GLP-1R agonists and uses thereof

Abstract

The present invention provides GLP-1R agonists, pharmaceutical compositions thereof and methods of use thereof. JPEG2026504883000094.jpg49170(I)

Description

[Technical Field]

[0001] This application claims priority from International Patent Applications PCT / CN2023 / 072748, PCT / CN2023 / 085615 and PCT / CN2023 / 093742, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to compounds, or pharmaceutically acceptable salts thereof, that are capable of binding to and activating the glucagon-like peptide-1 receptor (GLP-1R) and can be used in the treatment of metabolic disorders and related diseases, including, but not limited to, type 2 diabetes mellitus (T2DM), obesity, and non-alcoholic steatohepatitis (NASH). [Background technology]

[0003] Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted primarily from intestinal L cells after eating and drinking. GLP-1 plays an important role in enhancing insulin secretion, inhibiting glucagon release, and lowering blood glucose levels. Other functions of GLP-1 include delaying gastric emptying, suppressing appetite, and promoting beta-cell proliferation. The effects of GLP-1 are mediated by binding to GLP-1R, a glucose-dependent type B G protein-coupled receptor. Binding of GLP-1 to GLP-1R activates the heterotrimeric Gs protein, which subsequently enhances the activity of adenylate cyclase, thereby increasing the intracellular level of cyclic adenosine monophosphate (cAMP), and enhancing glucose-stimulated insulin secretion (Pflugers Archiv 1998, 435, 583-594; Basic and Clinical Pharmacology and Toxicology 2004, 95, 252-262). GLP-1 has a short half-life, remaining stable in the blood circulation for only 2-3 minutes, and is then inactivated by dipeptidyl peptidase 4 (DPP4) (European Journal of Biochemistry, 1993, Vol. 214, pp. 829-835; Endocrinology, 1995, Vol. 136, pp. 3585-3596; Diabetes, 2004, Vol. 53, pp. 654-662).

[0004] GLP-1R agonists have been widely studied to treat type 2 diabetes mellitus (T2DM), obesity, and related metabolic disorders. Based on their pharmacological properties, GLP-1R agonists can be divided into short-acting GLP-1R agonists (e.g., exenatide and lixisenatide) and long-acting GLP-1R agonists (e.g., exenatide-LAR, liraglutide, albiglutide, and dulaglutide). While there are reports in related literature, such as WO2006097537A2, these GLP-1R agonists are primarily administered via subcutaneous injection. The availability of oral GLP-1R agonists that are easy to administer is limited. For example, semaglutide, approved by the US FDA in 2019, is currently the only GLP-1R agonist that can be taken orally once daily.

[0005] Therefore, there is a strong need for novel GLP-1R agonists that have at least one of the following advantageous properties: ease of administration, solubility, drug interactions, efficacy, stability, selectivity, toxicity, drug tolerance, pharmacokinetics, and pharmacodynamics, as alternative pharmaceutical agents for treating metabolic disorders and related diseases (including, but not limited to, type 2 diabetes, obesity, and non-alcoholic steatohepatitis). In this regard, the present specification provides novel GLP-1R agonists. Summary of the Invention

[0006] The present invention relates to novel compounds, their pharmaceutically acceptable salts and pharmaceutical compositions, and their use as medicaments.

[0007] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] (I) During the ceremony, [ka] is a double bond or a single bond, X 1 , X 2 , X 5 and X 6 is independently selected from N and C; X 3 are O, S, N, and NR 7.3 and CR 7.3 is selected from X 4 is absent or N, C(O) and CR 7.4 is selected from Y 1 N and CR 8.1 is selected from Y 2 N and CR 8.2 is selected from Y 3 N and CR 8.3 is selected from Z1 is selected from N and C(O), Z 2 is selected from N and C; W is unsubstituted or independently R X substituted with at least one substituent selected from [ka] is selected from L is -CR C0 R D0 (CR C0 R D0 ) u -,-(CR C0 R D0 ) u O(CR C0 R D0 ) t -,-(CR C0 R D0 ) u NR A0 (CR C0 R D0 ) t -and-(CR C0 R D0 ) u S(O) r (CR C0 R D0 ) t - selected from Q 1 , Q 2 and Q 3 is C 3~10 selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; Each R 1 are independently hydrogen, halogen, and C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4Alkyl group, CN, NO2, -NR A1 R B1 , -OR A1 , -C(O)R A1 , -C(=NR E1 )R A1 , -C(=N - OR B1 )R A1 , -C(O)OR A1 , -OC(O)R A1 , -C(O)NR A1 R B1 , -C(O)NR A1 , -C(O)NR r R A1 , -C(O)NR A1 , -C(O)NR A1 , -C(O)NR A1 , -C(O)NR r , -C(O)NR A1 R B1 , -C(O)NR A1 , -C(O)NR E1 , -C(O)NR B1 , -C(O)NR A1 , -C(O)NR E1 , -C(O)NR A1 R B1 , -NR A1 , -C(O)R B1 , -C(=NR E1 , -C(=NR A1 R B1 , -NR A1 , -NR E1 , -C(=NR B1 , -OC(O)NR A1 R B1 , -NR A1 , -C(O)OR B1 , -NR A1 , -C(O)NR A1 R B1 , -NR A1 , -NR A1 , -C(S)NR B1 , -NR A1 , -C(=NR E1 , -C(=NR A1 R B1 , -S(O) r R A1 , -S(O)(=NR E1 , -S(O)(=NR B1 , -N = S(O)R A1 R B1, -S(O)2OR A1 , -OS(O)2R A1 , -NR A1 S(O) r R B1 , -NR A1 S(O)(=NR E1 )R B1 , -S(O) r NR A1 R B1 , -S(O)(=NR E1 )NR A1 R B1 , -NR A1 S(O)NR A1 R B1 , -NR A1 S(O)(=NR E1 )NR A1 R B1 , -P(O)R A1 R B1 and -P(O)(OR A1 )(OR B1 and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R X1 and is substituted with at least one substituent selected from Each R 2 are independently hydrogen, halogen, and C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl groups, CN, NO2, -NR A2 R B2 , -OR A2 , -C(O)R A2 , -C(=NR E2 )R A2 , -C(=N-OR B2 )R A2 , -C(O)OR A2, -OC(O)R A2 , -C(O)NR A2 R B2 , -C(O)NR A2 S(O)(=NR E2 )R B2 , -C(O)NR A2 S(O)(=NR E2 )NR A2 R B2 , -NR A2 C(O)R B2 , -C(=NR E2 )NR A2 R B2 , -NR A2 C(=NR E2 )R B2 , -OC(O)NR A2 R B2 , -NR A2 C(O)OR B2 , -NR A2 C(O)NR A2 R B2 , -NR A2 C(S)NR A2 R B2 , -NR A2 C(=NR E2 )NR A2 R B2 , -S(O)(=NR E2 )R B2 , -N=S(O)R A2 R B2 , -NR A2 S(O)(=NR E2 )R B2 , -S(O)(=NR E2 )NR A2 R B2 and -NR A2 S(O)(=NR E2 )NR A2 R B2 and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X2 and is substituted with at least one substituent selected from Each R 3 are independently hydrogen, halogen, and C 1~10 Alkyl group, C 2~10Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl groups, CN, NO2, -NR A3 R B3 , -OR A3 , -C(O)R A3 , -C(=NR E3 )R A3 , -C(=N-OR B3 )R A3 , -C(O)OR A3 , -OC(O)R A3 , -C(O)NR A3 R B3 , -C(O)NR A3 S(O) r R A3 , -C(O)NR A3 S(O)2OR A3 , -C(O)NR A3 S(O) r NR A3 R B3 , -C(O)NR A3 S(O)(=NR E3 )R B3 , -C(O)NR A3 S(O)(=NR E3 )NR A3 R B3 , -NR A3 C(O)R B3 , -C(=NR E3 )NR A3 R B3 , -NR A3 C(=NR E3 )R B3 , -OC(O)NR A3 R B3 , -NR A3 C(O)OR B3 , -NR A3 C(O)NR A3 R B3 , -NR A3 C(S)NR A3R B3 , -NR A3 C(=NR E3 )NR A3 R B3 , -S(O) r R A3 , -S(O)(=NR E3 )R B3 , -N=S(O)R A3 R B3 , -S(O)2OR A3 , -OS(O)2R A3 , -NR A3 S(O) r R B3 , -NR A3 S(O)(=NR E3 )R B3 , -S(O) r NR A3 R B3 , -S(O)(=NR E3 )NR A3 R B3 , -NR A3 S(O)NR A3 R B3 , -NR A3 S(O)(=NR E3 )NR A3 R B3 , -P(O)R A3 R B3 and -P(O)(OR A3 )(OR B3 and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R X3 and is substituted with at least one substituent selected from R 4 -C(O)OH, -C(O)NHS(O) r R A4 , -(CR c1 R d1 ) t NHS(O) r R A4 , a heterocyclyl group, and a heteroaryl group; R 5 is hydrogen, halogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl groups, CN, NO2, -NR A5 R B5 , -OR A5 and -C(O)R A5 and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from R X5 and is substituted with at least one substituent selected from Each R 6 are independently hydrogen, halogen, and C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl groups, CN, NO2, -NR A6 R B6 , -OR A6 and -C(O)R A6 and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from R X6 and is substituted with at least one substituent selected from Or, "R 5 and R 6 " or "Two R's 6 ", along with the atoms bonded to them, are C 3~10 a cycloalkyl group or a 4- to 12-membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the cycloalkyl and heterocyclyl groups are unsubstituted or independently selected from R X6 and is substituted with at least one substituent selected from R 7.3 and R 7.4 are independently hydrogen, halogen, C 1~10 Alkyl group, C2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl groups, CN, NO2, -NR A7 R B7 , -OR A7 , -C(O)R A7 , -C(=NR E7 )R A7 , -C(=N-OR B7 )R A7 , -C(O)OR A7 , -OC(O)R A7 , -C(O)NR A7 R B7 , -C(O)NR A7 S(O) r R A7 , -C(O)NR A7 S(O)2OR A7 , -C(O)NR A7 S(O) r NR A7 R B7 , -C(O)NR A7 S(O)(=NR E7 )R B7 , -C(O)NR A7 S(O)(=NR E7 )NR A7 R B7 , -NR A7 C(O)R B7 , -C(=NR E7 )NR A7 R B7 , -NR A7 C(=NR E7 )R B7 , -OC(O)NR A7 R B7 , -NR A7 C(O)OR B7 , -NR A7 C(O)NR A7 R B7 , -NR A7 C(S)NRA7 R B7 , -NR A7 C(=NR E7 )NR A7 R B7 , -S(O) r R A7 , -S(O)(=NR E7 )R B7 , -N=S(O)R A7 R B7 , -S(O)2OR A7 , -OS(O)2R A7 , -NR A7 S(O) r R B7 , -NR A7 S(O)(=NR E7 )R B7 , -S(O) r NR A7 R B7 , -S(O)(=NR E7 )NR A7 R B7 , -NR A7 S(O)NR A7 R B7 , -NR A7 S(O)(=NR E7 )NR A7 R B7 , -P(O)R A7 R B7 and -P(O)(OR A7 )(OR B7 and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R X7 and is substituted with at least one substituent selected from R 8.1 , R 8.2 and R 8.3 are independently hydrogen, halogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl groups, CN, NO2, -NR A8 R B8 , -OR A8 , -C(O)R A8 , -C(=NR E8 )R A8 , -C(=N-OR B8 )R A8 , -C(O)OR A8 , -OC(O)R A8 , -C(O)NR A8 R B8 , -C(O)NR A8 S(O) r R A8 , -C(O)NR A8 S(O)2OR A8 , -C(O)NR A8 S(O) r NR A8 R B8 , -C(O)NR A8 S(O)(=NR E8 )R B8 , -C(O)NR A8 S(O)(=NR E8 )NR A8 R B8 , -NR A8 C(O)R B8 , -C(=NR E8 )NR A8 R B8 , -NR A8 C(=NR E8 )R B8 , -OC(O)NR A8 R B8 , -NR A8 C(O)OR B8 , -NR A8 C(O)NR A8 R B8 , -NR A8 C(S)NR A8 R B8 , -NR A8 C(=NR E8 )NR A8 R B8 , -S(O) r R A8 , -S(O)(=NR E8 )RB8 , -N=S(O)R A8 R B8 , -S(O)2OR A8 , -OS(O)2R A8 , -NR A8 S(O) r R B8 , -NR A8 S(O)(=NR E8 )R B8 , -S(O) r NR A8 R B8 , -S(O)(=NR E8 )NR A8 R B8 , -NR A8 S(O)NR A8 R B8 , -NR A8 S(O)(=NR E8 )NR A8 R B8 , -P(O)R A8 R B8 and -P(O)(OR A8 )(OR B8 and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R X8 and is substituted with at least one substituent selected from R A0 is hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X0 and is substituted with at least one substituent selected from Each R A1 and R B1 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X1 and is substituted with at least one substituent selected from Or, R A1 and R B1 together with one or more atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, the ring being unsubstituted or containing 1, 2, or 3 R X1 may be substituted with a group, Each R A2 and R B2 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X2and is substituted with at least one substituent selected from Or, "R A2 and R B2 " together with the atom or atoms attached thereto form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the ring is unsubstituted or contains 1, 2, or 3 R X2 may be substituted with a group, Each R A3 and R B3 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X3 and is substituted with at least one substituent selected from Or, "R A3 and R B3 " together with the atom or atoms attached thereto form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the ring is unsubstituted or contains 1, 2, or 3 R X3 may be substituted with a group, R A4 is hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X4 and is substituted with at least one substituent selected from Each R A5 and R B5 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X5 and is substituted with at least one substituent selected from Or, "R A5 and R B5 " together with the atom or atoms attached thereto form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the ring is unsubstituted or contains 1, 2, or 3 R X5 may be substituted with a group, Each R A6 and R B6 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X6 and is substituted with at least one substituent selected from Or, "R A6 and R B6 " together with the atom or atoms attached thereto form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the ring is unsubstituted or contains 1, 2, or 3 R X6 may be substituted with a group, Each R A7 and R B7 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X7 and is substituted with at least one substituent selected from Or, R A7 and R B7 together with one or more atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, the ring being unsubstituted or containing 1, 2, or 3 R X7 may be substituted with a group, Each R A8 and R B8 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X8 and is substituted with at least one substituent selected from Or, R A8 and R B8 together with one or more atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, the ring being unsubstituted or containing 1, 2, or 3 R X8 may be substituted with a group, Each R C0 and R D0 are independently hydrogen, halogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X0and is substituted with at least one substituent selected from Or, R C0 and R D0 together with one or more carbon atoms attached thereto, C 3~10 a cycloalkyl group or a 4- to 12-membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the cycloalkyl and heterocyclyl groups are unsubstituted or independently selected from R X0 and is substituted with at least one substituent selected from Each R E1 , R E2 , R E3 , R E7 and R E8 are independently hydrogen, C 1~10 Alkyl groups, CN, NO2, -OR a1 , -SR a1 , -S(O) r R a1 , -C(O)R a1 , -C(O)OR a1 , -C(O)NR a1 R b1 and -S(O) r NR a1 R b1 wherein the alkyl group is unsubstituted or independently selected from R X and is substituted with at least one substituent selected from As a condition, Z 1 is N and X 2 is C and X 3 is CR 7.3 or N and X 4 does not exist and R 5 and R 6 or any two R 6 does not form a ring, and W [ka] and L is -CR C0 R D0 (CR C0 R D0 ) u - R when selected from C0 and R D0At least one of the following is CN, C 2~10 Alkenyl groups and C 2~10 R selected from alkynyl groups X0 is replaced by Each R X , R X0 , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 and R X8 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl groups, halogens, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 , -(CR c1 R d1 ) t OR b1 , -(CR c1 R d1 ) t C(O)R a1 , -(CR c1 R d1 ) t C(=NR e1 )R a1 , -(CR c1 R d1 ) t C(=N-OR b1 )R a1 , -(CR c1 R d1 ) t C(O)OR b1 , -(CR c1 R d1 ) t OC(O)R b1 , -(CRc1 R d1 ) t C(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(O)R b1 、-(CR c1 R d1 ) t C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )R b1 、-(CR c1 R d1 ) t OC(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(O)OR b1 、-(CR c1 R d1 ) t NR a1 C(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(S)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t S(O) r R b1 、-(CR c1 R d1 ) t S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) tN=S(O)R a1 R b1 , -(CR c1 R d1 ) t S(O)2OR b1 , -(CR c1 R d1 ) t OS(O)2R b1 , -(CR c1 R d1 ) t NR a1 S(O) r R b1 , -(CR c1 R d1 ) t NR a1 S(O)(=NR e1 )R b1 , -(CR c1 R d1 ) t S(O) r NR a1 R b1 , -(CR c1 R d1 ) t S(O)(=NR e1 )NR a1 R b1 , -(CR c1 R d1 ) t NR a1 S(O)NR a1 R b1 , -(CR c1 R d1 ) t NR a1 S(O)(=NR e1 )NR a1 R b1 , -(CR c1 R d1 ) t P(O)R a1 R b1 and -(CR c1 R d1 ) t P(O)(OR a1 )(OR b1 and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from RY and is substituted with at least one substituent selected from Each R a1 and R b1 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Y and is substituted with at least one substituent selected from Or, R a1 and R b1 together with one or more atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is optionally bound to one, two or three R Y may be substituted with a group, Each R c1 and R d1 are independently hydrogen, halogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Yand is substituted with at least one substituent selected from Or, R c1 and R d1 together with one or more carbon atoms bonded thereto form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and the ring is optionally bonded to one, two or three R Y may be substituted with a group, Each R e1 are independently hydrogen, C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, CN, NO2, -OR a2 , -SR a2 , -S(O) r R a2 , -C(O)R a2 , -C(O)OR a2 , -S(O) r NR a2 R b2 and -C(O)NR a2 R b2 is selected from Each R Y independently, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl groups, halogens, CN, NO2, -(CR c2 R d2 ) t NR a2 R b2 , -(CR c2 R d2 ) t OR b2 , -(CR c2 R d2 ) t C(O)R a2 , -(CRc2 R d2 ) t C(=NR e2 )R a2 、-(CR c2 R d2 ) t C(=N-OR b2 )R a2 、-(CR c2 R d2 ) t C(O)OR b2 、-(CR c2 R d2 ) t OC(O)R b2 、-(CR c2 R d2 ) t C(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(O)R b2 、-(CR c2 R d2 ) t C(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(=NR e2 )R b2 、-(CR c2 R d2 ) t OC(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(O)OR b2 、-(CR c2 R d2 ) t NR a2 C(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(S)NR a2 R b2 、-(CR c2 Rd2 ) t NR a2 C(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t S(O) r R b2 、-(CR c2 R d2 ) t S(O)(=NR e2 )R b2 、-(CR c2 R d2 ) t N=S(O)R a2 R b2 、-(CR c2 R d2 ) t S(O)2OR b2 、-(CR c2 R d2 ) t OS(O)2R b2 、-(CR c2 R d2 ) t NR a2 S(O) r R b2 、-(CR c2 R d2 ) t NR a2 S(O)(=NR e2 )R b2 、-(CR c2 R d2 ) t S(O) r NR a2 R b2 、-(CR c2 R d2 ) t S(O)(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t NR a2 S(O)2NR a2 R b2 、-(CR c2 R d2 ) t NR a2 S(O)(=NRe2 )NR a2 R b2 , -(CR c2 R d2 ) t P(O)R a2 R b2 and -(CR c2 R d2 ) t P(O)(OR a2 )(OR b2 ), each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from hydroxy group, CN, amino group, halogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino groups and di(C 1~10 substituted with at least one substituent selected from the group consisting of (alkyl)amino groups, Each R a2 and R b2 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino group, di(C 1~10 Alkyl)amino group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkylthio group, cycloalkylthio group, alkylamino group, cycloalkylamino group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from halogen, CN, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl group, hydroxy group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, amino group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino groups and di(C 1~10 substituted with at least one substituent selected from the group consisting of (alkyl)amino groups, Or, R a2 and R b2 together with one or more atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is optionally independently selected from halogen, CN, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl group, hydroxy group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, amino group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino groups and di(C 1~10 and optionally substituted with one or two substituents selected from: Each R c2 and R d2 are independently hydrogen, halogen, C 1~10 Alkyl group, C2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino group, di(C 1~10 Alkyl)amino group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkylthio group, cycloalkylthio group, alkylamino group, cycloalkylamino group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from halogen, CN, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl group, hydroxy group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, amino group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino groups and di(C 1~10 substituted with at least one substituent selected from the group consisting of (alkyl)amino groups, Or, R c2 and R d2 together with one or more carbon atoms bonded thereto form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and the ring is optionally independently selected from halogen, CN, C 1~10 Alkyl group, C 2~10 Alkenyl group, C2~10 Alkynyl group, C 3~10 Cycloalkyl group, hydroxy group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, amino group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino groups and di(C 1~10 and optionally substituted with one or two substituents selected from: Each R e2 are independently hydrogen, CN, NO2, C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, -C(O)C 1~4 Alkyl group, -C(O)C 3~10 Cycloalkyl groups, -C(O)OC 1~4 Alkyl group, -C(O)OC 3~10 Cycloalkyl groups, -C(O)N(C 1~4 alkyl)2, -C(O)N(C 3~10 cycloalkyl)2, -S(O)2C 1~4 Alkyl group, -S(O)2C 3~10 Cycloalkyl groups, -S(O)N(C 1~4 alkyl)2 and -S(O)2N(C 3~10 cycloalkyl)2; m, n, p, and q are independently selected from 0, 1, 2, 3, and 4; each r is independently selected from 0, 1, and 2; each t is independently selected from 0, 1, 2, 3, and 4; Each u is independently selected from 0, 1, 2, 3, and 4.

[0008] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or at least one pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] In another aspect, the present invention provides a method for modulating GLP-1R, comprising administering to a system or individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to modulate GLP-1R.

[0010] In another aspect, the present invention provides a method for treating, ameliorating or preventing a condition that inhibits the response of GLP-1R, comprising administering to a system or individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, optionally in combination with another therapeutic agent, to treat said condition.

[0011] The present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition mediated by the GLP-1R receptor. In certain embodiments, the compounds of the present disclosure can be used alone or in combination with a second therapeutic agent to treat a condition mediated by the GLP-1R.

[0012] The present disclosure also provides compounds of formula (I) or pharmaceutically acceptable salts thereof for treating conditions mediated by the GLP-1R receptor.

[0013] Specifically, the diseases described herein include, but are not limited to, autoimmune diseases, transplant-related diseases, infectious diseases, or diseases or conditions mediated by the GLP-1 receptor. The novel GLP-1R inhibitors provided herein have at least one of the advantageous properties of ease of administration, solubility, drug interactions, efficacy, stability, selectivity, toxicity, drug resistance, pharmacokinetics, and pharmacodynamics, and can be an alternative pharmaceutical for treating diseases and conditions mediated by the GLP-1 receptor (including, but not limited to, type 2 diabetes, obesity, and non-alcoholic steatohepatitis).

[0014] The present disclosure also provides a method for treating a disease or condition mediated by the GLP-1 receptor, comprising administering to a system or subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, optionally in combination with a second therapeutic agent, to treat said condition.

[0015] The present disclosure also provides use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or condition mediated by the GLP-1 receptor or modulating the GLP-1 receptor. Specifically, diseases or conditions mediated by the GLP-1 receptor include, but are not limited to, diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, arrhythmia, cerebral infarction, stroke, liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), dementia, Parkinson's disease, and diabetic nephropathy.

[0016] In the above methods of using the compounds according to the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a system including a cell or tissue, or to an individual, including a mammalian individual, for example a human or animal individual.

[0017] term Unless otherwise defined, all technical and scientific terms used in this patent have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise stated, the entire text of all patents, patent applications, and disclosed materials referenced in this patent are incorporated by reference. In the event that there are multiple definitions for the same term in this patent, the definition in this section shall prevail.

[0018] The general description above and the detailed description below are merely explanatory and not limiting of any claims. In this patent application, the use of the singular is to be understood to include the plural unless otherwise indicated. It should be noted that in the specification and claims, the singular refers to, for example, "one," "one," "the," and includes complex numbers unless the context indicates otherwise. It should also be noted that "or" means "and / or" unless otherwise indicated. Similar terms such as "comprises," "includes," and the like are not limiting.

[0019] Unless otherwise specified, the mass spectroscopy, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet / visible spectroscopy, and general pharmacological techniques used in this patent are conventional. Unless otherwise specified, the nomenclature, experimental methods, and techniques of analytical chemistry, organic synthetic chemistry, and drug and pharmaceutical chemistry in this patent are all known. Standard techniques can be used for chemical synthesis, chemical analysis, drug manufacture, formulation, and administration, and patient treatment. Reactions and purification techniques can be performed with reference to manufacturer's specifications, known conventional techniques, or methods described in this patent. The above techniques and manipulations can be performed using known general methods and those described in the references herein. In the specification, groups and substituents can be selected by one of ordinary skill in the art to form stable structures and compounds.

[0020] When substituents are represented by chemical formulas, the left-to-right representation of the substituents in the formula is the same as the right-to-left representation. For example, CH2O is the same as OCH2.

[0021] "Substituted" means that a hydrogen atom is replaced with a substituent. Note that the substituent on a particular atom is limited by its valency. When the bond connecting substituents shows a bond passing between two atoms in a ring, the substituent may be attached to any atom on the ring. When a substituent is listed but does not specify through which atom the substituent is attached to the remainder of the compound, the substituent may be attached through any atom in the substituent. Generally, when any substituent or group occurs multiple times in any component or compound, its definition at each occurrence is independent of its definition at every other occurrence. However, combinations of these substituents and / or variables are permissible only if such combinations result in stable compounds.

[0022] symbol" [ka] " represents the point of attachment to the rest of the molecule.

[0023] The structure of a compound may contain two or more variables (e.g., R 1 ) appear simultaneously, each variable is understood to be independently selected. As a non-limiting example, if a compound structure has two R 1 appear simultaneously, and one R 1 is a methyl group, and the other R 1 is F.

[0024] The term "optional" or "optionally" means that the event described below may or may not occur. The term covers situations in which the event may occur or may not occur.

[0025] As used herein, "C i~j The term "i- to j-membered" means that the moiety has i- to j-carbon atoms or i- to j-atoms. For example, "C 1~6"Alkyl group" means that the alkyl group has 1 to 6 carbon atoms. 3~10 A cycloalkyl group means that the cycloalkyl group has 3 to 10 carbon atoms.

[0026] "Hydrogen" is 1 H, 2 H, 3 Point to H.

[0027] Two or more R's n or R Xn (n is 1, 2, 3, 4, 5, 6, 7, etc.), then each R n Or each R Xn It should be understood that are independently selected.

[0028] When any variable (e.g., R) occurs more than one time in a compound structure, it is defined independently at each occurrence. Thus, for example, if a group is substituted with zero to two R, the group may optionally be substituted with at most two R, and R is independently selected at each occurrence. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0029] "One or more" or "at least one" means one, two, three, four, five, six, seven, eight, nine or more.

[0030] Unless otherwise explained, the term "hetero" refers to a heteroatom or heteroatom-containing group (i.e., a group containing heteroatoms), i.e., atoms other than carbon and hydrogen atoms or groups containing these atoms. Preferably, the heteroatoms are independently selected from O, N, S, P, etc. In embodiments involving two or more heteroatoms, the two or more heteroatoms may be the same, or the two or more heteroatoms may be partially or completely different.

[0031] The term "alkyl group," whether used alone or in combination with other terms, refers to a branched or straight-chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms. Unless otherwise specified, "alkyl group" refers to a C 1~10 Refers to alkyl groups. For example, "C 1~6 "C" in "Alkyl group" 1~6 " refers to a group having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. For example, "C 1~8 "Alkyl group" includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl groups.

[0032] The term "cycloalkyl group," whether used alone or in combination with other terms, refers to a saturated monocyclic or polycyclic (e.g., bicyclic or tricyclic) hydrocarbon ring system, typically having 3 to 16 ring atoms. The ring atoms of a cycloalkyl group are all carbon, and the group contains zero heteroatoms and zero double bonds. In polycyclic cycloalkyl groups, two or more rings may be fused together, bridged, or spiro-linked. Examples of monocyclic ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A bridged cycloalkyl group is a polycyclic ring system containing 3 to 10 carbon atoms and includes one or two alkylene bridges, each consisting of 1, 2, or 3 carbon atoms connecting two non-adjacent carbon atoms in the ring system. A cycloalkyl group may be fused with an aryl or heteroaryl group. In some embodiments, a cycloalkyl group is benzo-fused. Representative examples of bridged cyclic alkane systems include, but are not limited to, bicyclo[1.1.1]pentane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.03,7]nonane, and tricyclo[3.3.1.13,7]decane (adamantane). The cycloalkyl group may be attached to the parent molecular moiety through any substitutable atom in the ring system.

[0033] The term "cycloalkylene group" means a divalent cycloalkyl group. Examples of cycloalkylene groups include, but are not limited to, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, bicyclo[3.3.0]octene, bicyclo[2.2.1]octene, bicyclo[3.3.1]nonene, and the like.

[0034] The term "alkenyl group," whether used alone or in combination with other terms, refers to a straight-chain, branched-chain, or cyclic non-aromatic hydrocarbon group containing 2 to 10 carbon atoms and having at least one carbon-carbon double bond. In some embodiments, cyclic means monocyclic or polycyclic. In polycyclic alkenyl groups, two or more rings may be joined by fused, bridged, or spirocyclic rings. In some examples, one carbon-carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Thus, "C 2~6 "Alkenyl group" refers to an alkenyl group containing 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl groups. The straight, branched, or cyclic portions of the alkenyl group may contain double bonds and may be substituted, if a substituted alkenyl group is specified.

[0035] The term "cycloalkenyl group" refers to an alkenyl group having 3 to 30 carbon atoms (e.g., C3 to C4). 10 ) and a non-aromatic hydrocarbon ring system having one or more double bonds, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0036] The term "alkynyl group," whether used alone or in combination with other terms, refers to a straight-chain, branched-chain, or cyclic hydrocarbon group containing 2 to 10 carbon atoms and having at least one carbon-carbon triple bond. In some embodiments, there may be up to three carbon-carbon triple bonds. Thus, "C 2~6 "Alkynyl group" refers to an alkynyl group containing 2 to 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like. The straight, branched, or cyclic portions of an alkynyl group may contain triple bonds and may be substituted, if a substituted alkynyl group is specified.

[0037] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0038] The term "alkoxy group," whether used alone or in combination with other terms, refers to an alkyl group as defined above attached to an oxygen atom by a single bond. The alkoxy group and the molecule are attached via the oxygen atom. An alkoxy group may also be represented as -O-alkyl. 1~10 "Alkoxy group" refers to an alkoxy group containing 1 to 10 carbon atoms and may be a straight or branched chain structure. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.

[0039] The term "cycloalkoxy group," whether used alone or in combination with other terms, refers to a cycloalkyl group as defined above that is connected to an oxygen atom through a single bond. The cycloalkoxy group and the molecule are connected through the oxygen atom. A cycloalkoxy group may also be represented as -O-cycloalkyl. "C 3~10 "Cycloalkoxy" refers to a cycloalkoxy group containing 3 to 10 carbon atoms. The cycloalkoxy group may be fused with an aryl or heteroaryl group. In some embodiments, the cycloalkoxy group is benzofused. Cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0040] The term "alkylthio group," whether used alone or in combination with other terms, refers to an alkyl group as defined above that is connected to a sulfur atom through a single bond. The alkylthio group and the molecule are connected through the sulfur atom. The alkylthio group may also be represented as -S-alkyl. 1~10"Alkylthio group" refers to an alkylthio group containing 1 to 10 carbon atoms, and may have a linear or branched structure. Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hexylthio, and the like.

[0041] The term "cycloalkylthio group," whether used alone or in combination with other terms, refers to a cycloalkyl group as defined above connected to a sulfur atom through a single bond. The cycloalkylthio group and the molecule are connected through the sulfur atom. The cycloalkylthio group may also be represented as -S-cycloalkyl. "C 3~10 "Cycloalkylthio group" refers to a cycloalkylthio group containing 3 to 10 carbon atoms. The cycloalkylthio group may be fused with an aryl or heteroaryl group. In some embodiments, the cycloalkylthio group is benzofused. Examples of cycloalkylthio groups include, but are not limited to, cyclopropylthio, cyclobutylthio, and cyclohexylthio.

[0042] The term "alkylamino group," whether used alone or in combination with other terms, refers to an alkyl group as defined above that is connected to a nitrogen atom by a single bond. The alkylamino group and another molecule are connected through the nitrogen atom. The alkylamino group may be represented as -NH(alkyl). "C 1~10 The term "alkylamino group" refers to an alkylamino group containing 1 to 10 carbon atoms, and may have a linear or branched structure. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, and hexylamino groups.

[0043] The term "cycloalkylamino group," whether used alone or in combination with other terms, refers to a cycloalkyl group as defined above that is connected to a nitrogen atom through a single bond. The cycloalkylamino group and another molecule are connected through the nitrogen atom. The cycloalkylamino group may also be represented as -NH(cycloalkyl). "C 3~10 "Cycloalkylamino group" refers to a cycloalkylamino group containing 3 to 10 carbon atoms. The cycloalkylamino group may be fused with an aryl or heteroaryl group. In some embodiments, the cycloalkylamino group is benzofused. Cycloalkylamino groups include, but are not limited to, cyclopropylamino, cyclobutylamino, cyclohexylamino, and the like.

[0044] The term "di(alkyl)amino group," whether used alone or in combination with other terms, refers to two alkyl groups as defined above linked to a nitrogen atom by a single bond. The di(alkyl)amino group and the molecule are linked via the nitrogen atom. The di(alkyl)amino group may be represented as -N(alkyl). "Di(C 1~10 The term "di(C alkyl)amino group" refers to a group in which two alkyl groups each contain 1 to 10 carbon atoms. 1~10 It refers to an amino group having a linear or branched chain structure.

[0045] The term "aryl group," whether used alone or in combination with other terms, refers to an aryl group having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6~14 "C6 aryl" refers to a monovalent, monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system, in particular a ring having six carbon atoms (a "C6 aryl" group), e.g., a phenyl group, or a ring having ten carbon atoms (a "C6 aryl" group). 10 aryl group), such as a naphthyl group, or a ring having 14 carbon atoms ("C 14 An aryl group may be fused with a cycloalkyl group or a heterocyclyl group, for example an anthryl group.

[0046] Divalent groups formed from substituted benzene derivatives and having free valence electrons on ring atoms are named substituted phenylene groups. Divalent groups derived from monovalent polycyclic hydrocarbon groups whose names end in "-yl" are obtained by removing an additional hydrogen atom from the carbon atom containing the free valence electron, and their names are derived by adding "-idene" to the name of the monovalent group; for example, a naphthyl group with two bonding sites is called a naphthylene group.

[0047] The term "heteroaryl group," whether used alone or in combination with other terms, refers to a monovalent, monocyclic, bicyclic, or tricyclic aromatic ring system of 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms (a "5- to 14-membered heteroaryl" group), particularly one having 5, 6, 9, or 10 atoms and containing at least one heteroatom, which may be the same or different, selected from N, O, and S. A heteroaryl group may be fused with a cycloalkyl group or a heterocyclyl group. In some embodiments, a "heteroaryl group" refers to a 5- to 8-membered aromatic monocyclic ring containing 1 to 4 heteroatoms selected from N, O, and S, and in one embodiment 1 to 3 heteroatoms, the remainder of which are carbon atoms; an 8- to 12-membered bicyclic ring containing 1 to 6, in some embodiments 1 to 4, or in some embodiments 1 to 3 heteroatoms selected from N, O, and S, the remainder being carbon atoms, and at least one heteroatom occurring in an aromatic ring; and an 11- to 14-membered tricyclic ring containing 1 to 8, in some embodiments 1 to 6, or in some embodiments 1 to 4, or in some embodiments 1 to 3 heteroatoms selected from N, O and S, and the remainder being carbon atoms.

[0048] When the total number of S and O in the heteroaryl group is greater than 1, these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O in the heteroaryl group is 1 or less.

[0049] Examples of heteroaryl groups include, but are not limited to, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 3-pyrazinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, pyridazinyl, triazinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thienyl, and furyl groups.

[0050] Additionally, heteroaryl groups include, but are not limited to, indolyl, benzothienyl, benzofuryl, benzimidazolyl, benzotriazolyl, quinoxalinyl, quinolyl, and isoquinolyl groups. "Heteroaryl" also includes any N-oxidized derivative containing nitrogen heteroaryl groups.

[0051] Monovalent heteroaryl groups have names ending in "-yl" and the derived divalent radical is obtained by removing one additional hydrogen atom from the carbon atom containing the free valence electron, and the name of the divalent radical is the name of the monovalent radical with the addition of "-idene"; for example, a pyridyl group with two binding sites is called a pyridylidene group.

[0052] The term "heterocycle" (and the derivatives thereof, "heterocyclic" or "heterocyclyl group") broadly and generally refers to a saturated or unsaturated monocyclic or polycyclic (e.g., bicyclic) cyclic aliphatic hydrocarbon system, typically having 3 to 12 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 4 to 12, 5 to 12, 4 to 8, 4 to 7, 4 to 6, 5 to 6, or 7 to 9 ring atoms), including at least one (e.g., 2, 3, or 4) heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus (preferably oxygen, sulfur, or nitrogen). Two or more rings in a polycyclic ring system may be fused, bridged, or spirocyclic, and a heterocycle may be fused with an aryl or heteroaryl group. In some embodiments, a heterocycle is benzofused. Heterocycles further include ring systems substituted with one or more oxo or imino moieties. In some embodiments, the C, N, S, and P atoms in the heterocycle may be optionally substituted with oxo. In some embodiments, the C, S, and P atoms in the heterocycle may be optionally substituted with imino groups, and the imino groups may be unsubstituted or substituted. Any carbon atom or heteroatom on the heterocycle may be a bonding site, provided that a stable structure is formed. If the heterocycle has a substituent, the substituent may be bonded to any heteroatom or carbon atom on the heterocycle, provided that a stable chemical structure is formed.

[0053] Suitable heterocycles include, for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 3-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, 1-pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 1-hexahydropyridazinyl, 3-hexahydropyridazinyl, and 4-hexahydropyridazinyl. Also included are morpholinyl groups, such as 1-morpholinyl, 2-morpholinyl, 3-morpholinyl, and 4-morpholinyl groups. Illustrative examples of heterocycles having one or more oxo moieties include, but are not limited to, piperidyl-N-oxide, morpholinyl-N-oxide, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Bicyclic heterocycles include: [ka] Including, but not limited to:

[0054] The term "heterocyclyl group" refers to a divalent heterocyclyl group. An example of a heterocyclylene group is a divalent piperidine. A heterocyclyl group is attached to the rest of the molecule through a single bond and to the radical through a single bond. The points of attachment of the heterocyclylene group to the rest of the molecule and to the radical can be one atom in the heterocyclylene group or two single atoms in the heterocyclylene group. Additionally, the points of attachment to the rest of the molecule and / or the radical can be carbon atoms or heteroatoms.

[0055] As used herein, "aryl-alkyl" refers to an alkyl group, as defined above, substituted with an aryl group, as defined above. Exemplary aralkyl groups include, but are not limited to, benzyl, phenethyl, naphthylmethyl, and the like. In some implementations, the aralkyl group contains 7 to 20 or 7 to 11 carbon atoms. "Aryl C1~4 When using "C alkyl group", 1~4 " refers to the number of carbon atoms in the alkyl group portion, not the number of carbon atoms in the aryl group portion.

[0056] As used herein, a "heterocyclyl-alkyl group" refers to an alkyl group as defined above substituted with a heterocyclyl group as defined above. 1~4 When using "C alkyl group", 1~4 " refers to the number of carbon atoms in the alkyl group portion, not the number of carbon atoms in the heterocyclyl group portion.

[0057] As used herein, "cycloalkyl-alkyl group" refers to an alkyl group as defined above substituted with a cycloalkyl group as defined above. 3~10 Cycloalkyl-C 1~4 When using "C alkyl group", 3~10 " refers to the number of carbon atoms in the cycloalkyl group, not the number of carbon atoms in the alkyl group. 1~4 " refers to the number of carbon atoms in the alkyl group portion, not the number of carbon atoms in the cycloalkyl group portion.

[0058] As used herein, a "heteroaryl-alkyl group" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above. 1~4 When using "C alkyl group", 1~4 " refers to the number of carbon atoms in the alkyl group portion, not the number of carbon atoms in the heteroaryl group portion.

[0059] For the avoidance of doubt, when referring to substitution with, for example, alkyl, cycloalkyl, heterocyclylalkyl, aryl, and / or heteroaryl groups, it is intended to mean that these groups are substituted singly or that these groups are mixedly substituted, i.e., when R is an aryl-C 1~4alkyl group, and may be unsubstituted or substituted with at least one substituent, e.g., independently R X and the aryl group portion may be unsubstituted or may be substituted with 1, 2, 3, or 4 substituents selected independently from R X and the alkyl group portion may be unsubstituted or may be substituted with at least one, for example, 1, 2, 3, or 4, substituents selected from the group consisting of X may be substituted with at least one, for example 1, 2, 3 or 4, substituents selected from:

[0060] "Pharmaceutically acceptable salts" refers to pharmaceutically acceptable non-toxic bases or acids, including salts prepared with inorganic or organic bases and inorganic or organic acids. Salts of inorganic bases may be selected from, for example, aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, divalent manganese salts, potassium salts, sodium salts, and zinc salts. Furthermore, pharmaceutically acceptable salts of inorganic bases may be selected from ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Solid salts may exist in one or more crystalline forms or crystalline polymorphs, and may also exist in solvates such as hydrates. Pharmaceutically acceptable organic non-toxic base salts may be selected from, for example, primary amine salts, secondary amine salts, and tertiary amine salts, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0061] When the compound described in this patent is a base, it is necessary to prepare a salt thereof with at least one pharmaceutically acceptable non-toxic acid, which may be selected from inorganic and organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. In some embodiments, these acids may be selected, such as citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, and tartaric acid.

[0062] "Administering" a compound or a pharmaceutically acceptable salt thereof means providing a compound of the invention or a pharmaceutically acceptable salt thereof to an individual in need of treatment.

[0063] "Effective amount" means the amount of a compound or a pharmaceutically acceptable salt thereof that is capable of producing a biological or medical response in a tissue, system, animal, or human that is observable by a researcher, veterinarian, clinician, or other clinical worker.

[0064] "Composition" includes a product containing specific amounts of specific ingredients, and any product formed by directly or indirectly combining these specific amounts of specific ingredients. Pharmaceutical compositions include a product containing an active ingredient and an inactive ingredient as a carrier, and a product made by directly or indirectly combining, compounding, or aggregating any two or more ingredients, or by decomposing one or more ingredients, or by other types of reaction or interaction of one or more ingredients.

[0065] "Pharmaceutically acceptable" means compatible with the other ingredients in the formulation and not causing unacceptable toxicity to the user.

[0066] "Individual" refers to an individual suffering from a disease, condition, etc., and includes mammals and non-mammals. Mammals include any member of the mammalian family, including, but not limited to, humans, non-human primates such as chimpanzees, other primates, and monkeys, farm animals such as cows, horses, sheep, goats, and pigs, domestic animals such as rabbits, dogs, and cats, and laboratory animals including rodents such as rats, mice, and guinea pigs. Non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the present invention, the mammal is a human.

[0067] "Treatment" includes alleviating, reducing, or ameliorating a disease or condition, preventing other symptoms, improving or preventing underlying metabolic factors of a condition, and inhibiting a disease or condition, e.g., arresting the progression of a disease or condition, alleviating a disease or condition, promoting the alleviation of a disease or condition, or halting the symptoms of a disease or condition, extending to include prevention. "Treatment" also includes achieving therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to the definitive elimination or amelioration of the condition being treated. Therapeutic benefit is also achieved by definitively eliminating or ameliorating one or more physiological symptoms associated with an underlying disease, resulting in an improvement in the patient's condition despite the patient potentially having the underlying disease. Prophylactic benefit refers to the use of a composition to prevent a patient's risk of a disease that has not yet been diagnosed, or the use of a composition when a patient will develop one or more physiological symptoms of a disease.

[0068] A "protecting group" (PG) refers to a substituent that reacts with other functional groups on a compound to block or protect a particular functional group. For example, an "amino protecting group" refers to a substituent that is attached to an amino group to block or protect the amino functionality on a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethoxycarbonyl (Fmoc) protecting groups. Similarly, a "hydroxyl protecting group" refers to a hydroxyl substituent that can effectively block or protect the functionality of the hydroxyl group. Suitable protecting groups include, but are not limited to, acetyl and silyl groups. A "carboxyl protecting group" refers to a carboxyl substituent that effectively blocks or protects the functionality of the carboxyl group. Commonly used carboxyl protecting groups include -CHCHSOPh, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(diphenylphosphine)-ethyl, nitroethyl, etc. For a general description and use of protecting groups, see the reference T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0069] The "NH protecting group" includes a trichloroethoxycarbonyl group, a tribromoethoxycarbonyl group, a benzyloxycarbonyl group, a p-nitrobenzylformyl group, an o-bromobenzyloxycarbonyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a trifluoroacetyl group, a phenylacetyl group, a formyl group, an acetyl group, a benzoyl group, a t-pentyloxycarbonyl group, a t-butoxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a 3,4-dimethoxybenzyloxycarbonyl group, a 4-(phenylazo)benzyloxycarbonyl group, a 2-furfuryloxycarbonyl group, a diphenylmethoxycarbonyl group, a 1,1-dimethylpropoxycarbonyl group, an isopropoxycarbonyl group, a phthaloyl group, a succinyl group, an alanyl group, a leucyl group, a 1-adamantaneoxycarbonyl group, an 8-hydroxybenzoyl group, a ... Examples of suitable alkyl groups include, but are not limited to, alkyloxycarbonyl, benzyl, benzhydryl, trityl, 2-nitrophenylthio, methanesulfonyl, p-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylene, 2-ethoxycarbonylcyclohexylene, 2-ethoxycarbonylcyclopentylene, 2-acetylcyclohexylene, 3,3-dimethyl-5-oxycyclohexylene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl-2-oxy-2H-1,3-dioxol-4-yl-methyl, trimethylsilyl, triethylsilyl, and triphenylsilyl groups.

[0070] The "C(O)OH" protecting group includes methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, t-butyl, phenyl, naphthyl, benzyl, benzhydryl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetonyl, phenacyl, p-nitrophenacyl, p-bromophenacyl, p-methylphenylsulfonylphenacyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthal ... Examples of silyl groups include, but are not limited to, methyl, succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl groups.

[0071] The "OH or SH" protecting group is a benzyloxycarbonyl group, a 4-nitrobenzyloxycarbonyl group, a 4-bromobenzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, a 3,4-dimethoxybenzyloxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, a 1,1-dimethylpropoxycarbonyl group, an isopropoxycarbonyl group, an isobutyryloxycarbonyl group, a diphenylmethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a 2,2, 2-Tribromoethoxycarbonyl group, 2-(trimethylsilane)ethoxycarbonyl group, 2-(benzenesulfonyl)ethoxycarbonyl group, 2-(triphenylsulfonium group)ethoxycarbonyl group, 2-furfuryloxycarbonyl group, 1-adamantanoxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group, 4-ethoxy-1-naphthyloxycarbonyl group, 8-quinolyloxycarbonyl group, acetyl group, formic acid group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trif Fluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methyl These include, but are not limited to, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl groups.

[0072] The compounds of the present invention may exist as geometric isomers. The compounds of the present invention may have carbon-carbon or carbon-nitrogen double bonds in the E or Z configuration, where "E" indicates that the preferred substituents are on different sides of the carbon-carbon or carbon-nitrogen double bond according to the Cahn-Ingold-Prelog priority rules, and "Z" indicates that the preferred substituents are on the same side of the carbon-carbon or carbon-nitrogen double bond. The compounds of the present invention may also exist in the form of a mixture of "E" and "Z" isomers. Substituents around a cycloalkyl or heterocyclyl group may be designated as cis or trans configuration. The present invention also includes different isomers and mixtures thereof formed by different arrangements of the substituents around the adamantane ring system. The two substituents around one monocyclic ring in the adamantane ring system are designated as Z or E relative configuration. See, for example, CD Jones, M. Kaselj, RN Salvatore, WJ Le Noble J. Org. Chem. 1998, 63, 2758-2760.

[0073] The compounds of the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration. For definitions of "R" and "S," see IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. A compound containing asymmetrically substituted carbon atoms is racemic if it has equal amounts of R and S configurations. When the amount of one configuration is greater than the amount of the other, the configuration of the chiral carbon atom is represented by the predominant configuration, preferably greater than about 85-90%, more preferably greater than about 95-99%, and even more preferably greater than about 99% enantiomer. Thus, the present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

[0074] Isotopically enriched or labeled compounds The compounds of the present invention may exist in isotopically labeled or enriched form, and contain one or more atoms having atomic masses and mass numbers different from the atomic masses and mass numbers most common in nature. The isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine are 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 32 P, 35 S, 18 F, 36 Cl and 125 I includes, but is not limited to, I. Other isotopes of these atoms and / or other atoms are within the scope of the present invention.

[0075] In another embodiment, the isotopically labeled compound is deuterium ( 2 H), tritium ( 3 H) or 14 The isotopically labeled compounds of the present invention may be obtained by methods known to those skilled in the art. These isotopically labeled compounds may be obtained by replacing unlabeled reagents with isotopically labeled reagents, with reference to the examples and reaction schemes of the present invention. In some instances, a compound may be treated with an isotopically labeled reagent to replace an atom with an isotopic atom; for example, replacing hydrogen with deuterium may be achieved by exchange with a deuterated acid such as DSO / D0.

[0076] The isotope-labeled compounds of the present invention can be used as a benchmark for GLP-1R inhibitor binding studies. The isotope-containing compounds can be used in pharmaceutical research to evaluate the mechanism of action and metabolic pathway of the non-isotopically labeled parent compound and to study the metabolic degradation of the compound in vivo (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are very important in designing safe and effective therapeutic agents and can determine whether the active compound or metabolites of the parent compound used in the patient's body are toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic Press, London, 1985; Kato et al., J. Labeled Compounds. Radiopharmaceuticals, 36(10): 927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacology, 77, 79-88 (1999)).

[0077] Additionally, drugs containing non-reflecting active isotopes, e.g., deuterated drugs, are referred to as "heavy drugs" and can be used to treat diseases and conditions associated with GLP-1R activity. The proportion of a compound with a certain isotope above its natural abundance is referred to as enrichment. Examples of enrichment include, but are not limited to, about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, and about 100 mol%.

[0078] Stable isotope labeling of drugs can change their physicochemical properties, such as pKa and liquid solubility. If isotope substitution affects the region related to ligand-receptor interaction, these effects and changes may affect the pharmacological response of drug molecules. Although stable isotope-labeled molecules have some physical properties different from unlabeled molecules, their chemical and biological properties are the same. However, due to the increased mass of heavy isotopes, any chemical bonds involving heavy isotopes and other atoms are stronger than those of light isotopes. Accordingly, the presence of isotopes at metabolic or enzymatic conversion sites may slow down the reaction, resulting in changes in their pharmacokinetic characteristics or pharmacological effects compared to compounds that are not isotope-labeled.

[0079] In embodiment (1), the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] (I) During the ceremony, [ka] is a double bond or a single bond, X 1 , X 2 , X 5 and X 6 is independently selected from N and C; X 3 are O, S, N, and NR 7.3 and CR 7.3 is selected from X 4 is absent or N, C(O) and CR 7.4 is selected from Y 1 N and CR 8.1 is selected from Y 2 N and CR 8.2 is selected from Y 3 N and CR 8.3 is selected from Z 1is selected from N and C(O), Z 2 is selected from N and C; W is unsubstituted or independently R X substituted with at least one substituent selected from [ka] is selected from L is -CR C0 R D0 (CR C0 R D0 ) u -, -(CR C0 R D0 ) u O(CR C0 R D0 ) t -, -(CR C0 R D0 ) u NR A0 (CR C0 R D0 ) t -and-(CR C0 R D0 ) u S(O) r (CR C0 R D0 ) t - selected from Q 1 , Q 2 and Q 3 is C 3~10 selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; Each R 1 are independently hydrogen, halogen, and C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4Alkyl group, CN, NO2, -NR A1 R B1 , -OR A1 , -C(O)R A1 , -C(=NR E1 )R A1 , -C(=N-OR B1 )R A1 , -C(O)OR A1 , -OC(O)R A1 , -C(O)NR A1 R B1 , -C(O)NR A1 S(O) r R A1 , -C(O)NR A1 , -C(O)NR A1 , -C(O)NR A1 S(O) r NR A1 R B1 , -C(O)NR A1 , -C(O)NR<0001X344>)R B1 (There seems to be a typo in the original as 'X' in <0001X344> is likely incorrect. Assuming it should be E1 ) , -C(O)NR A1 , -C(O)NR<00X1347>[[END''' (There seems to be a typo in the original as 'X' in <00X1347> is likely incorrect. Assuming it should be E1 ))NR A1 R B1 , -NR A1 , -NR B1 , -C(=NR E1 )NR A1 R B1 , -NR A1 , -NR E1 )R B1 , -OC(O)NR A1 R B1 , -NR A1 , -NR B1 , -NR A1 , C(O)NR A1 R B1 , -NR A1 , -NR A1 R B1 , -NR A1 , -C(=NR E1 )NR A1 R B1 , -S(O) r R A1 , -S(O)(=NR E1 )R B1 , -N=S(O)R<X001376>(There seems to be a typo in the original as 'X' in <X001376> is likely incorrect. Assuming it should be A1 ) R B1 It should be noted that there are some potential typos in the original text as indicated above. The translated text attempts to follow the rules while accounting for these possible errors., -S(O)2OR A1 , -OS(O)2R A1 , -NR A1 S(O) r R B1 , -NR A1 S(O)(=NR E1 )R B1 , -S(O) r NR A1 R B1 , -S(O)(=NR E1 )NR A1 R B1 , -NR A1 S(O)NR A1 R B1 , -NR A1 S(O)(=NR E1 )NR A1 R B1 , -P(O)R A1 R B1 and -P(O)(OR A1 )(OR B1 and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R X1 and is substituted with at least one substituent selected from Each R 2 are independently hydrogen, halogen, and C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl groups, CN, NO2, -NR A2 R B2 , -OR A2 , -C(O)R A2 , -C(=NR E2 )R A2 , -C(=N-OR B2 )R A2 , -C(O)OR A2, -OC(O)R A2 , -C(O)NR A2 R B2 , -C(O)NR A2 S(O)(=NR E2 )R B2 , -C(O)NR A2 S(O)(=NR E2 )NR A2 R B2 , -NR A2 C(O)R B2 , -C(=NR E2 )NR A2 R B2 , -NR A2 C(=NR E2 )R B2 , -OC(O)NR A2 R B2 , -NR A2 C(O)OR B2 , -NR A2 C(O)NR A2 R B2 , -NR A2 C(S)NR A2 R B2 , -NR A2 C(=NR E2 )NR A2 R B2 , -S(O)(=NR E2 )R B2 , -N=S(O)R A2 R B2 , -NR A2 S(O)(=NR E2 )R B2 , -S(O)(=NR E2 )NR A2 R B2 and -NR A2 S(O)(=NR E2 )NR A2 R B2 and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R X2 and is substituted with at least one substituent selected from Each R 3 are independently hydrogen, halogen, and C 1~10 Alkyl group, C 2~10Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl groups, CN, NO2, -NR A3 R B3 , -OR A3 , -C(O)R A3 , -C(=NR E3 )R A3 , -C(=N-OR B3 )R A3 , -C(O)OR A3 , -OC(O)R A3 , -C(O)NR A3 R B3 , -C(O)NR A3 S(O) r R A3 , -C(O)NR A3 S(O)2OR A3 , -C(O)NR A3 S(O) r NR A3 R B3 , -C(O)NR A3 S(O)(=NR E3 )R B3 , -C(O)NR A3 S(O)(=NR E3 )NR A3 R B3 , -NR A3 C(O)R B3 , -C(=NR E3 )NR A3 R B3 , -NR A3 C(=NR E3 )R B3 , -OC(O)NR A3 R B3 , -NR A3 C(O)OR B3 , -NR A3 C(O)NR A3 R B3 , -NR A3 C(S)NR A3R B3 , -NR A3 C(=NR E3 )NR A3 R B3 , -S(O) r R A3 , -S(O)(=NR E3 )R B3 , -N=S(O)R A3 R B3 , -S(O)2OR A3 , -OS(O)2R A3 , -NR A3 S(O) r R B3 , -NR A3 S(O)(=NR E3 )R B3 , -S(O) r NR A3 R B3 , -S(O)(=NR E3 )NR A3 R B3 , -NR A3 S(O)NR A3 R B3 , -NR A3 S(O)(=NR E3 )NR A3 R B3 , -P(O)R A3 R B3 and -P(O)(OR A3 )(OR B3 and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R X3 and is substituted with at least one substituent selected from R 4 -C(O)OH, -C(O)NHS(O) r R A4 , -(CR c1 R d1 ) t NHS(O) r R A4 , a heterocyclyl group, and a heteroaryl group; R 5 is hydrogen, halogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl groups, CN, NO2, -NR A5 R B5 , -OR A5 and -C(O)R A5 and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from R X5 and is substituted with at least one substituent selected from Each R 6 are independently hydrogen, halogen, and C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl groups, CN, NO2, -NR A6 R B6 , -OR A6 and -C(O)R A6 and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from R X6 and is substituted with at least one substituent selected from Or, "R 5 and R 6 " or "Two R's 6 ", along with the atoms bonded to them, 3~10 a cycloalkyl group or a 4- to 12-membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the cycloalkyl and heterocyclyl groups are unsubstituted or independently selected from R X6 and is substituted with at least one substituent selected from R 7.3 and R 7.4 are independently hydrogen, halogen, C 1~10 Alkyl group, C2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl groups, CN, NO2, -NR A7 R B7 , -OR A7 , -C(O)R A7 , -C(=NR E7 )R A7 , -C(=N-OR B7 )R A7 , -C(O)OR A7 , -OC(O)R A7 , -C(O)NR A7 R B7 , -C(O)NR A7 S(O) r R A7 , -C(O)NR A7 S(O)2OR A7 , -C(O)NR A7 S(O) r NR A7 R B7 , -C(O)NR A7 S(O)(=NR E7 )R B7 , -C(O)NR A7 S(O)(=NR E7 )NR A7 R B7 , -NR A7 C(O)R B7 , -C(=NR E7 )NR A7 R B7 , -NR A7 C(=NR E7 )R B7 , -OC(O)NR A7 R B7 , -NR A7 C(O)OR B7 , -NR A7 C(O)NR A7 R B7 , -NR A7 C(S)NRA7 R B7 , -NR A7 C(=NR E7 )NR A7 R B7 , -S(O) r R A7 , -S(O)(=NR E7 )R B7 , -N=S(O)R A7 R B7 , -S(O)2OR A7 , -OS(O)2R A7 , -NR A7 S(O) r R B7 , -NR A7 S(O)(=NR E7 )R B7 , -S(O) r NR A7 R B7 , -S(O)(=NR E7 )NR A7 R B7 , -NR A7 S(O)NR A7 R B7 , -NR A7 S(O)(=NR E7 )NR A7 R B7 , -P(O)R A7 R B7 and -P(O)(OR A7 )(OR B7 and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R X7 and is substituted with at least one substituent selected from R 8.1 , R 8.2 and R 8.3 are independently hydrogen, halogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl groups, CN, NO2, -NR A8 R B8 , -OR A8 , -C(O)R A8 , -C(=NR E8 )R A8 , -C(=N-OR B8 )R A8 , -C(O)OR A8 , -OC(O)R A8 , -C(O)NR A8 R B8 , -C(O)NR A8 S(O) r R A8 , -C(O)NR A8 S(O)2OR A8 , -C(O)NR A8 S(O) r NR A8 R B8 , -C(O)NR A8 S(O)(=NR E8 )R B8 , -C(O)NR A8 S(O)(=NR E8 )NR A8 R B8 , -NR A8 C(O)R B8 , -C(=NR E8 )NR A8 R B8 , -NR A8 C(=NR E8 )R B8 , -OC(O)NR A8 R B8 , -NR A8 C(O)OR B8 , -NR A8 C(O)NR A8 R B8 , -NR A8 C(S)NR A8 R B8 , -NR A8 C(=NR E8 )NR A8 R B8 , -S(O) r R A8 , -S(O)(=NR E8 )RB8 , -N=S(O)R A8 R B8 , -S(O)2OR A8 , -OS(O)2R A8 , -NR A8 S(O) r R B8 , -NR A8 S(O)(=NR E8 )R B8 , -S(O) r NR A8 R B8 , -S(O)(=NR E8 )NR A8 R B8 , -NR A8 S(O)NR A8 R B8 , -NR A8 S(O)(=NR E8 )NR A8 R B8 , -P(O)R A8 R B8 and -P(O)(OR A8 )(OR B8 and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R X8 and is substituted with at least one substituent selected from R A0 is hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X0 and is substituted with at least one substituent selected from Each R A1 and R B1 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X1 and optionally substituted with at least one substituent selected from Or, R A1 and R B1 together with one or more atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, the ring being unsubstituted or containing 1, 2, or 3 R X1 may be substituted with a group, Each R A2 and R B2 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X2and optionally substituted with at least one substituent selected from Or, "R A2 and R B2 " together with the atom or atoms attached thereto form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, the ring being unsubstituted or containing 1, 2, or 3 R X2 may be substituted with a group, Each R A3 and R B3 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X3 and is substituted with at least one substituent selected from Or, "R A3 and R B3 " together with the atom or atoms attached thereto form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, the ring being unsubstituted or containing 1, 2, or 3 R X3 may be substituted with a group, R A4 is hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X4 and is substituted with at least one substituent selected from Each R A5 and R B5 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X5 and is substituted with at least one substituent selected from Or, "R A5 and R B5 " together with the atom or atoms attached thereto form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, the ring being unsubstituted or containing 1, 2, or 3 R X5 may be substituted with a group, Each R A6 and R B6 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X6 and is substituted with at least one substituent selected from Or, "R A6 and R B6 " together with the atom or atoms attached thereto form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, the ring being unsubstituted or containing 1, 2, or 3 R X6 may be substituted with a group, Each R A7 and R B7 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X7 and is substituted with at least one substituent selected from Or, R A7 and R B7 together with one or more atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, the ring being unsubstituted or containing 1, 2, or 3 RX7 may be substituted with a group, Each R A8 and R B8 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X8 and is substituted with at least one substituent selected from Or, R A8 and R B8 together with one or more atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, the ring being unsubstituted or containing 1, 2, or 3 R X8 may be substituted with a group, Each R C0 and R D0 are independently hydrogen, halogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R X0 and is substituted with at least one substituent selected from Or, R C0 and R D0 together with one or more carbon atoms attached thereto, C 3~10 a cycloalkyl group or a 4- to 12-membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the cycloalkyl and heterocyclyl groups are unsubstituted or independently selected from R X0 and is substituted with at least one substituent selected from Each R E1 , R E2 , R E3 , R E7 and R E8 are independently hydrogen, C 1~10 Alkyl groups, CN, NO2, -OR a1 , -SR a1 , -S(O) r R a1 , -C(O)R a1 , -C(O)OR a1 , -C(O)NR a1 R b1 and -S(O) r NR a1 R b1 wherein the alkyl group is unsubstituted or independently selected from R X and is substituted with at least one substituent selected from As a condition, Z 1 is N and X 2 is C and X 3 is CR 7.3 or N and X 4 does not exist and R 5 and R 6 or any two R 6 does not form a ring, and W [ka] and L is -CR C0 RD0 (CR C0 R D0 ) u - R when selected from C0 and R D0 At least one of the following is CN, C 2~10 Alkenyl groups and C 2~10 R selected from alkynyl groups X0 is replaced by Each R X , R X0 , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 and R X8 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl groups, halogens, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 , -(CR c1 R d1 ) t OR b1 , -(CR c1 R d1 ) t C(O)R a1 , -(CR c1 R d1 ) t C(=NR e1 )R a1 , -(CR c1 R d1 ) t C(=N-OR b1 )R a1 , -(CR c1 R d1 )t C(O)OR b1 、-(CR c1 R d1 ) t OC(O)R b1 、-(CR c1 R d1 ) t C(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(O)R b1 、-(CR c1 R d1 ) t C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )R b1 、-(CR c1 R d1 ) t OC(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(O)OR b1 、-(CR c1 R d1 ) t NR a1 C(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(S)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t S(O) r R b1 、-(CR c1 Rd1 ) t S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) t N=S(O)R a1 R b1 、-(CR c1 R d1 ) t S(O)2OR b1 、-(CR c1 R d1 ) t OS(O)2R b1 、-(CR c1 R d1 ) t NR a1 S(O) r R b1 、-(CR c1 R d1 ) t NR a1 S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) t S(O) r NR a1 R b1 、-(CR c1 R d1 ) t S(O)(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 S(O)2NR a1 R b1 、-(CR c1 R d1 ) t NR a1 S(O)(=NR e1 )NR a1 ​​​​​​​​​​​​​​​​​​​​)(OR b1 and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R Y and is substituted with at least one substituent selected from Each R a1 and R b1 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Y and is substituted with at least one substituent selected from Or, R a1 and R b1 together with one or more atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is optionally bound to one, two or three R Y may be substituted with a group, Each R c1 and R d1 are independently hydrogen, halogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Y and is substituted with at least one substituent selected from Or, R c1 and R d1 together with one or more carbon atoms bonded thereto form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and the ring is optionally bonded to one, two or three R Y may be substituted with a group, Each R e1 are independently hydrogen, C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, CN, NO2, -OR a2 , -SR a2 , -S(O) r R a2 , -C(O)R a2 , -C(O)OR a2 , -S(O) r NR a2 R b2 and -C(O)NR a2 R b2 is selected from Each R Y independently, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl groups, halogens, CN, NO2, -(CR c2 R d2 ) t NR a2 R b2 , -(CR c2 R d2 )t OR b2 、-(CR c2 R d2 ) t C(O)R a2 、-(CR c2 R d2 ) t C(=NR e2 )R a2 、-(CR c2 R d2 ) t C(=N-OR b2 )R a2 、-(CR c2 R d2 ) t C(O)OR b2 、-(CR c2 R d2 ) t OC(O)R b2 、-(CR c2 R d2 ) t C(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(O)R b2 、-(CR c2 R d2 ) t C(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(=NR e2 )R b2 、-(CR c2 R d2 ) t OC(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(O)OR b2 、-(CR c2 R d2 ) t NR a2 C(O)NR a2 R b2 、-(CR c2 Rd2 ) t NR a2 C(S)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t S(O) r R b2 、-(CR c2 R d2 ) t S(O)(=NR e2 )R b2 、-(CR c2 R d2 ) t N=S(O)R a2 R b2 、-(CR c2 R d2 ) t S(O)2OR b2 、-(CR c2 R d2 ) t OS(O)2R b2 、-(CR c2 R d2 ) t NR a2 S(O) r R b2 、-(CR c2 R d2 ) t NR a2 S(O)(=NR e2 )R b2 、-(CR c2 R d2 ) t S(O) r NR a2 R b2 、-(CR c2 R d2 ) t S(O)(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t NR a2 S(O)2NRa2 R b2 , -(CR c2 R d2 ) t NR a2 S(O)(=NR e2 )NR a2 R b2 , -(CR c2 R d2 ) t P(O)R a2 R b2 and -(CR c2 R d2 ) t P(O)(OR a2 )(OR b2 ), each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from hydroxy group, CN, amino group, halogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino groups and di(C 1~10 substituted with at least one substituent selected from the group consisting of (alkyl)amino groups, Each R a2 and R b2 are independently hydrogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino group, di(C1~10 Alkyl)amino group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkylthio group, cycloalkylthio group, alkylamino group, cycloalkylamino group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from halogen, CN, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl group, hydroxy group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, amino group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino groups and di(C 1~10 substituted with at least one substituent selected from the group consisting of (alkyl)amino groups, Or, R a2 and R b2 together with one or more atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is optionally independently selected from halogen, CN, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl group, hydroxy group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, amino group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino groups and di(C 1~10 and optionally substituted with one or two substituents selected from: Each R c2 and R d2 are independently hydrogen, halogen, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino group, di(C 1~10 Alkyl)amino group, heterocyclyl group, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups and heteroaryl-C 1~4 alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkylthio group, cycloalkylthio group, alkylamino group, cycloalkylamino group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from halogen, CN, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl group, hydroxy group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, amino group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino groups and di(C 1~10 substituted with at least one substituent selected from the group consisting of (alkyl)amino groups, Or, R c2 and R d2together with one or more carbon atoms bonded thereto form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and the ring is optionally independently selected from halogen, CN, C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl group, hydroxy group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, C 1~10 Alkylthio group, C 3~10 Cycloalkylthio group, amino group, C 1~10 Alkylamino group, C 3~10 Cycloalkylamino groups and di(C 1~10 and optionally substituted with one or two substituents selected from: Each R e2 are independently hydrogen, CN, NO2, C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl group, C 1~10 Alkoxy group, C 3~10 Cycloalkoxy group, -C(O)C 1~4 Alkyl group, -C(O)C 3~10 Cycloalkyl groups, -C(O)OC 1~4 Alkyl group, -C(O)OC 3~10 Cycloalkyl groups, -C(O)N(C 1~4 alkyl)2, -C(O)N(C 3~10 cycloalkyl)2, -S(O)2C 1~4 Alkyl group, -S(O)2C 3~10 Cycloalkyl groups, -S(O)N(C 1~4 alkyl)2 and -S(O)2N(C 3~10 cycloalkyl)2; m, n, p, and q are independently selected from 0, 1, 2, 3, and 4; each r is independently selected from 0, 1, and 2; each t is independently selected from 0, 1, 2, 3, and 4; Each u is independently selected from 0, 1, 2, 3, and 4.

[0080] In another embodiment, the compound according to embodiment (1) of the present invention or a pharmaceutically acceptable salt thereof, X 1 , X 2 , X 5 and X 6 is independently selected from N and C; X 3 are O, S, N, and NR 7.3 and CR 7.3 is selected from X 4 is absent or N, C(O) and CR 7.4 is selected from Y 1 N and CR 8.1 is selected from Y 2 N and CR 8.2 is selected from Y 3 N and CR 8.3 is selected from Z 1 is selected from N and C(O), Z 2 is selected from N and C; W is unsubstituted or independently R X substituted with at least one substituent selected from [ka] is selected from L is -CR C0 R D0 (CR C0 R D0 ) u -,-(CR C0 R D0 ) u O(CR C0 R D0 ) t -,-(CR C0 R D0 ) u NR A0 (CR C0 RD0 ) t -and-(CR C0 R D0 ) u S(O) r (CR C0 R D0 ) t - selected from Q 1 , Q 2 and Q 3 is C 3~10 selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; As a condition, Z 1 is N and X 2 is C and X 4 does not exist and R 5 and R 6 or any two R 6 does not form a ring, and W [ka] and L is -CR C0 R D0 (CR C0 R D0 ) u - R when selected from C0 and R D0 At least one of the following is CN, C 2~10 Alkenyl groups and C 2~10 R selected from alkynyl groups X0 is replaced by R 5 , R 6 , R 7.3 , R 7.4 , R 8.1 , R 8.2 , R 8.3 , R A0 , R C0 , R D0 , R X , R X0 , r, t and u are as defined in formula (I).

[0081] In another embodiment (2), the compound according to embodiment (1) of the present invention or a pharmaceutically acceptable salt thereof is 1is C(O).

[0082] In another embodiment (3), the compound according to embodiment (2) of the present invention or a pharmaceutically acceptable salt thereof is 1 is N.

[0083] In another embodiment (4), in the compound according to any one of embodiments (1) to (3) of the present invention or a pharmaceutically acceptable salt thereof, Z 2 is N.

[0084] In another embodiment (5), in the compound according to any one of embodiments (1) to (3) of the present invention or a pharmaceutically acceptable salt thereof, Z 2 is C.

[0085] In another embodiment, the compound according to any one of embodiments (1) to (5) of the present invention or a pharmaceutically acceptable salt thereof, [ka] The structure of the part is [ka] is selected from.

[0086] In another embodiment (6), in the compound according to any one of embodiments (1) to (5) of the present invention, or a pharmaceutically acceptable salt thereof, R 5 is hydrogen, halogen, C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl groups, CN, NO2, -NR A5 R B5 and-OR A5 and each alkyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from C 1~10 Alkyl group, C 3~10Cycloalkyl groups, halogens, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 is substituted with at least one substituent selected from

[0087] In another embodiment (7), the compound according to embodiment (6) of the present invention, or a pharmaceutically acceptable salt thereof, is 5 is selected from hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, —CN, —NO, —NH, and —OH. 5 is a methyl group.

[0088] In another embodiment (8), in the compound according to any one of embodiments (1) to (7) of the present invention or a pharmaceutically acceptable salt thereof, each R 6 are independently hydrogen, halogen, and C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl groups, CN, NO2, -NR A6 R B6 and-OR A6 and each alkyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, halogens, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1is substituted with at least one substituent selected from

[0089] In another embodiment (9), the compound according to embodiment (8) of the present invention, or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently selected at each occurrence from hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, —CN, —NO, —NH, and —OH. 5 is hydrogen.

[0090] In another embodiment (10), in the compound according to any one of the embodiments (1) to (5) of the present invention or a pharmaceutically acceptable salt thereof, "R 5 and R 6 " or "Two R's 6 ", along with the atoms bonded to them, are C 3~10 a cycloalkyl group or a 4-10 membered heterocyclyl group containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and the cycloalkyl and heterocyclyl groups are unsubstituted or independently selected from R X6 is substituted with at least one substituent selected from

[0091] In another embodiment (11), in the compound according to embodiment (10) of the present invention or a pharmaceutically acceptable salt thereof, "R 5 and R 6 " or "Two R's 6 ", along with the atoms bonded to them, are C 3~8 a cycloalkyl group or a 4-8 membered heterocyclyl group containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and the cycloalkyl and heterocyclyl groups are unsubstituted or independently C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, halogens, CN, NO2, -(CR c1 R d1 ) t NRa1 R b1 and -(CR c1 R d1 ) t OR b1 is substituted with at least one substituent selected from

[0092] In another embodiment, the compound according to any one of embodiments (1) to (9) of the present invention or a pharmaceutically acceptable salt thereof, [ka] The structure of the part is [ka] is selected from.

[0093] In another embodiment, the compound according to any one of embodiments (1) to (5), (10) and (11) of the present invention or a pharmaceutically acceptable salt thereof, [ka] The structure of the part is [ka] is selected from.

[0094] In another embodiment (12), in the compound according to any one of embodiments (1) to (11) of the present invention, or a pharmaceutically acceptable salt thereof, W is each unsubstituted or independently selected from R X substituted with at least one substituent selected from [ka] In another embodiment, each W is unsubstituted or independently selected from R X substituted with at least one substituent selected from [ka] is selected from.

[0095] In another embodiment (13), in the compound according to any one of embodiments (1) to (11) of the present invention, or a pharmaceutically acceptable salt thereof, W is unsubstituted or independently represents R X is substituted with at least one substituent selected from [ka] is.

[0096] In another embodiment (14), in the compound according to any one of embodiments (1) to (13) of the present invention, or a pharmaceutically acceptable salt thereof, Q 2 is selected from heterocyclyl groups, aryl groups and heteroaryl groups.

[0097] In another embodiment (15), the compound according to embodiment (14) of the present invention or a pharmaceutically acceptable salt thereof, is 2 teeth, [ka] is selected from.

[0098] In another embodiment (16), n is selected from 1, 2, and 3 in the compound according to any one of embodiments (1) to (15) of the present invention, or a pharmaceutically acceptable salt thereof.

[0099] In another embodiment (17), in the compound according to any one of embodiments (1) to (16) of the present invention, or a pharmaceutically acceptable salt thereof, each R 2 independently for each occurrence, C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C1~4 Alkyl group, NO2, -NR A2 R B2 and-OR A2 and each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R X2 is substituted with at least one substituent selected from

[0100] In another embodiment (18), the compound according to embodiment (17) of the present invention, or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently at each occurrence hydrogen, methyl, ethyl, isopropyl, pyranyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, -CN, -NO2, -NH2, -NHCH3, -OH, and [ka] wherein the methyl, ethyl, isopropyl, pyranyl, cyclopropyl, methoxy and ethoxy groups are unsubstituted or independently selected from C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, halogens, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 In another embodiment, each R 2 is independently selected at each occurrence from hydrogen, methyl, ethyl, isopropyl, pyranyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, -CN, -NO2, -NH2 and OH, and methyl, ethyl, isopropyl, pyranyl, cyclopropyl, methoxy and ethoxy are unsubstituted or independently C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, halogens, CN, NO2, -(CR c1 R d1 ) t NRa1 R b1 and -(CR c1 R d1 ) t OR b1 In another embodiment, each R 2 is independently selected at each occurrence from F and a methyl group.

[0101] In another embodiment, in the compound according to any one of embodiments (1) to (18) of the present invention or a pharmaceutically acceptable salt thereof, [ka] The structure of the part is [ka] In another embodiment, the compound of formula (I) is selected from [ka] The structure of the part is [ka] is selected from.

[0102] In another embodiment (19), in the compound according to any one of embodiments (1) to (18) of the present invention, or a pharmaceutically acceptable salt thereof, Q 1 is selected from heterocyclyl groups, aryl groups and heteroaryl groups.

[0103] In another embodiment (20), the compound according to embodiment (19) of the present invention or a pharmaceutically acceptable salt thereof, wherein Q 1 is selected from a phenyl group, a pyridyl group, and a pyrimidyl group.

[0104] In another embodiment (21), m is selected from 1, 2, and 3 in the compound according to any one of embodiments (1) to (20) of the present invention or a pharmaceutically acceptable salt thereof.

[0105] In another embodiment (22), in the compound according to any one of embodiments (1) to (21) of the present invention, or a pharmaceutically acceptable salt thereof, each R 1 independently for each occurrence, C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl group, NO2, -NR A1 R B1 and-OR A1 and each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R X1 is substituted with at least one substituent selected from

[0106] In another embodiment (23), the compound according to embodiment (22) of the present invention, or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected at each occurrence from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, —CN, —NO2, —NH2, and —OH, and methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy are unsubstituted or independently C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, halogens, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 In another embodiment, each R 1 is independently selected at each occurrence from F, a methyl group, and a cyclopropyl group. 1is independently selected at each occurrence from F and a methyl group.

[0107] In another embodiment, in the compound according to any one of embodiments (1) to (23) of the present invention or a pharmaceutically acceptable salt thereof, [ka] The structure of the part is [ka] is selected from.

[0108] In another embodiment (24), the compound according to any one of embodiments (1) to (23) of the present invention, or a pharmaceutically acceptable salt thereof, is 1 is N.

[0109] In another embodiment (25), the compound according to any one of embodiments (1) to (23) of the present invention, or a pharmaceutically acceptable salt thereof, is 1 is C.

[0110] In another embodiment (26), the compound according to any one of embodiments (1) to (25) of the present invention, or a pharmaceutically acceptable salt thereof, is 2 is N.

[0111] In another embodiment (27), the compound according to any one of embodiments (1) to (25) of the present invention, or a pharmaceutically acceptable salt thereof, is 2 is C.

[0112] In another embodiment (28), the compound according to any one of embodiments (1) to (27) of the present invention, or a pharmaceutically acceptable salt thereof, is 5 is N.

[0113] In another embodiment (29), the compound according to any one of embodiments (1) to (27) of the present invention, or a pharmaceutically acceptable salt thereof, is 5 is C.

[0114] In another embodiment (30), the compound according to any one of embodiments (1) to (29) of the present invention, or a pharmaceutically acceptable salt thereof, is 6 is N.

[0115] In another embodiment (31), the compound according to any one of embodiments (1) to (29) of the present invention, or a pharmaceutically acceptable salt thereof, is 6 is C.

[0116] In another embodiment (32), the compound according to any one of embodiments (1) to (31) of the present invention, or a pharmaceutically acceptable salt thereof, is 3 is selected from O and S.

[0117] In another embodiment (33), the compound according to any one of embodiments (1) to (31) of the present invention, or a pharmaceutically acceptable salt thereof, is 3 is N, NR 7.3 and CR 7.3 is selected from.

[0118] In another embodiment (34), the compound according to any one of embodiments (1) to (33) of the present invention, or a pharmaceutically acceptable salt thereof, is 4 is CR 7.4 is.

[0119] In another embodiment (35), the compound or pharmaceutically acceptable salt thereof according to any one of embodiments (1) to (31) and (33) of the present invention is 4 is N.

[0120] In another embodiment (36), the compound or pharmaceutically acceptable salt thereof according to any one of embodiments (1) to (31) and (33) of the present invention is 4 is C(O).

[0121] In another embodiment (37), the compound according to any one of embodiments (1) to (33) of the present invention, or a pharmaceutically acceptable salt thereof, is 4 does not exist.

[0122] In another embodiment (38), the compound according to embodiment (33) or (34) of the present invention, or a pharmaceutically acceptable salt thereof, is 7.3 and R 7.4 are independently hydrogen, halogen, C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl groups, CN, NO2, -NR A7 R B7 and-OR A7 and each alkyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, halogens, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 is substituted with at least one substituent selected from

[0123] In another embodiment (39), the compound according to embodiment (38) of the present invention or a pharmaceutically acceptable salt thereof, wherein R 7.3 and R 7.4are independently selected from hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, —CN, —NO, —NH, and —OH. 7.3 and R 7.4 is hydrogen.

[0124] In another embodiment (40), the compound according to any one of embodiments (1) to (39) of the present invention, or a pharmaceutically acceptable salt thereof, is 1 is N.

[0125] In another embodiment (41), the compound according to any one of embodiments (1) to (39) of the present invention, or a pharmaceutically acceptable salt thereof, is 1 is CR 8.1 is.

[0126] In another embodiment (42), the compound according to any one of embodiments (1) to (41) of the present invention, or a pharmaceutically acceptable salt thereof, is 2 is N.

[0127] In another embodiment (43), the compound according to any one of embodiments (1) to (41) of the present invention, or a pharmaceutically acceptable salt thereof, is 2 is CR 8.2 is.

[0128] In another embodiment (44), the compound according to any one of embodiments (1) to (43) of the present invention, or a pharmaceutically acceptable salt thereof, is 3 is CR 8.3 is.

[0129] In another embodiment (45), the compound according to any one of embodiments (1) to (43) of the present invention, or a pharmaceutically acceptable salt thereof, is 3 is N.

[0130] In another embodiment (46), in the compound according to any one of embodiments (41), (43) and (44) of the present invention, or a pharmaceutically acceptable salt thereof, R 8.1 , R 8.2 and R 8.3 are independently hydrogen, halogen, C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl groups, CN, NO2, -NR A8 R B8 and-OR A8 and each alkyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, halogens, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 is substituted with at least one substituent selected from

[0131] In another embodiment (47), the compound according to embodiment (46) of the present invention or a pharmaceutically acceptable salt thereof, wherein R 8.1 , R 8.2 and R 8.3 are independently selected from hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, —CN, —NO, —NH, and —OH. 8.1 , R 8.2 and R 8.3 is hydrogen.

[0132] In another embodiment, in the compound according to any one of embodiments (1) to (36) and (38) to (47) of the present invention, or a pharmaceutically acceptable salt thereof, [ka] The structure of the part is [ka] In another embodiment, the compound of formula (I) is selected from [ka] The structure of the part is [ka] is selected from.

[0133] In another embodiment, in the compound according to any one of embodiments (1) to (33), (37), and (40) to (47) of the present invention, or a pharmaceutically acceptable salt thereof, [ka] The structure of the part is [ka] In another embodiment, the compound of formula (I) is selected from [ka] The structure of the part is [ka] In another embodiment, the compound of formula (I) is selected from [ka] The structure of the part is [ka] In another embodiment, the compound of formula (I) is selected from [ka] The structure of the part is [ka] is selected from.

[0134] In another embodiment (48), in the compound according to any one of embodiments (1) to (47) of the present invention or a pharmaceutically acceptable salt thereof, L is -CR C0 R D0 (CR C0 R D0 ) u -It is.

[0135] In another embodiment (49), in the compound according to any one of embodiments (1) to (47) of the present invention or a pharmaceutically acceptable salt thereof, L is -(CR C0 R D0 ) u O(CR C0 R D0 ) t -,-(CR C0 R D0 ) u NR A0 (CR C0 R D0 ) t -and-(CR C0 R D0 ) u S(O) r (CR C0 R D0 ) t - is selected from.

[0136] In another embodiment (50), the compound according to embodiment (1) of the present invention or a pharmaceutically acceptable salt thereof is 1 is N and X 2 is C and X 3 is CR 7.3 or N and X 4 does not exist, R 5 and R 6or any two R 6 does not form a ring, and W is [ka] and L is -CR C0 R D0 (CR C0 R D0 ) u In another embodiment (50'), Z 1 is N and X 2 is C and X 4 does not exist, R 5 and R 6 or any two R 6 does not form a ring, and W is [ka] and L is -CR C0 R D0 (CR C0 R D0 ) u - is selected from.

[0137] In another embodiment (51), in the compound according to any one of embodiments (1) to (50) and (50′) of the present invention, or a pharmaceutically acceptable salt thereof, each R C0 and R D0 are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy groups, and the methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy groups are unsubstituted or independently selected from R X0 and is substituted with at least one substituent selected from Or, R C0 and R D0 together with one or more carbon atoms attached thereto, C 3~10 The cycloalkyl group may be unsubstituted or independently R X0 is substituted with at least one substituent selected from

[0138] In another embodiment (52), in the compound according to any one of embodiments (1) to (49) and (51) of the present invention, or a pharmaceutically acceptable salt thereof, R X0 is C 1~10 Alkyl group, C 2~10 Alkenyl group, C 2~10 Alkynyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl groups, halogens, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 , -(CR c1 R d1 ) t OR b1 and -(CR c1 R d1 ) t C(O)R a1 and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, halogens, CN, NO2, -(CR c2 R d2 ) t NR a2 R b2 , -(CR c2 R d2 ) t OR b2 and -(CR c2 R d2 ) t C(O)R a2 is substituted with at least one substituent selected from

[0139] In another embodiment (53), the compound according to embodiment (52) of the present invention or a pharmaceutically acceptable salt thereof, wherein R X0is selected from hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, vinyl, ethynyl, F, Cl, Br, —CN, —NO, —NH, and —OH.

[0140] In another embodiment, in the compound or pharmaceutically acceptable salt thereof according to any one of embodiments (1) to (49) and (51) to (53) of the present invention, L is [ka] In another embodiment, L is selected from: [ka] is selected from.

[0141] In another embodiment (54), the compound according to embodiment (50) or (51) of the present invention, or a pharmaceutically acceptable salt thereof, is X0 is selected from CN, a vinyl group, and an ethynyl group.

[0142] In another embodiment, in the compound according to any one of embodiments (50), (51) and (54) of the present invention, or a pharmaceutically acceptable salt thereof, L is [ka] is selected from.

[0143] In another embodiment (55), in the compound according to any one of embodiments (1) to (54) of the present invention, or a pharmaceutically acceptable salt thereof, R 4 -C(O)OH, -C(O)NHS(O) r R A4 , -(CR c1 R d1 ) t NHS(O) r R A4 and heteroaryl groups.

[0144] In another embodiment (56), the compound according to embodiment (55) of the present invention or a pharmaceutically acceptable salt thereof, wherein R 4 teeth, [ka] is selected from.

[0145] In another embodiment (57), the compound according to any one of embodiments (1) to (56) of the present invention, or a pharmaceutically acceptable salt thereof, is 3 is selected from heterocyclyl groups, aryl groups and heteroaryl groups.

[0146] In another embodiment (58), the compound according to embodiment (57) of the present invention or a pharmaceutically acceptable salt thereof, is 3 teeth, [ka] is selected from.

[0147] In another embodiment (59), in the compound according to any one of embodiments (1) to (58) of the present invention, or a pharmaceutically acceptable salt thereof, p is selected from 0, 1, 2, and 3.

[0148] In another embodiment (60), in the compound according to any one of embodiments (1) to (59) of the present invention, or a pharmaceutically acceptable salt thereof, each R 3 independently for each occurrence, C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, C 3~10 Cycloalkyl-C 1~4 Alkyl groups, heterocyclyl groups, heterocyclyl-C 1~4 Alkyl group, aryl group, aryl-C 1~4 Alkyl groups, heteroaryl groups, heteroaryl-C 1~4 Alkyl group, NO2, -NR A3 R B3 and-ORA3 and the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are unsubstituted or independently selected from R X3 is substituted with at least one substituent selected from

[0149] In another embodiment (61), the compound according to embodiment (60) of the present invention, or a pharmaceutically acceptable salt thereof, is 3 is independently selected at each occurrence from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, —CN, —NO2, —NH2, and —OH, and methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy are unsubstituted or independently C 1~10 Alkyl group, C 3~10 Cycloalkyl groups, halogens, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 In another embodiment, each R 3 is independently selected at each occurrence from a methyl group, an ethyl group, and a methoxy group.

[0150] In another embodiment, in the compound according to any one of embodiments (1) to (61) of the present invention or a pharmaceutically acceptable salt thereof, [ka] The structure of the part is [ka] is selected from.

[0151] In another embodiment (62), the compounds of the present invention, and pharmaceutically acceptable salts thereof, are selected from: [ka] [ka] [ka]

[0152] In another embodiment (63), the present invention provides a pharmaceutical composition comprising a compound according to any one of embodiments (1) to (62) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0153] In another embodiment (64), the present invention provides a method for treating, ameliorating, or preventing a condition responsive to GLP-1R inhibition, comprising administering to an individual in need thereof an effective amount of a compound according to any one of embodiments (1) to (62), or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, optionally in combination with a second therapeutic agent.

[0154] In another embodiment (65), there is provided the use of a compound according to any one of embodiments (1) to (62) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or condition mediated by the GLP-1 receptor, or modulating the GLP-1 receptor.

[0155] In another embodiment (66), the use according to embodiment (65) of the present invention, wherein the disease or disorder includes, but is not limited to, diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, arrhythmia, cerebral infarction, stroke, liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), dementia, Parkinson's disease, and diabetic nephropathy.

[0156] In another aspect, a kit is provided that includes a compound disclosed herein or a pharmaceutically acceptable salt thereof and instructions that include one or more forms of information selected from the disease state for which the composition should be administered, storage information for the composition, administration information, and instructions indicating how to administer the composition. In certain variations, the kit includes multiple dosage forms of the compound.

[0157] In another aspect, an article of manufacture is provided that includes a compound disclosed herein or a pharmaceutically acceptable salt thereof and packaging material. In one variation, the packaging material includes a container that houses the compound. In certain variations, the container includes a tag that indicates one or more components selected from the group consisting of a disease state for which the compound is administered, storage information, administration information, and / or instructions on how to administer the compound. In another variation, the article of manufacture includes multiple dosage forms of the compound.

[0158] In a further aspect, there is provided a method of treatment comprising administering a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0159] In another aspect, there is provided a method of inhibiting GLP-1R, comprising contacting GLP-1R with a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0160] In another aspect, there is provided a method of inhibiting GLP-1R, comprising causing a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to be present in the body of a subject, thereby inhibiting GLP-1R in the body.

[0161] In another aspect, there is provided a method of inhibiting GLP-1R comprising administering to an individual a first compound that inhibits GLP-1R in the body and that is converted in the body to a second compound that is a compound or variant of any one of one or more of the embodiments.

[0162] In another aspect thereof, there is provided a method of treating a disease state in which GLP-1R has pathological and / or symptomatic activity that contributes to the disease state, comprising causing a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to be present in the body of a subject.

[0163] In another aspect, there is provided a method of treating a disease state in which GLP-1R has pathological and / or symptomatic activity that contributes to the disease state, comprising administering to a subject a first compound that is converted in the body to a second compound that inhibits GLP-1R. Note that the compound of the invention may be either the first or the second compound.

[0164] In another aspect, methods are provided for treating disease states of pathologies and / or conditions where the disease state is caused by a GLP-1R gene mutation, including, but not limited to, diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, arrhythmias, cerebral infarction, stroke, liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), dementia, Parkinson's disease, and diabetic nephropathy.

[0165] In another aspect, the invention relates to the use of a compound of any of the above embodiments and variations as a medicament. In another aspect, the invention relates to the use of a compound of any of the above embodiments and variations in the manufacture of a medicament for inhibiting GLP-1R.

[0166] In another aspect, the invention relates to the use of a compound according to any of the above embodiments and variations in the manufacture of a medicament for treating a disease state in which GLP-1R has pathological and / or symptomatic activity that contributes to the disease state.

[0167] Administration and Pharmaceutical Compositions

[0168] In general, the compounds described in the present invention are administered in a therapeutically effective amount, either alone or in combination with one or more therapeutic agents, in any conventional and acceptable manner known in the art. The therapeutically effective amount can vary widely depending on the severity of the subject's disease, age and relative health, the efficacy of the compound used, and other factors known in the art. For example, in the treatment of neoplastic diseases and immune system diseases, the required dosage will vary depending on the mode of administration, the specific disease to be treated, and the desired effect.

[0169] Generally, satisfactory results can be obtained at a daily dosage of 0.001 to 100 mg / kg body weight, specifically about 0.03 to 2.5 mg / kg body weight. For larger mammals, such as humans, the daily dosage is about 0.5 mg to about 2000 mg, or more specifically 0.5 mg to 1000 mg, administered in a convenient form, for example, in divided doses four times daily or in sustained-release form. Suitable unit dosage forms for oral administration contain about 1 to 50 mg of the active ingredient.

[0170] The compounds according to the invention may be administered in the form of pharmaceutical compositions and may be administered by any common route, for example enterally, orally, for example in the form of tablets or capsules, parenterally, for example in the form of injectable solutions or suspensions, or topically, for example in the form of lotions, gels, ointments or creams, or intranasally or in the form of suppositories.

[0171] Pharmaceutical compositions comprising a compound of the present invention in free base or pharmaceutically acceptable salt form and at least one pharmaceutically acceptable carrier or diluent may be prepared by conventional mixing, granulating, coating, dissolving, or lyophilizing procedures. For example, pharmaceutical compositions may be prepared by combining a compound of the present invention with at least one pharmaceutically acceptable carrier or diluent and mixing with a pharmaceutically acceptable carrier or diluent in a conventional manner. A unit dosage form for oral administration may contain, for example, from about 0.1 mg to about 500 mg of active substance.

[0172] In one embodiment, the pharmaceutical composition is a solution, suspension, or dispersion of the active ingredient, e.g., an isotonic aqueous solution. In the case of a lyophilized composition containing the active ingredient alone or in admixture with a carrier such as mannitol, the dispersion or suspension may be prepared prior to use. The pharmaceutical composition may be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solubility enhancers, salts for regulating osmotic pressure, and / or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, and microbicides such as sorbic acid or benzoic acid. The solution or suspension may further contain a viscosity enhancer, including, but not limited to, sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatin, or a solubilizer such as Tween 80 (polyoxyethylene (20) sorbitan monooleate).

[0173] Suspensions in oil may contain, as the oily component, vegetable oils, synthetic, or semi-synthetic oils commonly used for injection purposes. Examples include, as the acid component, liquid fatty acid esters of long-chain fatty acids having 8 to 22 carbon atoms, or in some embodiments, 12 to 22 carbon atoms. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, arachidic acid, behenic acid, or corresponding unsaturated acids such as oleic acid, elaidic acid, erucic acid, brassidic acid, and linoleic acid, and may optionally contain an antioxidant such as vitamin E, 3-carotene, or 3,5-di-t-butyl-hydroxytoluene. The alcohol component of these fatty acid esters may have 6 carbon atoms and may be monohydric or polyhydric, e.g., monohydric, dihydric, or trihydric alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or pentanol or their isomers, ethylene glycol and glycerin.

[0174] Other suitable fatty acid esters include ethyl oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL® M2375 (polyoxyethylene glycerin), LABRAFIL® M1944 CS (unsaturated polyethylene glycolated glyceryl prepared by alcoholysis of almond oil, including glycerin esters and polyethylene glycol esters), LABRASOL TM (a saturated polyethylene glycolated glyceryl produced by alcoholyzing TCM, containing glycerin esters and polyethylene glycol esters, both available from GaKefosse, France), and / or MIGLYOL® 812 (a saturated fatty acid triglyceride with a chain length of C8 to C12, manufactured by Huls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, or peanut oil, but are not limited to these.

[0175] Pharmaceutical compositions for oral administration may be prepared, for example, by mixing the active ingredient with one or more solid carriers, if necessary pelletizing the mixture, and adding other excipients to process the mixture or particles to form tablets or tablet cores.

[0176] Suitable carriers include, but are not limited to, fillers, such as sugars such as lactose, sucrose, mannitol, or sorbitol, cellulose preparations and / or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, and adhesives, such as starches, such as corn starch, wheat starch, rice starch, or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone, and / or disintegrants, if necessary, such as the above-mentioned starches, carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Other excipients include flow conditioners and lubricants, such as silicic acid, talc powder, stearic acid or a salt thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol or a derivative thereof.

[0177] The tablet cores may be provided with a suitable coating, optionally an enteric coating, using in particular concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or coating solutions dissolved in suitable organic solvents or solvent mixtures, or solutions of suitable cellulose preparations for enteric coatings, such as cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate solutions. Dyes or pigments may be added to the tablets or tablet coatings, for example to mark the active ingredient to indicate desired or different dosages.

[0178] Pharmaceutical compositions for oral administration may further comprise hard capsules containing gelatin or sealed soft capsules containing gelatin and a plasticizer, such as glycerin or sorbitol. Hard capsules may contain the active ingredient in particulate form, mixed with a filler, such as corn starch, an adhesive, and / or a fluidizer, such as talc powder or magnesium stearate, and optionally a stabilizer. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid excipient, such as fatty oils, paraffin oil, or liquid polyethylene glycol or fatty acid esters of ethylene glycol or propylene glycol. Stabilizers and detergents, for example, of the polyoxyethylene sorbitol fatty acid ester type, may also be added to the soft capsules.

[0179] Pharmaceutical compositions suitable for rectal administration, such as suppositories, comprise a combination of the active ingredient with a suppository matrix. Suitable suppository matrices are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

[0180] Pharmaceutical compositions suitable for parenteral administration may contain the active ingredient in water-soluble form, for example, a water-soluble salt, or an aqueous injection suspension containing a viscosity-increasing substance, such as sodium carboxymethylcellulose, an aqueous solution of sorbitol, and / or dextran, and, if necessary, a stabilizer. The active ingredient, optionally together with an excipient, may be in lyophilized form or may be made into a solution by adding a suitable solvent before parenteral administration. The solution used may be, for example, used for parenteral administration, and may also be used for infusion. Injectable preparations are usually prepared under aseptic conditions by filling ampoules or vials into sealed containers.

[0181] The present invention further provides a pharmaceutical combination, e.g., a kit, comprising: a) a compound disclosed herein, which may be in free form or in the form of a pharmaceutically acceptable salt; and b) at least one auxiliary agent. The kit may also include instructions for use therein.

[0182] Combination therapy

[0183] The compounds or pharmaceutically acceptable salts described in this patent may be used alone or in combination with other therapeutic agents.

[0184] For example, the therapeutic effect of the compounds of the present invention can be increased by using an adjuvant (e.g., a complementary drug may have minimal therapeutic benefit when used alone, but may increase the therapeutic benefit of an individual when used in combination with another drug). Alternatively, for example, the compounds of the present invention can be used in combination with other therapeutic agents having similar therapeutic effects to increase the therapeutic benefit of an individual. For example, when treating gout, the clinical benefit can be increased by using a compound of the present invention in combination with another drug that treats gout. Alternatively, for example, if nausea is a side effect of using a compound of the present invention, an antiemetic drug can be used in combination. Alternatively, combined therapies include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy of the affected area, rest, dietary improvement, etc. Regardless of the disease, illness, or condition, the therapeutic benefit of the individual from the two therapies should be additive or synergistic.

[0185] When the compound of the present patent is used in combination with other therapeutic agents, the pharmaceutical composition of the compound of the present patent may be administered by the same route as the other drug, or may be administered by a different route due to different physical and chemical properties. For example, the compound of the present patent may be able to produce and maintain a good blood drug level when administered orally, while the other therapeutic agent may need to be administered intravenously. Therefore, the compound of the present patent may be administered simultaneously with the other therapeutic agent, sequentially, or separately. Example

[0186] There are several methods for synthesizing the compound of formula (I) or a pharmaceutically acceptable salt thereof, and representative methods are given in this example. However, the compound of formula (I) or a pharmaceutically acceptable salt thereof may also be synthesized by other synthetic schemes.

[0187] In certain compounds of formula (I), specific stereoisomers (e.g., chiral centers) may exist due to the bonding of atoms to other atoms. Synthesis of compounds of formula (I) or pharmaceutically acceptable salts thereof may result in mixtures of different isomers (enantiomers, diastereomers). Unless a particular configuration is specifically described, the recited compound includes any different stereoisomers that may exist.

[0188] The compounds of formula (I) may be prepared into pharmaceutically acceptable acid addition salts, for example, by reacting a compound of the present invention in the form of a free base with a pharmaceutically acceptable inorganic or organic acid, or by reacting a compound of formula (I) in the form of a free acid with a pharmaceutically acceptable inorganic or organic base. Suitable inorganic acids, organic acids, inorganic bases, and organic bases for preparing pharmaceutically acceptable salts of compounds of formula (I) are described in the definitions section of this application. Salt forms of compounds of formula (I) may also be prepared using salts of starting materials or intermediates.

[0189] The free acid or free base of the compound of formula (I) may be prepared by its corresponding base addition salt or acid addition salt. The acid addition salt form of the compound of formula (I) may be converted to the corresponding free base, for example, by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The base addition salt form of the compound of formula (I) may be converted to the corresponding free acid, for example, by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0190] The N-oxide of a compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared by a method known in the art. For example, the N-oxide may be obtained by reacting the non-oxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, permaleic benzoic acid, peracetic acid, m-chloroperbenzoic acid, etc.) in an inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at 0 to 80°C. Alternatively, the N-oxide of the compound of formula (I) may be prepared from the N-oxide of the starting material.

[0191] The non-oxidized form of the compound of formula (I) may be prepared by reacting its N-oxide with a reducing agent (e.g., sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide, etc.) in a corresponding inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80°C.

[0192] Protected derivatives of compounds of formula (I) may be prepared by methods known to those skilled in the art. For detailed techniques for adding and removing protecting groups, see T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

[0193] All markings and conventions used in these methods, routes, and examples are consistent with current scientific literature, e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry. Unless otherwise stated, standard one-letter or three-letter abbreviations generally refer to L-amino acid residues. Unless otherwise stated, all starting materials used were purchased from commercial vendors and were not further purified at the time of use.For example, the following abbreviations may be used in the examples and throughout the specification: g (gram), mg (milligram), L (liter), mL (milliliter), μL (microliter), psi (pounds per square inch), M (mole), mM (millimol), iv (intravenous), Hz (hertz), MHz (megahertz), mol (mole), mmol (millimol), RT (ambient temperature), min (minutes), h (hours), mp (melting point), TLC (thin layer chromatography), Rt (retention time), RP (reverse phase), MeO H (methanol), i-PrOH (isopropanol), TEA (triethylamine), TFA (trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), DME (1,2-dimethoxyethane), DCM (dichloromethane), DCE (dichloroethane), DMF (N,N-dimethylformamide), DMPU (N,N'-dimethylpropyleneurea), CDI (1,1-carbonyldiimidazole), I BCF (isobutyl chloroformate), HOAc (acetic acid), HOSu (N-hydroxysuccinimide), HOBT (1-hydroxybenzotriazole), Et2O (ethyl ether), EDCI (1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride), BOC (t-butoxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (dicyclohexylcarbodiimide), CBZ (benzyloxycarbonyl), Ac (acetyl), atm (atmospheric pressure), TMSE ( 2-(trimethylsilyl)ethyl), TMS (trimethylsilyl), TIPS (triisopropylsilyl), TBS (t-butyldimethylsilylene), DMAP (4-dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethyl), tBu (t-butyl), HPLC (high performance liquid chromatography), BOP (bis(2-oxo-3-oxazolidinyl)sulfinyl chloride), TBAF (tetra-n-butylammonium fluoride), mCPBA (m-chloroperbenzoic acid).

[0194] References to ether or EtO refer to ethyl ether, and brine refers to saturated aqueous NaCl. Unless otherwise stated, all temperatures are in degrees Celsius (°C) and all reactions are conducted in an inert atmosphere at room temperature.

[0195] 1 H NMR spectra were recorded using a Varian Mercury Plus 400 nuclear magnetic resonance spectrometer. Chemical shifts are expressed in ppm. Coupling constants are in hertz (Hz). Apparent diversity is described by splitting patterns, designated s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad).

[0196] Low-resolution mass spectrometry (MS) and compound purity data were obtained using a Shimadzu LC / MS single quadrupole system equipped with an electrospray ionization (ESI) detector, ultraviolet (UV) detectors (220 and 254 nm), and evaporative light scattering (ELSD) detector. Thin-layer chromatography was performed using 0.25 mm Superchemgroup silica gel plates (60F-254) containing 5% ethanolic phosphomolybdic acid, ninhydrin, and p-methoxybenzaldehyde solution, and was observed under a UV lamp. Flash column chromatography was performed using silica gel (200-300 mesh, Qingdao Ocean Chemical Industry Co., Ltd.). Synthesis scheme

[0197] The synthesis schemes for all compounds of the present invention are illustrated by the following schemes and examples. The starting materials used may be derived from commercially available products or may be prepared by existing process methods or by methods exemplified herein.

[0198] As shown in Scheme 1, compounds of formula I may be synthesized from intermediates of formula II and formula III, which are compounds known in the literature or may be prepared by a variety of methods well known to those skilled in the art. Coupling of formula III and formula II under standard amide bond forming conditions provides compounds of formula I. [ka] Scheme 1

[0199] As an example of preparing an intermediate of Formula II, Scheme 2 provides a method for synthesizing compound IIa. Compound IIa-A, whether commercially available, reported in the literature, or prepared by the methods described herein, can be subjected to a metal-catalyzed cross-coupling reaction with IIa-B to obtain compound IIa-C. Compound IIa-C can then be halogenated to give compound IIa-D. Cyanomethylation of IIa-D to IIa-E can also be carried out by functional group transformation of a side-chain-substituted aromatic hydrocarbon. IIa-E can then be converted to a cycloalkane ring to give IIa-F. Compound IIa-F can then be treated with hydroxylamine, further reacted with CDI (N,N'-carbonyldiimidazole), and finally hydrolyzed to give compound IIa. [ka] Scheme 2

[0200] In some cases, the sequence of the above synthetic schemes can be adjusted accordingly to facilitate the reaction or to avoid the formation of unwanted reaction products. In order to more fully understand the present invention, the following examples are provided. These examples are merely illustrative and should not be construed as limiting the present invention.

[0201] Example 1 3-((2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1-methyl-1H-indol-3-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (1) [ka]

[0202] Methyl 6-bromo-1-methyl-1H-indole-2-carboxylate (1a) The title compound, methyl 6-bromo-1-methyl-1H-indole-2-carboxylate (1a), was prepared according to the method described in patent WO2022147302.

[0203] Methyl 6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2-carboxylate (1b) To a mixture of Zn powder (678 mg, 10.41 mmol) in DMF (5 mL) at room temperature, TMSCl (1.0 mol / L THF solution, 0.38 mL, 0.372 mmol) and 1,2-dibromoethane (70.0 mg, 0.372 mmol) were added. After stirring the mixture at room temperature for 10 min, a solution of 4-iodo-2,2-dimethyltetrahydro-2H-pyran (1.80 g, 7.45 mmol) in DMF (5 mL) was added and stirring was continued for 30 min. Then, Pd(OAc) (100 mg, 0.446 mmol) and AmPhos (240 mg, 0.894 mmol) were added sequentially at room temperature, followed by methyl 6-bromo-1-methyl-1H-indole-2-carboxylate (1a) (1.0 g, 3.72 mmol), and the mixture was stirred at 50 °C for 2 h. The mixture was diluted with methyl t-butyl ether (MTBE) and water, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (20:1 to 10:1) to give the title compound, methyl 6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2-carboxylate (1b). MS-ESI (m / z): 302 [M+1] + .

[0204] Methyl 3-bromo-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2-carboxylate (1c) To a solution of methyl 6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2-carboxylate (1b) (200 mg, 0.662 mmol) in 5 mL of DMF was added dropwise a suspension of NBS (118 mg, 0.662 mmol) in 2 mL of DMF. The mixture was stirred at room temperature for 10 minutes, diluted with ethyl acetate (EtOAc), and quenched with saturated aqueous sodium sulfite (NaSO). The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate (MgSO), and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (20:1 to 3:1) to give the title compound, methyl 3-bromo-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2-carboxylate (1c). MS-ESI(m / z):380,382[M+1] + .

[0205] Methyl 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2-carboxylate (1d) Methyl 3-bromo-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2-carboxylate (1c) (180 mg, 0.473 mmol), sodium cyanoacetate (76 mg, 0.71 mmol), Pd(dba) (30 mg, 0.032 mmol), and XantPhos (40 mg, 0.097 mmol) were stirred in a mixture of diethylene glycol dimethyl ether (5 mL) at 140 °C for 40 min in a microwave oven. The mixture was cooled to room temperature and then diluted with water and ethyl acetate (EtOAc). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate (NaSO), and concentrated. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (20:1 to 5:1) to give the title compound methyl 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2-carboxylate (1d). MS-ESI (m / z): 341 [M+1] + .

[0206] 3-((2S)-1-cyano-2-methylcyclopropyl-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2-carboxylic acid (1e) To a solution of methyl 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2-carboxylate (1d) (140 mg, 0.411 mmol) and (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (56.8 mg, 0.411 mmol) in THF (8 mL) was added KHMDS (1.0 mol / L THF solution, 2.05 mL, 2.05 mmol) in an ice bath. The reaction mixture was stirred at 0 °C for 1 h, quenched with saturated citric acid solution (pH = 4-5), and extracted with ethyl acetate (EtOAc). The combined organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The residue was purified by preparative thin layer chromatography (PTLC) eluting with DCM / MeOH (20:1) to give the title compound 3-((2S)-1-cyano-2-methylcyclopropyl-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2-carboxylic acid (1e). MS-ESI (m / z): 367 [M+1] + .

[0207] (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (1f) The title compound (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (1f) was prepared according to the method described in Patent US2019225604A1.

[0208] (2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1-methyl-1H-indol-3-yl)-2-methylcyclopropane-1-carbonitrile (1g) 3-((2S)-1-cyano-2-methylcyclopropyl-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2-carboxylic acid (1e) (40 mg, 0.109 mmol), (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5 A mixture of 1,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (1f) (47 mg, 0.087 mmol), HATU (62 mg, 0.163 mmol), DIEA (42 mg, 0.327 mmol), and DMAP (6.6 mg, 0.054 mmol) was stirred at room temperature overnight. The reaction mixture was diluted with water and ethyl acetate (EtOAc). After that, the organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The residue was purified by preparative thin-layer chromatography (PTLC) eluting with DCM / ACN (150:40) to obtain the title compound (2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazoline). (4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1-methyl-1H-indol-3-yl)-2-methylcyclopropane-1-carbonitrile (1g) was obtained. MS-ESI (m / z): 838 [M+1] + .

[0209] (2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1-methyl-1H-indol-3-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide (1h) A mixture of (2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1-methyl-1H-indol-3-yl)-2-methylcyclopropane-1-carbonitrile (1g) (30 mg, 0.00357 mmol), aq. NHOH (50% 180 mg, 2.72 mmol) in IPA (2 mL) was stirred at 85 °C for 4 h. The reaction mixture was diluted with water and ethyl acetate (EtOAc), and the organic layer was separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate (NaSO), and concentrated to give the crude product (2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1-methyl-1H-indol-3-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide (1h), which was used directly in the next step. MS-ESI(m / z):871[M+1] + .

[0210] 3-((2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1-methyl-1H-indol-3-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (1) To a solution of (2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1-methyl-1H-indol-3-yl)-N-hydroxy-2-methylcyclopropane-1-carboximidamide (1h) (32 mg, 0.037 mmol) in DMSO (2.5 mL) was added DBU (14 mg, 0.092 mmol) and CDI (12 mg, 0.074 mmol). The reaction mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with ethyl acetate (EtOAc). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The residue was purified by preparative thin-layer chromatography (PTLC) eluting with DCM / MeOH (50:1) to give the title compound 3-((2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1-methyl-1H-indol-3-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (1). MS-ESI (m / z): 897 [M+1] + .

[0211] Example 2 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (2) [ka]

[0212] t-Butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2a) The title compound t-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (2a) was prepared according to the method described in patent US2019225604A1.

[0213] t-Butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(hydrazinecarboxamido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2b) To a solution of triphosgene (720 mg, 2.42 mmol) in DCM (25 mL) was added t-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2a) (500 mg, 1.33 mmol), followed by TEA (2.5 mL, 17.8 mmol). The reaction mixture was stirred at room temperature for 1 h and then added to a solution of hydrazine hydrate (1.66 g, 26.56 mmol) in tetrahydrofuran (THF, 10 mL). Stirring was continued at room temperature for 5–10 min. The reaction mixture was diluted with water and extracted with methyl t-butyl ether (MTBE). The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate (NaSO), and concentrated. The crude product was purified by recrystallization from a PE / MTBE (10:1) mixed solvent to obtain the title compound, t-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(hydrazinecarboxamido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (2b). MS-ESI (m / z): 433 [M+1] + .

[0214] t-Butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2c) To a solution of t-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(hydrazinecarboxamido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2b) (467 mg, 1.079 mmol) in EtOH (10 mL) was added CH(OMe) (911 mg, 8.58 mmol) and PTSA (10 mg, 0.052 mmol). The mixture was stirred at 80 °C for 2 h. After concentration, the residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1 to 2:1) to obtain the title compound t-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (2c). MS-ESI (m / z): 443 [M+1] + .

[0215] t-Butyl (S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2d) t-Butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (2c) (14 mg, 0.0316 mmol), 4-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (17.5 mg, 0.063 mmol), Cu(OAc) (8.6 mg, 0.047 mmol), TEMPO (9.8 mg, 0.063 mmol), 4A in DMF (0.5 mL). A mixture of MS (25 mg) and Py (5.0 mg, 0.063 mmol) was stirred at room temperature for 2.5 days. The reaction mixture was diluted with ethyl acetate and water, filtered, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate (NaSO), and concentrated. The residue was purified by preparative thin-layer chromatography (PTLC) eluting with DCM / ACN (15:1) to obtain the title compound t-butyl (S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (2d). MS-ESI (m / z): 591 [M+1] + .

[0216] (S)-2-(4-fluoro-1-methyl-1H-indazol-5-yl)-4-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2e) A mixture of t-butyl (S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (2d) (3.5 mg, 0.0059 mmol) in DCM (0.5 mL) and 4N HCl dioxane solution (0.5 mL) was stirred at room temperature for 0.5 h. The mixture was concentrated to give crude (S)-2-(4-fluoro-1-methyl-1H-indazol-5-yl)-4-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2e), which was used directly in the next step. MS-ESI (m / z): 491 [M+1] + .

[0217] 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (2) (S)-2-(4-fluoro-1-methyl-1H-indazol-5-yl)-4-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2e) (crude product), 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-( A mixture of (1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (US2019225604A1) (3.0 mg, 0.0073 mmol), HATU (4.5 mg, 0.0118 mmol), DMAP (2.0 mg, 0.016 mmol), and DIPEA (5.0 mg, 0.0387 mmol) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (EtOAc). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The residue was purified by preparative thin-layer chromatography (PTLC) eluting with EtOAc / PE (65:35) to give the title compound 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (2). MS-ESI (m / z): 884 [M+1] + .

[0218] Example 3 3-((2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)benzo[b]thiophen-3-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (3) [ka]

[0219] Ethyl 6-bromo-3-methylbenzo[b]thiophene-2-carboxylate (3a) Ethyl mercaptoacetate (3.04 g, 25.3 mmol) was added to a solution of 1-(4-bromo-2-fluorophenyl)ethan-1-one (5.0 g, 23 mmol) and K2CO3 (4.3 g, 31.1 mmol) in DMF (30 mL) at 0 °C. The mixture was stirred at room temperature for 16 h, then heated to 80 °C and stirred for 24 h. After filtration, the filtrate was washed with water, extracted with ethyl acetate (EtOAc), dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (20:1) to give the title compound, ethyl 6-bromo-3-methylbenzo[b]thiophene-2-carboxylate (3a). MS-ESI (m / z): 299, 301 [M+1] + .

[0220] Ethyl 6-bromo-3-(bromomethyl)benzo[b]thiophene-2-carboxylate (3b) NBS (3.4 g, 19.1 mmol) and AIBN (0.23 g, 1.77 mmol) were added to a solution of ethyl 6-bromo-3-methylbenzo[b]thiophene-2-carboxylate (3a) (2.4 g, 8.02 mmol) in CCl (72 mL) at room temperature. The reaction mixture was stirred at 80 °C for 2 hours, cooled to room temperature, and filtered. The filter cake was washed with ethyl acetate (EtOAc). The combined filtrate was diluted with water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate (NaSO), and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1:5) to give the title compound, ethyl 6-bromo-3-(bromomethyl)benzo[b]thiophene-2-carboxylate (3b). MS-ESI (m / z): 297, 299 [M-Br+H] + .

[0221] Ethyl 6-bromo-3-(cyanomethyl)benzo[b]thiophene-2-carboxylate (3c) To a solution of ethyl 6-bromo-3-(bromomethyl)benzo[b]thiophene-2-carboxylate (3b) (3.0 g, 8.02 mmol) in MeCN (50 mL) was added TMSCN (1.03 g, 10.4 mmol), followed by TABF (1 M in THF, 10.4 mL, 10.4 mmol). The reaction mixture was stirred at room temperature for 1 hour, then quenched with aqueous sodium bicarbonate and extracted with ethyl acetate (EtOAc). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate (NaSO), and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (20:1 to 8:1) to give the title compound, ethyl 6-bromo-3-(cyanomethyl)benzo[b]thiophene-2-carboxylate (3c). MS-ESI (m / z): 324, 326 [M+1]. + .

[0222] Ethyl 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylate (3d) To a mixture of Zn powder (264 mg, 4.07 mmol) in DMF (5 mL) was added TMSCl (1.0 mol / L in THF, 0.19 mL, 0.19 mmol) and 1,2-dibromoethane (34.8 mg, 0.185 mmol) at room temperature. After stirring the reaction mixture at room temperature for 10 min, a solution of 4-iodo-2,2-dimethyltetrahydro-2H-pyran (0.892 g, 3.70 mmol) in DMF (5 mL) was added and stirring was continued at room temperature for 30 min. Pd(OAc)2 (100 mg, 0.446 mmol) and AmPhos (240 mg, 0.894 mmol) were then added, followed by the addition of ethyl 6-bromo-3-(cyanomethyl)benzo[b]thiophene-2-carboxylate (3c) (0.6 g, 1.85 mmol). The reaction mixture was heated to 50 °C and stirred for 2 h. After completion of the reaction, it was diluted with methyl t-butyl ether and water. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (20:1 to 10:1) to give the title compound, ethyl 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylate (3d). MS-ESI (m / z): 358 [M+1]. + .

[0223] 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylic acid (3e) A solution of ethyl 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylate (3d) (320 mg, 0.893 mmol) and LiOH.HO (94 mg, 2.2 mmol) in MeOH / THF / HO (5 / 5 / 5 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water, adjusted to pH 5-6 with citric acid, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate (MgSO), and concentrated to give crude 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylate (3e), which was used directly in the next step. MS-ESI (m / z): 330 [M+1] + .

[0224] 2-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)benzo[b]thiophen-3-yl)acetonitrile (3f) A mixture of 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylic acid (3e) (37 mg, 0.113 mmol), (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (1f) (59 mg, 0.113 mmol), HATU (64 mg, 0.169 mmol), DIEA (0.1 mL, 0.565 mmol), and DMAP (20 mg, 0.163 mmol) in DMF (1 mL) was stirred at room temperature overnight. The mixture was diluted with water and EtOAc, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The residue was purified by preparative thin-layer chromatography (PTLC) eluting with PE / EtOAc (1:1) to obtain the title compound 2-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)benzo[b]thiophen-3-yl)acetonitrile (3f). MS-ESI (m / z): 801 [M+1] + .

[0225] (2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)benzo[b]thiophen-3-yl)-2-methylcyclopropane-1-carbonitrile (3g) In an ice bath, 2-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3- To a solution of (c)pyridine-5-carbonyl)benzo[b]thiophen-3-yl)acetonitrile (3f) (5.0 mg, 0.0062 mmol) and (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (0.86 mg, 0.0062 mmol) in THF (0.3 mL) was added KHMDS (1.0 mol / L THF solution, 0.1 mL, 0.1 mmol). The reaction mixture was stirred at 0 °C for 1 h, then quenched with saturated citric acid solution (pH = 4-5) and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The residue was purified by preparative thin-layer chromatography (PTLC) eluting with DCM / MeOH (20:1) to give the title compound (2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)benzo[b]thiophen-3-yl)-2-methylcyclopropane-1-carbonitrile (3g). MS-ESI (m / z): 841 [M+1] + .

[0226] 3-((2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)benzo[b]thiophen-3-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (3) The title compound, 3-((2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-indazol-5-yl)-benzo[b]thiophen-3-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (3) was synthesized according to the synthesis method in 1. (2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3 -(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)benzo[b]thiophen-3-yl)-2-methylcyclopropane-1-carbonitrile (3g). MS-ESI (m / z): 900 [M+1] + .

[0227] Example 4 3-((2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)benzofuran-3-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (4) [ka] The title compound, 3-((2S)-1-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c] For pyridine-5-carbonyl)benzofuran-3-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (4), the synthesis method for 3 was followed, replacing 1-(4-bromo-2-fluorophenyl)ethan-1-one and ethyl 2-mercaptoacetate with 1-(4-bromo-2-hydroxyphenyl)ethan-1-one and ethyl 2-bromoacetate. MS-ESI (m / z): 884 [M+1] + .

[0228] Examples 5-63 shown in Table 1 may be prepared from appropriate starting materials that are commercially available or known in the literature, following essentially the same steps or similar synthetic strategies or methods described in Examples 1-4. The structures and names of Examples 5-63 are shown in Table 1.

[0229] Table 1 [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] *: LC / MS data for the manufactured compound is obtained using the method specified above. The symbol " / / " indicates that the example can be obtained by preparing the appropriate intermediates and modifying them in the required order by methods known in the art.

[0230] Cell proliferation test The intracellular cAMP concentration was detected using TR-FRET to evaluate drug-induced GLP1R receptor activity. Cells were prepared in an experimental buffer solution (HBSS, 20 mM HEPES (pH 7.5), 0.1% BSA, 500 μM IBMX) and seeded into 384 cell culture plates at a seeding density of 2,000 cells per well, with a seeding volume of 15 μL per well. Compounds were diluted 3-fold in DMSO, followed by a 100-fold serial dilution in buffer. The maximum concentration of the compound to be measured was 12 μM. 5 μL of the working solution was added to the seeded 384 cell culture plates and incubated at 37°C for 30 minutes. The Eu-cAMP tracer was diluted 50-fold and the Ulight anti-cAMP was diluted 150-fold in detection buffer (cAMP Kit, Perkin-Elmer, cat#TRF0263). First, 10 μL of Eu-cAMP tracer was added to each experimental well, followed by 10 μL of Uligh anti-cAMP. The measurement plate was centrifuged at 200 g for 30 s at RT and incubated at 25°C for 1 h. Data were collected using an Envision 2105 microplate reader with an HTRF module. Excitation wavelength: 340 nm. Emission wavelengths: 665 nm and 615 nm.

[0231] Formula:Activity%=100(Signal cmpd Signal Ave_PC ) / (Signal Ave_VC Signal Ave_PC The activity of each concentration of the test compound against the positive drug was calculated based on the EC 50 Obtain values ​​and nonlinear regression curve fitting.

[0232] Table 2 [Table 2]

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (I) (In the formula, 【Chemistry 2】 is a double bond or a single bond, X １ , X ２ , X ５ and X ６ is independently selected from N and C; X ３ is O, S, N, NR ７．３ and CR ７．３ is selected from X ４ is absent or is N, C(O) and CR ７．４ is selected from Y １ is N and CR ８．１ is selected from Y ２ is N and CR ８．２ is selected from Y ３ is N and CR ８．３ is selected from Z １ is selected from N and C(O); Z ２ is selected from N and C; W is unsubstituted or independently represents R Ｘ substituted with at least one substituent selected from 【Transformation 3】 is selected from L is -CR Ｃ０ R Ｄ０ (CR Ｃ０ R Ｄ０ ) ｕ -, - (CR Ｃ０ R Ｄ０ ) ｕ O (CR Ｃ０ R Ｄ０ ) ｔ -, - (CR Ｃ０ R Ｄ０ ) ｕ NR Ａ０ (CR Ｃ０ R Ｄ０ ) ｔ - and - (CR Ｃ０ R Ｄ０ ) ｕ S (O) ｒ (CR Ｃ０ R Ｄ０ ) ｔ - is selected from, Q １ , Q ２ and Q ３ is C ３～１０ selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; Each R １ is independently hydrogen, halogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl group, heteroaryl group, heteroaryl-C １～４ Alkyl groups, CN, NO ２ , -NR Ａ１ R Ｂ１ , -OR Ａ１ , -C(O)R Ａ１ , -C(=NR Ｅ１ ) R Ａ１ , -C(=N-OR Ｂ１ ) R Ａ１ , -C(O)OR Ａ１ , -OC(O)R Ａ１ , —C(O)NR Ａ１ R Ｂ１ , —C(O)NR Ａ１ S (O) ｒ R Ａ１ , —C(O)NR Ａ１ S (O) ２ OR Ａ１ , —C(O)NR Ａ１ S (O) ｒ NR Ａ１ R Ｂ１ , —C(O)NR Ａ１ S(O) (=NR Ｅ１ ) R Ｂ１ , —C(O)NR Ａ１ S(O) (=NR Ｅ１ ) NR Ａ１ R Ｂ１ , -NR Ａ１ C(O)R Ｂ１ , -C(=NR Ｅ１ ) NR Ａ１ R Ｂ１ , -NR Ａ１ C (=NR Ｅ１ ) R Ｂ１ , —OC(O)NR Ａ１ R Ｂ１ , -NR Ａ１ C(O)OR Ｂ１ , -NR Ａ１ C(O)NR Ａ１ R Ｂ１ , -NR Ａ１ C(S)NR Ａ１ R Ｂ１ , -NR Ａ１ C (=NR Ｅ１ ) NR Ａ１ R Ｂ１ , -S(O) ｒ R Ａ１ , -S(O)(=NR Ｅ１ ) R Ｂ１ , -N=S(O)R Ａ１ R Ｂ１ , -S(O) ２ OR Ａ１ , -OS(O) ２ R Ａ１ , -NR Ａ１ S (O) ｒ R Ｂ１ , -NR Ａ１ S(O) (=NR Ｅ１ ) R Ｂ１ , -S(O) ｒ NR Ａ１ R Ｂ１ , -S(O)(=NR Ｅ１ ) NR Ａ１ R Ｂ１ , -NR Ａ１ S (O) ２ NR Ａ１ R Ｂ１ , -NR Ａ１ S(O) (=NR Ｅ１ ) NR Ａ１ R Ｂ１ , -P(O)R Ａ１ R Ｂ１ and -P(O)(OR Ａ１ ) (OR Ｂ１ and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R Ｘ１ and is substituted with at least one substituent selected from Each R ２ is independently hydrogen, halogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl group, heteroaryl group, heteroaryl-C １～４ Alkyl groups, CN, NO ２ , -NR Ａ２ R Ｂ２ , -OR Ａ２ , -C(O)R Ａ２ , -C(=NR Ｅ２ ) R Ａ２ , -C(=N-OR Ｂ２ ) R Ａ２ , -C(O)OR Ａ２ , -OC(O)R Ａ２ , —C(O)NR Ａ２ R Ｂ２ , —C(O)NR Ａ２ S(O) (=NR Ｅ２ ) R Ｂ２ , —C(O)NR Ａ２ S(O) (=NR Ｅ２ ) NR Ａ２ R Ｂ２ , -NR Ａ２ C(O)R Ｂ２ , -C(=NR Ｅ２ ) NR Ａ２ R Ｂ２ , -NR Ａ２ C (=NR Ｅ２ ) R Ｂ２ , —OC(O)NR Ａ２ R Ｂ２ , -NR Ａ２ C(O)OR Ｂ２ , -NR Ａ２ C(O)NR Ａ２ R Ｂ２ , -NR Ａ２ C(S)NR Ａ２ R Ｂ２ , -NR Ａ２ C (=NR Ｅ２ ) NR Ａ２ R Ｂ２ , -S(O)(=NR Ｅ２ ) R Ｂ２ , -N=S(O)R Ａ２ R Ｂ２ , -NR Ａ２ S(O) (=NR Ｅ２ ) R Ｂ２ , -S(O)(=NR Ｅ２ ) NR Ａ２ R Ｂ２ and -NR Ａ２ S(O) (=NR Ｅ２ ) NR Ａ２ R Ｂ２ and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｘ２ and is substituted with at least one substituent selected from Each R ３ is independently hydrogen, halogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl group, heteroaryl group, heteroaryl-C １～４ Alkyl groups, CN, NO ２ , -NR Ａ３ R Ｂ３ , -OR Ａ３ , -C(O)R Ａ３ , -C(=NR Ｅ３ ) R Ａ３ , -C(=N-OR Ｂ３ ) R Ａ３ , -C(O)OR Ａ３ , -OC(O)R Ａ３ , —C(O)NR Ａ３ R Ｂ３ , —C(O)NR Ａ３ S (O) ｒ R Ａ３ , —C(O)NR Ａ３ S (O) ２ OR Ａ３ , —C(O)NR Ａ３ S (O) ｒ NR Ａ３ R Ｂ３ , —C(O)NR Ａ３ S(O) (=NR Ｅ３ ) R Ｂ３ , —C(O)NR Ａ３ S(O) (=NR Ｅ３ ) NR Ａ３ R Ｂ３ , -NR Ａ３ C(O)R Ｂ３ , -C(=NR Ｅ３ ) NR Ａ３ R Ｂ３ , -NR Ａ３ C (=NR Ｅ３ ) R Ｂ３ , —OC(O)NR Ａ３ R Ｂ３ , -NR Ａ３ C(O)OR Ｂ３ , -NR Ａ３ C(O)NR Ａ３ R Ｂ３ , -NR Ａ３ C(S)NR Ａ３ R Ｂ３ , -NR Ａ３ C (=NR Ｅ３ ) NR Ａ３ R Ｂ３ , -S(O) ｒ R Ａ３ , -S(O)(=NR Ｅ３ ) R Ｂ３ , -N=S(O)R Ａ３ R Ｂ３ , -S(O) ２ OR Ａ３ , -OS(O) ２ R Ａ３ , -NR Ａ３ S (O) ｒ R Ｂ３ , -NR Ａ３ S(O) (=NR Ｅ３ ) R Ｂ３ , -S(O) ｒ NR Ａ３ R Ｂ３ , -S(O)(=NR Ｅ３ ) NR Ａ３ R Ｂ３ , -NR Ａ３ S (O) ２ NR Ａ３ R Ｂ３ , -NR Ａ３ S(O) (=NR Ｅ３ ) NR Ａ３ R Ｂ３ , -P(O)R Ａ３ R Ｂ３ and -P(O)(OR Ａ３ ) (OR Ｂ３ and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R Ｘ３ and is substituted with at least one substituent selected from R ４ is -C(O)OH, -C(O)NHS(O) ｒ R Ａ４ , -(CR ｃ１ R ｄ１ ) ｔ NHS (O) ｒ R Ａ４ , a heterocyclyl group, and a heteroaryl group; R ５ is hydrogen, halogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl groups, CN, NO ２ , -NR Ａ５ R Ｂ５ , -OR Ａ５ and -C(O)R Ａ５ and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from R Ｘ５ and is substituted with at least one substituent selected from Each R ６ is independently hydrogen, halogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl groups, CN, NO ２ , -NR Ａ６ R Ｂ６ , -OR Ａ６ and -C(O)R Ａ６ and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from R Ｘ６ and is substituted with at least one substituent selected from Or, "R ５ and R ６ " or "Two R's ６ " together with the atoms bonded to them are C ３～１０ a cycloalkyl group or a 4- to 12-membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the cycloalkyl and heterocyclyl groups are unsubstituted or independently selected from R Ｘ６ and is substituted with at least one substituent selected from R ７．３ and R ７．４ are independently hydrogen, halogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl group, heteroaryl group, heteroaryl-C １～４ Alkyl groups, CN, NO ２ , -NR Ａ７ R Ｂ７ , -OR Ａ７ , -C(O)R Ａ７ , -C(=NR Ｅ７ ) R Ａ７ , -C(=N-OR Ｂ７ ) R Ａ７ , -C(O)OR Ａ７ , -OC(O)R Ａ７ , —C(O)NR Ａ７ R Ｂ７ , —C(O)NR Ａ７ S (O) ｒ R Ａ７ , —C(O)NR Ａ７ S (O) ２ OR Ａ７ , —C(O)NR Ａ７ S (O) ｒ NR Ａ７ R Ｂ７ , —C(O)NR Ａ７ S(O) (=NR Ｅ７ ) R Ｂ７ , —C(O)NR Ａ７ S(O) (=NR Ｅ７ ) NR Ａ７ R Ｂ７ , -NR Ａ７ C(O)R Ｂ７ , -C(=NR Ｅ７ ) NR Ａ７ R Ｂ７ , -NR Ａ７ C (=NR Ｅ７ ) R Ｂ７ , —OC(O)NR Ａ７ R Ｂ７ , -NR Ａ７ C(O)OR Ｂ７ , -NR Ａ７ C(O)NR Ａ７ R Ｂ７ , -NR Ａ７ C(S)NR Ａ７ R Ｂ７ , -NR Ａ７ C (=NR Ｅ７ ) NR Ａ７ R Ｂ７ , -S(O) ｒ R Ａ７ , -S(O)(=NR Ｅ７ ) R Ｂ７ , -N=S(O)R Ａ７ R Ｂ７ , -S(O) ２ OR Ａ７ , -OS(O) ２ R Ａ７ , -NR Ａ７ S (O) ｒ R Ｂ７ , -NR Ａ７ S(O) (=NR Ｅ７ ) R Ｂ７ , -S(O) ｒ NR Ａ７ R Ｂ７ , -S(O)(=NR Ｅ７ ) NR Ａ７ R Ｂ７ , -NR Ａ７ S (O) ２ NR Ａ７ R Ｂ７ , -NR Ａ７ S(O) (=NR Ｅ７ ) NR Ａ７ R Ｂ７ , -P(O)R Ａ７ R Ｂ７ and -P(O)(OR Ａ７ ) (OR Ｂ７ and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R Ｘ７ and is substituted with at least one substituent selected from R ８．１ , R ８．２ and R ８．３ are independently hydrogen, halogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl group, heteroaryl group, heteroaryl-C １～４ Alkyl groups, CN, NO ２ , -NR Ａ８ R Ｂ８ , -OR Ａ８ , -C(O)R Ａ８ , -C(=NR Ｅ８ ) R Ａ８ , -C(=N-OR Ｂ８ ) R Ａ８ , -C(O)OR Ａ８ , -OC(O)R Ａ８ , —C(O)NR Ａ８ R Ｂ８ , —C(O)NR Ａ８ S (O) ｒ R Ａ８ , —C(O)NR Ａ８ S (O) ２ OR Ａ８ , —C(O)NR Ａ８ S (O) ｒ NR Ａ８ R Ｂ８ , —C(O)NR Ａ８ S(O) (=NR Ｅ８ ) R Ｂ８ , —C(O)NR Ａ８ S(O) (=NR Ｅ８ ) NR Ａ８ R Ｂ８ , -NR Ａ８ C(O)R Ｂ８ , -C(=NR Ｅ８ ) NR Ａ８ R Ｂ８ , -NR Ａ８ C (=NR Ｅ８ ) R Ｂ８ , —OC(O)NR Ａ８ R Ｂ８ , -NR Ａ８ C(O)OR Ｂ８ , -NR Ａ８ C(O)NR Ａ８ R Ｂ８ , -NR Ａ８ C(S)NR Ａ８ R Ｂ８ , -NR Ａ８ C (=NR Ｅ８ ) NR Ａ８ R Ｂ８ , -S(O) ｒ R Ａ８ , -S(O)(=NR Ｅ８ ) R Ｂ８ , -N=S(O)R Ａ８ R Ｂ８ , -S(O) ２ OR Ａ８ , -OS(O) ２ R Ａ８ , -NR Ａ８ S (O) ｒ R Ｂ８ , -NR Ａ８ S(O) (=NR Ｅ８ ) R Ｂ８ , -S(O) ｒ NR Ａ８ R Ｂ８ , -S(O)(=NR Ｅ８ ) NR Ａ８ R Ｂ８ , -NR Ａ８ S (O) ２ NR Ａ８ R Ｂ８ , -NR Ａ８ S(O) (=NR Ｅ８ ) NR Ａ８ R Ｂ８ , -P(O)R Ａ８ R Ｂ８ and -P(O)(OR Ａ８ ) (OR Ｂ８ and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R Ｘ８ and is substituted with at least one substituent selected from R Ａ０ is hydrogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, C １～１０ Alkoxy group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｘ０ and is substituted with at least one substituent selected from Each R Ａ１ and R Ｂ１ are independently hydrogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, C １～１０ Alkoxy group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｘ１ and is substituted with at least one substituent selected from Or, R Ａ１ and R Ｂ１ together with the atom or atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, the ring being unsubstituted or containing 1, 2 or 3 R Ｘ１ may be substituted with a group, Each R Ａ２ and R Ｂ２ are independently hydrogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, C １～１０ Alkoxy group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｘ２ and is substituted with at least one substituent selected from Or, "R Ａ２ and R Ｂ２ " together with the atom or atoms attached thereto constitute a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, the ring being unsubstituted or containing 1, 2 or 3 R Ｘ２ may be substituted with a group, Each R Ａ３ and R Ｂ３ are independently hydrogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, C １～１０ Alkoxy group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｘ３ and is substituted with at least one substituent selected from Or, "R Ａ３ and R Ｂ３ " together with the atom or atoms attached thereto constitute a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, the ring being unsubstituted or containing 1, 2 or 3 R Ｘ３ may be substituted with a group, R Ａ４ is hydrogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, C １～１０ Alkoxy group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｘ４ and is substituted with at least one substituent selected from Each R Ａ５ and R Ｂ５ are independently hydrogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, C １～１０ Alkoxy group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｘ５ and is substituted with at least one substituent selected from Or, "R Ａ５ and R Ｂ５ " together with the atom or atoms attached thereto constitute a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, the ring being unsubstituted or containing 1, 2 or 3 R Ｘ５ may be substituted with a group, Each R Ａ６ and R Ｂ６ are independently hydrogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, C １～１０ Alkoxy group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｘ６ and is substituted with at least one substituent selected from Or, "R Ａ６ and R Ｂ６ " together with the atom or atoms attached thereto constitute a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, the ring being unsubstituted or containing 1, 2 or 3 R Ｘ６ may be substituted with a group, Each R Ａ７ and R Ｂ７ are independently hydrogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, C １～１０ Alkoxy group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｘ７ and is substituted with at least one substituent selected from Or, R Ａ７ and R Ｂ７ together with the atom or atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, the ring being unsubstituted or containing 1, 2 or 3 R Ｘ７ may be substituted with a group, Each R Ａ８ and R Ｂ８ are independently hydrogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, C １～１０ Alkoxy group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｘ８ and is substituted with at least one substituent selected from Or, R Ａ８ and R Ｂ８ together with the atom or atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, the ring being unsubstituted or containing 1, 2 or 3 R Ｘ８ may be substituted with a group, Each R Ｃ０ and R Ｄ０ are independently hydrogen, halogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, C １～１０ Alkoxy group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｘ０ and is substituted with at least one substituent selected from Or, R Ｃ０ and R Ｄ０ together with one or more carbon atoms attached thereto, C ３～１０ a cycloalkyl group or a 4- to 12-membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and the cycloalkyl and heterocyclyl groups are unsubstituted or independently selected from R Ｘ０ and is substituted with at least one substituent selected from Each R Ｅ１ , R Ｅ２ , R Ｅ３ , R Ｅ７ and R Ｅ８ are independently hydrogen, C １～１０ Alkyl groups, CN, NO ２ , -OR ａ１ , -SR ａ１ , -S(O) ｒ R ａ１ , -C(O)R ａ１ , -C(O)OR ａ１ , —C(O)NR ａ１ R ｂ１ and -S(O) ｒ NR ａ１ R ｂ１ wherein the alkyl group is unsubstituted or independently selected from R Ｘ and is substituted with at least one substituent selected from As a condition, Z １ is N and X ２ is C and X ３ is CR ７．３ or N, and X ４ does not exist, and R ５ and R ６ or any two R ６ does not form a ring, and W 【Chemistry 4】 and L is -CR Ｃ０ R Ｄ０ (CR Ｃ０ R Ｄ０ ) ｕ -, R Ｃ０ and R Ｄ０ At least one of ２～１０ Alkenyl group and C ２～１０ R selected from alkynyl groups Ｘ０ is replaced by Each R Ｘ , R Ｘ０ , R Ｘ１ , R Ｘ２ , R Ｘ３ , R Ｘ４ , R Ｘ５ , R Ｘ６ , R Ｘ７ and R Ｘ８ are independently hydrogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl group, heteroaryl group, heteroaryl-C １～４ Alkyl groups, halogens, CN, NO ２ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ R ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ OR ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ C(O)R ａ１ , -(CR ｃ１ R ｄ１ ) ｔ C (=NR ｅ１ ) R ａ１ , -(CR ｃ１ R ｄ１ ) ｔ C(=N-OR ｂ１ ) R ａ１ , -(CR ｃ１ R ｄ１ ) ｔ C(O)OR ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ O.C.(O.)R. ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ C(O)NR ａ１ R ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ C(O)R ｂ１ 、-(CR ｃ１ R ｄ１ ) ｔ C(=NR ｅ１ )NR ａ１ R ｂ１ 、-(CR ｃ１ R ｄ１ ) ｔ NR ａ１ C(=NR ｅ１ )R ｂ１ 、-(CR ｃ１ R ｄ１ ) ｔ OC(O)NR ａ１ R ｂ１ 、-(CR ｃ１ R ｄ１ ) ｔ NR ａ１ C(O)OR ｂ１ 、-(CR ｃ１ R ｄ１ ) ｔ NR ａ１ C(O)NR ａ１ R ｂ１ 、-(CR ｃ１ R ｄ１ ) ｔ NR ａ１ C(S)NR ａ１ R ｂ１ 、-(CR ｃ１ R ｄ１ ) ｔ NR ａ１ C(=NR ｅ１ )NR ａ１ R ｂ１ 、-(CR ｃ１ R ｄ１ ) ｔ S(O) ｒ R ｂ１ 、-(CR ｃ１ R ｄ１ ) ｔ S(O)(=NR ｅ１ )R ｂ１ 、-(CR ｃ１ R ｄ１ ) ｔ N=S(O)R ａ１ R ｂ１ 、-(CR ｃ１ R ｄ１ ) ｔ S (O) ２ OR ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ OS (O) ２ R ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ S (O) ｒ R ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ S(O) (=NR ｅ１ ) R ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ S (O) ｒ NR ａ１ R ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ S(O) (=NR ｅ１ ) NR ａ１ R ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ S (O) ２ NR ａ１ R ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ S(O) (=NR ｅ１ ) NR ａ１ R ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ P(O)R ａ１ R ｂ１ and - (CR ｃ１ R ｄ１ ) ｔ P(O)(OR ａ１ ) (OR ｂ１ and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from R Ｙ and is substituted with at least one substituent selected from Each R ａ１ and R ｂ１ are independently hydrogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｙ and is substituted with at least one substituent selected from Or, R ａ１ and R ｂ１ together with one or more atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is optionally bound to one, two or three R Ｙ may be substituted with a group, Each R ｃ１ and R ｄ１ are independently hydrogen, halogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｙ and is substituted with at least one substituent selected from Or, R ｃ１ and R ｄ１ together with one or more carbon atoms bonded thereto form a 3- to 12-membered ring containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the ring is optionally bonded to one, two, or three R Ｙ may be substituted with a group, Each R ｅ１ are independently hydrogen, C １～１０ Alkyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl groups, CN, NO ２ , -OR ａ２ , -SR ａ２ , -S(O) ｒ R ａ２ , -C(O)R ａ２ , -C(O)OR ａ２ , -S(O) ｒ NR ａ２ R ｂ２ and -C(O)NR ａ２ R ｂ２ is selected from Each R Ｙ are independently １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl group, heteroaryl group, heteroaryl-C １～４ Alkyl groups, halogens, CN, NO ２ , -(CR ｃ２ R ｄ２ ) ｔ NR ａ２ R ｂ２ , -(CR ｃ２ R ｄ２ ) ｔ OR ｂ２ , -(CR ｃ２ R ｄ２ ) ｔ C(O)R ａ２ , -(CR ｃ２ R ｄ２ ) ｔ C (=NR ｅ２ ) R ａ２ , -(CR ｃ２ R ｄ２ ) ｔ C(=N-OR ｂ２ ) R ａ２ , -(CR ｃ２ R ｄ２ ) ｔ C(O)OR ｂ２ , -(CR ｃ２ R ｄ２ ) ｔ O.C.(O.)R. ｂ２ , -(CR ｃ２ R ｄ２ ) ｔ C(O)NR ａ２ R ｂ２ , -(CR ｃ２ R ｄ２ ) ｔ NR ａ２ C(O)R ｂ２ , -(CR ｃ２ R ｄ２ ) ｔ C (=NR ｅ２ ) NR ａ２ R ｂ２ 、-(CR ｃ２ R ｄ２ ) ｔ NR ａ２ C(=NR ｅ２ )R ｂ２ 、-(CR ｃ２ R ｄ２ ) ｔ OC(O)NR ａ２ R ｂ２ 、-(CR ｃ２ R ｄ２ ) ｔ NR ａ２ C(O)OR ｂ２ 、-(CR ｃ２ R ｄ２ ) ｔ NR ａ２ C(O)NR ａ２ R ｂ２ 、-(CR ｃ２ R ｄ２ ) ｔ NR ａ２ C(S)NR ａ２ R ｂ２ 、-(CR ｃ２ R ｄ２ ) ｔ NR ａ２ C(=NR ｅ２ )NR ａ２ R ｂ２ 、-(CR ｃ２ R ｄ２ ) ｔ S(O) ｒ R ｂ２ 、-(CR ｃ２ R ｄ２ ) ｔ S(O)(=NR ｅ２ )R ｂ２ 、-(CR ｃ２ R ｄ２ ) ｔ N=S(O)R ａ２ R ｂ２ 、-(CR ｃ２ R ｄ２ ) ｔ S(O) ２ OR ｂ２ 、-(CR ｃ２ R ｄ２ ) ｔ OS(O) ２ R ｂ２ 、-(CR ｃ２ R ｄ２ ) ｔ NR ａ２ S (O) ｒ R ｂ２ , -(CR ｃ２ R ｄ２ ) ｔ NR ａ２ S(O) (=NR ｅ２ ) R ｂ２ , -(CR ｃ２ R ｄ２ ) ｔ S (O) ｒ NR ａ２ R ｂ２ , -(CR ｃ２ R ｄ２ ) ｔ S(O) (=NR ｅ２ ) NR ａ２ R ｂ２ , -(CR ｃ２ R ｄ２ ) ｔ NR ａ２ S (O) ２ NR ａ２ R ｂ２ , -(CR ｃ２ R ｄ２ ) ｔ NR ａ２ S(O) (=NR ｅ２ ) NR ａ２ R ｂ２ , -(CR ｃ２ R ｄ２ ) ｔ P(O)R ａ２ R ｂ２ and - (CR ｃ２ R ｄ２ ) ｔ P(O)(OR ａ２ ) (OR ｂ２ each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group is unsubstituted or independently selected from the group consisting of hydroxy, CN, amino, halogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C １～１０ Alkoxy group, C ３～１０ Cycloalkoxy group, C １～１０ Alkylthio group, C ３～１０ Cycloalkylthio group, C １～１０ Alkylamino group, C ３～１０ Cycloalkylamino groups and di(C １～１０ substituted with at least one substituent selected from the group consisting of alkyl)amino groups, Each R ａ２ and R ｂ２ are independently hydrogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, C １～１０ Alkoxy group, C ３～１０ Cycloalkoxy group, C １～１０ Alkylthio group, C ３～１０ Cycloalkylthio group, C １～１０ Alkylamino group, C ３～１０ Cycloalkylamino group, di(C １～１０ alkyl)amino group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkylthio group, cycloalkylthio group, alkylamino group, cycloalkylamino group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from halogen, CN, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, hydroxy group, C １～１０ Alkoxy group, C ３～１０ Cycloalkoxy group, C １～１０ Alkylthio group, C ３～１０ Cycloalkylthio group, amino group, C １～１０ Alkylamino group, C ３～１０ Cycloalkylamino groups and di(C １～１０ substituted with at least one substituent selected from the group consisting of alkyl)amino groups, Or, R ａ２ and R ｂ２ together with one or more atoms bonded thereto, form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is optionally independently selected from halogen, CN, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, hydroxy group, C １～１０ Alkoxy group, C ３～１０ Cycloalkoxy group, C １～１０ Alkylthio group, C ３～１０ Cycloalkylthio group, amino group, C １～１０ Alkylamino group, C ３～１０ Cycloalkylamino groups and di(C １～１０ and optionally substituted with one or two substituents selected from: Each R ｃ２ and R ｄ２ are independently hydrogen, halogen, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, C １～１０ Alkoxy group, C ３～１０ Cycloalkoxy group, C １～１０ Alkylthio group, C ３～１０ Cycloalkylthio group, C １～１０ Alkylamino group, C ３～１０ Cycloalkylamino group, di(C １～１０ alkyl)amino group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl groups, heteroaryl groups and heteroaryl-C １～４ alkyl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, alkoxy group, cycloalkoxy group, alkylthio group, cycloalkylthio group, alkylamino group, cycloalkylamino group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from halogen, CN, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, hydroxy group, C １～１０ Alkoxy group, C ３～１０ Cycloalkoxy group, C １～１０ Alkylthio group, C ３～１０ Cycloalkylthio group, amino group, C １～１０ Alkylamino group, C ３～１０ Cycloalkylamino groups and di(C １～１０ substituted with at least one substituent selected from the group consisting of alkyl)amino groups, Or, R ｃ２ and R ｄ２ together with the one or more carbon atoms bonded thereto, form a 3- to 12-membered ring containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the ring is optionally independently selected from halogen, CN, C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, hydroxy group, C １～１０ Alkoxy group, C ３～１０ Cycloalkoxy group, C １～１０ Alkylthio group, C ３～１０ Cycloalkylthio group, amino group, C １～１０ Alkylamino group, C ３～１０ Cycloalkylamino groups and di(C １～１０ and optionally substituted with one or two substituents selected from: Each R ｅ２ are independently hydrogen, CN, NO ２ , C １～１０ Alkyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, C １～１０ Alkoxy group, C ３～１０ cycloalkoxy group, —C(O)C １～４ Alkyl group, —C(O)C ３～１０ Cycloalkyl groups, —C(O)OC １～４ Alkyl group, —C(O)OC ３～１０ Cycloalkyl groups, —C(O)N(C １～４ alkyl) ２ , -C(O)N(C ３～１０ cycloalkyl) ２ , -S(O) ２ C １～４ Alkyl group, —S(O) ２ C ３～１０ cycloalkyl group, —S(O) ２ N (C １～４ alkyl) ２ and -S(O) ２ N (C ３～１０ cycloalkyl) ２ is selected from m, n, p, and q are independently selected from 0, 1, 2, 3, and 4; each r is independently selected from 0, 1, and 2; each t is independently selected from 0, 1, 2, 3, and 4; Each u is independently selected from 0, 1, 2, 3, and 4.

2. Z １ is C(O), or a pharmaceutically acceptable salt thereof.

3. Z １ is N, or a pharmaceutically acceptable salt thereof.

4. Z ２ The compound according to any one of claims 1 to 3, wherein is N, or a pharmaceutically acceptable salt thereof.

5. Z ２ The compound according to any one of claims 1 to 3, wherein is C, or a pharmaceutically acceptable salt thereof.

6. R ５ is hydrogen, halogen, C １～１０ Alkyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl groups, CN, NO ２ , -NR Ａ５ R Ｂ５ and -OR Ａ５ wherein each alkyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from C １～１０ Alkyl group, C ３～１０ Cycloalkyl groups, halogens, CN, NO ２ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ R ｂ１ and - (CR ｃ１ R ｄ１ ) ｔ OR ｂ１ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, substituted with at least one substituent selected from:

7. R ５ represents hydrogen, a methyl group, a difluoromethyl group, a trifluoromethyl group, an ethyl group, a difluoroethyl group, a trifluoroethyl group, an isopropyl group, a cyclopropyl group, a methoxy group, an ethoxy group, F, Cl, Br, —CN, or —NO ２ , -NH ２ and -OH, or a pharmaceutically acceptable salt thereof.

8. Each R ６ is independently hydrogen, halogen, C １～１０ Alkyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl groups, CN, NO ２ , -NR Ａ６ R Ｂ６ and -OR Ａ６ wherein each alkyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from C １～１０ Alkyl group, C ３～１０ Cycloalkyl groups, halogens, CN, NO ２ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ R ｂ１ and - (CR ｃ１ R ｄ１ ) ｔ OR ｂ１ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, substituted with at least one substituent selected from:

9. Each R ６ is independently at each occurrence hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, —CN, or —NO ２ , -NH ２ and -OH, or a pharmaceutically acceptable salt thereof.

10. "R ５ and R ６ " or "Two R's ６ " together with the atoms bonded to them are C ３～１０ a cycloalkyl group or a 4- to 10-membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the cycloalkyl and heterocyclyl groups are unsubstituted or independently selected from R Ｘ６ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, substituted with at least one substituent selected from:

11. "R ５ and R ６ " or "Two R's ６ " together with the atoms bonded to them are C ３～８ and forming a cycloalkyl group or a 4-8 membered heterocyclyl group containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein the cycloalkyl and heterocyclyl groups are unsubstituted or independently C １～１０ Alkyl group, C ３～１０ Cycloalkyl groups, halogens, CN, NO ２ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ R ｂ１ and - (CR ｃ１ R ｄ１ ) ｔ OR ｂ１ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, substituted with at least one substituent selected from:

12. W is unsubstituted or independently R Ｘ substituted with at least one substituent selected from 【Transformation 5】 The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from:

13. W is unsubstituted or independently represents R Ｘ is substituted with at least one substituent selected from 【Transformation 6】 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein:

14. Q ２ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is selected from a heterocyclyl group, an aryl group, and a heteroaryl group.

15. Q ２ teeth, 【Transformation 7】 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, selected from:

16. 16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein n is selected from 1, 2 and 3.

17. Each R ２ is independently expressed as C １～１０ Alkyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl group, heteroaryl group, heteroaryl-C １～４ Alkyl group, NO ２ , -NR Ａ２ R Ｂ２ and -OR Ａ２ and each alkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｘ２ The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, substituted with at least one substituent selected from:

18. Each R ２ is independently at each occurrence hydrogen, methyl, ethyl, isopropyl, pyranyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, —CN, —NO ２ , -NH ２ , -NHCH ３ , —OH and 【Transformation 8】 wherein the methyl, ethyl, isopropyl, pyranyl, cyclopropyl, methoxy and ethoxy groups are unsubstituted or independently selected from C １～１０ Alkyl group, C ３～１０ Cycloalkyl groups, halogens, CN, NO ２ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ R ｂ１ and - (CR ｃ１ R ｄ１ ) ｔ OR ｂ１ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, substituted with at least one substituent selected from:

19. Q １ The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein is selected from a heterocyclyl group, an aryl group, and a heteroaryl group.

20. Q １ 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein is selected from a phenyl group, a pyridyl group, and a pyrimidyl group.

21. 21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein m is selected from 1, 2 and 3.

22. Each R １ is independently expressed as C １～１０ Alkyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl group, heteroaryl group, heteroaryl-C １～４ Alkyl group, NO ２ , -NR Ａ１ R Ｂ１ and -OR Ａ１ and each alkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from R Ｘ１ The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, substituted with at least one substituent selected from:

23. Each R １ is independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, —CN, —NO ２ , -NH ２ and —OH, and the methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy groups are unsubstituted or independently selected from C １～１０ Alkyl group, C ３～１０ Cycloalkyl groups, halogens, CN, NO ２ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ R ｂ１ and - (CR ｃ１ R ｄ１ ) ｔ OR ｂ１ 23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, substituted with at least one substituent selected from:

24. X １ The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein

25. X １ The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein

26. X ２ The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein

27. X ２ The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein

28. X ５ The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein

29. X ５ The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein

30. X ６ The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein

31. X ６ The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein

32. X ３ is selected from O and S, or a pharmaceutically acceptable salt thereof.

33. X ３ is N, NR ７．３ and CR ７．３ 32. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, selected from:

34. X ４ is CR ７．４ 34. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein:

35. X ４ The compound according to any one of claims 1 to 31 and 33, or a pharmaceutically acceptable salt thereof, wherein

36. X ４ The compound according to any one of claims 1 to 31 and 33, or a pharmaceutically acceptable salt thereof, wherein is C(O).

37. X ４ The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein is not present.

38. R ７．３ and R ７．４ are independently hydrogen, halogen, C １～１０ Alkyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl groups, CN, NO ２ , -NR Ａ７ R Ｂ７ and -OR Ａ７ wherein each alkyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from C １～１０ Alkyl group, C ３～１０ Cycloalkyl groups, halogens, CN, NO ２ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ R ｂ１ and - (CR ｃ１ R ｄ１ ) ｔ OR ｂ１ 35. The compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, substituted with at least one substituent selected from:

39. R ７．３ and R ７．４ are independently hydrogen, a methyl group, a difluoromethyl group, a trifluoromethyl group, an ethyl group, a difluoroethyl group, a trifluoroethyl group, an isopropyl group, a cyclopropyl group, a methoxy group, an ethoxy group, F, Cl, Br, —CN, or —NO ２ , -NH ２ and -OH; or a pharmaceutically acceptable salt thereof.

40. Y １ The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein

41. Y １ is CR ８．１ 40. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein:

42. Y ２ The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein

43. Y ２ is CR ８．２ 42. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein:

44. Y ３ is CR ８．３ 44. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein:

45. Y ３ The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein

46. R ８．１ , R ８．２ and R ８．３ are independently hydrogen, halogen, C １～１０ Alkyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl groups, CN, NO ２ , -NR Ａ８ R Ｂ８ and -OR Ａ８ wherein each alkyl group, cycloalkyl group, and heterocyclyl group is unsubstituted or independently selected from C １～１０ Alkyl group, C ３～１０ Cycloalkyl groups, halogens, CN, NO ２ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ R ｂ１ and - (CR ｃ１ R ｄ１ ) ｔ OR ｂ１ 45. The compound of any one of claims 41, 43 and 44, or a pharmaceutically acceptable salt thereof, substituted with at least one substituent selected from:

47. R ８．１ , R ８．２ and R ８．３ are independently hydrogen, a methyl group, a difluoromethyl group, a trifluoromethyl group, an ethyl group, a difluoroethyl group, a trifluoroethyl group, an isopropyl group, a cyclopropyl group, a methoxy group, an ethoxy group, F, Cl, Br, —CN, or —NO ２ , -NH ２ and -OH; or a pharmaceutically acceptable salt thereof.

48. L is -CR Ｃ０ R Ｄ０ (CR Ｃ０ R Ｄ０ ) ｕ 48. The compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein

49. L is -(CR Ｃ０ R Ｄ０ ) ｕ O (CR Ｃ０ R Ｄ０ ) ｔ -, - (CR Ｃ０ R Ｄ０ ) ｕ NR Ａ０ (CR Ｃ０ R Ｄ０ ) ｔ - and - (CR Ｃ０ R Ｄ０ ) ｕ S (O) ｒ (CR Ｃ０ R Ｄ０ ) ｔ 48. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, selected from:

50. Z １ is N and X ２ is C and X ３ is CR ７．３ or N, and X ４ does not exist, and R ５ and R ６ or any two R ６ does not form a ring, and W is 【Chemistry 9】 and L is -CR Ｃ０ R Ｄ０ (CR Ｃ０ R Ｄ０ ) ｕ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

51. Each R Ｃ０ and R Ｄ０ are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy groups, and the methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy groups are unsubstituted or independently selected from R Ｘ０ and is substituted with at least one substituent selected from Or, R Ｃ０ and R Ｄ０ together with one or more carbon atoms attached thereto, C ３～１０ Forms a cycloalkyl group, which is unsubstituted or independently R Ｘ０ 51. The compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, substituted with at least one substituent selected from:

52. R Ｘ０ is C １～１０ Alkyl group, C ２～１０ Alkenyl group, C ２～１０ Alkynyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl group, heteroaryl group, heteroaryl-C １～４ Alkyl groups, halogens, CN, NO ２ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ R ｂ１ , -(CR ｃ１ R ｄ１ ) ｔ OR ｂ１ and - (CR ｃ１ R ｄ１ ) ｔ C(O)R ａ１ and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is unsubstituted or independently selected from C １～１０ Alkyl group, C ３～１０ Cycloalkyl groups, halogens, CN, NO ２ , -(CR ｃ２ R ｄ２ ) ｔ NR ａ２ R ｂ２ , -(CR ｃ２ R ｄ２ ) ｔ OR ｂ２ and - (CR ｃ２ R ｄ２ ) ｔ C(O)R ａ２ 52. The compound according to any one of claims 1 to 49 and 51, or a pharmaceutically acceptable salt thereof, substituted with at least one substituent selected from:

53. R Ｘ０ represents hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, vinyl, ethynyl, F, Cl, Br, —CN, —NO ２ , -NH ２ and -OH; or a pharmaceutically acceptable salt thereof.

54. R Ｘ０ The compound according to any one of claims 50 to 51, or a pharmaceutically acceptable salt thereof, wherein is selected from CN, a vinyl group, and an ethynyl group.

55. R ４ is -C(O)OH, -C(O)NHS(O) ｒ R Ａ４ , -(CR ｃ１ R ｄ１ ) ｔ NHS (O) ｒ R Ａ４ and heteroaryl groups, or a pharmaceutically acceptable salt thereof.

56. R ４ teeth, 【Chemistry 10】 56. The compound of claim 55, or a pharmaceutically acceptable salt thereof, selected from:

57. Q ３ is selected from a heterocyclyl group, an aryl group, and a heteroaryl group, or a pharmaceutically acceptable salt thereof.

58. Q ３ teeth, 【Chemistry 11】 58. The compound of claim 57, selected from:

59. 59. The compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, wherein p is selected from 0, 1, 2 and 3.

60. Each R ３ is independently expressed as C １～１０ Alkyl group, C ３～１０ Cycloalkyl group, C ３～１０ Cycloalkyl-C １～４ Alkyl group, heterocyclyl group, heterocyclyl-C １～４ Alkyl group, aryl group, aryl-C １～４ Alkyl group, heteroaryl group, heteroaryl-C １～４ Alkyl group, NO ２ , -NR Ａ３ R Ｂ３ and -OR Ａ３ and the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are unsubstituted or independently selected from R Ｘ３ 60. The compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, substituted with at least one substituent selected from:

61. Each R ３ is independently at each occurrence hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, —CN, —NO ２ , -NH ２ and —OH, and the methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy groups are unsubstituted or independently selected from C １～１０ Alkyl group, C ３～１０ Cycloalkyl groups, halogens, CN, NO ２ , -(CR ｃ１ R ｄ１ ) ｔ NR ａ１ R ｂ１ and - (CR ｃ１ R ｄ１ ) ｔ OR ｂ１ or a pharmaceutically acceptable salt thereof, wherein the compound of claim 60 is substituted with at least one substituent selected from:

62. A compound selected from the following and pharmaceutically acceptable salts thereof: 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】

63. 63. A pharmaceutical composition comprising a compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

64. 63. A method for treating, ameliorating or preventing a condition responsive to GLP-1R inhibition, comprising administering to an individual in need thereof an effective amount of a compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, optionally in combination with a second therapeutic agent.

65. 63. Use of a compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or condition mediated by the GLP-1 receptor or modulating the GLP-1 receptor.

66. 66. The use of claim 65, wherein the disease or condition includes, but is not limited to, diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, arrhythmia, cerebral infarction, stroke, liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), dementia, Parkinson's disease, and diabetic nephropathy.

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