 (s, 3H), 3.76–3.64 (m, 3H), 1.26 (s, 3H), 1.18 (s, 3H). ES / MS: 295.0 (M+H+).

[0852]

[0853] 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3- [(3S)-4,4-Dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylic acid methyl ester (intermediate I-101)In a 200 mL flask, a suspension of 2-[(4-bromo-2,5-difluoro-phenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylic acid methyl ester (intermediate I-82, 2329 mg, 4.86 mmol), bis(pinacol)diboron (1506 mg, 5.93 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (541 mg, 0.729 mmol), and potassium propionate (1635 mg, 14.6 mmol) in dioxane (24 mL) was degassed with argon for 5 minutes, and then heated at 110 °C for 50 minutes. The mixture was cooled to room temperature. Sodium carbonate (2000 mmol / L, 5.48 mL, 11.0 mmol) was added to the mixture. The mixture was stirred at room temperature for 5 minutes. Add [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (358 mg, 0.483 mmol) and 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (intermediate I-3, 2238 mg, 7.29 mmol) to the mixture. Degas the mixture with argon for 5 minutes, then heat at 90 °C for 1 hour and 15 minutes. Dilute the mixture with EtOAc and filter through Celite. The filtrate was washed with brine, dried over sodium sulfate, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylic acid (intermediate I-101), the structure of which was confirmed by X-ray crystallography. ES / MS: 626.6 (M+H+).1H NMR (400MHz, chloroform-d) δ8.56(s,1H),8.02(dd,J=8.5,1.5Hz,1H),7.79(dd,J=9.7,5.6Hz,2H),7.70 (dt,J=14.3,7.6Hz,2H),7.53(dt,J=7.3,1.1Hz,1H),7.49(dd,J=7.9,1.5Hz,1H),7.43(dd,J=9 .3,1.5Hz,1H),7.09(dd,J=11.3,6.0Hz,1H),6.86(d,J=8.1Hz,1H),5.61(s,2H),4.73-4.56(m, 2H), 4.46-4.32 (m, 34H), 3.96 (d, J = 6.8Hz, 4H), 3.81 (d, J = 8.7Hz, 1H), 1.36 (s, 3H), 0.69 (s, 3H).

[0854] Preparation of intermediate I-101 (Method 2) :

[0855]

[0856] (S)-4-(2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetamide Methyl benzoate (I-101-1)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate HATU (12.2 g, 32.3 mmol) was added to a solution of 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetic acid (intermediate I-7, 10.1 g, 25.3 mmol) and (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate (intermediate I-80, 6.07 g, 23.0 mmol) in DMF (36 mL) and MeCN (36 mL), followed by the addition of N,N-diisopropylethylamine (19.6 mL, 112 mmol), and the resulting solution was stirred overnight at room temperature. The mixture was then diluted with EtOAc and washed successively with saturated NH4Cl, 10% LiCl, saturated NaHCO3 (×2), 1N NaOH, and brine. The organic phase was dried over MgSO4, filtered, and concentrated to give (S)-4-(2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetamyl)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate (intermediate I-101-1), which was further processed under the assumption of 100% yield. ES / MS: 645.2 (M+1).

[0857] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(4,4-di- Methyltetrahydrofuran-3-yl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (intermediate I-101) Trifluoromethanesulfonic anhydride (5.79 mL, 34.4 mmol) was added dropwise to a solution of (S)-4-(2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetamyl)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate (I-101-1, 14.8 g, 23.0 mmol) and triphenylphosphine oxide (9.59 g, 34.4 mmol) in DCM at 0 °C under argon atmosphere for 10 minutes. The mixture was stirred for 15 minutes, brought to room temperature, and stirred for 25 minutes. The reaction system was quenched with saturated NaHCO3, and the phases were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, concentrated, and purified by silica gel rapid column chromatography (EtOAc / Hex gradient) to obtain (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (intermediate I-101).

[0858] Preparation of intermediate I-102 :

[0859]

[0860] 2-Bromo-6-[(4-Chloro-2-fluoro-phenyl)methoxy]pyridine (Intermediate I-102) (4-Chloro-2-fluoro-phenyl)methanol (800 mg, 5.0 mmol, 1.1 equivalents), 2-bromo-6-fluoropyridine (800 mg, 4.6 mol, 1.0 equivalents), and cesium carbonate (2.3 g, 6.8 mmol, 1.5 equivalents) were added to a round-bottom flask. Anhydrous acetonitrile (15 mL) was added, and the resulting mixture was heated to reflux and stirred for 12 hours. After cooling to room temperature, the mixture was filtered through a Celite stopper and then concentrated under vacuum. The residue was purified by column chromatography (silica gel, EtOAc / hexane gradient) to give the title compound. ES / MS m / z: 317.8 (M+H) + .

[0861] Preparation of intermediate I-103 :

[0862]

[0863] 2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3- [(3S)-4,4-Dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylic acid methyl ester (intermediate I-103) To a 25-mL microwave-safe vial, add methyl 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylic acid (intermediate I-82, 800 mg, 1.67 mmol, 1.0 equivalent), PdCl2(dppf)2 (186 mg, 0.25 mmol, 0.15 equivalent), potassium propionate (560 mg, 5.01 mmol, 3.0 equivalent), and B2Pin2 (510 mg, 2.00 mol, 1.2 equivalent). Add anhydrous 1,4-dioxane (10 mL) and purge the resulting mixture with argon for 2 minutes. Seal the mixture and microwave to 120°C with stirring for 1 hour. After cooling to room temperature, 2-bromo-6-[(4-chloro-2-fluoro-phenyl)methoxy]pyridine (intermediate I-102, 580 mg, 1.84 mmol, 1.1 equivalents), PdCl2(dppf)2 (62 mg, 0.0834 mmol, 0.05 equivalents), and 2M Na2CO3 aqueous solution (2.0 mL, 4.17 mmol, 2.5 equivalents) were added separately. The resulting mixture was heated to 100 °C under argon atmosphere and stirred for 3 hours, then cooled to room temperature and filtered through a Celite stopper and MgSO4. The filtrate was concentrated and purified by column chromatography (silica gel, EtOAc / hexane gradient) to give the title compound. ES / MS m / z: 635.6 (M+H) + .

[0864] Preparation of intermediate I-104 :

[0865]

[0866] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyl) Tetrahydrofuran-3-yl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (intermediate I-104) 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetic acid (intermediate I-7, 500 mg, 1.26 mmol), methyl 4-amino-3-[(4,4-dimethyltetrahydrofuran-3-yl)amino]benzoate (intermediate I-25, 365 mg, 1.38 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (573 mg, 1.51 mmol) were mixed in DMF (5.00 mL), and N,N-diisopropylethylamine (1.09 mL, 6.28 mmol) was added. The mixture was stirred at room temperature for 3 hours. The mixture was partitioned between EtOAc and saturated NH4Cl aqueous solution. The organic phase was dried, filtered, and concentrated under vacuum. The crude product was dissolved in acetic acid (2 mL) and heated to 100 °C for 72 hours. The resulting mixture was then concentrated under vacuum and washed with EtOAc and saturated NaHCO3 aqueous solution. The organic phase was dried, filtered, and concentrated under vacuum. The title compound was obtained by rapid silica gel chromatography (EtOAc / hexane). ES / MS m / z 627.2 (M+H) + .

[0867] Preparation of intermediate I-105 :

[0868]

[0869] 4-Bromo-2-[(4-Chloro-2-fluoro-phenyl)methoxy]pyrimidine (Intermediate I-105)Add (186 mg, 1.16 mmol) of (4-chloro-2-fluoro-phenyl)methanol to 50 mL of RBF and then to 6 mL of THF. Place the flask under nitrogen and cool to 0 °C. Add potassium tert-butoxide (1.05 mL, 0.362 mmol, 1 M THF) dropwise and stir the solution at 0 °C for 15 minutes. Add 250 mg, 1.05 mmol, of 4-bromo-2-methanesulfonyl-pyrimidine to 6 mL of THF in a separate 50 mL RBF and cool the mixture to -78 °C. Place the first solution (deprotonated alcohol) in a syringe and add it dropwise to the second solution at -78 °C. Stir the solution at -78 °C for 1 hour, then add 1 mL of water dropwise and warm the solution to room temperature. Dilute the solution with EtOAc and water, and add 2 mL of saturated NH4Cl aqueous solution to acidify the solution. Then separate the layers and extract the aqueous layer once with EtOAc. The combined organic layers were dried over MgSO4, filtered, concentrated, and purified by silica gel rapid column chromatography (EtOAc / Hex gradient) to obtain 4-bromo-2-[(4-chloro-2-fluoro-phenyl)methoxy]pyrimidine (intermediate I-105). ES / MS m / z: 318.9 (M+H) + .

[0870] Preparation of intermediate I-106 :

[0871]

[0872] (S)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluoro-4-nitrobenzoate (intermediate I-) 106) N,N-diisopropylethylamine (8.86 mL, 50.9 mmol) was added to a solution of methyl 3,5-difluoro-4-nitrobenzoate (2.21 g, 10.2 mmol) and (S)-4,4-dimethyltetrahydrofuran-3-amine hydrochloride (intermediate I-99, 1.70 g, 11.2 mmol) in tetrahydrofuran (12.5 mL) and N,N-dimethylformamide (6.0 mL). The mixture was stirred overnight at 70 °C and then cooled to room temperature. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound, which could be used for subsequent steps without further purification.

[0873] Preparation of intermediate I-107 :

[0874]

[0875] (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (intermediate I-) 107)Methyl (S)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluoro-4-nitrobenzoate (intermediate I-106, 2.88 g, 10.2 mmol) was dissolved in EtOAc and placed under argon. 10% carbon-supported palladium (1.08 g, 1.02 mmol) was added to the mixture, and then the mixture was placed under hydrogen. The mixture was stirred overnight, then filtered through a Celite filter and concentrated under vacuum. Purification by silica gel rapid column chromatography (EtOAc / hexane gradient) yielded methyl (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (intermediate I-107). ES / MS m / z: 283.2 (M+H) + .

[0876] Preparation of intermediate I-108 :

[0877]

[0878] (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamyl)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino Methyl 5-fluorobenzoate (I-108-1) To a solution of (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (intermediate I-107, 2000 mg, 7.08 mmol) and 2-(4-bromo-2,5-difluorophenyl)acetic acid (1867 mg, 7.44 mmol) in MeCN (10.0 mL) cooled to 0 °C, 1-methylimidazole (2.91 g, 2.82 mL, 35.4 mmol) was added, followed by N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (2.39 g, 8.50 mmol). The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was concentrated under vacuum to obtain methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (I-108-1), which can be proceeded to the next step without further purification.

[0879] 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluorobenzene methyl 5-imidazolium carboxylate (intermediate I-108)Phosphorus oxychloride (2.6 g, 17 mmol, 1.6 mL) was added to 21 mL of methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (I-108-1, 2.2 g, 4.3 mmol) in 1,2-dichloroethane. The solution was heated to 80 °C for 24 hours and then cooled to room temperature. An aliquot of 20 mL of water was added and stirred for 1 hour, followed by the addition of an aqueous sodium hydroxide solution (26 mL, 51 mmol, 2 M). The mixture was diluted with DCM, the layers were separated, and the organic phase was washed with brine, dried over MgSO4, filtered, and concentrated. The methyl ester of 2-[(4-bromo-2,5-difluoro-phenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluorobenzimidazole-5-carboxylic acid (intermediate I-108) was obtained by silica gel chromatography (EtOAc / hexane gradient). ES / MS m / z: 497.0 (M+H) + .

[0880] Preparation of intermediate I-109 :

[0881]

[0882] 4-[(6-bromo-3-fluoro-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (Intermediate I-109) Cesium carbonate (15.2 g, 25.6 mmol) was added to a solution of 6-bromo-2-chloro-3-fluoropyridine (4.90 g, 23.3 mmol) and 3-fluoro-4-(hydroxymethyl)benzonitrile (3.87 g, 25.6 mmol) in acetonitrile (40 mL). The mixture was stirred overnight at 60 °C and then cooled to room temperature. The mixture was diluted with water, extracted three times with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification was achieved by silica gel rapid column chromatography (EtOAc / hexane gradient) to give 4-[(6-bromo-3-fluoro-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (intermediate I-109). ES / MS m / z: 326.1 (M+H) + .

[0883] Preparation of intermediate I-110 :

[0884]

[0885] 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-5-fluoro-2-pyridyl]-2,5-difluoro-phenyl]methyl Methyl ester of [(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluoro-benzimidazole-5-carboxylic acid (intermediate I-110)Add methyl 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluorobenzimidazole-5-carboxylate (intermediate I-108, 400 mg, 0.69 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentanane (184 mg, 0.73 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (77.7 mg, 0.1 mmol), potassium propionate (233 mg, 2.08 mmol), and 2.5 mL of 1,4-dioxane to a 2 mL microwave-safe vial. Bubble the mixture through argon gas for 5 minutes, then heat in a microwave at 120 °C for 1 hour. Sodium carbonate (0.72 mL, 1.44 mmol, 2 M) was then added, followed by 4-[(6-bromo-3-fluoro-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (intermediate I-109, 247 mg, 0.76 mmol). The mixture was heated to 110 °C for 1 hour, then filtered, concentrated, and purified by silica gel chromatography (EtOAc / hexane gradient) to give methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-5-fluoro-2-pyridyl]-2,5-difluorophenyl]methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluorobenzimidazole-5-carboxylic acid (intermediate I-110). ES / MS m / z: 663.6 (M+H) + .

[0886] Preparation of intermediate I-111 :

[0887]

[0888] (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyl) Methyl tetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxylate (intermediate I-111)Add methyl 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluorobenzimidazole-5-carboxylate (intermediate I-108, 45 mg, 0.09 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentanane (24 mg, 0.09 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (10.2 mg, 0.01 mmol), potassium propionate (30.4 mg, 0.27 mmol), and 2.5 mL of 1,4-dioxane to a 2 mL microwave-safe vial. Bubble the mixture through argon gas for 5 minutes, then heat in a microwave at 120 °C for 1 hour. Sodium carbonate (0.09 mL, 0.188 mmol, 2 M) was then added, followed by 4-bromo-2-[(4-chloro-2-fluoro-phenyl)methoxy]pyrimidine (intermediate I-105, 46.0 mg, 0.14 mmol). The mixture was heated to 110 °C for 1 hour, then filtered, concentrated, and purified by silica gel chromatography (EtOAc / hexane gradient) to give (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (intermediate I-111). ES / MS m / z: 656.1 (M+H) + .

[0889] Preparation of intermediate I-112 :

[0890]

[0891] (4-Chloro-6-fluoropyridin-3-yl)methanol (I-112-1) NaBH4 (117 mg, 3.09 mmol) was added to a solution of 4-chloro-6-fluoronicotinaldehyde (470 mg, 2.95 mmol) in 12 mL MeOH at 0 °C, and the solution was stirred for 5 minutes. The reaction mixture was quenched with saturated NH4Cl and concentrated. It was dissolved in EtOAc, washed with water and then with brine, dried over MgSO4, filtered, and concentrated to give (4-chloro-6-fluoropyridin-3-yl)methanol (I-112-1). ES / MS: 161.9 (M+H) + .

[0892] 4-Chloro-5-(chloromethyl)-2-fluoropyridine (I-112-2)Thionyl chloride (0.53 mL, 7.4 mmol) was added to a solution of (4-chloro-6-fluoropyridin-3-yl)methanol (I-112-1, 476 mg, 2.95 mmol) in DCM (25 mL), and the resulting solution was stirred for 1 hour. More thionyl chloride (0.53 mL, 7.4 mmol) was added, and the resulting solution was stirred for 1 hour. More thionyl chloride (0.21 mL, 2.9 mmol) was added, and the resulting solution was stirred for 30 minutes. The mixture was concentrated, dissolved again in DCM, and saturated NaHCO3 was slowly added dropwise. The phases were separated, the organic phase was dried over MgSO4, filtered, and concentrated to obtain 4-chloro-5-(chloromethyl)-2-fluoropyridinium (I-112-2). 1H NMR (400MHz, chloroform-d) δ 8.30 (s, 1H), 7.05 (d, J = 2.7Hz, 1H), 4.67 (s, 2H).

[0893] 5-(((6-bromopyridin-2-yl)oxy)methyl)-4-chloro-2-fluoropyridine (I-112-3) A slurry of 6-bromopyridin-2-ol (557 mg, 3.2 mmol), 4-chloro-5-(chloromethyl)-2-fluoropyridine (I-112-2, 480 mg, 2.7 mmol), and Cs₂CO₃ (2.17 g, 6.7 mmol) in a CAN container (9 mL) was heated at 70 °C for 30 min. The mixture was filtered through a Celite filter, concentrated, and purified by silica gel rapid column chromatography (EtOAc / Hex gradient) to give 5-(((6-bromopyridin-2-yl)oxy)methyl)-4-chloro-2-fluoropyridine (I-112-3). ES / MS: 317.0 (M+H) + .

[0894] 5-(((6-bromopyridin-2-yl)oxy)methyl)-4-chloro-2-(1H-1,2,3-triazol-1-yl)pyridine (intermediate) I-112)A slurry of 5-(((6-bromopyridin-2-yl)oxy)methyl)-4-chloro-2-fluoropyridine (I-112-3, 110 mg, 0.31 mmol), 1H-1,2,3-triazole (0.018 mL, 0.31 mmol), and K₂CO₃ (87 mg, 0.63 mmol) in DMSO (1.4 mL) was heated at 70 °C for 4 hours. The mixture was diluted with brine and extracted twice with EtOAc. The combined organic phases were dried over MgSO₄, filtered, concentrated, and purified by silica gel rapid column chromatography (EtOAc / Hex gradient) to give 5-(((6-bromopyridin-2-yl)oxy)methyl)-4-chloro-2-(1H-1,2,3-triazol-1-yl)pyridine (intermediate I-112), as the earlier eluting isomer of the two isomers. ¹H NMR (400MHz, chloroform-d) δ 8.66 (s, ¹H), 8.58 (s, ¹H), 8.31 (s, ¹H), 7.84 (d, J = 1.2Hz, ¹H), 7.48 (t, J = 7.8Hz, ¹H), 7.13 (d, J = 7.5Hz, ¹H), 6.79 (d, J = 8.2Hz, ¹H), 5.54 (s, 2H).

[0895] Preparation of intermediate I-113 :

[0896]

[0897] (S)-2-(4-(6-((4-chloro-6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)methoxy)pyridin-2-yl)- 2,5-Difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (intermediate I-) 113)A slurry of (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (intermediate I-82, 20 mg, 0.04 mmol), bis(pinacolyl)diboron (13.8 mg, 0.05 mmol), potassium propionate (14 mg, 0.125 mmol), and bis(diphenylphosphine)ferrocene]palladium(II) dichloride (4.6 mg, 0.006 mmol) in dioxane (1 mL) was bubbled with argon for 5 minutes, sealed, and heated at 110 °C for 1 hour. The mixture was cooled to room temperature, sodium carbonate (2 M, 0.05 mL, 0.1 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Add a solution of bis(diphenylphosphine)ferrocene]palladium(II) dichloride (3.1 mg, 0.004 mmol) and 5-(((6-bromopyridin-2-yl)oxy)methyl)-4-chloro-2-(1H-1,2,3-triazol-1-yl)pyridine (intermediate I-112) in dioxane (1 mL), degas the mixture with Ar for 5 minutes, and then heat at 90 °C for 2 hours. The mixture was diluted with EtOAc, washed with brine (2×), dried over MgSO4, filtered, concentrated, and purified by silica gel rapid chromatography (EtOAc / hexane gradient) to give (S)-2-(4-(6-((4-chloro-6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (intermediate I-113). ES / MS m / z: 686.1 (M+H) + .

[0898] Preparation of intermediate I-114 :

[0899]

[0900] 4-[(6-bromo-2-pyridyl)oxymethyl]benzonitrile (intermediate I-114) A mixture of 4-(bromomethyl)benzonitrile (200 mg, 1.0 mmol), 6-bromopyridin-2-ol (180 mg, 1.0 mmol), and cesium carbonate (400 mg, 1.2 mmol) was stirred in acetonitrile (5 mL) at room temperature for 3 hours. The mixture was filtered through a Celite filter and concentrated under vacuum to give 4-[(6-bromo-2-pyridyl)oxymethyl]benzonitrile (intermediate I-114). ES / MS m / z: 289.2 (M+H) + .

[0901] Preparation of intermediate I-115 :

[0902]

[0903] 2-[[4-[6-[(4-cyanophenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[(3S)- [4,4-Dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylic acid methyl ester (intermediate I-115) To methyl 2-[(4-bromo-3-fluoro-phenyl)methyl]-3-[[(2S)-oxetane-2-yl]methyl]benzimidazole-5-carboxylic acid (intermediate I-82, 30 mg, 0.0626 mmol), bis(pinacol)diboron (23 mg, 0.090 mmol), potassium propionate (23 mg, 0.208 mmol), Pd(dppf)Cl2 (7.7 mg, 0.0104 mmol), and dioxane (1.5 mL) were added. The mixture was degassed under argon for 30 seconds and heated at 100 °C for 16 hours. Then sodium carbonate (2 M aqueous solution, 0.070 mL, 0.14 mmol) was added, and the mixture was stirred at room temperature for 1 minute. Then, more Pd(dppf)Cl2 (3.9 mg, 0.0052 mmol) was added, followed by 4-[(6-bromo-2-pyridyl)oxymethyl]benzonitrile (intermediate I-114, 20 mg, 0.0692 mmol). The mixture was sealed under argon and heated at 90 °C for 3 hours. The organic layer was purified directly by silica gel rapid chromatography (EtOAc / Hex gradient) to give methyl 2-[[4-[6-[(4-cyanophenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylic acid (intermediate I-115). ES / MS m / z: 609.5 [M+H] + .

[0904] Preparation of intermediate I-116 :

[0905]

[0906] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorophenyl)methyl acetate (I- 116-1)A mixture of (4-bromo-2,3,6-trifluorophenyl)acetic acid methyl ester (26.0 g, 91.9 mmol, 1.0 equivalent), bis(pinacol)diboron (30.3 g, 119.4 mmol, 1.3 equivalent), Pd(dppf)Cl2 (3.36 g, 4.6 mmol, 0.05 equivalent), and potassium propionate (36.1 g, 321.7 mmol, 3.5 equivalent) in dioxane (400 mL) was degassed with argon. The mixture was stirred overnight at 100 °C. The mixture was cooled to room temperature, and then an aqueous solution of Na₂CO₃ (2.0 M, 92 mL, 183.8 mmol, 2.0 equivalents), Pd(dppf)Cl₂ (3.36 g, 4.6 mmol, 0.05 equivalents), and 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (intermediate I-3, 28.2 g, 91.9 mmol, 1.0 equivalents) were added. The mixture was degassed with argon, and then stirred at 100 °C for 2 hours. The mixture was diluted with EtOAc (1000 mL) and washed with brine (500 mL × 2). The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (petroleum ether / EtOAc gradient) to give methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorophenyl)acetate (I-116-1). ¹H NMR (400 MHz, DMSO-d6): δ 7.93–7.90 (m, 2H), 7.78–7.72 (m, 2H), 7.65–7.60 (m, 1H), 7.56–7.54 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.59 (s, 2H), 3.88 (s, 2H), 3.68 (s, 3H). ES / MS m / z: 431.0 [M+H] + .

[0907] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorophenyl)acetic acid (intermediate) I-116)A solution of methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorophenyl)acetic acid (I-116-1, 12.0 g, 27.9 mmol, 1.0 equivalent) and an aqueous solution of LiOH (2 M, 16.8 mL, 33.5 mmol, 1.3 equivalent) in CH3CN (130 mL) was stirred at room temperature for 5 hours. The mixture was acidified to pH 6 with 1 N HCl. The precipitated solid was collected by filtration and washed with water (10 mL × 2), then dried to give 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorophenyl)acetic acid (intermediate I-116). 1H NMR (400MHz, DMSO-d6): δ7.93-7.90(m,2H),7.89-7.86(m,2H),7.50-7.42(m,2H),6.98(d,J=8.4Hz,1H),5.58(s,2H),3.28(s,2H).ES / MS m / z:417.0[M+H] + .

[0908] Preparation of intermediate I-117 :

[0909]

[0910] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorobenzyl)-1-(4,4- Methyl dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazolium-6-carboxylate (intermediate 117)To a solution of 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorophenyl)acetic acid (intermediate I-116, 320 mg, 0.77 mmol) in DMF (20 mL), methyl 4-amino-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate (intermediate I-80, 203 mg, 0.77 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (292 mg, 0.77 mmol) and DIPEA (0.4 mL, 2.31 mmol) were added. The resulting solution was stirred at room temperature for 2 hours, and then the mixture was poured into 100 mL of saturated sodium bicarbonate solution and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with 20 mL of brine and dried over MgSO4. The organic layer was dried and concentrated. The resulting residue was dissolved in 5.0 mL of acetic acid and stirred at 100 °C for 16 hours. The mixture was cooled and the solvent was removed under vacuum. The mixture was diluted with 50 mL of EtOAc and washed with 50 mL of saturated NaHCO3 aqueous solution. The organic layer was dried over sodium sulfate. The organic layer was dried and concentrated. It was purified by silica gel chromatography (elution: EtOAc / hexane) to give (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (intermediate 117). ES / MS: 645.7 (M+H) + .

[0911] Preparation of intermediate I-118 :

[0912]

[0913] (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyl) Methyl tetrahydrofuran-3-yl)-1H-benzo[d]imidazolium-6-carboxylate (intermediate I-118)Add (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazolium-6-carboxylate (intermediate I-82, 100 mg, 0.21 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (15.5 mg, 0.021 mmol), bis(pinacolyl)diboron (80 mg, 0.3 mmol), and potassium propionate (70 mg, 0.63 mmol) to a vial, followed by 1,4-dioxane (1.0 mL). Bubble argon gas through the solution for 3 minutes, then heat the mixture to 110 °C for 70 minutes. Add sodium carbonate aqueous solution (2.00 M, 0.21 mL, 0.42 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (6.6 mg, 0.009 mmol), and 4-bromo-2-[(4-chloro-2-fluoro-phenyl)methoxy]pyrimidine (intermediate I-105, 99.3 mg, 0.3 mol) to the mixture. Bubbling argon gas through the solution for 3 minutes was performed, followed by heating the mixture to 100 °C for 45 minutes. The mixture was filtered through a Celite filter, washed with DCM, and concentrated under vacuum. The crude residue was purified by silica gel rapid column chromatography (0%-100% EtOAc / hexane) to give (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (intermediate I-118). ES / MS m / z: 637.8 (M+H) + ).

[0914] Preparation of intermediate I-119 :

[0915]

[0916] 2-(4-bromo-2,3,6-trifluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazolium Methyl azole-6-carboxylate (intermediate I-119)To a solution of 2-(4-bromo-2,3,6-trifluorophenyl)acetic acid (1.2 g, 4.46 mmol) in ACN (50 mL), methyl 4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (intermediate I-25, 1.26 g, 4.46 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (1.5 g, 5.35 mmol), and 1-methylimidazole (1.83 mL, 22.3 mmol) were added. The resulting solution was stirred at room temperature for 16 hours, after which the mixture was poured into 100 mL of saturated sodium bicarbonate solution and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with 50 mL of brine and dried over MgSO4. The organic layer was dried and concentrated. The mixture was purified by silica gel chromatography (eluent: EtOAc / hexane) to give intermediate I-119-1, which was dissolved in 50.0 mL of acetic acid. The mixture was stirred at 120 °C for 40 hours. The mixture was cooled and the solvent was removed. The mixture was diluted with 100 mL of EtOAc and washed with 100 mL of saturated NaHCO3 aqueous solution. The organic layer was dried over sodium sulfate. The organic layer was dried and concentrated. It was purified by rapid silica gel column chromatography (eluent: EtOAc / hexane) to give methyl 2-(4-bromo-2,3,6-trifluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxylic acid (intermediate I-119). ES / MS: 515.6 (M+H) + .

[0917] Preparation of intermediate I-120 :

[0918]

[0919] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorobenzyl)-1-(4,4-dimethyl) Methyl tetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxylate (intermediate I-120)Add [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (43.2 mg, 0.058 mmol), bis(pinacolyl)diboron (222 mg, 0.87 mmol), and potassium propionate (196 mg, 1.75 mmol) to methyl 2-(4-bromo-2,3,6-trifluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazol-6-carboxylate (intermediate I-119, 300 mg, 0.58 mmol), then add 1,4-dioxane (3.0 mL). Bubble argon gas through the solution for 3 minutes, then heat the mixture to 110 °C for 90 minutes. Add sodium carbonate aqueous solution (2.00 M, 0.58 mL, 1.16 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (18.1 mg, 0.024 mmol), and 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (intermediate I-3, 268 mg, 0.87 mmol) to the mixture. Bubble the solution with argon for 3 minutes, then heat the mixture to 100 °C for 60 minutes. Filter the mixture through a Celite filter, elute with DCM, and concentrate the filtrate under vacuum. The crude residue was purified by silica gel rapid column chromatography (EtOAc / Hex gradient) to give methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazolium-6-carboxylate (intermediate I-120). ES / MS m / z: 663.5 (M+H) + ).

[0920] Preparation of intermediate I-121 :

[0921]

[0922] tert-butyl 2,3-difluoro-4-nitrobenzoate A solution of 2,3-difluoro-4-nitrobenzoic acid (1.00 g, 4.92 mmol) in THF (15 mL) was treated with di-tert-butyl dicarbonate (2.15 g, 9.9 mmol) at ambient temperature, followed by treatment with 4-dimethylaminopyridine (180 mg, 1.5 mmol). The resulting mixture was heated to 40 °C for 3 hours. After completion, the mixture was poured into water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO4, and purified by silica gel chromatography (eluent: EtOAc / hexane) to give tert-butyl 2,3-difluoro-4-nitrobenzoate.

[0923] 4-Amino-2-fluoro-3-((2-methoxyethyl)amino)tert-butyl benzoate (intermediate I-121)2,3-Difluoro-4-nitrobenzene tert-butyl ester (200 mg, 0.77 mmol) was dissolved in THF (2 mL), followed by the addition of 2-methoxyethylamine (0.080 mL, 0.93 mmol) and diisopropylethylamine (0.40 mL, 2.3 mmol). The resulting mixture was heated to 60 °C for 16 hours. After completion, the mixture was directly concentrated, and the crude residue was dissolved in EtOAc (25 mL) and washed with saturated NH4Cl aqueous solution (2 × 5 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO4, concentrated, and allowed to proceed without purification. Crude 2-fluoro-3-((2-methoxyethyl)amino)-4-nitrobenzene tert-butyl ester was dissolved in EtOH (5 mL), followed by the addition of iron (216 mg, 3.9 mmol) and saturated NH4Cl aqueous solution (2 mL). The resulting mixture was heated to 60 °C for 3 hours. After completion, the solids were removed by washing and filtration with EtOAc (20 mL) and MeOH (20 mL). The filtrate was then concentrated, dissolved in EtOAc (25 mL), and washed with water (5 mL) and brine (5 mL). The organic layer was then dried over MgSO4 and purified by silica gel chromatography (elution: EtOAc / hexane) to give tert-butyl 4-amino-2-fluoro-3-((2-methoxyethyl)amino)benzoate (intermediate I-121). ES / MS: 284.9 (M+H) + ).

[0924] Preparation of intermediate I-122 :

[0925]

[0926] 2-(4-bromo-2,5-difluorobenzyl)-7-fluoro-1-(2-methoxyethyl)-1H-benzo[d]imidazol-6-carboxylic acid tert-butyl Ester (Intermediate I-122)To a solution of 2-(4-bromo-2,5-difluoro-phenyl)acetic acid (318 mg, 1.27 mmol) and tert-butyl 4-amino-2-fluoro-3-(2-methoxyethylamino)benzoate (intermediate I-121, 250 mg, 0.9 mmol) in MeCN (8 mL), 1-methylimidazole (0.35 mL, 4.4 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (TCFH, 300 mg, 1.1 mmol) were added. The solution was stirred at room temperature for 2 hours, diluted with EtOAc, and washed with HCl (1 M, aqueous solution). The organic layer was concentrated to give tert-butyl 4-[[2-(4-bromo-2,5-difluoro-phenyl)acetyl]amino]-2-fluoro-3-(2-methoxyethylamino)benzoate (I-122-1), which was dissolved in 5 mL DCE and 0.38 mL acetic acid. The mixture was stirred at 60°C for 4 hours. The reaction system was quenched with NaHCO3 and extracted twice with DCM. The organic phase was washed with brine, dried, filtered, concentrated, and purified by silica gel rapid chromatography (EtOAc / hexane gradient) to give 2-(4-bromo-2,5-difluorobenzyl)-7-fluoro-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester (intermediate I-122). 1H NMR (400MHz, chloroform-d) δ7.86(dd,J=8.6,6.7Hz,1H),7.65(d,J=8.6Hz,1H),7.35(dd,J=8.7,5.6Hz,1H ), 7.13 (dd, J = 8.3, 6.4Hz, 1H), 4.62-4.40 (m, 4H), 3.78 (t, J = 5.1Hz, 2H), 3.29 (s, 3H), 1.64 (s, 9H).

[0927] Preparation of intermediate I-123 :

[0928]

[0929] 2-(4-(6-((4-cyanobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-7-fluoro-1-(2-methoxyethyl) 1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester (intermediate I-123)A suspension of 2-(4-bromo-2,5-difluorobenzyl)-7-fluoro-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester (intermediate I-122, 50 mg, 0.1 mmol), bis(pinacolyl)diboron (34 mg, 0.135 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (11.5 mg, 0.016 mmol), and potassium propionate (35 mg, 0.3 mmol) in dioxane (2 mL) was degassed with Ar for 20 minutes. The mixture was sealed and heated at 100 °C for 2 hours. Sodium carbonate (2.0 M, 0.1 mL, 0.2 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Add [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (6 mg, 0.008 mmol) and 4-[(6-bromo-3-fluoro-2-pyridinyl)oxymethyl]-3-fluorobenzonitrile (intermediate I-109, 34 mg, 0.1 mmol), degas the mixture with Ar2 for 10 min, then seal and heat at 90 °C for 3 h. Dilute the mixture with EtOAc and wash with brine. Dry the organic extract with sodium sulfate and separate chromatographically (eluent: EtOAc / hexane) to give 2-(4-(6-((4-cyanobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-7-fluoro-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester (intermediate I-123). ES / MS m / z: 665.2 (M+H + ).

[0930] Preparation of intermediate I-1001 :

[0931]

[0932] (1R,3R,5R)-3-[(2-amino-5-methoxycarbonyl-aniline)methyl]-2-azabicyclo[3.1.0]hexane tert-butyl alkyl-2-carboxylic acid (intermediate I-1001)Following the manner described for intermediate I-1, (1R,3R,5R)-3-[(2-amino-5-methoxycarbonyl-aniline)methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester was prepared by replacing 2-methoxyethylamine with (1R,3R,5R)-3-(aminomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester. ES / MS:362.2(M+H+).1H NMR (400MHz, chloroform-d) δ7.39(d,J=8.1Hz,1H),7.15(s,1H),6.63(d,J=8.1Hz,1H),4.58(t,J=11.0Hz,1H),3.87(s,3H),3.64(d,J=7.3Hz,1H),3.2 7-3.09(m,1H),3.00(t,J=11.0Hz,1H),2.56(q,J=11.7Hz,1H),1.95-1.70(m,1H),1.53(s,10H),0.81(q,J=7.1Hz,1H),0.57(d,J=5.7Hz,1H).

[0933] Preparation of intermediate I-1002 :

[0934]

[0935] 2-Bromo-4-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]pyrimidine (I-1002) Potassium tert-butoxide (0.333 g, 2.97 mmol) was added to a solution of [2-fluoro-4-(trifluoromethyl)phenyl]methanol (1.1 g, 5.65 mmol) in tetrahydrofuran (3 mL). The solution was then stirred at room temperature for 5 minutes. Next, 2-bromo-4-fluoropyrimidine (0.500 g, 2.83 mmol) in N,N-dimethylformamide (5 mL) was added, and the mixture was cooled to -78 °C. The mixture was then removed from the dry ice bath and stirred at room temperature over a weekend. Subsequently, the mixture was diluted with EtOAc and washed with 5% LiCl (2×) and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by rapid chromatography (eluent: EtOAc / hexane) to give the desired product. ES / MS: 351.0, 353.0 (M+H) + ¹H NMR (400MHz, chloroform-d) δ 8.31 (d, J = 5.7Hz, 1H), 7.66 (t, J = 7.5Hz, 1H), 7.48 (dd, J = 8.0, 1.5Hz, 1H), 7.41 (dd, J = 9.7, 1.7Hz, 1H), 6.79 (d, J = 5.7Hz, 1H), 5.56 (s, 2H). ¹⁹F NMR (376MHz, chloroform-d) δ -63.43, -115.50 (d, J = 7.5Hz).

[0936] Preparation of intermediate I-1003 :

[0937]

[0938] [2-Fluoro-4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methanol (I-1003) A suspension of (4-bromo-2-fluoro-phenyl)methanol (100 mg, 0.49 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1-(trifluoromethyl)pyrazole (153 mg, 0.59 mmol), 1,1'-bis(diisopropylphosphine)ferrocene palladium dichloride (29 mg, 0.049 mmol), and potassium carbonate (200 mg, 1.4 mmol) in 99.8% anhydrous 1,4-dioxane (2 mL) and water (1 mL) was degassed with argon for 5 min and then heated at 100 °C for 1 h. After completion, the mixture was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by rapid chromatography (eluent: EtOAc / hexane) to obtain the desired product. ES / MS: 261.2 (M+H) + 1H NMR (400MHz, chloroform-d) δ 8.06 (s, 1H), 8.04 (t, J = 0.9Hz, 1H), 7.51 (t, J = 7.8Hz, 1H), 7.33 (dd, J = 7.8, 1.7Hz, 1H), 7.22 (dd, J = 10.8, 1.7Hz, 1H), 4.82 (s, 2H). 19F NMR (376MHz, chloroform-d) δ -61.00, -119.32.

[0939] Preparation of intermediate I-1004 :

[0940]

[0941] methyl 6-(1,2,4-triazol-1-yl)pyridine-3-carboxylic acid A suspension of methyl 6-chloropyridine-3-carboxylate (500 mg, 2.91 mmol), 1H-1,2,4-triazole (282 mg, 4.08 mmol), and potassium carbonate (564 mg, 4.08 mmol) in NMP (10 mL) was heated overnight at 80 °C. Afterward, the mixture was diluted with EtOAc and washed with 5% LiCl (2×) and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by rapid chromatography (elution: EtOAc / hexane) to obtain the desired product. ES / MS: 205.2 (M+H) +¹H NMR (400MHz, chloroform-d) δ 9.27 (s, ¹H), 9.10 (dd, J = 2.2, 0.8Hz, ¹H), 8.51 (dd, J = 8.6, 2.2Hz, ¹H), 8.15 (s, ¹H), 8.01 (dd, J = 8.5, 0.8Hz, ¹H), 4.01 (s, ³H).

[0942] 6-(1,2,4-triazol-1-yl)pyridine-3-carboxylic acid A solution of methyl 6-(1,2,4-triazol-1-yl)pyridine-3-carboxylate (200 mg, 0.980 mmol) and lithium hydroxide monohydrate (215 mg, 5.12 mmol) in CH3CN (9 mL) and water (3 mL) was stirred overnight at room temperature. The mixture was then diluted with EtOAc. The pH was adjusted to approximately 6 with 1 N HCl (2.8 mL), and the solution was filtered and air-dried to obtain the desired product, which could be used in the next step without further purification. ES / MS: 191.2 (M+H + ).1H NMR (400MHz, DMSO-d6) δ9.48 (s, 1H), 9.01 (d, J = 2.2Hz, 1H), 8.52 (dd, J = 8.5, 2.2Hz, 1H), 8.38 (s, 1H), 7.99 (d, J = 8.6Hz, 1H).

[0943] [6-(1,2,4-triazol-1-yl)-3-pyridyl]methanol (I-1004) 1,1'-carbonyldiimidazole (261 mg, 1.61 mmol) was added to a solution of 6-(1,2,4-triazol-1-yl)pyridine-3-carboxylic acid (153 mg, 0.805 mmol) in THF (6 mL). The solution was stirred fo...

Claims

1. A compound of formula (II): (II) Or its pharmaceutically acceptable salt, wherein R 1 To be optionally controlled by 1, 2 or 3 R 4 Substituted phenyl or 6-membered heteroaryl; X 1 -C(H) = or -C(R) 8 = X 4 -C(H)=, -C(R) 8 = or N; Each R 4 Independently halogenated or -CN; Each R B Independently for C 1-9 Alkyl, C 1-8 Halogenated alkyl groups or halogens; Each R 8 Independently hydrogen or halogen; and n can be 0, 1, 2, or 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 1 It is a phenyl group that has been substituted with halogen or -CN.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 1 For those substituted with halogen or -CN .

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 for: , , , , , or .

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8 It can be F or Cl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: .

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: 。 8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: 。 9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: 。 10. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.

12. Use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or condition mediated by glucagon-like peptide-1 receptor (GLP-1R), wherein the GLP-1R-mediated disease or condition is a liver disease or metabolic disease.

13. The use according to claim 12, wherein the disease or condition includes liver disease.

14. The use according to claim 13, wherein the disease or condition includes liver fibrosis or non-alcoholic fatty liver disease (NAFLD).

15. The use according to claim 14, wherein the disease or condition includes non-alcoholic steatohepatitis (NASH), cirrhosis, compensated liver fibrosis, decompensated liver fibrosis, hepatocellular carcinoma, primary biliary cirrhosis (PBC), or primary sclerosing cholangitis (PSC).

16. The use according to claim 13, wherein the disease or condition includes non-alcoholic fatty liver disease (NAFLD).

17. The use according to claim 14, wherein the disease or condition includes non-alcoholic steatohepatitis (NASH).

18. The use according to claim 12, wherein the disease or condition includes metabolic diseases.

19. The use according to claim 18, wherein the disease or condition includes type 1 diabetes or insulin resistance.

20. The use according to claim 12, wherein the disease or condition includes type II diabetes, prediabetes, idiopathic type I diabetes, latent autoimmune diabetes, adolescent-onset adult-onset diabetes, early-onset diabetes, malnutrition-related diabetes, gestational diabetes, hyperglycemia, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, obesity, eating disorders, sleep apnea, and weight gain. The following conditions may be associated with diabetes, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, left ventricular hypertrophy, Parkinson's disease, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, angina pectoris, premenstrual syndrome, thrombosis, atherosclerosis, impaired glucose metabolism, restenosis, dementia, or Alzheimer's disease.

21. The use according to claim 12, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.

22. The use according to claim 21, wherein the additional therapeutic agent comprises an anti-obesity agent, said anti-obesity agent including but not limited to peptide YY or analogues thereof, neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 agonists, NPYR5 antagonists, cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors, human islet peptide (HIP), melanocortin receptor 4 agonists (MC4R), melanin condensing hormone receptor 1 antagonists, farnesoid X receptor (FXR) agonists, apoptosis signal-regulated kinase (ASK-1) inhibitors, zonisamide, phentermine alone or in combination with topiramate, norepinephrine / dopamine reuptake inhibitors, opioid receptor antagonists, combinations of norepinephrine / dopamine reuptake inhibitors and opioid receptor antagonists, GDF-15 analogues, sibutramine, cholecystokinin agonists, amylin and its analogues, leptin and its analogues, serotonergic agents, methionine aminopeptidase 2 ( MetAP2 inhibitors, benzomorpholine, diethylamine acetone, benzylphenamine, SGLT2 inhibitors, SGLTL1 inhibitors, dual SGLT2 / SGLT1 inhibitors, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, biotin, MAS receptor modulators, or glucagon receptor agonists alone or in combination with another GLP-1R agonist, peroxisome proliferator-activated receptor α (PPARα) agonists, fish oil, acetyl-CoA carboxylase (ACC) inhibitors, TGFβ antagonists, GFRAL agonists, and / or their pharmaceutically acceptable salts.

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