GLP-1R agonists and uses thereof

Abstract

The present invention provides a GLP-1R agonist, a pharmaceutical composition thereof, and a method of use thereof.

Description

[0001] This application claims priority to International Patent Applications PCT / CN2023 / 072748, PCT / CN2023 / 085615, and PCT / CN2023 / 093742, the entire contents of which are incorporated by reference in their entirety. TECHNICAL FIELD

[0002] The present application relates to a class of compounds or pharmaceutically acceptable salts thereof, which can bind and activate glucagon-like peptide-1 receptor (GLP-1R) and can be used for the treatment of metabolic disorders and related diseases, including but not limited to type 2 diabetes (T2DM), obesity, and nonalcoholic steatohepatitis (NASH). SUMMARY

[0003] Glucagon-like peptide-1 (GLP-1) is a peptide hormone that is mainly secreted by intestinal L cells after eating. GLP-1 plays a key role in lowering blood glucose concentration by enhancing insulin secretion and suppressing glucagon release. Other functions of GLP-1 include delaying gastric emptying, suppressing appetite, and promoting beta cell proliferation. The action of GLP-1 is mediated by binding to GLP-1R, which is a glucose-dependent class B G protein-coupled receptor. Binding of GLP-1 to GLP-1R activates the heterotrimeric Gs protein, which subsequently enhances the activity of adenylyl cyclase, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP) levels, thereby enhancing glucose-stimulated insulin secretion (Pflügers Archiv 1998, 435, 583-594; Basic & Clinical Pharmacology & Toxicology 2004, 95, 252-262). Due to the short half-life of GLP-1, it can only exist stably in the blood circulation for 2-3 minutes and will be inactivated by dipeptidyl peptidase 4 (DPP4) (European Journal of Biochemistry 1993, 214, 829-835; Endocrinology 1995, 136, 3585-3596; Diabetes 2004, 53, 654-662).

[0004] GLP-1R agonists have been extensively studied for the treatment of type 2 diabetes mellitus (T2DM), obesity and related metabolic diseases. According to the pharmacological properties, GLP-1R agonists can be classified 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). There are also related literatures reported, such as WO2006097537A2, however, the above GLP-1R agonists are mainly administered by subcutaneous injection. The availability of oral GLP-1R agonists for easy administration 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 a day.

[0005] Therefore, there is an urgent need for new GLP-1R agonists with at least one of the following advantageous properties: easy administration, solubility, drug interactions, potency, stability, selectivity, toxicity, drug resistance, pharmacokinetic and pharmacodynamic properties, as alternative drugs for the treatment of metabolic disorders and related diseases, including but not limited to type 2 diabetes mellitus, obesity and non-alcoholic steatohepatitis. In this regard, the present application provides a new class of GLP-1R agonists. SUMMARY

[0007] The present application relates to a new class of compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof, and their use as medicaments.

[0008] In one aspect, the present application provides a compound represented by Formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein,

[0011] is a double bond or a single bond;

[0012] X 1 , X 2 , X 5 and X 6 are independently selected from N and C;

[0013] X 3 is selected from O, S, N, NR 7.3 and CR 7.3 ;

[0014] X 4 is absent or selected from N, C(O) and CR 7.4 ;

[0015] Y 1 is selected from N and CR 8.1 ;

[0016] Y 2 Selected from N and CR 8.2 ;

[0017] Y 3 Selected from N and CR 8.3 ;

[0018] Z 1 Selected from N and C(O);

[0019] Z 2 Selected from N and C;

[0020] W selected It is either not replaced or selected independently from R X Substituents of the substituents;

[0021] L is selected from -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 -;

[0022] Q 1 Q 2 and Q 3 Selected from C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0023] Each R 1 Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, 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 S(O)2OR 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 )RB1 -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)2NR 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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X1 ;

[0024] each R 2 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, C 1-10 1-6 alkyl, C 2-10 1-6 alkenyl, C 2-10 1-6 alkynyl, C 3-10 3-6 cycloalkyl, C 3-10 3-6 cycloalkyl-C 1-4 1-6 alkyl, heterocyclyl, heterocyclyl-C 1-4 1-6 alkyl, aryl, aryl-C 1-4 1-6 alkyl, heteroaryl, heteroaryl-C 1-4 1-6 alkyl, 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 RB2 -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 wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X2 ;

[0025] each R 3 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, 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 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)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)2NR 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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R X3 Substituents of the substituents;

[0026] R 4 Selected from -C(O)OH and -C(O)NHS(O) r R A4 、-(CR c1 R d1 ) t NHS(O) r R A4 Heterocyclic and heteroaryl groups;

[0027] R 5 Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, CN, NO2, -NR A5 R B5 -OR A5 and -C(O)R A5wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X5 ;

[0028] each R 6 is independently selected at each occurrence from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, CN, NO2, -NR A6 R B6 , -OR A6 , and -C(O)R A6 wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X6 ;

[0029] or "R 5 and R 6 " or "two R 6 " together with the atom to which they are attached form a C 3-10 cycloalkyl or a 4-12 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorous, wherein cycloalkyl and heterocyclyl are unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X6 ;

[0030] R 7.3 and R 7.4 are independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, 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)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)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)2NR 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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent selected independently from R X7 ;

[0031] R 8.1 , R 8.2 , and R 8.3 are independently selected from the group consisting of hydrogen, halogen, C 1-10 1-6 alkyl, C 2-10 1-6 alkenyl, C 2-10 1-6 alkynyl, C 3-10 3-6 cycloalkyl, C 3-10 3-6 cycloalkyl-C 1-4 1-6 alkyl, heterocyclyl, heterocyclyl-C 1-4 1-6 alkyl, aryl, aryl-C 1-4 1-6 alkyl, heteroaryl, heteroaryl-C 1-4 1-6 alkyl, 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 )RB8 -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)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)2NR 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 B8each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X8 ;

[0032] R A0 is selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X0 ;

[0033] each R A1 and R B1 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X1 ;

[0034] or R A1 and R B1 together with the single or multiple atom to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R X1 groups;

[0035] each R A2 and R B2 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X2 ;

[0036] or "R A2 and R B2 " together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R X2 groups;

[0037] each R A3 and R B3 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X3 ;

[0038] or "R A3 and R B3 " together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R X3 groups;

[0039] R A4 is selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X4

[0040] each R A5 and R B5 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X5

[0041] or "R A5 and R B5 " together with the single or multiple atom to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R X5

[0042] each R A6 and R B6 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X6

[0043] or "R A6 and R B6 ​​​​together with the single or multiple atoms to which they are attached, form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R X6 groups;

[0044] each R A7 and R B7 are independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X7 ;

[0045] or R A7 and R B7 together with the single or multiple atoms to which they are attached, form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R X7 groups;

[0046] each R A8 and R B8 are independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X8 ;

[0047] or R A8 and R B8together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R X8 groups;

[0048] each R C0 and R D0 are independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X0 ;

[0049] or R C0 and R D0 together with the single or multiple carbon atoms to which they are attached form a C 3-10 cycloalkyl or a 4-12 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl and heterocyclyl are unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X0 ;

[0050] each R E1 , R E2 , R E3 , R E7 and R E8 are independently selected from the group consisting of hydrogen, C 1-10 alkyl, 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 alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X ;

[0051] with the proviso that when Z1 is N, X 2 is C, X 3 is CR 7.3 or N, X 4 is absent, R 5 and R 6 or any two R 6 are not ringed, W is and L is selected from -CR C0 R D0 (CR C0 R D0 ) u when R C0 and R D0 at least one of R X0 is substituted with R X0 is selected from CN, C 2-10 alkenyl and C 2-10 alkynyl;

[0052] each R X , R X0 , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 and R X8 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, halogen, 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 c1R 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 、-(CRc1 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)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 R b1 、-(CR c1 R d1 ) t P(O)Ra1 R b1 and -(CR c1 R d1 ) t P(O)(OR a1 )(OR b1 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ;

[0053] each R a1 and R b1 is independently selected from the group consisting of hydrogen, C 1-10 1-6 alkyl, C 2-10 1-6 alkenyl, C 2-10 1-6 alkynyl, C 3-10 3-6 cycloalkyl, C 3-10 3-6 cycloalkyl-C 1-4 1-6 alkyl, heterocyclyl, heterocyclyl-C 1-4 1-6 alkyl, aryl, aryl-C 1-4 1-6 alkyl, heteroaryl and heteroaryl-C 1-4 1-6 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ;

[0054] or R a1 and R b1 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring is optionally substituted with 1, 2 or 3 R Y groups;

[0055] each R c1 and R d1 is independently selected from the group consisting of hydrogen, halogen, C 1-10 1-6 alkyl, C 2-10 1-6 alkenyl, C 2-10 1-6 alkynyl, C 3-10 3-6 cycloalkyl, C 3-10 3-6 cycloalkyl-C 1-4 1-6 alkyl, heterocyclyl, heterocyclyl-C 1-4 1-6 alkyl, aryl, aryl-C 1-4 1-6 alkyl, heteroaryl and heteroaryl-C 1-4 1-6 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ;

[0056] or R c1 and R d1Together with the single or multiple carbon atoms attached to them, they form a 3-12 membered ring containing 0, 1, or 2 independent heteroatoms selected from oxygen, sulfur, and nitrogen, which may optionally be separated by 1, 2, or 3 R atoms. Y Group substitution;

[0057] Each R e1 Independently selected from hydrogen and C 1-10 Alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, 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 ;

[0058] Each R Y Selected independently from C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, halogen, 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 、-(CRc2 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 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)2NR 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 ) tP(O)(OR a2 )(OR b2 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of hydroxy, CN, amino, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino;

[0059] each R a2 and R b2 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, hydroxy, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino;

[0060] or Ra2 and R b2 Together with the single or multiple atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus. The ring may optionally be composed of 1 or 2 heteroatoms independently selected from halogen, CN, C, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0061] Each R c2 and R d2 Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino, di(C) 1-10 Alkyl)amino, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclic, aryl, and heteroaryl is unsubstituted or is selected independently from at least one halogen, C1, C2, C3, C4, C5, C6, C6, C7 ... 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0062] or R c2 and R d2 together with the single or multiple carbon atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, which ring is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, hydroxy, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino;

[0063] each R e2 is independently selected from the group consisting of hydrogen, CN, NO2, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, -C(O)C 1-4 alkyl, -C(O)C 3-10 cycloalkyl, -C(O)OC 1-4 alkyl, -C(O)OC 3-10 cycloalkyl, -C(O)N(C 1-4 alkyl)2, -C(O)N(C 3-10 cycloalkyl)2, -S(O)2C 1-4 alkyl, -S(O)2C 3-10 cycloalkyl, -S(O)2N(C 1-4 alkyl)2and -S(O)2N(C 3-10 cycloalkyl)2;

[0064] m, n, p and q are independently selected from 0, 1, 2, 3 and 4;

[0065] each r is independently selected from 0, 1 and 2;

[0066] each t is independently selected from 0, 1, 2, 3 and 4;

[0067] each u is independently selected from 0, 1, 2, 3 and 4.

[0068] In another aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) or at least one pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0069] In another aspect, the present application provides a method for modulating GLP-1R, comprising administering to a system or subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, thereby modulating GLP-1R.

[0070] In another aspect, the present application also provides a method for treating, ameliorating or preventing a condition responsive to the inhibition of GLP-1R, 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, or optionally in combination with another therapeutic agent, to treat the aforementioned conditions.

[0071] In addition, the present disclosure provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a GLP-1R-mediated condition. In particular embodiments, the compounds of the present disclosure can be used alone or in combination with a second therapeutic agent to treat a GLP-1R-mediated condition.

[0072] In addition, the present disclosure discloses a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in treating a GLP-1R-mediated condition.

[0073] In particular, the conditions described herein include, but are not limited to, autoimmune diseases, transplant-related diseases, infectious diseases, or GLP-1 receptor-mediated diseases or conditions. The novel GLP-1R inhibitors provided herein have at least one of the following advantageous properties: ease of administration, solubility, drug interactions, potency, stability, selectivity, toxicity, resistance, pharmacokinetic and pharmacodynamic properties, and can serve as an alternative drug for treating GLP-1 receptor-mediated diseases or conditions, including but not limited to type 2 diabetes, obesity, and nonalcoholic steatohepatitis.

[0074] In addition, the present disclosure provides a method of treating a GLP-1 receptor-mediated disease or condition, 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, and optionally in combination with a second therapeutic agent, thereby treating the disease or condition.

[0075] In addition, the present disclosure provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a GLP-1 receptor-mediated disease or condition or modulating GLP-1 receptor. In particular, the GLP-1 receptor-mediated 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, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), dementia, Parkinson's disease, and diabetic nephropathy.

[0076] In the above methods of using the compounds of the application, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered to a system comprising cells or tissues, or to an individual, including a mammalian individual, such as a human or animal individual.

[0077] Definitions

[0078] 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. All patents, patent applications, published materials referred to in this patent are incorporated by reference in their entirety. In the event of a conflict in terminology, the present section controls.

[0079] It should be understood that the general description and the detailed description are exemplary and explanatory only and are not restrictive of any of the claims. As used in this application, the singular encompasses the plural unless specifically stated otherwise. It should also be noted that in this specification and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" as used in this specification is representative of the term "and / or" unless the context clearly dictates otherwise. In addition, the terms "comprises", "comprising", "includes", "including" and the like can be used herein and are meant to be inclusive and to constitute synonyms for the term "comprising".

[0080] Unless otherwise indicated, the mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet / visible spectroscopy, and pharmacological techniques used in this patent are conventional in the art. Unless specifically defined, the nomenclature used in this patent in Analytical Chemistry, Organic Synthesis, Medicinal and Pharmaceutical Chemistry involves terminology generally used in those fields. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical formulation, and delivery, and treatment of patients. Techniques for reaction and purification can be found in the literature or in references such as those described herein, or can be performed according to known conventional techniques, or as described in the methods described herein. The foregoing techniques and procedures can be readily adapted to the preparation and use of the compounds described herein, and can be practiced in the absence of undue experimentation by persons of ordinary skill in the art. In the specification, groups and substituents are selected to provide stable compounds and compounds useful for therapeutic treatments. In the specification, groups and substituents are selected to provide stable compounds and compounds useful for therapeutic treatments.

[0081] When a chemical formula is used to designate a substituent, the substituent is written from left to right as written in the chemical formula. For example, CH2O is the same as OCH2.

[0082] "Substituted" means that a hydrogen atom is replaced by a substituent. It is to be noted that the substituents on a particular atom are limited by the valency of that atom. If a bond to a substituent group appears through a ring atom, then the substituent can be attached to any atom of the ring. When a substituent is recited without indication of how it is attached to the rest of the compound, then the substituent can be attached either by a bond to any suitable atom of the rest of the compound. In general, when any substituent or group occurs more than one time in any constituent or compound, its definition is independent of its occurrence(s) in any other site of the constituent or compound. However, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0083] The symbol represents the point of attachment of the rest of the molecule.

[0084] It is understood that when two or more variables (such as R 1 ) occur on the same atom, each variable is independently selected. 1 As a non-limiting example, when two R 1 groups occur on the same atom, one R i-j group is methyl and the other is F.

[0085] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur. The term encompasses the options of the event occurring or of the event not occurring.

[0086] The term "C i-j " or "i-j membered" as used herein means that the moiety has i-j carbon atoms or i-j atoms. For example, "C 1-6 alkyl" means that the alkyl group has 1-6 carbon atoms. Likewise, C 3-10 cycloalkyl means that the cycloalkyl group has 3-10 carbon atoms.

[0087] "Halogen" or "halo" means 1 F, 2 Cl, 3 Br, and n I.

[0088] It is understood that when there are two or more R n or R Xn groups (n is 1, 2, 3, 4, 5, 6, 7, etc.), each R n or each R Xn is independently selected.

[0089] When any variable (such as R) occurs more than one time in a compound, its definition in each instance is independent of its definition at every other place in which that variable is used. Thus, for example, if a group is substituted with 0-2 R, then the group can optionally be substituted with up to two R, and R is selected independently in each instance. In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0090] "one or more" or "at least one" means one, two, three, four, five, six, seven, eight, nine, or more.

[0091] Unless otherwise indicated, the term "hetero" refers to a heteroatom or a heteroatom group (i.e., a group containing a heteroatom), i.e., an atom other than carbon and hydrogen atoms or a group containing such atoms. Preferably, the heteroatom is independently selected from O, N, S, P, and the like. In embodiments involving two or more heteroatoms, the two or more heteroatoms can be the same, or the two or more heteroatoms can be partially or entirely different

[0092] "alkyl," whether used alone or as part of a larger term such as "alkylthio" or "alkylamino," refers to a straight or branched chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms. Unless otherwise indicated, "alkyl" refers to C 1-10 alkyl. For example, "C 1-6 alkyl" includes, but is not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, and octyl. 1-6 " C 1-8 alkyl" includes, but is not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, and octyl.

[0093] "Cycloalkyl" whether used alone or in combination with other terminology, means a saturated monocyclic or polycyclic (e.g., bicyclic or tricyclic) hydrocarbon ring system, typically having from 3 to 16 ring atoms. The ring atoms of a cycloalkyl group are all carbon, and a cycloalkyl group contains zero heteroatoms and zero double bonds. In polycyclic cycloalkyl groups, two or more rings can be fused together, or bridged together, or spiro-cyclic. Examples of monocyclic systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bridged cycloalkyls are polycyclic systems containing 3-10 carbon atoms, which contain one or two alkylene bridges, each alkylene bridge consisting of 1, 2, or 3 carbon atoms, which connect two non-adjacent carbon atoms of the ring system. Cycloalkyl groups can be fused to aryl or heteroaryl groups. In some embodiments, the cycloalkyl group is benzo-fused. Representative examples of bridged cycloalkyl systems include, but are not limited to, bicyclo[l. l. l]pentane, bicyclo[3. l. l]heptane, bicyclo[2.2. l]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3. l]nonane, bicyclo[4.2. l]nonane, tricyclo[3.3. l.03,7]nonane, and tricyclo[3.3. l.13,7]decane (adamantane). Cycloalkyl groups can be attached to the parent molecular moiety through any atom of the ring system that can be substituted.

[0094] The term "cycloalkylene" means a divalent cycloalkyl group. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononene, cyclodecene, bicyclo[3.3.0]octylene, bicyclo[2.2.1]octylene, bicyclo[3.3.1]nonylene, and the like.

[0095] "Alkenyl" whether used alone or in combination with other terminology, means a straight, branched, or cyclic hydrocarbon group having from 2 to 10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, cyclic means a single ring or multiple rings. In multiple ring alkenyl groups, two or more rings can be fused together, or bridged together, or spiro-cyclic. In some embodiments, there is 1 carbon-carbon double bond, up to 4 non-aromatic carbon-carbon double bonds can be present. Thus, "C 2－6 "Alkenyl" means an alkenyl group having from 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The straight chain, branched, or cyclic moieties of the alkenyl group can contain double bonds, and if indicated, substituted alkenyl groups can be substituted.

[0096] The term "cycloalkenyl" means a non-aromatic hydrocarbon ring system having from 3 to 30 carbon atoms (e.g., C3-C 10 ) and one or more double bonds. Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.

[0097] "Alkynyl," used either alone or in combination with other terms, refers to straight, branched or cyclic hydrocarbon groups having from 2 to 10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, there can be up to 3 carbon-carbon triple bonds. Thus, "C2-6alkynyl" refers to an alkynyl group having from 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 portion of the alkynyl group can contain the triple bond, if the substituted alkynyl group is indicated.

[0098] "Halogen" means fluorine, chlorine, bromine, iodine.

[0099] "Alkoxy," used either alone or in combination with other terms, refers to an alkyl group as defined above attached to the molecule through an oxygen atom. The alkoxy group can be represented as -O-alkyl. "C 1-10 "Alkoxy" refers to an alkoxy group containing 1 to 10 carbon atoms, which can be linear or branched. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy, isopropoxy, butoxy, pentoxy, hexyloxy, and the like.

[0100] "Cycloalkoxy," used either alone or in combination with other terms, refers to a cycloalkyl group as defined above attached to the molecule through an oxygen atom. The cycloalkoxy group can be represented as -O-cycloalkyl. "C 3-10 "Cycloalkoxy" refers to a cycloalkoxy group containing 3 to 10 carbon atoms. The cycloalkoxy group can be fused to an aryl or heteroaryl group. In some embodiments, the cycloalkoxy group is benzo-fused. Cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, and the like.

[0101] "Alkylthio," used either alone or in combination with other terms, refers to an alkyl group as defined above attached to the molecule through a sulfur atom. The alkylthio group can be represented as -S-alkyl. "C 1-10 "Alkylthio" refers to an alkylthio group containing 1 to 10 carbon atoms, which can be linear or branched. Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, and hexylthio, and the like.

[0102] "Cycloalkylthio," used either alone or in combination with other terms, refers to a cycloalkyl group as defined above attached to the molecule through a sulfur atom. The cycloalkylthio group can be represented as -S-cycloalkyl. "C 3-10 "Cycloalkylthio" refers to a cycloalkylthio group containing 3 to 10 carbon atoms. The cycloalkylthio group can be fused to an aryl or heteroaryl group. In some embodiments, the cycloalkylthio group is benzo-fused. Cycloalkylthio groups include, but are not limited to, cyclopropylthio, cyclobutylthio, and cyclohexylthio, and the like.

[0103] "Alkylamino," used alone or in combination with other terms, refers to an alkyl group as defined above attached to the nitrogen atom by a single bond. The alkylamino group is attached to a molecule through the nitrogen atom. The alkylamino group can be represented as -NH(alkyl). "Di(C 1-10 "Alkylamino" refers to an alkylamino group containing 1 to 10 carbon atoms, which can be straight-chained or branched. Alkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, and hexylamino groups.

[0104] "Cycloalkylamino," used alone or in combination with other terms, refers to a cycloalkyl group as defined above attached to the nitrogen atom by a single bond. The cycloalkylamino group is attached to a molecule through the nitrogen atom. The cycloalkylamino group can be represented as -NH(cycloalkyl). "Di(C 3-10 "Cycloalkylamino" refers to a cycloalkylamino group containing 3 to 10 carbon atoms. The cycloalkylamino group can be fused to an aryl or heteroaryl group. In some embodiments, the cycloalkylamino group is benzo-fused. Cycloalkylamino groups include, but are not limited to, cyclopropylamino, cyclobutylamino, and cyclohexylamino groups.

[0105] "Di(alkyl)amino," used alone or in combination with other terms, refers to two alkyl groups as defined above attached to the nitrogen atom by single bonds. The di(alkyl)amino group is attached to a molecule through the nitrogen atom. The di(alkyl)amino group can be represented as -N(alkyl)2. "Di(C 1-10 "Di(alkyl)amino" refers to a di(C 1-10 alkyl)amino group in which each alkyl moiety contains 1 to 10 carbon atoms, which can be straight-chained or branched.

[0106] "Aryl," used alone or in combination with other terms, refers to a monovalent, monocyclic, bicyclic or tricyclic, aromatic hydrocarbon ring system having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6-14 "Aryl" refers to a monovalent, monocyclic, bicyclic or tricyclic, aromatic hydrocarbon ring system having 6 carbon atoms ("C6aryl" group), such as phenyl; or having 10 carbon atoms ("C 10 "Aryl" refers to a monovalent, monocyclic, bicyclic or tricyclic, aromatic hydrocarbon ring system having 6 carbon atoms ("C6aryl" group), such as phenyl; or having 10 carbon atoms ("C 14 "Aryl" refers to a monovalent, monocyclic, bicyclic or tricyclic, aromatic hydrocarbon ring system having 6 carbon atoms ("C6aryl" group), such as phenyl; or having 10 carbon atoms ("C

[0107] A divalent group formed from a substituted phenyl derivative and having a free valence electron on a ring atom is named as a substituted phenylene group. A divalent group derived from a monovalent polycyclic hydrocarbon group whose name ends in "-yl" by removing one hydrogen atom from a carbon atom that contains a free valence electron is named by adding "-idene" to the name of the monovalent group, e.g., naphthyl with two attachment sites is called naphthylidene.

[0108] "Heteroaryl," used alone or in combination with other terms, refers to a monovalent, monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms ("5- to 14-membered heteroaryl" groups), particularly 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. Heteroaryl groups can be fused with cycloalkyl or heterocyclic groups. In some embodiments, "heteroaryl" refers to...

[0109] Aromatic monocyclic compounds ranging from 5 to 8 yuan, containing 1 to 4 molecules selected from N, O, and S, in certain...

[0110] In the examples, there are 1 to 3 heteroatoms, and the rest are carbon atoms; and

[0111] An 8- to 12-membered bicyclic ring containing 1 to 6 heteroatoms selected from N, O, and S, in some embodiments 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, with the remainder being carbon atoms.

[0112] The atoms, and at least one heteroatom of which appears in the aromatic ring; and

[0113] The 11- to 14-membered tricyclic ring contains 1 to 8 heteroatoms selected from N, O, and S, in some embodiments 1 to 6, in some embodiments 1 to 4, or in some embodiments 1 to 3, with the remainder being carbon atoms.

[0114] When the total number of S and O atoms in a heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group is not greater than 2. In some embodiments, the total number of S and O atoms in a heteroaryl group is not greater than 1.

[0115] Examples of heteroaryl groups include, but are not limited to, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 3-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, pyridazinyl, triazinyl, pyrroleyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thiophenyl, and furanyl.

[0116] Furthermore, heteroaryl groups include, but are not limited to, indolyl, benzothiophene, benzofuranyl, benzimidazolyl, benzotriazolyl, quinoxalinyl, quinolinyl, and isoquinolinyl. "Heteroaryl" includes any nitrogen-containing heteroaryl derivative with N oxide.

[0117] Monovalent heteroaryl groups are named in the "-yl" suffix, and the divalent groups derived from them are obtained by removing one hydrogen atom from a carbon atom that has a free valence. The divalent groups are named by appending "-idene" to the name of the monovalent radical, e.g., pyridyl with two points of attachment is named pyridylidene.

[0118] "Heterocycle" (and derivatives thereof such as "heterocyclic" or "heterocyclyl") refers broadly to saturated or unsaturated, monocyclic or polycyclic (e.g., bicyclic) ring systems, typically having from 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) having at least one (e.g., 2, 3, or 4) heteroatom(s) independently selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorus (preferably oxygen, sulfur, nitrogen). In polycyclic ring systems, two or more rings can be linked via a fused, bridged, or spiro linkage, and a heterocycle can be fused to an aryl or heteroaryl group. In some embodiments, the heterocycle is benzo-fused. Heterocycles also 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 are optionally substituted with oxo. In some embodiments, the C, S, and P atoms in the heterocycle are optionally substituted with imino, and the imino can be unsubstituted or substituted. Either a carbon atom or a heteroatom on the heterocycle can be a point of attachment, provided that a stable structure results. When the heterocycle has a substituent, the substituent can be attached to any heteroatom or carbon atom on the heterocycle, provided that a stable chemical structure results.

[0119] 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-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl, 1-hexahydropyridazinyl, 3-hexahydropyridazinyl, and 4-hexahydropyridazinyl. Morpholine groups are also included, for example, 1-morpholinyl, 2-morpholinyl, 3-morpholinyl, and 4-morpholinyl. Examples of heterocycles having one or more oxo moieties include, but are not limited to, piperidinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Bicyclic heterocycles include, but are not limited to:

[0120]

[0121] The term "heterocyclyl" refers to a divalent heterocyclic group. An example of a heterocyclyl group is a divalent piperidine. The heterocyclyl group is attached to the remainder of the molecule by a single bond and to the radical by a single bond. The points of attachment of the heterocyclyl group to the remainder of the molecule and to the radical can be through one atom in the heterocyclyl group or through two separate atoms in the heterocyclyl group. In addition, the points of attachment to the remainder of the molecule and / or to the radical can be through a carbon atom or a heteroatom.

[0122] "Aryl-alkyl" as used herein refers to an aryl group as defined above substituting an alkyl group as defined above. Exemplary aralkyl groups include, but are not limited to, benzyl, phenethyl and naphthylmethyl groups, and the like. In some embodiments, the aralkyl group contains 7 to 20 or 7 to 11 carbon atoms. When "aryl-C 1-4 alkyl" is used, "C 1-4 " refers to the number of carbon atoms in the alkyl portion and not the aryl portion.

[0123] "Heterocyclyl-alkyl" as used herein refers to a heterocyclyl group as defined above substituting an alkyl group as defined above. When "heterocyclyl-C 1-4 alkyl" is used, "C 1-4 " refers to the number of carbon atoms in the alkyl portion and not the heterocyclyl portion.

[0124] "Cycloalkyl-alkyl" as used herein refers to a cycloalkyl group as defined above substituting an alkyl group as defined above. When "C 3-10 ycloalkyl-C 1-4 alkyl" is used, "C 3-10 " refers to the number of carbon atoms in the cycloalkyl portion and not the alkyl portion. When "C 1-4 ycloalkyl-C 1-4 alkyl" is used, "C 1-4 " refers to the number of carbon atoms in the alkyl portion and not the cycloalkyl portion.

[0125] "Heteroaryl-alkyl" as used herein refers to a heteroaryl group as defined above substituting an alkyl group as defined above. When "heteroaryl-C 1-4 alkyl" is used, "C 1-4 " refers to the number of carbon atoms in the alkyl portion and not the heteroaryl portion.

[0126] To avoid ambiguity, for example, when referring to an alkyl group, a cycloalkyl group, a heterocyclylalkyl group, an aryl group, and / or a heteroaryl group, it is intended that each of these groups is substituted individually, or that these groups are substituted in combination. That is, if R is an aryl-C 1-4 alkyl group, and can be unsubstituted or substituted with at least one substituent, such as 1, 2, 3, or 4 substituents independently selected from R X , it is understood that the aryl portion can be unsubstituted or substituted with at least one, such as 1, 2, 3, or 4 substituents independently selected from R Xsubstituted with at least one substituent independently selected from R X substituents.

[0127] "Pharmaceutically acceptable salt" refers to salts of compounds of the present application derived from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases can be selected from, for example: aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc salts. Further, salts derived from pharmaceutically acceptable inorganic bases can be selected from ammonium, calcium, magnesium, potassium, sodium salts. In solid salts, one or more crystal morphologies, or polymorphs, can exist, or solvates, such as hydrates, can exist. Salts derived from pharmaceutically acceptable organic non-toxic bases can be selected from, for example: primary, secondary, and tertiary amines, substituted amines including 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, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine.

[0128] When the compounds of the present application are basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. For example, salts can be prepared from acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic acid, etc. In some embodiments, acids can be selected from, for example: citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, tartaric acids.

[0129] "Administering" or "administration" of a compound or a pharmaceutically acceptable salt thereof means providing a compound of the present application or a pharmaceutically acceptable salt thereof to an individual in need of treatment.

[0130] "Effective amount" means that amount of a compound or a pharmaceutically acceptable salt thereof which is sufficient to effect a biological or medical response of a tissue, system, animal, or human which is being sought by the researcher, veterinarian, medical doctor, or other clinician.

[0131] "Composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combining or dissolving the specified ingredients in the specified amounts. In regard to pharmaceutical compositions, the combination must include at least one active ingredient; other ingredients can be present as carriers, excipients, or stabilizers.

[0132] "Pharmaceutically acceptable" means that which is compatible with the other ingredients of a formulation and not deleterious to the user at dosages commonly employed.

[0133] "Individual" refers to an individual having a disease, disorder, or the like, and includes mammals and non-mammals. Mammals include, but are not limited to, humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one embodiment of the application, the mammal is a human.

[0134] "Treat" includes alleviating, abating or ameliorating a disease or condition, preventing the onset of other symptoms, improving or preventing a symptom or a metabolic factor that contributes to the symptom, inhibiting the disease or condition, e.g., arresting the development of a disease or condition, relieving or improving the symptoms of a disease or condition, causing regression of a disease or condition, and extending to prophylaxis. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that the patient can experience an improvement in the overall quality of life. By prophylactic benefit is meant that the composition is used in susceptible subjects, preferably in healthy subjects, prior to the onset of disease, to enhance their immune system and / or to prevent the manifestation of the disease.

[0135] "Protecting group" (Pg) refers to a group of substituents which, when attached to a functional group, mask or protect that functional group from undesired reactions while permitting the compound to undergo a desired chemical reaction. For example, an "amino-protecting group" refers to a substituent which, when attached to an amino group, masks or protects the functionality of the amino group of a compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group which permits the functionality of the hydroxy group to be protected from undesired reactions. Suitable protecting groups include, but are not limited to, acetyl and silyl groups. A "carboxy-protecting group" refers to a substituent of a carboxy group which permits the functionality of the carboxy group to be protected from undesired reactions. Common carboxy-protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulphenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0136] "N-hydroxy-protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, t-amyl-oxycarbonyl, t-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropyloxycarbonyl, isopropyloxycarbonyl, phthalyl, succinyl, alanyl, leucinyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, benzhydryl, triphenylmethyl, 2-nitrophenylsulfenyl, methanesulfonyl, p-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-l-naphthylidene, 3-hydroxy-4-pyridinylidene, cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxocyclohexylidene, diphenylphosphinyl, dibenzylphosphinyl, 5-methyl-2-oxo-2H-l,3-dioxolene-4-yl-methyl, trimethylsilyl, triethylsilyl and triphenylsilyl.

[0137] "C(O)OH" protecting groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, 1,1-dimethylpropyl, n-butyl, t-butyl, phenyl, naphthyl, benzyl, benzhydryl, triphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl) methyl, acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methylsulfonylbenzoylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, acetyloxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidyimethyl, succinimidylmethyl, 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-butytmethoxyphenylsilyl.

[0138] "OH or SH" protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, 1,1-dimethylpropyloxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthalyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formacyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl, and t-butytmethoxyphenylsilyl.

[0139] Geometric isomers can exist in the compounds of the present application. Carbon-carbon double bonds or carbon-nitrogen double bonds in the compounds of the present application can exist in either the E or Z configuration, where "E" means that the more highly preferred substituent is on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond according to the Cahn-Ingold-Prelog priority rules, and "Z" means that the more highly preferred substituent is on the same side of the carbon-carbon double bond or carbon-nitrogen double bond. The compounds of the present application can also exist as mixtures of "E" and "Z" isomers. Substituents around a cycloalkyl or heterocyclyl ring can be assigned a cis or trans configuration. In addition, the present application includes different isomers formed by the different arrangement of substituents around the adamantane ring system and mixtures thereof. Two substituents around a single ring in the adamantane ring system are assigned a Z or E relative configuration. See, for example, C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758-2760.

[0140] The compounds of the present application can contain asymmetrically substituted carbon atoms in the R or S configuration, as defined by IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds containing asymmetrically substituted carbon atoms are racemic if the R and S configurations are present in equal amounts. If one configuration is present in greater amounts than the other, the configuration of the chiral carbon atom is indicated by the configuration present in the greater amount, preferably with an enantiomeric excess of about 85-90%, more preferably about 95-99%, and even more preferably about 99% or greater. Thus, the present application includes racemic mixtures, individual and absolute stereoisomers, and mixtures of individual and absolute stereoisomers.

[0141] Isotopically enriched or labeled compounds

[0142] The compounds of the present application can exist in isotopically enriched or labeled forms, containing one or more atoms which differ from the most common or abundant mass of that atom in nature. The isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms commonly encountered include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125I. Other isotopes of these atoms and / or other atoms are also within the scope of the present application.

[0143] In another embodiment, the isotopically labeled compounds contain deuterium ( 2 H), tritium ( 3 H), or 14 C isotopes. Isotopically labeled compounds of the present application can generally be prepared by

[0144] metabolic fate of compounds in vivo (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important for the design of safe and effective therapeutic agents, as it is possible for patients to be exposed to either the active compound in vivo or to a metabolite of the parent compound that is toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al, J. Labelled Compounds. Radiopharmaceuticals, 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacology, 77, 79-88 (1999)).

[0145] In addition, pharmaceuticals containing non-reflective active isotopes, such as deuterated pharmaceuticals, known as "heavy drugs," can be used to treat diseases and conditions associated with GLP-1R activity. A compound is enriched when the proportion of a certain isotope exceeds its natural abundance. Enriched amounts include, but are not limited to, for example, from 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 to about 100 mol %.

[0146] Pharmaceutically stable isotopically labeled compounds can alter their physicochemical properties, such as pKa and liquid solubility. If the isotopic substitution affects the region of the molecule relevant to ligand-receptor interactions, these effects and alterations can affect the pharmacodynamic response of the drug molecule. Certain physical properties of a stable isotopically labeled molecule differ from the unlabeled molecule, while the chemical and biological properties are the same, but with one important difference: because of the increased mass of the heavy isotope, any chemical bond that contains a heavy isotope and another atom is stronger than the bond with the light isotope. Correspondingly, the presence of an isotope at a site of metabolism or enzymatic transformation slows that reaction, and thus can alter its pharmacokinetic profile or pharmacodynamics compared to the non-isotopically labeled compound.

[0147] In an embodiment (1), the present application provides a compound represented by Formula (I):

[0148]

[0149] or a pharmaceutically acceptable salt thereof, wherein,

[0150] is a double bond or a single bond;

[0151] X 1 , X 2 , X 5 , and X 6 are independently selected from N and C;

[0152] X 3 is selected from O, S, N, NR 7.3 , and CR 7.3 ;

[0153] X 4 is absent or is selected from N, C(O), and CR 7.4 ;

[0154] Y 1 is selected from N and CR 8.1 ;

[0155] Y 2 is selected from N and CR 8.2 ;

[0156] Y 3 is selected from N and CR 8.3 ;

[0157] Z 1 is selected from N and C(O);

[0158] Z 2 is selected from N and C;

[0159] W is selected from which is unsubstituted or substituted with at least one R XSubstituents of the substituents;

[0160] L is selected from -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 -;

[0161] Q 1 Q 2 and Q 3 Selected from C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0162] Each R 1 Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, 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 A1S(O) r R A1 , -C(O)NR A1 S(O)2OR 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)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 , -NRA1 S(O)2NR 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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R X1 Substituents of the substituents;

[0163] Each R 2 Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, 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 RB2 -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 wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent selected independently from R X2 ;

[0164] each R 3 is, at each occurrence, independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, 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)NRA3 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 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)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 RB3 , -NR A3 S(O)2NR 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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X3 ;

[0165] R 4 is selected from the group consisting of -C(O)OH, -C(O)NHS(O) r R A4 , -(CR c1 R d1 ) t NHS(O) r R A4 , heterocyclyl and heteroaryl;

[0166] R 5 is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, CN, NO2, -NR A5 R B5 , -OR A5 and -C(O)R A5 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X5 ;

[0167] each R 6 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, CN, NO2, -NR A6 R B6 , -OR A6 and -C(O)RA6 wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X6 ;

[0168] or "R 5 and R 6 " or "two R 6 " together with the atom(s) to which they are attached form a C 3-10 cycloalkyl or a 4-12 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorous, wherein cycloalkyl and heterocyclyl are unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X6 ;

[0169] R 7.3 and R 7.4 are independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, 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 A7R 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)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)2NR 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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R X7 Substituents of the substituents;

[0170] R 8.1 , R 8.2 and R 8.3 are independently selected from hydrogen, halogen, C 1-10 1-6alkyl, C 2-10 2-6alkenyl, C 2-10 2-6alkynyl, C 3-10 3-6cycloalkyl, C 3-10 3-6cycloalkyl-C 1-4 1-6alkyl, heterocyclyl, heterocyclyl-C 1-4 1-6alkyl, aryl, aryl-C 1-4 1-6alkyl, heteroaryl, heteroaryl-C 1-4 1-6alkyl, 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)NRA8 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)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)2NR 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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R X8 Substituents of the substituents;

[0171] R A0 Selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, heterocyclic, heterocyclic -C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X0

[0172] each R A1 and R B1 are independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X1 ;

[0173] or R A1 and R B1 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R X1 groups;

[0174] each R A2 and R B2 are independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X2 ;

[0175] or "R A2 and R B2 " together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R​X2 groups;

[0176] each R A3 and R B3 are independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X3 ;

[0177] or "R A3 and R B3 " together with the single or multiple atom to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R X3 groups;

[0178] R A4 is selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X4 ;

[0179] each R A5 and R B5 are independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X5 ;

[0180] or "R A5 and R B5 " together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R X5 groups;

[0181] each R A6 and R B6 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X6 ;

[0182] or "R A6 and R B6 " together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R X6 groups;

[0183] each R A7 and R B7 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X7 ;

[0184] or R A7 and R B7 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R X7 groups;

[0185] each R A8 and R B8 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X8 ;

[0186] or R A8 and R B8 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, which ring can be unsubstituted or substituted with 1, 2 or 3 R X8 groups;

[0187] each R C0 and R D0 is independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of RX0 Substituents of the substituents;

[0188] Or R C0 and R D0 Together with the single or multiple carbon atoms attached to them, they form a C 3-10 Cycloalkyl or 4-12 membered heterocyclic groups containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein the cycloalkyl and heterocyclic groups are unsubstituted or are composed of at least one heteroatom independently selected from R. X0 Substituents of the substituents;

[0189] Each R E1 R E2 R E3 R E7 and R E8 Independently selected from hydrogen and C 1-10 Alkyl, 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 is selected independently from R X Substituents of the substituents;

[0190] The condition is when Z 1 It is N, X 2 It is C, X 3 It is CR 7.3 Or N, X 4 It does not exist, R 5 and R 6 Or any two R 6 Non-circular, W is And L is selected from -CR C0 R D0 (CR C0 R D0 ) u - When, then R C0 and R D0 At least one of them is R X0 Replace, R X0 Selected from CN, C 2-10 alkenyl and C 2-10 alkynyl group;

[0191] Each R X R X0 RX1 R X2 R X3 R X4 R X5 R X6 R X7 and R X8 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, halogen, 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 ) tC(=NR e1 )NR a1 R b1 、 c1 R d1 ) t NR a1 C(=NR e1 )R b1 、 c1 R d1 ) t OC(O)NR a1 R b1 、 c1 R d1 ) t NR a1 C(O)OR b1 、 c1 R d1 ) t NR a1 C(O)NR a1 R b1 、 c1 R d1 ) t NR a1 C(S)NR a1 R b1 、 c1 R d1 ) t NR a1 C(=NR e1 )NR a1 R b1 、 c1 R d1 ) t S(O) r R b1 、 c1 R d1 ) t S(O)(=NR e1 )R b1 、 c1 R d1 ) t N=S(O)R a1 R b1 、 c1 R d1 ) t S(O)2OR b1 、 c1 R d1 ) t OS(O)2R b1 、 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 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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R Y Substituents of the substituents;

[0192] Each R a1 and R b1 Independently selected from hydrogen and C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ;

[0193] or R a1 and R b1 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is optionally substituted with 1, 2 or 3 R Y groups;

[0194] each R c1 and R d1 is independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ;

[0195] or R c1 and R d1 together with the single or multiple carbon atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring is optionally substituted with 1, 2 or 3 R Y groups;

[0196] each R e1 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, 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 ;

[0197] each R Y is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, halo, 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 Rd2 ) 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)2OR b2 、-(CR c2 R d2 ) t OS(O)2R b2 、-(CR c2 R d2 ) t NR a2 S(O) r R b2 、-(CRc2 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)(=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, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from at least one of the following groups: hydroxyl, C1, N2, amino, halogen, C2, C3, N2 ... 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0198] Each R a2 and R b2 Independently selected from hydrogen and C 1-10 Alkyl, C2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from the group consisting of halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, hydroxy, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino;

[0199] or R a2 and R b2 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is optionally substituted by 1 or 2 substituents independently selected from the group consisting of halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, hydroxy, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino;

[0200] each R c2 and R d2 is independently selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from the group consisting of halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, hydroxy, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino;

[0201] or R c2 and R d2 together with the single or multiple carbon atom to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring is optionally substituted by 1 or 2 substituents independently selected from the group consisting of halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, hydroxy, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino;

[0202] each R e2 is independently selected from the group consisting of hydrogen, CN, NO2, C1-10 Alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, -C(O)C 1-4 Alkyl, -C(O)C 3-10 Cycloalkyl, -C(O)OC 1-4 Alkyl, -C(O)OC 3-10 Cycloalkyl, -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, -S(O)2N(C 1-4 alkyl)2 and -S(O)2N(C 3-10 cycloalkyl)2;

[0203] m, n, p, and q are independently selected from 0, 1, 2, 3, and 4;

[0204] Each r is independently selected from 0, 1, and 2;

[0205] Each t is independently selected from 0, 1, 2, 3, and 4;

[0206] Each u is independently selected from 0, 1, 2, 3, and 4.

[0207] In another embodiment, the present invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein,

[0208] X 1 X 2 X 5 and X 6 Independently selected from N and C;

[0209] X 3 Selected from O, S, N, NR 7.3 and CR 7.3 ;

[0210] X 4 It does not exist or is selected from N, C(O) and CR 7.4 ;

[0211] Y 1 Selected from N and CR 8.1 ;

[0212] Y 2 Selected from N and CR 8.2 ;

[0213] Y 3 Selected from N and CR8.3 ;

[0214] Z 1 is selected from N and C(O);

[0215] Z 2 is selected from N and C;

[0216] W is selected from which is unsubstituted or substituted with at least one substituent independently selected from R X ;

[0217] L is selected from -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 - ;

[0218] Q 1 , Q 2 and Q 3 are selected from C 3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0219] provided that when Z 1 is N, X 2 is C, X 4 is absent, R 5 and R 6 or any two R 6 do not form a ring, W is and L is selected from -CR C0 R D0 (CR C0 R D0 ) u -, at least one of R C0 and R D0 is substituted with R X0 , RX0 selected from CN, C 2-10 alkenyl and C 2-10 alkynyl;

[0220] wherein 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).

[0221] In another embodiment (2), the present application provides the compounds of embodiment (1), or a pharmaceutically acceptable salt thereof, wherein Z 1 is C(O).

[0222] In another embodiment (3), the present application provides the compounds of embodiment (2), or a pharmaceutically acceptable salt thereof, wherein Z 1 is N.

[0223] In another embodiment (4), the present application provides the compounds of any one of embodiments (1)-(3), or a pharmaceutically acceptable salt thereof, wherein Z 2 is N.

[0224] In another embodiment (5), the present application provides the compounds of any one of embodiments (1)-(3), or a pharmaceutically acceptable salt thereof, wherein Z 2 is C.

[0225] In another embodiment, the present application provides the compounds of any one of embodiments (1)-(5), or a pharmaceutically acceptable salt thereof, wherein the structure of the moiety of formula (I) is selected from

[0226] In another embodiment (6), the present application provides the compounds of any one of embodiments (1)-(5), or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, CN, NO2, -NR A5 R B5 , and -OR A5wherein each alkyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halo, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 .

[0227] In another embodiment (7), the present application provides the compound of embodiment (6), or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, -CN, -NO2, -NH2, and -OH. In another embodiment, R 5 is methyl.

[0228] In another embodiment (8), the present application provides the compound of any one of embodiments (1)-(7), or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently selected from hydrogen, halo, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, CN, NO2, -NR A6 R B6 and -OR A6 wherein each alkyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halo, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 .

[0229] In another embodiment (9), the present application provides the compound of embodiment (8), or a pharmaceutically acceptable salt thereof, wherein each R 6is independently selected at each occurrence from hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, CI, Br, -CN, -N02, -NH2, and -OH. In another embodiment, R 5 is hydrogen.

[0230] In another embodiment (10), the application provides the compound of any one of embodiments (1)-(5), or a pharmaceutically acceptable salt thereof, wherein "R 5 and R 6 " or "two R 6 " together with the atoms to which they are attached form a C 3-10 cycloalkyl or 4-10 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein cycloalkyl and heterocyclyl are unsubstituted or substituted with at least one substituent independently selected from R X6 .

[0231] In another embodiment (11), the application provides the compound of embodiment (10), or a pharmaceutically acceptable salt thereof, wherein "R 5 and R 6 " or "two R 6 " together with the atoms to which they are attached form a C 3-8 cycloalkyl or 4-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein cycloalkyl and heterocyclyl are unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, N02, -(CR c1 R d1 ) t NR a1 R b1 , and -(CR c1 R d1 ) t OR b1 .

[0232] In another embodiment, the application provides the compound of any one of embodiments (1)-(9), or a pharmaceutically acceptable salt thereof, wherein the structure of the moiety of Formula (I) is selected from

[0233] In another embodiment, the application provides the compound of any one of embodiments (1)-(5) and (10)-(11), or a pharmaceutically acceptable salt thereof, wherein the structure of the moiety of Formula (I) is selected from

[0234] In another embodiment (12), the application provides the compound of any one of embodiments (1)-(11), or a pharmaceutically acceptable salt thereof, wherein W is selected from each of which is unsubstituted or substituted with at least one substituent independently selected from R X In another embodiment, W is selected from each of which is unsubstituted or substituted with at least one substituent independently selected from R X

[0235] In another embodiment (13), the application provides the compound of any one of embodiments (1)-(11), or a pharmaceutically acceptable salt thereof, wherein W is which is unsubstituted or substituted with at least one substituent independently selected from R X

[0236] In another embodiment (14), the application provides the compound of any one of embodiments (1)-(13), or a pharmaceutically acceptable salt thereof, wherein Q 2 is selected from heterocyclyl, aryl, and heteroaryl.

[0237] In another embodiment (15), the application provides the compound of embodiment (14), or a pharmaceutically acceptable salt thereof, wherein Q 2 is selected from

[0238] In another embodiment (16), the application provides the compound of any one of embodiments (1)-(15), or a pharmaceutically acceptable salt thereof, wherein n is selected from 1, 2, and 3.

[0239] In another embodiment (17), the application provides the compound of any one of embodiments (1)-(16), or a pharmaceutically acceptable salt thereof, wherein each R 2 , at each occurrence, is independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, NO2, -NR A2 R B2 , and -OR A2 , wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X2 ​​substituted with at least one substituent independently selected from the group consisting of C

[0240] In another embodiment (18), the application provides a compound of embodiment (17), or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected at each occurrence from the group consisting of hydrogen, methyl, ethyl, isopropyl, pyranyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, -CN, -NO2, -NH2, -NHCH3, -OH, and wherein methyl, ethyl, isopropyl, pyranyl, cyclopropyl, methoxy, and ethoxy are unsubstituted or substituted with at least one substituent independently selected from the group consisting of C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 In another embodiment, wherein each R 2 is independently selected at each occurrence from the group consisting of hydrogen, methyl, ethyl, isopropyl, pyranyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, -CN, -NO2, -NH2, and OH, wherein methyl, ethyl, isopropyl, pyranyl, cyclopropyl, methoxy, and ethoxy are unsubstituted or substituted with at least one substituent independently selected from the group consisting of C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 In another embodiment, wherein each R 2 is independently selected at each occurrence from the group consisting of F and methyl.

[0241] In another embodiment, the application provides a compound of any one of embodiments (1)-(18), or a pharmaceutically acceptable salt thereof, wherein the structure of the moiety of Formula (I) is selected from the group consisting of In another embodiment, wherein the structure of the moiety of Formula (I) is selected from the group consisting of

[0242] In another embodiment (19), the present application provides the compound of any one of embodiments (1)-(18), or a pharmaceutically acceptable salt thereof, wherein Q 1 is selected from heterocyclyl, aryl, and heteroaryl.

[0243] In another embodiment (20), the present application provides the compound of embodiment (19), or a pharmaceutically acceptable salt thereof, wherein Q 1 is selected from phenyl, pyridyl, and pyrimidinyl.

[0244] In another embodiment (21), the present application provides the compound of any one of embodiments (1)-(20), or a pharmaceutically acceptable salt thereof, wherein m is selected from 1, 2, and 3.

[0245] In another embodiment (22), the present application provides the compound of any one of embodiments (1)-(21), or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected at each occurrence from C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, NO2, -NR A1 R B1 and -OR A1 , wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X1 .

[0246] In another embodiment (23), the present application provides the compound of embodiment (22), 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, wherein methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy are unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1substituted with 1 to 3 substituents independently selected from the group consisting of F, Cl, Br, -CN, -NO2, -OH, -OCF3, -OCH3, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -C1-4alkyl, -C3-6cycloalkyl, -C(=O)R', -C(=O)OR', -C(=O)NHR', and -C(=O)NR' R' is independently selected from the group consisting of H, F, Cl, Br, -CN, -NO2, -OH, -OCF3, -OCH3, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -C1-4alkyl, and -C3-6cycloalkyl. 1 In another embodiment, each occurrence of R 1 is independently selected from the group consisting of F and methyl.

[0247] In another embodiment, the present application provides a compound of any one of embodiments (1) to (23), or a pharmaceutically acceptable salt thereof, wherein the structure of the moiety is selected from the group consisting of

[0248] In another embodiment (24), the present application provides a compound of any one of embodiments (1) to (23), or a pharmaceutically acceptable salt thereof, wherein X 1 is N.

[0249] In another embodiment (25), the present application provides a compound of any one of embodiments (1) to (23), or a pharmaceutically acceptable salt thereof, wherein X 1 is C.

[0250] In another embodiment (26), the present application provides a compound of any one of embodiments (1) to (25), or a pharmaceutically acceptable salt thereof, wherein X 2 is N.

[0251] In another embodiment (27), the present application provides a compound of any one of embodiments (1) to (25), or a pharmaceutically acceptable salt thereof, wherein X 2 is C.

[0252] In another embodiment (28), the present application provides a compound of any one of embodiments (1) to (27), or a pharmaceutically acceptable salt thereof, wherein X 5 is N.

[0253] In another embodiment (29), the present application provides a compound of any one of embodiments (1) to (27), or a pharmaceutically acceptable salt thereof, wherein X 5 is C.

[0254] In another embodiment (30), the present application provides a compound of any one of embodiments (1) to (29), or a pharmaceutically acceptable salt thereof, wherein X 6 is N.

[0255] In another embodiment (31), the present application provides a compound of any one of embodiments (1) to (29), or a pharmaceutically acceptable salt thereof, wherein X 6 is C.

[0256] In another embodiment (32), the application provides the compound of any one of embodiments (1)-(31), or a pharmaceutically acceptable salt thereof, wherein X 3 is selected from O and S.

[0257] In another embodiment (33), the application provides the compound of any one of embodiments (1)-(31), or a pharmaceutically acceptable salt thereof, wherein X 3 is selected from N, NR 7.3 and CR 7.3 .

[0258] In another embodiment (34), the application provides the compound of any one of embodiments (1)-(33), or a pharmaceutically acceptable salt thereof, wherein X 4 is CR 7.4 .

[0259] In another embodiment (35), the application provides the compound of any one of embodiments (1)-(31) and (33), or a pharmaceutically acceptable salt thereof, wherein X 4 is N.

[0260] In another embodiment (36), the application provides the compound of any one of embodiments (1)-(31) and (33), or a pharmaceutically acceptable salt thereof, wherein X 4 is C(O).

[0261] In another embodiment (37), the application provides the compound of any one of embodiments (1)-(33), or a pharmaceutically acceptable salt thereof, wherein X 4 is absent.

[0262] In another embodiment (38), the application provides the compound of any one of embodiments (33)-(34), or a pharmaceutically acceptable salt thereof, wherein R 7.3 and R 7.4 are each selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, CN, NO2, -NR A7 R B7 and -OR A7 , wherein each alkyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ).t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 substituted with a substituent selected from the group consisting of F, Cl, Br, -CN, -NO2, -NH2, and -OH.

[0263] In another embodiment (39), the application provides a compound of embodiment (38), or a pharmaceutically acceptable salt thereof, wherein R 7.3 and R 7.4 are independently selected from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, -CN, -NO2, -NH2, and -OH. In another embodiment, R 7.3 and R 7.4 are hydrogen.

[0264] In another embodiment (40), the application provides a compound of any one of embodiments (1)-(39), or a pharmaceutically acceptable salt thereof, wherein Y 1 is N.

[0265] In another embodiment (41), the application provides a compound of any one of embodiments (1)-(39), or a pharmaceutically acceptable salt thereof, wherein Y 1 is CR 8.1 .

[0266] In another embodiment (42), the application provides a compound of any one of embodiments (1)-(41), or a pharmaceutically acceptable salt thereof, wherein Y 2 is N.

[0267] In another embodiment (43), the application provides a compound of any one of embodiments (1)-(41), or a pharmaceutically acceptable salt thereof, wherein Y 2 is CR 8.2 .

[0268] In another embodiment (44), the application provides a compound of any one of embodiments (1)-(43), or a pharmaceutically acceptable salt thereof, wherein Y 3 is CR 8.3 .

[0269] In another embodiment (45), the application provides a compound of any one of embodiments (1)-(43), or a pharmaceutically acceptable salt thereof, wherein Y 3 is N.

[0270] In another embodiment (46), the present application provides the compound of any one of embodiments (41) and (43)-(44), or a pharmaceutically acceptable salt thereof, wherein R 8.1 , R 8.2 , and R 8.3 are each independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, CN, NO2, -NR A8 R B8 , and -OR A8 , wherein each alkyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 , and -(CR c1 R d1 ) t OR b1 .

[0271] In another embodiment (47), the present application provides the compound of embodiment (46), or a pharmaceutically acceptable salt thereof, wherein R 8.1 , R 8.2 , and R 8.3 are each independently selected from hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, -CN, -NO2, -NH2, and -OH. In another embodiment, R 8.1 , R 8.2 , and R 8.3 are hydrogen.

[0272] In another embodiment, the present application provides the compound of any one of embodiments (1)-(36) and (38)-(47), or a pharmaceutically acceptable salt thereof, wherein the structure of the moiety of Formula (I) is selected from In another embodiment, wherein the structure of the moiety of Formula (I) is

[0273] In another embodiment, the present application provides the compound of any one of embodiments (1)-(33), (37), and (40)-(47), or a pharmaceutically acceptable salt thereof, wherein the structure of the the structure of the moiety is selected from In another embodiment, wherein the compound of formula (I) is the structure of the moiety is selected from In another embodiment, wherein the compound of formula (I) is the structure of the moiety is selected from In another embodiment, wherein the compound of formula (I) is the structure of the moiety is selected from

[0274] In another embodiment (48), the present application provides the compound of any one of embodiments (1)-(47), or a pharmaceutically acceptable salt thereof, wherein L is -CR C0 R D0 (CR C0 R D0 ) u -.

[0275] In another embodiment (49), the present application provides the compound of any one of embodiments (1)-(47), or a pharmaceutically acceptable salt thereof, wherein L is selected from -(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 -.

[0276] In another embodiment (50), the present application provides the compound of embodiment (1), or a pharmaceutically acceptable salt thereof, wherein Z 1 is N, X 2 is C, X 3 is CR 7.3 or N, X 4 is absent, R 5 and R 6 or any two R 6 do not form a ring, W is And L is selected from -CR C0 R D0 (CR C0 R D0 ) u - In another implementation (50'), where Z 1 It is N, X 2 It is C, X 4 It does not exist, R 5 and R 6 Or any two R 6 Non-circular, W is And L is selected from -CR C0 R D0 (CR C0 R D0 ) u -

[0277] In another embodiment (51), the invention provides a compound or a pharmaceutically acceptable salt thereof of any one of embodiments (1)-(50) and (50'), wherein each R C0 and R D0 The radical is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy, wherein methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy are unsubstituted or are selected independently from R. X0 Substituents of the substituents;

[0278] Or R C0 and R D0 Together with the single or multiple carbon atoms attached to them, they form a C 3-10 Cycloalkyl, wherein the cycloalkyl group is unsubstituted or is selected independently from R X0 Substituents are substituted.

[0279] In another embodiment (52), the present invention provides a compound or a pharmaceutically acceptable salt thereof of any one of embodiments (1)-(49) and (51), wherein R X0 Selected from C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, halogen, CN, NO2, -(CR) c1 R d1 ) t NR a1 Rb1 -(CR c1 R d1 ) t OR b1 and -(CR c1 R d1 ) t C(O)R a1 wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent selected from the group consisting of C 1-10 alkyl, C 3-10 cycloalkyl, halo, 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 .

[0280] In another embodiment (53), the present application provides the compound according to embodiments (52), or a pharmaceutically acceptable salt thereof, wherein R X0 is selected from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, ethenyl, ethynyl, F, Cl, Br, -CN, -NO2, -NH2, and -OH.

[0281] In another embodiment, the present application provides the compound according to any one of embodiments (1)-(49) and (51)-(53), or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of In another embodiment, L is selected from the group consisting of

[0282] In another embodiment (54), the present application provides the compound according to any one of embodiments (50)-(51), or a pharmaceutically acceptable salt thereof, wherein R X0 is selected from the group consisting of CN, ethenyl, and ethynyl.

[0283] In another embodiment, the present application provides the compound according to any one of embodiments (50)-(51) and (54), or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of

[0284] In another embodiment (55), the application provides a compound of any one of embodiments (1)-(54), or a pharmaceutically acceptable salt thereof, wherein R 4 selected from -C(O)OH, -C(O)NHS(O) r R A4 , -(CR c1 R d1 ) t NHS(O) r R A4 and heteroaryl.

[0285] In another embodiment (56), the application provides a compound of embodiment (55), or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from

[0286] In another embodiment (57), the application provides a compound of any one of embodiments (1)-(56), or a pharmaceutically acceptable salt thereof, wherein Q 3 is selected from heterocyclyl, aryl, and heteroaryl.

[0287] In another embodiment (58), the application provides a compound of embodiment (57), or a pharmaceutically acceptable salt thereof, wherein Q 3 is selected from

[0288] In another embodiment (59), the application provides a compound of any one of embodiments (1)-(58), or a pharmaceutically acceptable salt thereof, wherein p is selected from 0, 1, 2, and 3.

[0289] In another embodiment (60), the application provides a compound of any one of embodiments (1)-(59), or a pharmaceutically acceptable salt thereof, wherein each R 3 , at each occurrence, is independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, NO2, -NR A3 R B3 , and -OR A3 , wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are unsubstituted or substituted with at least one substituent independently selected from R X3 .

[0290] In another embodiment (61), the present application provides the compound of embodiment (60), or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected at each occurrence from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, CI, Br, -CN, -NO2, -NH2, and -OH, wherein methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy are unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 is independently selected at each occurrence from methyl, ethyl, and methoxy. 3 In another embodiment, each R

[0291] In another embodiment, the present application provides the compound of any one of embodiments (1)-(61), or a pharmaceutically acceptable salt thereof, wherein the structure of the moiety of Formula (I) is selected from

[0292] In another embodiment (62), the present application provides the compound selected from:

[0293]

[0294]

[0295]

[0296]

[0297] and pharmaceutically acceptable salts thereof.

[0298] In another embodiment (63), the present application provides a pharmaceutical composition comprising the compound of any one of embodiments (1)-(62), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0299] In another embodiment (64), the present application provides a method of treating, ameliorating, or preventing a condition responsive to the inhibition of GLP-1R comprising administering to an individual in need thereof an effective amount of the compound of any one of embodiments (1)-(62), or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, optionally in combination with a second therapeutic agent.​

[0300] In another embodiment (65), the present application provides the use of a compound of any one of embodiments (1)-(62), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a GLP-1 receptor-mediated disease or disorder or for the modulation of GLP-1 receptor.

[0301] In another embodiment (66), the present application provides the use of embodiment (65), wherein the disease or disorder comprises, but is not limited to, diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, cardiac arrhythmia, cerebral infarction, stroke, liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), dementia, Parkinson’s disease, and diabetic nephropathy.

[0302] In another aspect thereof, a kit is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and instructions comprising one or more forms of information selected from the group consisting of an indication of a disease state for which the composition is to be administered, storage information for the composition, dosing information, and instructions on how to administer the composition. In a particular variant, the kit comprises the compound in multiple dosage forms.

[0303] In another aspect thereof, an article of manufacture is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and packaging material. In one variant, the packaging material comprises a container for containing the compound. In a particular variant, the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information, and / or instructions on how to administer the compound. In another variant, the article of manufacture comprises the compound in multiple dosage forms.

[0304] In a further aspect thereof, a method of treatment is provided comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0305] In another aspect, a method of inhibiting GLP-1R is provided comprising contacting a compound disclosed herein, or a pharmaceutically acceptable salt thereof, with GLP-1R.

[0306] In another aspect, a method of inhibiting GLP-1R is provided comprising causing a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to be present in the body of a subject to inhibit GLP-1R in vivo.

[0307] In another aspect, a method of inhibiting GLP-1R is provided, comprising administering to an individual a first compound that is converted in vivo to a second compound, wherein the second compound inhibits GLP-1R in vivo, and the second compound is a compound and variations of any of the above embodiments.

[0308] In another aspect thereof, a method of treating a disease state in which GLP-1R has an activity that contributes to the pathology and / or symptomology of the disease state is provided, the method comprising causing a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to be present in a subject in a therapeutically effective amount.

[0309] In another aspect thereof, a method of treating a disease state in which GLP-1R has an activity that contributes to the pathology and / or symptomology of the disease state is provided, the method comprising administering to a subject a first compound that is converted in vivo to a second compound, wherein the second compound inhibits GLP-1R in vivo. Note that the compound of the present invention can be the first or the second compound.

[0310] In another aspect, a method of treating a disease state in which a mutation in the GLP-1R gene contributes to the pathology and / or symptoms of the disease state is provided, including but 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, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), dementia, Parkinson’s disease, and diabetic nephropathy.

[0311] In another aspect, the present invention relates to the use of a compound of any of the above embodiments and variations as a medicament. In another aspect, the present invention relates to the use of a compound according to any of the above embodiments and variations in the manufacture of a medicament for inhibiting GLP-1R.

[0312] In another aspect thereof, the present 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 an activity that contributes to the pathology and / or symptomology of the disease state.

[0313] Dosing and pharmaceutical compositions

[0314] In general, the compounds of the present application will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities including topical, oral, systemic, and parenteral (including intravenous, intramuscular, intraperitoneal, or subcutaneous injection). Therapeutically effective amounts of the compounds of the present application can vary according to factors such as the purpose of the administration (e.g., treatment or prevention), the age and relative health of the subject, the nature and severity of the disorder, the manner and site of administration, and other factors well known to those skilled in the art. For example, in the treatment of neoplastic and immune system disorders, the dose can vary from about 0.03 to 2.5 mg / kg of body weight per day, taken in a single or divided doses.

[0315] In general, satisfactory results can be obtained when the daily dosage is from 0.001 to 100 mg / kg body weight, specifically from about 0.03 to 2.5 mg / kg body weight. The daily dosage for larger mammals, e.g., humans, can be from about 0.5 mg to about 2000 mg, or more specifically, from 0.5 mg to 1000 mg, administered in divided doses, e.g., four times a day or in sustained release form. Suitable unit dosage forms for oral administration include from about 1 to 50 mg of the active ingredient.

[0316] The compounds of the present application can be administered in a pharmaceutical composition by any of the accepted modes of administration for agents that serve similar utilities, including topical, oral, systemic, and parenteral (including intravenous, intramuscular, intraperitoneal, or subcutaneous injection). Topical administration can also involve the use of transdermal delivery systems, infusions, sprays, and creams.

[0317] Pharmaceutical compositions containing the compounds of the present application in free form or in pharmaceutically acceptable salt form can be manufactured by mixing the active ingredient with a pharmaceutical carrier, e.g., a sterile aqueous solution, as is well known in the art. Such compositions will contain a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, to be administered to a subject in a unit or dose or unit dose regimen. Examples of pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium

[0318] In one embodiment, the pharmaceutical composition is a solution of the active ingredient, including suspensions or dispersions, in a sterile aqueous medium. The dispersions or suspensions can be prepared prior to use, in the case of a lyophilized composition containing only the active ingredient or the active ingredient mixed with a carrier such as mannitol. The pharmaceutical composition can be sterilized and / or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts and / or buffers, as desired. Suitable preservatives include, but are not limited to, antioxidants, such as ascorbic acid, microbicides, such as sorbic acid or benzoic acid. The solution or suspension can also contain thickening agents, including, but not limited to, carboxymethylcellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone, gelatin, or solubilizing agents, such as Tween 80 (polyoxyethylene (20) sorbitan monooleate).

[0319] The suspension in oil may contain vegetable oil, synthetic or semi-synthetic oil as the oily component, often for injection purposes. Examples include liquid fatty acid esters containing long-chain fatty acids having 8 to 22 carbon atoms, or in some embodiments, 12 to 22 carbon atoms, as the acid component. 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, benzyl acid, or corresponding unsaturated acids such as oleic acid, transoleic acid, erucic acid, brassinolic acid, and linoleic acid, and may contain antioxidants such as vitamin E, 3-carotene, or 3,5-di-tert-butyl-hydroxytoluene if desired. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, such as mono-, di-, or trivalent alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol, or pentanol or their isomers, ethylene glycol, and glycerol.

[0320] Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, and isopropyl palmitate. M2375 (polyoxyethylene glycerin), M1944CS (unsaturated polyethylene glycol-modified glycerol esters prepared by alcoholysis of almond oil, containing glycerol esters and polyethylene glycol esters), LABRASOL TM (Saturated polyethylene glycol-modified glycerol esters prepared by alcoholysis of TCM, comprising glycerol esters and polyethylene glycol esters; both available from GaKefosse, France), and / or 812 (a saturated fatty acid triglyceride with a chain length of C8 to C12 from Hüls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, or peanut oil.

[0321] Pharmaceutical compositions for oral administration can be prepared, for example, by mixing the active ingredient with one or more solid carriers, granulating the resulting mixture if desired, and processing the mixture or granules by adding additional excipients to form tablets or tablet cores.

[0322] 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 dicalcium phosphate, and binders such as starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as the aforementioned starches, carboxymethyl starch, croscarmellose, alginate or its salts, such as sodium alginate. Additional excipients include flow conditioners and lubricants such as silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol or its derivatives.

[0323] Suitable, optionally enteric, coatings for tablets can be provided by the use of, inter alia, concentrated sugar solutions, which can include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide, or coating solutions dissolved in suitable organic solvents or solvent mixtures, or, for enteric coatings, solutions of suitable cellulose preparations, such as cellulose acetate phthalate or hydroxypropyl methyl cellulose phthalate. Dyes or pigments can be added to the tablets or tablet coatings, e.g., for identification purposes or to indicate different doses of the active ingredient.

[0324] Pharmaceutical compositions for oral administration can also include hard capsules, including gelatin or soft sealed capsules containing gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules can contain the active ingredient in the form of granules, for example, mixed with fillers such as corn starch, binders and / or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid excipient, such as fatty oils, paraffin oil or liquid polyethylene glycols, or fatty acid esters of glycol or propylene glycol, to which stabilizers and detergents, such as fatty acid esters of polyoxyethylene sorbitol, can also be added.

[0325] Pharmaceutical compositions suitable for rectal administration, such as suppositories, comprise the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic glycerol triesters, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

[0326] Pharmaceutical compositions suitable for parenteral administration can comprise the active ingredient in a water soluble form, such as a water soluble salt or an aqueous injection suspension comprising a viscosity increasing substance, such as sodium carboxymethyl cellulose, an aqueous solution of sorbitol and / or dextran, and, if necessary, stabilizers. The active ingredient, optionally with excipients, can also be in a freeze-dried form and can be made into a solution by adding a suitable solvent before parenteral administration. Solutions used, for example, for parenteral administration, can also be used as infusion solutions. The preparation of injection formulations is usually carried out under sterile conditions, filled into, for example, ampoules or vials, and sealed in containers.

[0327] The present application also provides a pharmaceutical combination, such as a kit, comprising a) a compound as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one auxiliary agent. The kit can comprise instructions for its use.

[0328] Combination therapy

[0329] The compounds or pharmaceutically acceptable salts described in this patent can be used alone or in combination with other therapeutic agents.

[0330] For example, the use of an adjuvant can enhance the therapeutic effect of a compound of the application (e.g., a therapeutic benefit is minimal when the adjuvant is used alone, but the therapeutic benefit to the individual is enhanced when the adjuvant is used in combination with another agent), or, for example, the use of a compound of the application in combination with another therapeutic agent that also has a therapeutic effect can enhance the therapeutic benefit to the individual. For example, in the treatment of gout, the use of a compound of the application in combination with another agent used to treat gout can enhance the clinical benefit. Or, for example, if the adverse effect of using a compound of the application is nausea, then an anti-nausea agent can be used in combination. Or, for example, combination therapy can also include, but is not limited to, physical therapy, psychological therapy, radiation therapy, compression therapy of the affected area, rest, dietary modification, etc. Regardless of the disease, disorder, or condition, the therapeutic benefit to the individual of the two therapies should have an additive or synergistic effect.

[0331] In the case of the use of a compound of the application in combination with another therapeutic agent, the pharmaceutical composition of the compound of the application can be administered by the same route of administration as the other agent, or the route of administration can be different due to physical and chemical incompatibilities. For example, a compound of the application can be administered orally and can produce good blood levels that are maintained for a reasonable period of time, while another therapeutic agent can need to be administered intravenously. Thus, a compound of the application and another therapeutic agent can be administered simultaneously, sequentially, or separately. Examples

[0332] There are many ways to synthesize a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the representative methods are illustrated in the examples. However, it should be noted that a compound of formula (I) or a pharmaceutically acceptable salt thereof can also be synthesized by other synthetic schemes.

[0333] In certain compounds of formula (I), the connection between atoms and other atoms can result in the presence of special stereoisomers (e.g., chiral centers). The synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof can produce mixtures of different isomers (enantiomers, diastereomers). Unless a particular stereochemical configuration is specified, the compounds listed include all possible stereoisomers.

[0334] A compound of formula (I) can also be prepared as a pharmaceutically acceptable acid addition salt, for example, by reacting the free base form of a compound of the application with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a compound of formula (I) can be prepared as a pharmaceutically acceptable base addition salt by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. The pharmaceutically acceptable salts of the compounds of formula (I) which are appropriate for use in the present application are those derived from pharmaceutically acceptable inorganic and organic acids and bases. The salts can be obtained by using the appropriate salts of the starting materials or intermediates.

[0335] The free acid or the free base of a compound of formula (I) can be prepared from its corresponding base addition salt or acid addition salt. An acid addition salt form of a compound of formula (I) can be converted into the corresponding free base, for example by treatment with a suitable base (e.g. ammonium hydroxide solution, sodium hydroxide, etc.). A base addition salt form of a compound of formula (I) can be converted into the corresponding free acid, for example by treatment with a suitable acid (e.g. hydrochloric acid, etc.).

[0336] An N-oxide of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods known in the art. For example, an N-oxide can be prepared by reacting a non-oxidized form of a compound of formula (I) with an oxidizing agent (e.g. trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, and meta-chloroperoxybenzoic acid, etc.) in an inert organic solvent (e.g. halogenated hydrocarbons such as dichloromethane, etc.) at a temperature between 0 °C and 80 °C. Alternatively, an N-oxide of a compound of formula (I) can also be prepared from an N-oxide of the starting material.

[0337] A non-oxidized form of a compound of formula (I) can be prepared by reacting an N-oxide thereof with a reducing agent (e.g. sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, and phosphorus tribromide, etc.) in a corresponding inert organic solvent (e.g. acetonitrile, ethanol, and aqueous dioxane, etc.) at a temperature between 0 °C and 80 °C.

[0338] A protected derivative of a compound of formula (I) can be prepared by methods well known to those skilled in the art. For a detailed description of the techniques applicable to the introduction and removal of protecting groups see: T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

[0339] The methods, routes and reagents used in the examples are consistent with the current scientific literature, e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard one-letter or three-letter abbreviations are generally used for L-form amino acid residues, unless otherwise specified. All starting materials used are purchased from commercial suppliers unless otherwise noted and are used without further purification. For example, the following abbreviations can be used throughout the examples and the specification: g (gram), mg (milligram), L (liter), mL (milliliter), μL (microliter), psi (pounds per square inch), M (molar), mM (millimolar), i.v. (intravenous), Hz (hertz), MHz (megahertz), mol (moles), mmol (millimoles), RT (room temperature), min (minute), h (hour), mp (melting point), TLC (thin layer chromatography), Rt (retention time), RP (reverse phase), MeOH (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), IBCF (isobutyl chloroformate), HOAc (acetic acid), HOSu (N-hydroxysuccinimide), HOBT (1-hydroxybenzotriazole), Et20 (diethyl ether), EDCI (1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride), BOC (tert-butoxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (dicyclohexylcarbodiimide), CBZ (benzyloxycarbonyl), Ac (acetyl), atm (atmosphere), TMSE (2-(trimethylsilyl)ethyl), TMS (trimethylsilyl), TIPS (triisopropylsilyl), TBS (tert-butyldimethylsilyl), DMAP (4-dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethyl), tBu (tert-butyl), HPLC (high performance liquid chromatography), BOP (bis(2-oxo-3-oxazolidinyl)phosphonic chloride), TBAF (tetra-n-butylammonium fluoride), mCPBA (meta-chloroperoxybenzoic acid).

[0340] Ether or Et20 means diethyl ether; brine means saturated NaCl aqueous solution. All temperatures are in degrees Celsius (°C) and all reactions were run at room temperature under an inert atmosphere, unless otherwise specified.

[0341] 1HNMR spectra were recorded on a Varian Mercury Plus 400 NMR spectrometer. Chemical shifts are expressed in ppm. Coupling constants are in Hertz (Hz). Apparent multiplicities are described in split mode and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad).

[0342] Low resolution mass spectrometry (MS) and compound purity data were obtained from a Shimadzu LC / MS single quadrupole system equipped with an electrospray ion detector (ESI), ultraviolet detector (220 and 254 nm) and evaporative light scattering detector (ELSD). Thin layer chromatography was performed on 0.25 mm precoated silica gel plates (60F-254), 5% molybdenum-phosphoric acid in ethanol, ninhydrin or p-methoxybenzaldehyde solution and visualized under UV light. Flash column chromatography was performed using silica gel (200-300 mesh, Qingdao Haian Chemical Industry Co. Ltd.).

[0343] Synthetic schemes

[0344] [1] The synthetic schemes for all compounds of the present application are illustrated by the following schemes and examples. The starting materials used are either commercially available or can be prepared according to known procedures or the procedures exemplified herein.

[0345] As shown in Scheme 1, compounds of Formula I can be synthesized by the coupling of intermediates of Formula II with intermediates of Formula III, which are either known compounds in the literature, or can be prepared by a variety of methods well known to those skilled in the art. Formula III can be readily coupled with Formula II under standard amide bond forming conditions to give compounds of Formula I.

[0346]

[0347] Scheme 1

[0348] As an example for the preparation of intermediates of Formula II, Scheme 2 provides a synthesis of compound IIa. Compound IIa-A, which is either commercially available or prepared according to procedures reported in the literature or procedures described herein, can be coupled with IIa-B through metal-catalyzed cross-coupling reactions to give compound IIa-C. Compound IIa-C can be halogenated to give compound IIa-D. The cyanomethylation from IIa-D to IIa-E can be prepared through functional group transformation of the side chain of the arene. The formation of the cycloalkane ring from IIa-E gives IIa-F. Compound IIa-F can be treated with hydroxylamine first, then with CDI (N,N'-carbonyldiimidazole), and finally hydrolysis to give compound IIa.

[0349]

[0350] Scheme 2

[0351] In certain cases, the above synthetic schemes can be adjusted in order to facilitate the reaction or to avoid the production of unnecessary reaction products. In order to enable a fuller understanding of the present application, the following examples are provided. These examples are merely illustrative and should not be considered to be limiting of the present application.

[0352] Example 1

[0353] 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)

[0354]

[0355] Methyl 6-bromo-1-methyl-1H-indole-2-carboxylate (1a)

[0356] The title compound methyl 6-bromo-1-methyl-1H-indole-2-carboxylate (1a) was prepared according to the method described in patent WO2022147302.

[0357] Methyl 6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2-carboxylate (1b)

[0358] To a mixture of Zn dust (678 mg, 10.41 mmol) in DMF (5 mL) was added TMSCl (1.0 mol / L in THF, 0.38 mL, 0.372 mmol) and 1,2-dibromoethane (70.0 mg, 0.372 mmol) at room temperature. After the mixture was stirred at room temperature for 10 minutes, a solution of 4-iodo-2,2-dimethyltetrahydro-2H-pyran (1.80 g, 7.45 mmol) in DMF (5 mL) was added and the stirring was continued for 30 minutes. Then, Pd(OAc)2 (100 mg, 0.446 mmol) and AmPhos (240 mg, 0.894 mmol) were added successively 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 hours. The mixture was diluted with methyl tert-butyl ether (MTBE) and water, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel with PE / EtOAc (20:1~10:1) as eluent 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]+ .

[0359] Methyl 3-bromo-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-indole-2- carboxylate (1c)

[0360] 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 DMF (5 mL) was added dropwise a suspension of NBS (118 mg, 0.662 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 10 min, diluted with ethyl acetate (EtOAc) and quenched with saturated aqueous sodium sulfite (Na2SO3). The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel 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] + .

[0361] Methyl 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-methyl-1H- indole-2-carboxylate (1d)

[0362] A mixture of 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), Pd2(dba)3 (30 mg, 0.032 mmol) and XantPhos (40 mg, 0.097 mmol) in diethylene glycol dimethyl ether (5 mL) was stirred at 140 °C in a microwave for 40 min. The mixture was cooled to room temperature, diluted with water and ethyl acetate (EtOAc). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel 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] + .

[0363] 3-((2S)-1-cyano-2-methylcyclopropyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1- methyl-1H-indole-2-carboxylic acid (1e)

[0364] 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- dithiolane 2,2-dioxide (56.8 mg, 0.411 mmol) in THF (8 mL) was added KHMDS (1.0 mol / L in THF, 2.05 mL, 2.05 mmol) under ice bath. The reaction mixture was stirred at 0 °C for 1 h, quenched with saturated citric acid solution (pH = 4-5), extracted with ethyl acetate (EtOAc). The organic phases were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The residue was purified by preparative thin layer chromatography (PTLC) with DCM / MeOH (20:1) as eluent 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] + .

[0365] (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)

[0366] 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 procedure described in patent US2019225604A1.

[0367] (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)

[0368] A mixture of 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-4,5,6,7-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) in DMF (1 mL) was stirred at room temperature overnight. The reaction was diluted with water and ethyl acetate (EtOAc), the organic layer was separated and washed with water, saturated brine, dried over anhydrous sodium sulfate (Na2SO4) and concentrated. The residue was purified by preparative thin layer chromatography (PTLC) eluted with DCM / ACN (150:40) 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)- 1-methyl-1H-indol-3-yl)-2-methylcyclopropane-1-carbonitrile (1g). MS-ESI (m / z): 838 [M+1] + .

[0369] (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-carboxamidine (1h)

[0370] 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. NH2OH (50% 180 mg, 2.72 mmol) in IPA (2 mL) was stirred at 85 °C for 4 h. After the reaction was diluted with water and ethyl acetate (EtOAc), the organic layer was separated, washed with water, saturated brine successively, dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The crude (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-carboxamidine (1h) was used directly in the next step. MS-ESI (m / z): 871 [M+1] + .

[0371] 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)

[0372] 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-carboxamidine (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 h, 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) eluted 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] + .

[0373] Example 2

[0374] 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)

[0375]

[0376] tert-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)

[0377] The title compound tert-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) was prepared according to the procedure described in patent US2019225604A1.

[0378] tert-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)

[0379] To a solution of triphosgene (720 mg, 2.42 mmol) in DCM (25 mL) was added tert-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). After the reaction mixture was stirred at room temperature for 1 h, it was 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, and the reaction was diluted with water and extracted with methyl tert-butyl ether (MTBE). The organic layer was washed successively with water, saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The crude product was purified by recrystallization from a PE / MTBE (10:1) mixed solvent to give the title compound tert-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). MS-ESI (m / z): 433 [M+1] + .

[0380] tert-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)

[0381] To a solution of tert-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)3 (911 mg, 8.58 mmol) and PTSA (10 mg, 0.052 mmol). The mixture was stirred at 80 °C for 2 h. Concentration, the residue was purified by column chromatography on silica gel eluting with PE / EtOAc (10:1 ~ 2:1) to give the title compound tert-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). MS-ESI (m / z): 443 [M+1] + .

[0382] Tert-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)

[0383] A mixture of tert-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) (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)2(8.6 mg, 0.047 mmol), TEMPO (9.8 mg, 0.063 mmol), 4A MS (25 mg) and Py (5.0 mg, 0.063 mmol) in DMF (0.5 mL) 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 (Na2SO4), and concentrated. The residue was purified by preparative thin layer chromatography (PTLC) with DCM / ACN (15:1) as the eluent to give the title compound tert-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). MS-ESI (m / z): 591 [M+1] + .

[0384] (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)

[0385] A mixture of tert-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) (3.5 mg, 0.0059 mmol) and 4N HCl solution in dioxane (0.5 mL) was stirred in DCM (0.5 mL) 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] + .

[0386] 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)

[0387] A mixture of (S)-2-(4-fluoro-l-methyl-lH-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-l,2,4-triazol-3-one (2e) ((crude), 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)- l-((lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)-lH-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) in DMF (0.5 mL) was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate (EtOAc). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate (Na2S04) and concentrated. The residue was purified by preparative thin layer chromatography (PTLC) with EtOAc / PE (65:35) to give the title compound 3-((lS,2S)-l-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(l-(4-fluoro-l- methyl-lH-indazol-5-yl)-5-oxo-l,5-dihydro-4H-l,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)- lH-indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)-one (2). MS-ESI (m / z): 884 [M+l] + .

[0388] Example 3

[0389] 3-((2S)-l-(6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-l-methyl- lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-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)-l,2,4-oxadiazol-5(4H)-one (3)

[0390]

[0391] Ethyl 6-bromo-3-methylbenzo[b]thiophene-2-carboxylate (3a)

[0392] 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) was added ethyl mercaptoacetate (3.04 g, 25.3 mmol) at 0 °C. After the mixture was stirred at room temperature for 16 h, it was warmed to 80 °C and stirred for another 24 h. The reaction was filtered, and the filtrate was washed with water, extracted with ethyl acetate (EtOAc), dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel eluted 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] + .

[0393] Ethyl 6-bromo-3-(bromomethyl)benzo[b]thiophene-2-carboxylate (3b)

[0394] To a solution of ethyl 6-bromo-3-methylbenzo[b]thiophene-2-carboxylate (3a) (2.4 g, 8.02 mmol) in CCl4(72 mL) was added NBS (3.4 g, 19.1 mmol) and AIBN (0.23 g, 1.77 mmol) at room temperature. After the reaction was stirred at 80 °C for 2 h, it was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (EtOAc), and the combined filtrate was diluted with water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel eluted 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] + .

[0395] Ethyl 6-bromo-3-(cyanomethyl)benzo[b]thiophene-2-carboxylate (3c)

[0396] 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). After the reaction mixture was stirred at room temperature for 1 h, the reaction was quenched with aqueous sodium bicarbonate solution 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 column chromatography on silica gel 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] + .

[0397] Ethyl 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2- carboxylate (3d)

[0398] To a mixture of Zn dust (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 the reaction mixture was stirred at room temperature (RT) 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 at RT was continued for 30 min. Then Pd(OAc)2 (100 mg, 0.446 mmol) and AmPhos (240 mg, 0.894 mmol) were added successively, followed by ethyl 6-bromo-3-(cyanomethyl)benzo[b]thiophene-2-carboxylate (3c) (0.6 g, 1.85 mmol). The reaction system was heated to 50 °C and stirred for 2 h. After the reaction was completed, the mixture was diluted with methyl tert-butyl ether and water, and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel 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] + .

[0399] 3-(Cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylic acid (3e)

[0400] 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.H2O (94 mg, 2.2 mmol) in MeOH / THF / H2O (5 / 5 / 5 mL) was stirred at room temperature for 1 h. The reaction was diluted with water and the pH was adjusted to 5-6 with citric acid and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate (MgSO4) and concentrated to give crude 3-(cyanomethyl)-6-(2,2-dimethyltetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylic acid (3e) which was used directly in the next step. MS-ESI (m / z): 330 [M+1] + .

[0401] 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)

[0402] 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, 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) with PE / EtOAc (1:1) as eluent to give 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] + .

[0403] (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-methyl- cyclopropane-1-carbonitrile (3g)

[0404] To a solution of 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) (5.0 mg, 0.0062 mmol) and (R)-4- methyl-1,3,2-dithietane 2,2-dioxide (0.86 mg, 0.0062 mmol) in THF (0.3 mL) was added KHMDS (1.0 mol / L in THF, 0.1 mL, 0.1 mmol) under ice-bath. The reaction 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 with water, saturated brine, dried over anhydrous sodium sulfate (Na2SO4) and concentrated. The residue was purified by preparative thin layer chromatography (PTLC) with DCM / MeOH (20:1) as eluent 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] + .

[0405] 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)

[0406] 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)benzo[b] thiophen-3-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (3) was synthesized according to the procedure in 1, replacing (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) with (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] + .

[0407] Example 4

[0408] 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)

[0409]

[0410] 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)benzofuran- 3-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (4) was prepared according to the synthetic procedure in 3, 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] + .

[0411] Examples 5-63 listed in Table 1 were prepared essentially / can be prepared by the same procedures or using similar synthetic strategies or methods described in Examples 1-4, from appropriate starting materials that are commercially available or known in the literature. The structures and names of Examples 5-63 are listed in Table 1.

[0412] Table 1

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422] *: LC / MS data of the prepared compounds were obtained using the methods specified above.

[0423] The symbol " / / " indicates that the example can be prepared by art-known methods to make appropriate intermediates and necessary sequential modifications.

[0424] Cell proliferation assay

[0425] The intracellular cAMP concentration was detected by TR-FRET method to evaluate the activity of GLP1R receptor induced by drugs. Cells were prepared in experimental buffer solution (HBSS, 20 mM HEPES (pH 7.5), 0.1% BSA, 500 μΜ IBMX) and seeded into 384 cell culture plates at a density of 2000 cells per well with a seeding volume of 15 μL. The compounds were diluted 3-fold with DMSO and 10 concentration gradients, and diluted 100-fold in buffer. The maximum concentration point of the test compound was 12 μΜ. The seeded 384 cell plate was added with 5 μL of prepared working solution and incubated at 37 °C for 30 min. The Eu-cAMP tracer was diluted 50-fold and the Ulight anti-cAMP was diluted 150-fold with detection buffer (cAMP Kit, Perkin-Elmer, cat# TRF0263). First, 10 μL of Eu-cAMP tracer was added to each experimental well, and then 10 μL of Ulight anti-cAMP was added to each experimental well. The assay plate was centrifuged at 200 g, RT for 30 s and incubated at 25 °C for 1 h. The data were collected using Envision2105 microplate reader with HTRF module. Excitation wavelength: 340 nm, emission wavelength: 665 nm and 615 nm.

[0426] The activity of each concentration of the test compound on the positive drug was calculated by the formula Activity% = 100 (Signal cmpd Signal Ave_PC ) / (Signal Ave_VC Signal Ave_PC ) x 100, and the EC 50 value and nonlinear regression curve fitting were obtained using GraphPad Prism software.

[0427] Table 2

[0428] Examples cAMP assay EC 50 (nM) 2 0.511 3 0.406 6 0.087 29 0.093 30 0.044 31 0.182

Claims

1. The compound represented by formula (I): Or its pharmaceutically acceptable salt, wherein, is a double or single bond; X 1 , X 2 , X 5 and X 6 are independently selected from N and C; X 3 selected from O, S, N, NR 7.3 and CR 7.3 ; X 4 N, C(O) and CR 7.4 ; Y 1 selected from N and CR 8.1 ; Y 2 selected from N and CR 8.2 ; Y 3 selected from N and CR 8.3 ; Z 1 is selected from N and C(O); Z 2 selected from N and C; W is selected from which is unsubstituted or substituted with at least one substituent independently selected from R X ; L is selected from -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 - ; Q 1 , Q 2 and Q 3 are selected from C 3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl; each R 1 is, at each occurrence, independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, 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 S(O)2OR 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)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)2NR 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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R X1 Substituents of the substituents; each R 2 is, at each occurrence, independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, 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 wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X2 ; each R 3 is, at each occurrence, independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, 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 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)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)2NR 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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R X3 Substituents of the substituents; R 4 selected from -C(O)OH, -C(O)NHS(O) r R A4 , -(CR c1 R d1 ) t NHS(O) r R A4 , heterocyclyl and heteroaryl; R 5 selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, CN, NO2, -NR A5 R B5 , -OR A5 , and -C(O)R A5 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X5 ; each R is independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6haloalkylthio, C1-C6haloalkylsulfinyl, C1-C6haloalkylsulfonyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkenyl, C3-C8cycloalkenyl-C1-C6alkyl, heterocyclyl, heterocyclyl-C1-C6alkyl, aryl, aryl-C1-C6alkyl, heteroaryl, heteroaryl-C1-C6alkyl, -CN, -NO2, -N(R 6 )2, -N(R 1-10 )C(O)R 2-10 , -C(O)N(R 2-10 )2, -C(O)R 3-10 , -C(O)OR 3-10 , -OR 1-4 , -SR 1-4 , -S(O)R A6 , -S(O)2R B6 , -S(O)2N(R A6 )2, -S(O)N(R A6 )2, -P(R X6 )2, -P(O)R or "R 5 and R 6 " or "two R 6 " together with the atom to which they are attached form a C 3-10 cycloalkyl or 4-12 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, wherein cycloalkyl and heterocyclyl are unsubstituted or substituted with at least one substituent independently selected from R X6 . R 7.3 and R 7.4 are independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, 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)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)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)2NR 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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R X7 Substituents of the substituents; R 8.1 , R 8.2 , and R 8.3 are independently selected from hydrogen, halogen, C 1-10 1-6alkyl, C 2-10 1-6alkenyl, C 2-10 1-6alkynyl, C 3-10 3-6cycloalkyl, C 3-10 3-6cycloalkyl-C 1-4 1-6alkyl, heterocyclyl, heterocyclyl-C 1-4 1-6alkyl, aryl, aryl-C 1-4 1-6alkyl, heteroaryl, heteroaryl-C 1-4 1-6alkyl, 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 )R B8 -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)2NR 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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R X8 Substituents of the substituents; R A0 Selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, heterocyclic, heterocyclic -C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R X0 Substituents each R A1 and R B1 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X1 ; or R A1 and R B1 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, which ring can be unsubstituted or substituted with 1, 2, or 3 R X1 groups; each R A2 and R B2 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X2 ; or "R A2 and R B2 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, which ring can be unsubstituted or substituted with 1, 2, or 3 R X2 groups; each R A3 and R B3 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X3 ; or "R A3 and R B3 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, which ring can be unsubstituted or substituted with 1, 2, or 3 R X3 groups; R A4 selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X4 ; each R A5 and R B5 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X5 ; or "R A5 and R B5 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, which ring can be unsubstituted or substituted with 1, 2, or 3 R X5 groups; each R A6 and R B6 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X6 ; or "R A6 and R B6 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, which ring can be unsubstituted or substituted with 1, 2, or 3 R X6 groups; each R A7 and R B7 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X7 ; or R A7 and R B7 together with the single or multiple atoms to which they are attached collectively form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, which ring can be unsubstituted or substituted with 1, 2, or 3 R X7 groups; each R A8 and R B8 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X8 ; or R A8 and R B8 together with the single or multiple atoms to which they are attached collectively form a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, which ring can be unsubstituted or substituted with 1, 2, or 3 R X8 groups; each R C0 and R D0 is independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X0 ; or R C0 and R D0 together with the single or multiple carbon atoms to which they are attached form a C 3-10 cycloalkyl or 4-12 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorus, wherein cycloalkyl and heterocyclyl are unsubstituted or substituted with at least one substituent independently selected from R X0 ; each R E1 , R E2 , R E3 , R E7 and R E8 are independently selected from the group consisting of hydrogen, C 1-10 alkyl, 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 alkyl is unsubstituted or substituted by at least one substituent independently selected from R X ; The condition is when Z 1 It is N, X 2 It is C, X 3 It is CR 7.3 Or N, X 4 It does not exist, R 5 and R 6 Or any two R 6 Non-circular, W is And L is selected from -CR C0 R D0 (CR C0 R D0 ) u - When, then R C0 and R D0 At least one of them is R X0 Replace, R X0 Selected from CN, C 2-10 alkenyl and C 2-10 alkynyl group; each R X , each R X0 , each R X1 , each R X2 , each R X3 , each R X4 , each R X5 , each R X6 , each R X7 , and each R X8 is independently selected from hydrogen, C 1-10 1-6alkyl, C 2-10 2-6alkenyl, C 2-10 2-6alkynyl, C 3-10 3-8cycloalkyl, C 3-10 3-8cycloalkyl-C 1-4 1-6alkyl, heterocyclyl, heterocyclyl-C 1-4 1-6alkyl, aryl, aryl-C 1-4 1-6alkyl, heteroaryl, heteroaryl-C 1-4 1-6alkyl, halogen, 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 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)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 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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from R Y Substituents of the substituents; each R a1 and R b1 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ; or R a1 and R b1 together with the single or multiple atoms to which they are attached comprise a 4-12 membered heterocyclic ring containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, which ring is optionally substituted with 1, 2, or 3 R Y groups; each R c1 and R d1 is independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ; or R c1 and R d1 together with the single or multiple carbon atoms to which they are attached form a 3-12 membered ring containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen, which ring is optionally substituted with 1, 2, or 3 R Y groups; each R is independently selected from the group consisting of hydrogen, C e1 alkyl, C 1-10 alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, 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 ; each R Y is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, halo, 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 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)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)(=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 ), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is selected independently from at least one hydroxyl, C1N, amino, halogen, C2N, C4N ... 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups; each R a2 and R b2 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, hydroxy, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino; or R a2 and R b2 together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is optionally substituted with 1 or 2 substituents independently selected from halo, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, hydroxy, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino; each R c2 and R d2 is independently selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, hydroxy, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino; or R c2 and R d2 together with the single or multiple carbon atoms to which they are attached form a 3-12 membered ring containing 0, 1, or 2 heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen, which ring is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, hydroxy, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino, and di(C 1-10 alkyl)amino; Each R e2 Independently selected from hydrogen, CN, NO2, C 1-10 Alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, -C(O)C 1-4 Alkyl, -C(O)C 3-10 Cycloalkyl, -C(O)OC 1-4 Alkyl, -C(O)OC 3-10 Cycloalkyl, -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, -S(O)2N(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.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is C(O). 1 is C(O).

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N. 1 is N.

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

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

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, CN, NO2, -NR A5 R B5 , and -OR A5 , wherein each alkyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 , and -(CR c1 R d1 ) t OR b1 .

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, CI, Br, -CN, -N02, -NH2, and -OH.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein, each R 6 is independently selected at each occurrence from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, CN, NO2, -NR A6 R B6 and -OR A6 wherein each alkyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 ​ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein, Each R 6 Each time it appears, it is independently selected from hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, -CN, -NO2, -NH2, and -OH.

10. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein "R" 5 and R 6 "or two Rs" 6 "Together with the atoms they are bonded to, they form a C." 3-10 Cycloalkyl or 4-10 membered heterocyclic groups containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur and nitrogen, wherein the cycloalkyl and heterocyclic groups are unsubstituted or contain at least one heteroatom independently selected from R. X6 Substituents are substituted.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein, R 5 and R 6 "or two Rs" 6 "Together with the atoms they are bonded to, they form a C." 3-8 Cycloalkyl or a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur and nitrogen, wherein the cycloalkyl and heterocyclic group are unsubstituted or substituted with at least one substituent, said substituent being independently selected from C14. 1-10 Alkyl, C 3-10 Cycloalkyl, halogen, CN, NO2, -(CR) c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 .

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein W is selected from each of which is unsubstituted or substituted with at least one substituent independently selected from R X .

13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein W is which is unsubstituted or substituted with at least one substituent independently selected from R X .

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

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein Q 2 selected from 16. The compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, wherein n is selected from 1, 2 and 3.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected for each occurrence from C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, NO2, -NR A2 R B2 and -OR A2 wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X2 .

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected at each occurrence from hydrogen, methyl, ethyl, isopropyl, pyranyl, cyclopropyl, methoxy, ethoxy, F, CI, Br, -CN, -NO2, -NH2, -NHCH3, -OH, and wherein methyl, ethyl, isopropyl, pyranyl, cyclopropyl, methoxy, and ethoxy are unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 .

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

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

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

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected for each occurrence from C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, NO2, -NR A1 R B1 and -OR A1 wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X1 .

23. The compound of claim 22, 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, CI, Br, -CN, -NO2, -NH2, and -OH, wherein methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy are unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 .

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein X 1 is N.

25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein X is C. 1 is C.

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

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

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

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

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

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

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein X 3 is selected from O and S.

33. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein X 3 is selected from N, NR 7.3 and CR 7.3 .

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein X 4 is CR 7.4 .

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

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

37. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein X 4 is absent.

38. The compound of any one of claims 33-34, or a pharmaceutically acceptable salt thereof, wherein R 7.3 and R 7.4 are each selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, CN, NO2, -NR A7 R B7 , and -OR A7 , wherein each alkyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 , and -(CR c1 R d1 ) t OR b1 .

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R 7.3 and R 7.4 are each selected from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, CI, Br, -CN, -NO2, -NH2, and -OH.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein Y 1 is N.

41. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein Y 1 is CR 8.1 .

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

43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein Y 2 is CR 8.2 .

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein Y 3 is CR 8.3 .

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

46. The compound of any one of claims 41 and 43-44, or a pharmaceutically acceptable salt thereof, wherein R 8.1 , R 8.2 , and R 8.3 are independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, CN, NO2, -NR A8 R B8 , and -OR A8 , wherein each alkyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 , and -(CR c1 R d1 ) t OR b1 .

47. The compound of claim 46, 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, -NO2, -NH2, and -OH.

48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, wherein L is -CR C0 R D0 (CR C0 R D0 ) u - 49. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, wherein L is selected from -(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 -.

50. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z 1 It is N, X 2 It is C, X 3 It is CR 7.3 Or N, X 4 It does not exist, R 5 and R 6 Or any two R 6 Non-circular, W is And L is selected from -CR C0 R D0 (CR C0 R D0 ) u - 51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein each R C0 and R D0 is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy, wherein methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy are unsubstituted or substituted with at least one substituent independently selected from R X0 . or R C0 and R D0 together with the single or multiple carbon atoms to which they are attached form a C 3-10 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from R X0 .

52. The compound of any one of claims 1-49 and 51, or a pharmaceutically acceptable salt thereof, wherein R X0 is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, halo, 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 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent selected from the group consisting of C 1-10 alkyl, C 3-10 cycloalkyl, halo, 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 .

53. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein R X0 is selected from hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, isopropyl, cyclopropyl, methoxy, ethoxy, ethenyl, ethynyl, F, Cl, Br, -CN, -NO2, -NH2, and -OH.

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

55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein R 4 selected from -C(O)OH, -C(O)NHS(O) r R A4 -(CR c1 R d1 ) t NHS(O) r R A4 and heteroaryl.

56. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein R 4 selected from 57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt thereof, wherein Q 3 is selected from heterocyclyl, aryl, and heteroaryl.

58. The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein Q 3 selected from 59. The compound of any one of claims 1-58 or a pharmaceutically acceptable salt thereof, wherein p is selected from 0, 1, 2 and 3.

60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected for each occurrence from C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, NO2, -NR A3 R B3 and -OR A3 wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are unsubstituted or substituted with at least one substituent independently selected from R X3 .

61. The compound of claim 60, or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected at each occurrence from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, CI, Br, -CN, -NO2, -NH2, and -OH, wherein methyl, ethyl, isopropyl, cyclopropyl, methoxy, and ethoxy are unsubstituted or substituted with at least one substituent independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 .

62. The compounds are selected from: And its pharmaceutically acceptable salts.

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

64. A method of treating, improving, or preventing a condition that inhibits the response to GLP-1R, comprising administering to an individual in need an effective amount of a compound of any one of claims 1-62 or a pharmaceutically acceptable salt thereof, or at least one of such pharmaceutical compositions, and optionally in combination with a second therapeutic agent.

65. Use of any compound of claims 1-62 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing GLP-1 receptor-mediated diseases or conditions or for modulating GLP-1 receptors.

66. The use according to 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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