Nitrogen-containing heterocyclic compound and application thereof

Abstract

The invention discloses a nitrogen-containing heterocyclic compound and application thereof. The invention provides a compound as shown in formula I or pharmaceutically acceptable salt thereof, which has the advantages of excellent activity and novel structure as a GLP-1R micromolecule agonist.

Description

TECHNICAL FIELD

[0001] The present application relates to nitrogen-containing heterocyclic compounds and their use. BACKGROUND

[0002] Glucagon-like peptide-1 (GLP-1) is a peptide hormone, mainly synthesized and secreted by L cells located in the ileum and colon, and its action is mediated by the receptor GLP-1R, also known as Glucagon-like peptide-1 receptor. GLP-1R belongs to the G protein-coupled receptor family present on the cell membrane, and is mainly distributed in pancreatic beta cells and alpha cells, gastrointestinal tract, central nervous system and cardiovascular system, etc. GLP-1 mediates intracellular signal transduction through GLP-1R, and can cause accumulation of second messenger cyclic adenosine monophosphate (cAMP) when activated. In the pancreas, GLP-1 induces glucose-dependent insulin secretion. It increases insulin secretion and reduces glucagon secretion. In the central nervous system, the agonism of GLP-1R has the effects of increasing satiety, reducing food intake, nausea, promoting nerve cell survival, etc. In other tissue systems, the agonism of GLP-1R also plays a role in reducing blood pressure, improving microvascular function, reducing inflammation, reducing gastric emptying, reducing blood glucose, increasing insulin sensitivity, and reducing glycolysis. Therefore, GLP-1R receptor agonism can have a metabolic regulating effect through multiple biological mechanisms.

[0003] The early developed GLP-1 receptor agonists are GLP-1 analogs, all of which belong to peptide substances, including liraglutide, semaglutide, etc. Through genetic engineering methods and formulation improvements, long-acting, orally available polypeptide drugs have been developed, but oral polypeptides are still subject to various unfavorable restrictions such as dosing time, dosage, gastrointestinal disturbance, etc. Therefore, in the treatment of cardiometabolic diseases and related diseases (including but not limited to NASH, obesity and type 2 diabetes), there is still a need for compounds with ideal therapeutic properties, metabolic properties and / or ease of implementation, such as GLP-1R small molecule agonists. In view of the importance of GLP-1R small molecule agonists, there is an urgent need to develop GLP-1R small molecule agonists with novel structures. SUMMARY

[0004] The technical problem to be solved by the present application is to overcome the defect that the structure of the GLP-1R small molecule agonist in the prior art is relatively single. To this end, the present application provides a class of nitrogen-containing heterocyclic compounds as GLP-1R small molecule agonists, which have the advantages of excellent activity and novel structure.

[0005] The present application provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0006]

[0007] wherein R 1 independently -COOH, substituted C 1b alkyl, 1-6 alkyl, 5-8 membered heteroaryl substituted with one or more R 1f 5-8 membered heteroaryl substituted with one or more R

[0008] R 1a independently C 1-6 alkyl, hydroxy, -O-C 1-6 alkyl, or -N(R 1aa )(R 1ab ); R 1aa and R 1ab independently H, C 1-6 alkyl, cyano, hydroxy, -O-C 1-6 alkyl, -S(=O)2-C 1-6 alkyl, or -S(=O)2-N(C 1-6 alkyl)2;

[0009] R 1b independently halogen or hydroxy;

[0010] R 1c independently hydroxy or C 1-6 alkyl;

[0011] R 1d independently hydroxy or -NH-C 1-6 alkyl;

[0012] R 1e independently -NH-C(=O)-NH-C 1-6 alkyl, or -NH-(5-8 membered heteroaryl);

[0013] R 1f independently oxo or hydroxy;

[0014] R 2 is C 1-6 alkyl, -C 1-6 alkylene-R 2a , 3-6 membered heterocycloalkyl substituted with one or more R 2b 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl substituted with one or more R 2c C 3-6 cycloalkyl, 5-8 membered heteroaryl, or 5-8 membered heteroaryl substituted with one or more R 2d ;

[0015] R2a It is a 3-6 membered heterocyclic alkyl group, with one or more R 2aa Substituted 3-6 membered heterocyclic alkyl groups, C 3-6 cycloalkyl, with one or more R 2ab Replacement C 3-6 cycloalkyl, 5-8 membered heteroaryl, with one or more R 2ac Substituted 5-8 aryl or -OC 1-6 alkyl;

[0016] R 2aa R 2ab R 2ac R 2b R 2c and R 2d Independent of D, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, amino, -N(C) 1-6 Alkyl)2、-NH-C 1-6 Alkyl, cyano, hydroxyl, oxo The alkyl and cycloalkyl groups are optionally separated by one or more R 2aaa replace;

[0017] R 2aaa It can be independently hydroxyl, halogen, cyano or amino;

[0018] L1 is -C(=O)-, -O-, -S-, and is controlled by one or more L 1a Replacement C 1-6 Alkylene or -N(L) 1b )-;

[0019] L 1a Independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, amino, -N(C) 1-6 Alkyl)2、-NH-C 1-6 Alkyl, C 6-10 Aryl, 5-8 membered heteroaryl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, C 3-6 cycloalkyl or C 3-6 Cycloalkenyl;

[0020] L 1a In, the C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C 1-6 Alkyl groups are optionally surrounded by one or more L 1aa Replaced, each L 1aaindependently halogen, oxo, cyano, hydroxyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 3-6 cycloalkyl or C 3-6 cycloalkenyl;

[0021] L 1a , wherein the C 6-10 aryl, 5-8 membered heteroaryl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 3-6 cycloalkyl and C 3-6 cycloalkenyl is optionally substituted with one or more L 1ab , each L 1ab is independently halogen, oxo, cyano, hydroxyl, C 1-6 alkyl, -O-C 1-6 alkyl, amino, -N(C 1-6 alkyl)2, -NH-C 1-6 alkyl or amino;

[0022] L 1b is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1ba cycloalkyl substituted with one or more L 3-6 , 3-6 membered heterocycloalkyl substituted with one or more L 1bb , -S(=O)2-L 1bc or -S(=O)2-N(L 1bd )(L 1be );

[0023] L 1ba and L 1bb are independently C 1-6 alkyl, -O-C 1-6 alkyl, halogen, hydroxyl, amino or cyano;

[0024] L 1bc is C 1-6 alkyl or C 3-6 cycloalkyl;

[0025] L 1bd and L 1be are independently H, C 1-6 alkyl or C 3-6 cycloalkyl;

[0026] Ring A is C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl or 3-12 membered heterocycloalkenyl;

[0027] R 3 is independently H, halogen, cyano, amino, nitro, hydroxyl, C 1-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -O-C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl or 5-8 membered heteroaryl; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -O-C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-8 membered heteroaryl are optionally substituted with one or more R 3a ;

[0028] R 3a independently halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -O-C 1-6 alkyl, amino, -N(C 1-6 alkyl)2, or -NH-C 1-6 alkyl; said alkyl, alkenyl and alkynyl are optionally substituted with one or more R 3aa ; 3aa independently halogen, hydroxyl, cyano, amino, nitro, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0029] Ring B is 5-8 membered heteroaryl; the number of heteroatoms in said 5-8 membered heteroaryl is 1-4, independently N, O or S, and wherein at least one is N;

[0030] R 4 independently halogen, cyano, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -O-C 1-6 alkyl, amino, -N(C 1-6 alkyl)2, -NH-C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 4a ;

[0031] R 4a independently halogen, hydroxyl, cyano, amino or nitro;

[0032] L2 is C 1-6 heteroalkylene; said C 1-6The heteroatoms in the heteroalkylene group are 1-2, independently N, O or S;

[0033] Ring C is C 6-12 aryl or 5-12 membered heteroaryl;

[0034] R 5 independently H, halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -O-C 1-6 alkyl, amino, -N(C 1-6 alkyl)2, -NH-C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 5a ;

[0035] said R 5a independently halogen, cyano, amino, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -O-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH-C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 5aa ;

[0036] R 5aa independently halogen, hydroxyl, cyano, amino or nitro;

[0037] n, o, p and m are independently 0, 1, 2, 3 or 4;

[0038] The number of heteroatoms in each heteroaryl, heterocycloalkyl and heterocycloalkenyl group in the compound of formula I, except for the heteroaryl group in ring B, is independently 1-4, independently N, O or S.

[0039] In one aspect of the application, in the compound of formula I, each C 1-6 alkyl is independently C 1-3 alkyl, for example methyl.

[0040] In one aspect of the application, in the compound of formula I, each halogen is independently F, Cl, Br or I.

[0041] In one aspect of the application, in the compound of formula I, R 1 in each heteroaryl group, the heteroatoms are independently N or O, for example

[0042] In one embodiment of the present application, each C 1-6 alkylene is independently C 1-3 alkylene, such as methylene.

[0043] In one embodiment of the present application, each C 3-12 cycloalkyl is independently C 3-8 cycloalkyl.

[0044] In one embodiment of the present application, each C 3-12 cycloalkenyl is independently C 3-8 cycloalkenyl.

[0045] In one embodiment of the present application, each 3-12 membered heterocycloalkyl is independently a 3-8 membered heterocycloalkyl.

[0046] In one embodiment of the present application, each 3-12 membered heterocycloalkenyl is independently a 3-8 membered heterocycloalkenyl.

[0047] In one embodiment of the present application, each C 6-12 aryl is independently C 6-10 aryl.

[0048] In one embodiment of the present application, each 5-12 membered heteroaryl is independently a 5-8 membered heteroaryl.

[0049] In one embodiment of the present application, n is 1, 2, 3 or 4, preferably 1.

[0050] In one embodiment of the present application, o is 0, 1, 2, 3 or 4, preferably 0 or 1.

[0051] In one embodiment of the present application, p is 0, 1, 2, 3 or 4, preferably 0.

[0052] In one embodiment of the present application, m is 1, 2, 3 or 4, preferably 2.

[0053] In one embodiment of the present application, R 1 is -COOH,

[0054] In one embodiment of the present application, R 1 is -COOH.

[0055] In one embodiment of the present application, n is 1.

[0056] In one embodiment of the present application, is For example

[0057]

[0058] In a preferred embodiment of the present application, R 2 is -C 1-6 alkylene-R 2a , preferably -C 1-3 alkylene-R 2a , for example -CH2-R 2a .

[0059] In a preferred embodiment of the present application, R 2a is 3-6 membered heterocycloalkyl; the number of heteroatoms in said 3-6 membered heterocycloalkyl is preferably 1 or 2, independently preferably O or S; said 3-6 membered heterocycloalkyl is preferably oxetane.

[0060] In a preferred embodiment of the present application, R 2 is

[0061] In a preferred embodiment of the present application, L1is C 1a alkylene, preferably C 1-6 alkylene substituted by one or more L 1a , preferably C 1-3 alkylene substituted by one or more L 1a , for example methylene substituted by one or more L 1a .

[0062] In a preferred embodiment of the present application, L 1a is hydrogen.

[0063] In a preferred embodiment of the present application, L1is methylene.

[0064] In a preferred embodiment of the present application, R 3 is independently C 1-6 alkyl, preferably C 1-3 alkyl.

[0065] In a preferred embodiment of the present application, R 3 is methyl.

[0066] In a preferred embodiment of the present application, o is 0 or 1.

[0067] In a preferred embodiment of the present application, in ring A, said C 3-12 ycloalkyl, C 3-12 ycloalkenyl, 3-12 membered heterocycloalkyl and 3-12 membered heterocycloalkenyl is independently monocyclic or bicyclic; when said C 3-12 ycloalkyl, C 3-12 ycloalkenyl, 3-12 membered heterocycloalkyl and 3-12 membered heterocycloalkenyl is bicyclic, it is independently preferably bridged, spiro or fused.

[0068] In one embodiment of the present application, ring A is a 3-12 membered heterocycloalkyl, preferably a 3-8 membered heterocycloalkyl.

[0069] In one embodiment of the present application, in ring A, the 3-12 membered heterocycloalkyl has 1 or 2 heteroatoms.

[0070] In one embodiment of the present application, in ring A, the 3-12 membered heterocycloalkyl has a heteroatom which is N.

[0071] In one embodiment of the present application, ring A is a 6 membered heterocycloalkyl having 1 or 2 heteroatoms, the heteroatom being N, for example piperidinyl or piperazinyl.

[0072] In one embodiment of the present application, is is preferably for example

[0073] In one embodiment of the present application, in ring B, the 5-8 membered heteroaryl has 1-3 heteroatoms, preferably 1-2 heteroatoms, more preferably 2 heteroatoms.

[0074] In one embodiment of the present application, in ring B, the 5-8 membered heteroaryl has a heteroatom which is N.

[0075] In one embodiment of the present application, ring B is a 6 membered heteroaryl having 1 or 2 heteroatoms, the heteroatom being N, for example pyrimidinyl or pyridinyl.

[0076] In one embodiment of the present application, p is 0.

[0077] In one embodiment of the present application, is

[0078] In one embodiment of the present application, L2 is C 1-3 heteroalkylene, preferably -C 1-3 alkylene-O-, for example -C 1-3 alkylene-O-*, * representing the end attached to ring C.

[0079] In one embodiment of the present application, in L2, the C 1-6 heteroalkylene has 1 heteroatom.

[0080] In one embodiment of the present application, in L2, the C 1-6 heteroalkylene has a heteroatom which is O.

[0081] In one embodiment of the present application, L2 is

[0082] In an embodiment of the present application, L2 is * represents one end connected with ring C.

[0083] In an embodiment of the present application, ring C is C 6-10 monocyclic aryl.

[0084] In an embodiment of the present application, ring C is phenyl.

[0085] In an embodiment of the present application, R 5 independently halogen or cyano.

[0086] In an embodiment of the present application, R 5 independently F, Cl or cyano.

[0087] In an embodiment of the present application, m is 2.

[0088] In an embodiment of the present application, is * represents one end connected with L2; preferably is

[0089] In an embodiment of the present application, the compound of formula I is any one of the following structures:

[0090]

[0091] or a stereoisomer thereof, or a mixture of the corresponding stereoisomers.

[0092] The present application also provides a pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0093] The present application also provides use of the compound of formula I, a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of a GLP-1R agonist.

[0094] The present application also provides use of the compound of formula I, a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of a medicament for preventing and / or treating a disease related to GLP-1R.

[0095] In an embodiment of the present application, the disease related to GLP-1R is diabetes, diabetic complications, metabolic syndrome, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, Parkinson's disease, Alzheimer's disease or cardiovascular and cerebrovascular diseases; the cardiovascular and cerebrovascular diseases are hypertension, hyperglycemia, hyperlipidemia, atherosclerotic coronary heart disease or stroke.

[0096] Unless otherwise defined, each term of the present application can be defined as follows:

[0097] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the connection of the corresponding functional group to other segments or functional groups in the compound through this site. As used herein, "R1", "R1", and "R" are used interchangeably. 1 The meanings of "" are the same and they can be used interchangeably. The same definition applies to other symbols such as R2.

[0098] When defining or further defining any variable, unless otherwise specified, the definition or definition applies to all groups of the same name appearing in that variable; for example, R x Can be "-C 1-12 Alkylene-C 3-10 cycloalkyl-R x1 At this point, "R" is specified. x In the middle, the "C" mentioned 1-12 "alkylene" is C 1-8 "alkylene", and "R" x In the context, the -C 1-12 Alkylene-C 3-10 cycloalkyl-R x1 The "C" in 1-12 "alkylene" is C 1-8 "alkylene" has the same meaning; for example, R x It can be "C" 1-6 Alkyl or -C 3-10 cycloalkyl-C 1-6 "alkyl", where "R" is specified. x In the middle, the "C" mentioned 1-6 Each alkyl group is independently C10. 1-3 Alkyl group, and R x In, the C 1-6 Alkyl and -C 3-10 cycloalkyl-C 1-6 The "C" in alkyl 1-6 Each alkyl group is independently C10. 1-3 "alkyl" has the same meaning.

[0099] When the term "each" is used to define a variable, it means that all functional groups with the same name involved in the technical solution can be defined independently; for example, in a technical solution, R x For "C" 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 Alkyl", R y For "H or C" 1-6 Alkyl"; here a is defined as: in the technical solution, "each" C 1-6 Alkyl groups are independently C 1-3 Alkyl; Definition b: R x and Ry In particular, the C 1-6 alkyl and C 1-6 In "C 1-6 alkyl", each occurrence of "C 1-3 alkyl" is independently C 5 Definitions a and b have the same effect.

[0100] As used herein, a dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for substituent that is named before the dash. For example, "-CH2-" is attached at the 2 position of the parent moiety, while "CH2-" indicates the 1 position of the parent moiety.

[0101] When any variable (e.g. R 5 ) occurs more than one time in a compound, each definition of that variable is independent of the others and each occurrence is treated as non-interdependent.

[0102] The term "one or more" when referring to a variable that is "more than one" means that each such variable is independent of the others; for example, "methyl substituted with one or more halogens" can be -CH2Br, -CHBr2, -CF3, or

[0103] The term "more than one" means 2, 3, or 4.

[0104] The term "halogen" means F, Cl, Br, or I.

[0105] The term "alkyl" means a straight or branched chain alkyl group having the indicated number of carbon atoms (e.g. C1-C6). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, and the like.

[0106] The term "oxo" means two hydrogens on a methylene group are replaced with oxygen, i.e. methylene is replaced with carbonyl.

[0107] The term "alkylene" means a straight chain or branched chain divalent hydrocarbon radical having the indicated number of carbon atoms (e.g. C1-C6). Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, 1-methylpropylene, butylene, and the like.

[0108] The term "heteroalkylene" means a straight chain or branched chain divalent radical of the indicated number of carbon atoms (e.g. C1-C6), the indicated number of heteroatoms (e.g. 1 or 2), and the indicated number of types of heteroatoms (e.g. 1, 2, or 3 of N, O, and S).

[0109] The term "alkenyl" means a straight or branched chain hydrocarbon radical having the indicated number of carbon atoms (e.g. C2-C6) and containing one or more double bonds. The double bond(s) can be internal or terminal.

[0110] The term "alkynyl" refers to a straight or branched chain hydrocarbon group having a specified number of carbon atoms (e.g., C2-C6) containing one or more triple bonds. The one or more carbon-carbon triple bonds can be internal or terminal.

[0111] The term "cycloalkyl" refers to a saturated cyclic group having a specified number of ring carbon atoms (e.g., C3-C8), the ring atoms consisting solely of carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0112] The term "cycloalkenyl" refers to an unsaturated cyclic group having a specified number of ring carbon atoms (e.g., C3-C 12 ), the ring atoms consisting solely of carbon atoms, containing one or more double bonds.

[0113] The term "heterocycloalkyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 3-8 membered), a specified number of heteroatoms (e.g., 1 or 2), and a specified kind of heteroatoms (1, 2, or 3 of N, O, and S). Examples of heterocycloalkyl groups include, but are not limited to, oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, or piperazinyl, and the like.

[0114] The term "aryl" refers to a conjugated cyclic group having a specified number of carbon atoms (e.g., C6-C 10 ) that satisfies the 4n+2 rule, having aromaticity, being monocyclic or polycyclic (e.g., 2 or 3). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, or fluorenyl.

[0115] The term "heteroaryl" refers to a conjugated cyclic group having a specified number of ring atoms (e.g., 5-10 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified kind of heteroatoms (one or more of N, O, and S), having aromaticity, being monocyclic or polycyclic. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, diazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoxazolyl, thiadiazolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, indolizinyl, phenoxazinyl, phenothiazinyl, benzoxazolyl, or benzisoxazolyl.

[0116] The term "heterocycloalkenyl" refers to a monocyclic or bicyclic ring system containing partial unsaturation alkenyl, containing 3-10 ring carbon atoms and at least one ring atom selected from nitrogen, sulfur and oxygen atoms; wherein the heterocycloalkenyl is non-aromatic and does not contain any aromatic rings. Examples of heterocycloalkenyl include, but are not limited to, dihydrofuryl, dihydrothienyl, dihydropyrrolyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridinyl, 3,4-dihydro-2H-pyran, pyranyl, thiopyranyl, dihydropyridinyl, dihydropyrazinyl, dihydropyrimidinyl, oxazinyl, dihydrotetrazolyl, octahydroisoquinolinyl, 3H-indolyl, dihydroisoquinolinyl, dihydroquinolinyl or 4H-quinolizinyl.

[0117] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application prepared from a relatively nontoxic, pharmaceutically acceptable acid or base. Alkali addition salts can be prepared from the neutral form of the compounds of the present application by contacting the compounds in pure solution or in a suitable inert solvent with a sufficient amount of the pharmaceutically acceptable base to produce the desired salt. Acid addition salts can be prepared by contacting the neutral form of the compounds of the present application in pure solution or in a suitable inert solvent with a sufficient amount of the pharmaceutically acceptable acid to produce the desired salt.

[0118] The term "pharmaceutical excipient" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, which is generally divided into two categories: excipients and additives. Please refer to the Chinese Pharmacopoeia (2020 Edition) Volume IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0119] The term "agonist" refers to a compound that can activate a specific receptor and trigger the corresponding physiological response, which binds to the receptor on the cell surface or in the cell, mimics the action of natural ligands (such as hormones, neurotransmitters, etc.), changes the conformation of the receptor or activates the signal transduction pathway associated with the receptor.

[0120] In the present application, the "agonist" can be used in vivo in mammalian organisms; it can also be used in vitro, mainly as experimental purposes, such as providing a standard or control sample for comparison, or being made into a kit according to the conventional method in the art.

[0121] The term "treatment" refers to therapeutic treatment. When used in relation to a particular condition, treatment refers to: (1) relieving the disease or condition, or one or more of the biological manifestations thereof, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more of the biological manifestations of the condition, (3) ameliorating one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment, or (4) slowing the development of the condition or one or more of the biological manifestations thereof.

[0122] The term "prevention" refers to maintaining health in a subject with respect to a disease or condition referred to herein for a period of time. It will be appreciated that the period of time depends on the amount of pharmaceutical compound that has been administered and the individual factors of the subject discussed elsewhere in the specification. It will be appreciated that prevention can not be effective in all subjects treated with a compound according to the application. However, the term requires that prevention is preferably effective in a statistically significant portion of the subjects of a cohort or population that is susceptible to the disease or condition referred to herein or to a concomitant symptom. Preferably, in this case, a group or population of subjects is envisaged that would develop the disease or condition referred to herein if no preventive measures according to the application were taken. Whether a portion is statistically significant can be determined immediately by the skilled person using various well-known statistical evaluation tools discussed elsewhere in the specification.

[0123] The above-mentioned preferred conditions can be combined in any way, i.e. to obtain preferred embodiments of the application.

[0124] The reagents and starting materials used in the present application are commercially available.

[0125] The present application is positively advanced in that it is excellent in activity and novel in structure. DETAILED DESCRIPTION

[0126] The present application will be further illustrated by the following examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples, for which specific conditions are not mentioned, are selected according to the conventional methods and conditions, or according to the instructions of the commercial products.

[0127] Example 1

[0128] Preparation of Compound 1

[0129]

[0130] Synthesis of 4-((4-chloropyrimidin-2-yl)methoxy)-3-fluorobenzonitrile (1a)

[0131] A mixture of 3-fluoro-4-hydroxybenzonitrile (2.46 g, 18 mmol), Cs2CO3(9.6 g, 30 mmol) and 4-chloro-2-(chloromethyl)pyrimidine (2.44 g, 15 mmol) was added with DMF (100 mL) under electromagnetic stirring at room temperature for 2 h, then quenched with water (300 mL) and extracted with EtOAc (150 mL x 3), the organic phase was combined and washed with saturated brine, dried over Na2SO4, filtered and the solvent was removed by rotary evaporation. The crude residue was purified by silica gel column chromatography (EtOAc / petroleum ether as eluent) to give the target compound (1a) as a white solid (2.68 g, 68%), LC-MS: [M+H] + = 264.1.

[0132] Synthesis of 3-fluoro-4-((4-selenohydroxypyrimidin-2-yl)methoxy)benzonitrile (1b)

[0133] NaOH (480 mg, 12 mmol) and elemental selenium powder (950 mg, 12 mmol) were dissolved in 50 mL of DMF, protected by N2, hydrazine hydrate (80%, 380 μL, 6 mmol) was injected, heated to 40 °C and stirred for 2 h. A DMF solution of intermediate 1a (1.58 g, 6 mmol) was added to the reaction system, heated to 160 °C and stirred for 4 h, TLC showed that the reaction was complete. The reaction was filtered, extracted with equal volumes of water and EtOAc, dried over Na2SO4, filtered and the solvent was removed by rotary evaporation. The crude residue was purified by silica gel column chromatography (EtOAc / petroleum ether as eluent) to give compound 1b as a yellow solid (572 mg, 31%). LC-MS: [M+H] + = 310.0.

[0134] Synthesis of tert-butyl 4-((2-((4-cyano-2-fluorophenoxy)methyl)pyrimidin-4- yl)seleno)piperidine-1-carboxylate (1c)

[0135] A mixture of 1-Boc-4-methanesulfonyloxy piperidine (168 mg, 0.6 mmol), intermediate 1b (185 mg, 0.6 mmol), Cs2CO3(260 mg, 0.8 mmol) and DMF (2 mL) was stirred at 90 °C for 3 h. The mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with water (10 mL), saturated brine (10 mL), dried over Na2SO4, filtered and the solvent was removed by rotary evaporation. The crude residue was purified by silica gel column chromatography to give compound 1c as an oil (115 mg, 39%). LC-MS: [M+H] + = 493.1.

[0136] Synthesis of (S)-2-((4-((2-((4-cyano-2-fluorophenoxy)methyl)pyrimidin-4-yl) seleno yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (1e)

[0137] Dissolve intermediate 1c (100 mg, 0.2 mmol) in 10 mL EtOAc, add p-TSA-H20 (502 mg, 2.64 mmol), heat and stir at 60 °C, monitor the reaction progress by TLC. After the reaction is complete, evaporate the solvent to get compound 1d crude, which is directly used in the next step without purification.

[0138] Dissolve the above intermediate 1d crude in 10 mL MeCN, add the starting material (S)-2-(chloromethyl)-1-(oxetan-2ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (58 mg, 0.20 mmol) and K2CO3 (138 mg, 1.00 mmol), heat to 50 °C and stir, monitor the reaction completion by TLC, remove the solvent by rotary evaporation, purify the residue by column chromatography (eluent: dichloromethane:methanol = 100:1) to get compound 1e (53 mg, 41%) as a light white oil. LC-MS: [M+H] = 651.1. +

[0139] Preparation of compound 1

[0140] Dissolve intermediate 1e (39 mg, 0.06 mmol) in 5 mL MeCN, add 1,5,7- triazido bicyclo(4.4.0)dec-5-ene (38 mg, 0.27 mmol) in water, stir at room temperature overnight. Monitor the reaction completion by TLC, adjust the pH to 5-6 using aqueous citric acid solution. Extract with DCM, dry over Na2S04, filter and remove the solvent by rotary evaporation. Purify the residue by column chromatography (eluent: dichloromethane:methanol = 30:1) to get compound 1 (16 mg, 43%). LC-MS: [M+H] = 637.1. +

[0141] Example 2

[0142] Preparation of compound 2

[0143]

[0144] Synthesis of 4-chloro-2-((4-chloro-2-fluorophenoxy)methyl)pyrimidine (2a)

[0145] ​​A mixture of 4-chloro-2-fluorophenol (1.32 g, 9 mmol), Cs2CO3(4.8 g, 15 mmol) and 4-chloro-2-(chloromethyl)pyrimidine (1.22 g, 7.5 mmol) was added with DMF (50 mL) under electromagnetic stirring at room temperature for 2 hours, then quenched with water (200 mL) and extracted with EtOAc (100 mL x 3), the organic phase was combined, washed with saturated brine, dried over Na2SO4, filtered and the solvent was removed by rotary evaporation. The crude residue was purified by silica gel column chromatography (EtOAc / petroleum ether as eluent) to obtain the target compound (2a) as a white solid (1.45 g, 71 %), LC-MS: [M+H] + = 273.0.

[0146] Synthesis of 2-((4-chloro-2-fluorophenoxy)methyl)pyrimidine-4-selenol (2b)

[0147] NaOH (400 mg, 10 mmol) and elemental selenium powder (790 mg, 10 mmol) were dissolved in 50 mL of DMF, protected by N2, hydrazine hydrate (80%, 320 μL, 5 mmol) was injected, heated to 40 °C and stirred for 2 h. A DMF solution of intermediate 2a (1.36 g, 5 mmol) was added to the reaction system, heated to 160 °C and stirred for 3.5 h. TLC showed that the reaction was complete. The reaction was filtered, extracted with equal volumes of water and EtOAc, dried over Na2SO4, filtered and the solvent was removed by rotary evaporation. The crude residue was purified by silica gel column chromatography (EtOAc / petroleum ether as eluent) to obtain compound 2b as a yellow solid (680 mg, 43 %). LC-MS: [M+H] + = 319.0.

[0148] Synthesis of 4-((2-((4-chloro-2-fluorophenoxy)methyl)pyrimidin-4-yl)seleno)methanesulfonate (2c)

[0149] A mixture of 1-Boc-4-methanesulfonyloxy piperidine (140 mg, 0.5 mmol), intermediate 2b (158 mg, 0.5 mmol), Cs2CO3(260 mg, 0.8 mmol) and DMF (2 mL) was stirred at 90 °C for 3 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with water (10 mL), saturated brine (10 mL), dried over Na2SO4, filtered and the solvent was removed by rotary evaporation. The crude residue was purified by silica gel column chromatography to obtain compound 2c as an oil (87 mg, 35 %). LC-MS: [M+H] + = 502.1.

[0150] Synthesis of (S)-2-((4-((2-((4-chloro-2-fluorophenoxy)methyl)pyrimidin-4-yl) seleno yl)piperidin- 1 -yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1 H-benzo [d] imidazole-6-carboxylic acid methyl ester (2e)

[0151] Intermediate 2c (80 mg, 0.16 mmol) was dissolved in 10 mL EtOAc, p-TSA-H20 (502 mg, 2.64 mmol) was added, and the reaction was stirred at 60 °C. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was evaporated to give compound 2d as a crude product, which was directly used in the next step without purification.

[0152] The above crude product 2d (10 mg, 0.02 mmol) was dissolved in 10 mL MeCN, and (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid methyl ester (8 mg, 0.03 mmol) and K2C03(42 mg, 0.30 mmol) were added. The reaction was stirred at 50 °C. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by rotary evaporation. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 100: 1) to give compound 2 (8 mg, 70%) as a white solid. LC-MS: [M+H] = 646.1. + = 660.1.

[0153] Preparation of compound 2

[0154] Intermediate 2d (39 mg, 0.06 mmol) was dissolved in 5 mL MeCN, and an aqueous solution of 1,5,7-triazidabicyclo(4.4.0)dec-5-ene (38 mg, 0.27 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed, the pH was adjusted to 5-6 using an aqueous citric acid solution. The reaction was extracted with DCM, dried over Na2S04, filtered, and the solvent was removed by rotary evaporation. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 30: 1) to give compound 2 (13 mg, 34%) as a white solid. LC-MS: [M+H] = 646.1. + = 646.1.

[0155] Example 3

[0156] Preparation of compound 3

[0157] Preparation of intermediate INT-1

[0158]

[0159] Tert-butyl (2S,4R)-4-hydroxy-2-methylpiperidine-l-carboxylate (800 mg, 3.72 mmol), DIPEA (1.92 g, 14.86 mmol) were dissolved in DCM (30 mL), and a solution of methanesulfonic anhydride (1.62 g, 9.28 mmol) in DCM (5 mL) was added. The reaction was stirred at 0 °C for 3 h, diluted with EtOAc (200 mL), and washed with water (100 mL x 2). The organic phase was dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation to give the target intermediate INT-1 (1.11 g) as a colorless oil, which was used in the next step without further purification. LC-MS: [M+H] = 294.1. + = 294.1.

[0160]

[0161] Synthesis of tert-butyl (2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)pyrimidin-4- yl)selanyl)-2-methylpiperidine-l-carboxylate (3a)

[0162] A mixture of intermediate INT-1 (295 mg, 1 mmol), intermediate 1b (308 mg, 1 mmol), Cs2CO3(520 mg, 1.6 mmol), and DMF (5 mL) was stirred at 90 °C for 3 h. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The organic layer was washed with water (20 mL), saturated brine (20 mL), dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation. The crude residue was purified by silica gel column chromatography to give compound 3a (187 mg, 37%) as an oil. LC-MS: [M+H] = 507.1. + = 507.1.

[0163] Synthesis of methyl 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)pyrimidin-4- yl)selanyl)-2-methylpiperidin-l-yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate (3c)

[0164] Intermediate 3a (150 mg, 0.3 mmol) was dissolved in 10 mL EtOAc, p-TSA-H2O (502 mg, 2.64 mmol) was added, and the reaction was stirred at 60 °C with TLC monitoring of the reaction progress. After the reaction was completed, the solvent was evaporated to give crude compound 3b, which was directly used in the next step without purification.

[0165] The above crude intermediate 3b was dissolved in 10 mL MeCN, the starting material (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid methyl ester (88 mg, 0.30 mmol) and K2CO3(138 mg, 1.00 mmol) were added, the temperature was raised to 50 °C and stirred, TLC was used to monitor the completion of the reaction, the solvent was removed by rotary evaporation, and the residue was purified by column chromatography (eluent: dichloromethane:methanol = 100:1) to obtain compound 3c (72 mg, 36%) as a light white oil. LC-MS: [M+H] + = 665.2.

[0166] Preparation of compound 3

[0167] The intermediate 3c (67 mg, 0.1 mmol) was dissolved in 5 mL MeCN, and an aqueous solution of 1,5,7-triazidobicyclo(4.4.0)dec-5-ene (70 mg, 0.5 mmol) was added, and stirred at room temperature overnight. TLC was used to monitor the completion of the reaction, and the pH was adjusted to 5-6 using an aqueous citric acid solution. DCM was used for extraction, Na2SO4was used for drying, filtration was performed, and the solvent was removed by rotary evaporation. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 30:1) to obtain compound 3 (24 mg, 37%). LC-MS: [M+H] + = 651.1.

[0168] Example 4

[0169] Preparation of compound 4

[0170]

[0171] Synthesis of (2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)pyrimidin-4-yl)selanyl)-2- methylpiperidine-1-carboxylic acid tert-butyl ester (4a)

[0172] A mixture of intermediate INT-1 (295 mg, 1 mmol), intermediate 2b (318 mg, 1 mmol), Cs2CO3(520 mg, 1.6 mmol), and DMF (5 mL) was stirred at 90 °C for 3 hours. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The organic layer was washed with water (20 mL), saturated brine (20 mL), dried over Na2SO4, filtered, and the solvent was removed by rotary evaporation. The crude residue was purified by silica gel column chromatography to obtain compound 4a (165 mg, 32%) as an oil. LC-MS: [M+H] + = 516.1.

[0173] Synthesis of 2-(((2S,4S)-4-((2-(((4-chloro-2-fluorophenoxy)methyl)pyrimidin-4-yl)seleno)-2-methylpiperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (4c)

[0174] Intermediate 4a (155 mg, 0.3 mmol) was dissolved in 10 mL of EtOAc, and p-TSA·H2O (502 mg, 2.64 mmol) was added. The mixture was heated and stirred at 60 °C, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to obtain crude compound 4b, which was directly added to the next step without purification.

[0175] Dissolve the crude intermediate product 4b in 10 mL of MeCN, add the starting material (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (88 mg, 0.30 mmol) and K2CO3 (138 mg, 1.00 mmol), heat to 50 °C and stir. Monitor the reaction by TLC until complete. Remove the solvent by rotary evaporation. Purify the residue by column chromatography (eluent: dichloromethane:methanol = 100:1) to give a light white oily substance 4c (81 mg, 40%). LC-MS: [M+H] + =674.1.

[0176] Preparation of compound 4

[0177] Intermediate 4b (54 mg, 0.08 mmol) was dissolved in 5 mL of MeCN, and an aqueous solution of 1,5,7-triazidobicyclo(4.4.0)dec-5-ene (38 mg, 0.27 mmol) was added. The mixture was stirred overnight at room temperature. After TLC analysis, the pH was adjusted to 5-6 using an aqueous citric acid solution. Extraction was performed using DCM, and the mixture was dried over Na2SO4. The solvent was removed by filtration and rotary evaporation. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 30:1) to give compound 4 (22 mg, 42%). LC-MS: [M+H] + =660.1.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in, R 1 Independently -COOH, by one or more R 1b Replacement C 1-6 alkyl, 5-8 aryl groups, with one or more R groups 1f Substituted 5-8 aryl or R 1a Independently for C substituted with one or more halogens 1-6 Alkyl, hydroxyl, -OC 1-6 Alkyl or -N(R) 1aa (R) 1ab ); R 1aa and R 1ab H and C independently 1-6 Alkyl, cyano, hydroxyl, -OC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl or -S(=O)2-N(C) 1-6 Alkyl)2; R 1b Independent of halogen or hydroxyl; R 1c Independently hydroxyl or C 1-6 alkyl; R 1d Independently hydroxyl or -NH-C 1-6 alkyl; R 1e Independently -NH-C(=O)-NH-C 1-6 Alkyl or -NH- (5-8 membered heteroaryl); R 1f Independently oxidized or hydroxylated; R 2 C 1-6 Alkyl, -C 1-6 Alkylene-R 2a 3-6 membered heterocyclic alkyl groups, with one or more R 2b Substituted 3-6 membered heterocyclic alkyl groups, C 3-6 cycloalkyl, with one or more R 2c Replacement C 3-6 Cycloalkyl, 5-8 membered heteroaryl, or with one or more R 2d Substituted 5-8 aryl groups; R 2a It is a 3-6 membered heterocyclic alkyl group, with one or more R 2aa Substituted 3-6 membered heterocyclic alkyl groups, C 3-6 cycloalkyl, with one or more R 2ab Replacement C 3-6 cycloalkyl, 5-8 membered heteroaryl, with one or more R 2ac Substituted 5-8 aryl or -OC 1-6 alkyl; R 2aa R 2ab R 2ac R 2b R 2c and R 2d Independent of D, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, amino, -N(C) 1-6 Alkyl)2、-NH-C 1-6 Alkyl, cyano, hydroxyl, oxo The alkyl and cycloalkyl groups are optionally separated by one or more R 2aaa replace; R 2aaa It can be independently hydroxyl, halogen, cyano or amino; L1 is -C(=O)-, -O-, -S-, and is controlled by one or more L 1a Replacement C 1-6 Alkylene or -N(L) 1b )-; L 1a Independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, amino, -N(C) 1-6 Alkyl)2、-NH-C 1-6 Alkyl, C 6-10 Aryl, 5-8 membered heteroaryl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, C 3-6 cycloalkyl or C 3-6 Cycloalkenyl; L 1a In, the C 1-6 Alkyl, -OC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C 1-6 Alkyl groups are optionally surrounded by one or more L 1aa Replaced, each L 1aa Independently halogenated, oxo-, cyano-, hydroxyl-, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, C 3-6 cycloalkyl or C 3-6 Cycloalkenyl; L 1a In, the C 6-10 Aryl, 5-8 membered heteroaryl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl, C 3-6 cycloalkyl and C 3-6 The cycloalkenyl group is optionally surrounded by one or more L 1ab Replace, each L 1ab Independently halogen, oxo, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, amino, -N(C) 1-6 Alkyl)2、-NH-C 1-6 Alkyl or amino; L 1b For hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, with one or more L 1ba Replacement C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, with one or more L 1bb Substituted 3-6 membered heterocyclic alkyl groups, -S(=O)2-L 1bc or -S(=O)2-N(L 1bd (L) 1be ); L 1ba and L 1bb Independently for C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, hydroxyl, amino, or cyano groups; L 1bc C 1-6 Alkyl or C 3-6 cycloalkyl; L 1bd and L 1be H and C independently 1-6 Alkyl or C 3-6 cycloalkyl; Ring A is C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, or 3-12 membered heterocyclic alkenyl; R 3 Independently, it can be H, halogen, cyano, amino, nitro, hydroxyl, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-8 quinone heteroaryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl and 5-8 heteroaryl groups are optionally separated by one or more R 3a replace; R 3a Independently halogen, cyano, amino, nitro, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, amino, -N(C) 1-6 alkyl)2 or -NH-C 1-6 Alkyl; the alkyl, alkenyl, and ynyl groups are optionally separated by one or more R 3aa Replace; R 3aa Independently halogen, hydroxyl, cyano, amino, nitro, C 3-6 cycloalkyl or 3-6 membered heterocyclic alkyl; Ring B is a 5-8 membered heteroaryl group; the number of heteroatoms in the 5-8 membered heteroaryl group is 1-4, and the heteroatoms are independently N, O or S, and at least one of them is N; R 4 Independently halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, amino, -N(C) 1-6 Alkyl)2、-NH-C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl; the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic alkyl may optionally be represented by one or more R 4a replace; R 4a It can be halogen, hydroxyl, cyano, amino, or nitro independently; L2 is C 1-6 Heteroalkyl; the C 1-6 The heteroatom in the heteroalkylene group is 1-2, and the heteroatom is independently N, O or S; Ring C is C 6-12 Aryl or 5-12 heteroaryl groups; R 5 Independently, it can be H, halogen, cyano, amino, nitro, hydroxyl, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, amino, -N(C) 1-6 Alkyl)2、-NH-C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl; the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic alkyl may optionally be represented by one or more R 5a replace; The R 5a Independently halogen, cyano, amino, nitro, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl; the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic alkyl may optionally be represented by one or more R 5aa replace; R 5aa It can be halogen, hydroxyl, cyano, amino, or nitro independently; n, o, p, and m are independently 0, 1, 2, 3, or 4; Except for the heteroaryl group in ring B, each heteroaryl group, heterocyclic alkyl group, and heterocyclic alkenyl group in Formula I has 1 to 4 heteroatoms independently, and the heteroatoms are independently N, O, or S.

2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) In compound I, each C 1-6 Alkyl groups are independently C 1-3 Alkyl groups, such as methyl groups; (2) In the compound of formula I, each halogen is independently F, Cl, Br or I; (3) In compound I, R 1 In each heteroaryl group, the heteroatom is independently either N or O, for example... (4) In compound I, each C 1-6 Alkylene is independently C 1-3 Alkyl groups, such as methylene groups; (5) In compound I of formula (5), each C 3-12 The cycloalkyl group is independently C 3-8 cycloalkyl; (6) In compound I of formula (6), each C 3-12 The cycloalkenyl group is independently C 3-8 Cycloalkenyl; (7) In the compound of formula I, each 3-12 membered heterocyclic alkyl group is independently a 3-8 membered heterocyclic alkyl group; (8) In the compound of formula I, each 3-12 membered heterocyclic alkenyl group is independently a 3-8 membered heterocyclic alkenyl group; (9) In compound I of formula (9), each C 6-12 The aryl group is independently C 6-10 Aryl; (10) In the compound of formula I, each 5-12 member heteroaryl group is independently a 5-8 member heteroaryl group; (11) n is 1, 2, 3 or 4, preferably 1; (12) o is 0, 1, 2, 3 or 4, preferably 0 or 1; (13) p is 0, 1, 2, 3 or 4, preferably 0; (14) m is 1, 2, 3 or 4, preferably 2.

3. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 2 -C 1-6 Alkylene-R 2a Preferably -C 1-3 Alkylene-R 2a For example, -CH2-R 2a ; (2)R 2a It is a 3-6 membered heterocyclic alkyl group; the number of heteroatoms in the 3-6 membered heterocyclic alkyl group is preferably 1 or 2, and the heteroatoms are preferably O or S independently; the 3-6 membered heterocyclic alkyl group is preferably oxobutane; (3) L1 is a group of L1s. 1a Replacement C 1-6 Alkylene, preferably by one or more L 1a Replacement C 1-3 Alkylene, for example, by one or more L 1a Substituted methylene; (4)R 3 Independently for C 1-6 Alkyl group, preferably C 1-3 alkyl; (5) In ring A, the C 3-12 cycloalkyl, C 3-12 The cycloalkenyl, 3-12 membered heterocyclic alkyl, and 3-12 membered heterocyclic alkenyl are independently monocyclic or bicyclic; when the C 3-12 cycloalkyl, C 3-12 When the cycloalkenyl, 3-12-membered heterocyclic alkyl and 3-12-membered heterocyclic alkenyl are bicyclic, they are independently preferred to be bridged rings, spiro rings or fused rings; (6) Ring A is a 3-12 membered heterocyclic alkyl group, preferably a 3-8 membered heterocyclic alkyl group; (7) In ring A, the number of heteroatoms in the 3-12 membered heterocyclic alkyl group is 1 or 2; (8) In ring A, the heteroatom in the 3-12 membered heterocyclic alkyl group is N; (9) In ring B, the number of heteroatoms in the 5-8 membered heteroaryl group is 1-3, preferably 1-2, and more preferably 2; (10) In ring B, the heteroatom in the 5-8 membered heteroaryl group is N; (11) L2 is C 1-3 Heteroalkyl, preferably -C 1-3 Alkylene -O-, for example -C 1-3 Alkylene -O-, * represents the end connected to the ring C; (12) In L2, the C 1-6 There is one heteroatom in the heteroalkylene group; (13) In L2, the C 1-6 The heteroatom in the heteroalkylene group is O; (14) Ring C is C 6-10 Monocyclic aryl; (15)R 5 It can be halogenated or cyano-based independently; (16) for * represents the end connected to L2; (17) for (18) for (19) for 4. The compound of formula I as claimed in claim 3, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 -COOH, (2) n is 1; (3)R 2 for (4)L 1a It is hydrogen; (5) L1 is a methylene group; (6)R 3 It is methyl; (7) o is 0 or 1; (8) Ring A is a 6-membered heterocyclic alkyl group with 1 or 2 heteroatoms and N heteroatoms, such as piperidinyl or piperazineyl; (9) for For example (10) p is 0; (11) Ring B is a 6-membered heteroaryl group with 1 or 2 heteroatoms and N heteroatoms, such as pyrimidinyl or pyridinyl; (12) L2 is L2 is preferred * represents the end connected to ring C; (13) Ring C is phenyl; (14)R 5 It can be F, Cl, or cyano independently; (15) m is 2; (16) for (17) for 5. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula I has any of the following structures: Or its stereoisomers, or mixtures thereof with the corresponding stereoisomers.

6. A pharmaceutical composition comprising a compound of formula I as described in any one of claims 1-5 or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

7. The use of a compound of formula I as described in any one of claims 1-5, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 6 in the preparation of a GLP-1R agonist.

8. Use of a compound of formula I as described in any one of claims 1-5, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 6 in the preparation of a medicament for the prevention and / or treatment of diseases associated with GLP-1R.

9. The application as described in claim 8, characterized in that, The diseases associated with GLP-1R are diabetes, diabetic complications, metabolic syndrome, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, Parkinson's disease, Alzheimer's disease, or cardiovascular and cerebrovascular diseases. The cardiovascular and cerebrovascular diseases mentioned are hypertension, hyperglycemia, hyperlipidemia, atherosclerotic coronary heart disease, or stroke.

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