Substituted bicyclic derivative, preparation method therefor, and use thereof

Abstract

The present invention relates to a substituted bicyclic derivative, a preparation method therefor, a pharmaceutical composition containing the derivative, and a pharmaceutical use thereof. Specifically, the present invention relates to a substituted bicyclic derivative as shown in general formula (I), a preparation method therefor, and a stereoisomer, a tautomer, a deuterated compound, a pharmaceutically acceptable salt and a pharmaceutical composition thereof, as well as a use thereof as a therapeutic agent, particularly as a 20-HETE formation inhibitor, wherein the definition of each substituent in general formula (I) is the same as that in the description.

Description

Substituted bicyclic derivatives, processes for their preparation and uses thereof TECHNICAL FIELD

[0001] The present invention relates to a substituted bicyclic derivative, processes for its preparation and pharmaceutical compositions containing the derivative and its use as a therapeutic agent, in particular as an inhibitor of 20-HETE production. BACKGROUND

[0002] 20-hydroxyeicosatetraenoic acid (20-HETE) is an arachidonic acid (AA) monooxygenated metabolite produced by cytochrome P450 (CYP) enzymes. The major enzyme for 20-HETE production in mice is Cyp4a12, and enzymes in rats that produce 20-HETE include Cyp4a1, Cyp4a2 and Cyp4a3. The major enzymes for 20-HETE production in humans are Cyp4a11 and Cyp4f2. 20-HETE is highly vasoactive and is a key regulator of microvascular tone, promoting vascular smooth muscle contraction, endothelial dysfunction, inflammation and cell proliferation. In vivo and in vitro studies have demonstrated that 20-HETE is a potent vasoconstrictor eicosanoid and is involved in cerebral microvascular autoregulation.

[0003] 20-HETE synthesis is increased after ischemic events, and 20-HETE synthesis inhibitors can protect neurons and prevent post-injury dysfunction of cerebral blood flow, brain edema and blood brain barrier (BBB), for example, inhibition of 20-HETE formation has neuroprotective effects in animal models of transient focal ischemia (TFI), cardiac arrest (CA), stroke and subarachnoid hemorrhage (SAH).

[0004] A number of clinical studies have shown that the expression level of 20-HETE is significantly increased in hypertension, stroke, coronary artery disease, myocardial infarction, acute renal failure, chronic kidney disease, polycystic kidney disease, and tumor growth and metastasis, end-organ damage and fibrosis, and a variety of diseases.

[0005] It is currently believed that 20-HETE is involved in the mechanism of hypertension development, including: increasing intracellular Ca 2+ concentration, promoting vascular smooth muscle contraction; reducing NO bioavailability in vascular endothelial cells, inhibiting endothelial nitric oxide synthase activity, promoting reactive oxygen species generation, inducing vascular endothelial cell dysfunction; promoting vascular smooth muscle cell proliferation and migration, inducing vascular remodeling; promoting angiotensin converting enzyme, Ang II and angiotensin type 1 receptor activity. 20-HETE is likely to become a drug target for the prevention and treatment of hypertension.

[0006] 20-HETE also plays an important role in the occurrence and progression of obesity, insulin resistance and metabolic syndrome. Preclinical animal models show that 20-HETE levels are correlated with weight gain and metabolic syndrome, including hyperglycemia, diabetes, and diabetes-related retinopathy and nephropathy. Clinical studies show that 20-HETE levels in urine and plasma are correlated with body mass index (BMI) and significantly increased in obese, diabetic and metabolic syndrome patients. Mice overexpressing Cyp4al2-20-HETE synthase develop obesity, hyperglycemia, hyperinsulinemia and impaired glucose tolerance when fed a high-fat diet. Insulin resistance also occurs in the skeletal muscle, liver and adipose tissue of these animals.

[0007] Studies have found that the orphan receptor GPR75 is a specific receptor for 20-HETE, which is a proximal signaling mechanism for 20-HETE-induced hypertension and vascular dysfunction. Knocking out GPR75 or GPCR kinase-interacting protein-1 can prevent 20-HETE-mediated endothelial growth factor receptor phosphorylation and angiotensin converting enzyme induction. By sequencing 650,000 people and identifying individuals with rare protective mutations, it was found that at least individuals with non-active copies of the GPR75 gene had lower body mass index (BMI) and tended to weigh about 12 pounds less than individuals without mutations, with a 54% reduction in obesity risk and improved diabetes parameters, including reduced blood sugar. In a study comparing mice with a knockout GPR75 gene with normal mice, it was found that mice with a knockout GPR75 gene had significant resistance to weight gain and improved blood sugar control. Inhibition of GPR75 may provide a therapeutic strategy for obesity.

[0008] Given the important role of the 20-HETE / GPR75 pathway in the occurrence and development of the above diseases, 20-HETE ligand generation inhibitors or GPR75 receptor antagonists may provide a new direction for the treatment of various metabolic diseases (obesity, diabetes and its complications, etc.) and cardiovascular diseases (myocardial infarction, cardiac arrest, etc.).

[0009] There is no new drug on the market for 20-HETE target inhibitors. HET0016 is a highly active and selective 20-HETE inhibitor, but due to its poor solubility and short half-life, it has not entered clinical development. In recent years, 20-SOLA with better water solubility has been used as a 20-HETE antagonist tool for animal studies related to the treatment of related diseases. BEBT-809 developed by BepiWEB is in the preclinical stage. Therefore, there is still a lot of room for exploration in the related research of 20-HETE target, and it is of great scientific value and research significance to find new 20-HETE generation inhibitors with high efficiency, high selectivity and good in vivo properties. SUMMARY

[0010] In order to solve the above technical problems, the present application provides a compound represented by general formula (I) or a stereoisomer, a tautomer, a deuterated compound or a pharmaceutically acceptable salt thereof:

[0011] wherein:

[0012] Ring A is selected from a bicyclic aryl, a bicyclic heteroaryl or a bicyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of a monocyclic aryl or a monocyclic heteroaryl with a monocyclic heterocyclyl or a monocyclic cycloalkyl;

[0013] Ring B is selected from a 5-10 membered heteroaryl or a 5-10 membered heterocyclyl;

[0014] Ring C is selected from a 5-10 membered heteroaryl or a 4-10 membered heterocyclyl;

[0015] L is selected from -(CR a R b ) p -, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -C(O)O-, -N(R c )C(O)-, -C(O)N(R c )-, -C(O)N(R c )(CR a R b )-, -N(R c )C(O)(CR a R b )-, -C(O)(CR a R b )-, -(CR a R b )C(O)-, -O-, -N(R c )-, -S-, wherein p is selected from 0, 1 or 2, R a , R b and R c are each independently selected from a hydrogen atom or a C 1-6 alkyl group;

[0016] Y is selected from a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, a 3-8 membered heterocyclyl group, a C 6-10 aryl group, a 5-10 membered heteroaryl group, -SF5, -OR 4 , -OC(=O)R 4 , -C(=O)R 4 , -C(=O)OR 4 , -N(R 5 )C(=O)R6 -N(R 5 )C(=O)OR 6 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -S(=O) r NR 5 R 6 or -S(=O) r R 4 wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -OR 7 , =O, -C(=O)R 7 , -C(=O)OR 7 , -OC(=O)R 7 , -NR 8 R 9 , -C(=O)NR 8 R 9 , -S(=O)2NR 8 R 9 , -N(R 8 )C(=O)R 9 or -N(R 8 )C(=O)OR 9 ;

[0017] R 1 is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, hydroxy, cyano or -NR 5 R 6substituted by one or more substituents selected from the group consisting of C

[0018] R 2 each independently is selected from the group consisting of a hydrogen atom, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy; wherein said alkyl or alkoxy is optionally further substituted by one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, hydroxyl, or cyano;

[0019] R 3 each independently is selected from the group consisting of a hydrogen atom, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy; wherein said alkyl or alkoxy is optionally further substituted by one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, hydroxyl, or cyano;

[0020] and / or, two R 3 together with the atom to which they are attached form a 4-8 membered heterocyclyl, wherein the 4-8 membered heterocyclyl contains one or more N, O or S(O) r and said 4-8 membered heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of C 1- 6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, hydroxyl, or cyano;

[0021] R 4 each independently is selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -C(=0)R 7 , -C(=0)OR 7 , -OC(=0)R 7 , -NR 8 R 9 , -C(=0)NR 8 R 9 , -SO2NR 8 R 9 or -NR 8 C(=0)R 9substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -C(=0)R

[0022] R 5 and R 6 each independently is selected from the group consisting of a hydrogen atom, a hydroxy group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein said alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =0, -C(=0)R 7 , -C(=0)OR 7 , -OC(=0)R 7 , -NR 8 R 9 , -C(=0)NR 8 R 9 , -SO2NR 8 R 9 , or -NR 8 C(=0)R 9 ;

[0023] or, R 5 and R 6 together with the atom to which they are attached form a 4-8 membered heterocyclyl group, wherein the 4-8 membered heterocyclyl group contains one or more N, O or S(O) r and said 4-8 membered heterocyclyl group is optionally further substituted by one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =0, -C(=0)R 7 , -C(=0)OR 7 , -OC(=0)R 7 , -NR 8 R 9 , -C(=0)NR 8 R 9 , -SO2NR 8 R 9 , or -NR 8 C(=0)R 9 ;

[0024] R 7 , R 8 and R 9 each independently is selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a carboxyl group, or a carboxylate group;

[0025] m is 0, 1, 2, 3, or 4;

[0026] n is 0, 1, 2, 3, or 4;

[0027] q is 0, 1, 2, or 3;

[0028] each r is independently 0, 1, or 2.

[0029] A preferred embodiment of the present application provides a compound according to Formula (I), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein ring C is selected from 4-10 membered heterocyclyl, more preferably piperidinyl.

[0030] A preferred embodiment of the present application provides a compound according to Formula (I), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein L is selected from -CH2-, -CH2CH2-, -C(O)-, -C(O)NH-, -C(O)NHCH2-, -NHC(O)-, -CH2C(O)-, or -S(O)2-.

[0031] A preferred embodiment of the present application provides a compound according to Formula (I), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein L is selected from -CH2-.

[0032] A preferred embodiment of the present application provides a compound according to Formula (I), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein is selected from

[0033] A preferred embodiment of the present application provides a compound according to Formula (I), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R 3 each R is independently selected from a hydrogen atom or C 1-6 alkyl, preferably a hydrogen atom or methyl.

[0034] A preferred embodiment of the present application provides a compound according to Formula (I), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein ring B is selected from 5-10 membered heteroaryl, more preferably 5 membered heteroaryl.

[0035] A preferred embodiment of the present application provides a compound according to Formula (I), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein ring B is selected from the following groups:

[0036] A preferred embodiment of the present application provides a compound according to Formula (I), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R 2 each R is independently selected from a hydrogen atom or C 1-6alkyl, preferably a hydrogen atom or a methyl group.

[0037] In a preferred embodiment of the present application, the compound of general formula (I) is selected from the group consisting of:

[0038] In a preferred embodiment of the present application, the compound of general formula (I) is selected from the group consisting of:

[0039] In a preferred embodiment of the present application, the compound of general formula (I) is selected from the group consisting of:

[0040] In a preferred embodiment of the present application, the compound of general formula (I) is selected from the group consisting of: is selected from the group consisting of:

[0041] In a preferred embodiment of the present application, the compound of general formula (I) is selected from the group consisting of: 1 each independently selected from the group consisting of a hydrogen atom, a halogen or a C 1-6 alkyl, preferably a hydrogen atom, a fluorine or a methyl group.

[0042] In a preferred embodiment of the present application, the compound of general formula (I) is selected from the group consisting of:

[0043] or a stereoisomer, a tautomer, a deuterated analogue or a pharmaceutically acceptable salt thereof.

[0044] Note: If there is a discrepancy in the structure drawn and the name given to that structure, the structure drawn will control.

[0045] Further, the present application provides a pharmaceutical composition comprising an effective amount of a compound of general formula (I) or a stereoisomer, a tautomer, a deuterated analogue or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0046] The present application provides a use of a compound of Formula (I) or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition as described above) as a medicament (i.e., for treatment).

[0047] The present application provides a use of a compound of Formula (I) or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition as described above) in the manufacture of an inhibitor of 20-HETE production.

[0048] The present application provides a method of treating a disease associated with 20-HETE signaling pathway, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition as described above).

[0049] The present application also provides a use of a compound of Formula (I) or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition as described above) in the manufacture of a medicament for treating a disease associated with 20-HETE signaling pathway.

[0050] In preferred embodiments of the present application, the disease associated with 20-HETE signaling pathway is selected from obesity, metabolic syndrome, dyslipidemia, diabetes, diabetic retinopathy, diabetic cerebrovascular disease, diabetic neuropathy, insulin resistance, hyperglycemia, hyperlipidemia, diabetic nephropathy, hypertension, cataract, osteoporosis, hyperuricemia, multiple infections caused by diabetes, non-alcoholic fatty amine disease, non-alcoholic fatty liver disease, fibrosis, heart disease, stroke, liver cirrhosis, metabolic acidosis, ketosis, cardiovascular discomfort, epilepsy, atherosclerosis, Parkinson's disease, myocardial infarction, acute renal failure, chronic kidney disease, polycystic kidney disease, tumors, end-organ damage, Alzheimer's disease, wherein the diabetes is preferably type I diabetes, type II diabetes, gestational diabetes, idiopathic TID, early-onset T2DM, maturity-onset diabetes of the young, youth-onset atypical diabetes, malnutrition-related diabetes, adult-onset latent autoimmune diabetes.

[0051] The present application provides a use of a compound of Formula (I) or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition of the foregoing) in the manufacture of a medicament for the treatment of obesity, metabolic syndrome, dyslipidemia, diabetes, diabetic retinopathy, diabetic cerebrovascular disorder, diabetic neuropathy, insulin resistance, hyperglycemia, hyperlipidemia, diabetic nephropathy, hypertension, cataract, osteoporosis, hyperuricemia, various infections caused by diabetes, non-alcoholic steatohepatitis, fibrosis, heart disease, stroke, liver cirrhosis, metabolic acidosis, ketosis, cardiovascular discomfort, epilepsy, atherosclerosis, Parkinson's disease, myocardial infarction, acute renal failure, chronic kidney disease, polycystic kidney disease, tumors, end-organ damage, Alzheimer's disease, wherein the diabetes is preferably Type I diabetes, Type II diabetes, gestational diabetes, idiopathic TID, early-onset T2DM, maturity-onset diabetes of the young, atypical diabetes mellitus of youth, malnutrition-related diabetes, latent autoimmune diabetes in adults.

[0052] The present application also provides a method of treating obesity, metabolic syndrome, dyslipidemia, diabetes, diabetic retinopathy, diabetic cerebrovascular disorder, diabetic neuropathy, insulin resistance, hyperglycemia, hyperlipidemia, diabetic nephropathy, hypertension, cataract, osteoporosis, hyperuricemia, various infections caused by diabetes, non-alcoholic steatohepatitis, fibrosis, heart disease, stroke, liver cirrhosis, metabolic acidosis, ketosis, cardiovascular discomfort, epilepsy, atherosclerosis, Parkinson's disease, myocardial infarction, acute renal failure, chronic kidney disease, polycystic kidney disease, tumors, end-organ damage, Alzheimer's disease, wherein the diabetes is preferably Type I diabetes, Type II diabetes, gestational diabetes, idiopathic TID, early-onset T2DM, maturity-onset diabetes of the young, atypical diabetes mellitus of youth, malnutrition-related diabetes, latent autoimmune diabetes in adults, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition of the foregoing).

[0053] Detailed description of the application

[0054] Unless otherwise indicated, the following terms used in the specification and claims are defined as follows:

[0055] "Alkyl" when used as a group or part of a group refers to a straight-chain or branched-chain saturated hydrocarbon group having the indicated number of carbon atoms. 20 straight-chain or branched-chain aliphatic hydrocarbon groups. Preferably, C1-C 10alkyl, more preferably C1-C6alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. Alkyl groups can be substituted or unsubstituted.

[0056] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Preferred are C2-C 10 6alkenyl, most preferably C2-C4alkenyl. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups can be optionally substituted or unsubstituted.

[0057] "Alkynyl" refers to an aliphatic hydrocarbon group containing one carbon-carbon triple bond, which can be straight-chain or branched. Preferred are C2-C 10 6alkynyl, most preferably C2-C4alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.

[0058] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more ring-forming atoms are carbon atoms, the ring contains 0, 1, or multiple double bonds, and includes monocyclic, polycyclic, fused, bridged, and spirocyclic rings, preferably 3- to 7-membered monocyclic or 5- to 18-membered bicyclic or tricyclic.

[0059] Examples of "monocycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, Monocycloalkyl groups can be substituted or unsubstituted.

[0060] "Spiroalkyl" refers to a polycyclic group of 5 to 18 members, having two or more cyclic structures sharing one carbon atom between the rings (referred to as a spiro atom), containing 0, 1, or multiple double bonds within the rings, but no ring having a fully conjugated pi-electron system, preferably 6 to 14 members, more preferably 7 to 10 members. Spiroalkyl groups are classified as spiro, bi-, or polycyclic, preferably spiro and bi-, preferably 4 / 5, 4 / 4, 4 / 6, 3 / 6, 5 / 5, or 5 / 6 membered. Non-limiting examples of "spiroalkyl" groups include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl, Spiroalkyl groups can be substituted or unsubstituted.

[0061] "Fused ring alkyl" refers to a all-carbon polycyclic group of 5 to 18 members, having two or more cyclic structures sharing a pair of carbon atoms between the rings, one or more rings can contain 0, 1, or multiple double bonds within the rings, but no ring having a fully conjugated pi-electron system, preferably 6 to 14 members, more preferably 6 to 10 members. Fused ring alkyl groups are classified as bi-, tri-, tetra-, or polycyclic, preferably bi- or tri-, more preferably 3 / 5, 5 / 5, or 5 / 6 membered bi-cyclic fused ring alkyl. Non-limiting examples of "fused ring alkyl" groups include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetradeca-hydrophenanthryl, Fused ring alkyl groups can be substituted or unsubstituted.

[0062] "Bridged ring alkyl" refers to a all-carbon polycyclic group of 5 to 18 members, having two or more cyclic structures sharing two non-adjacent carbon atoms between the rings, one or more rings can contain 0, 1, or multiple double bonds within the rings, but no ring having a fully conjugated pi-electron system, preferably 6 to 14 members, more preferably 7 to 10 members. Bridged ring alkyl groups are classified as bi-, tri-, tetra-, or polycyclic, preferably bi-, tri-, or tetra-, more preferably bi- or tri-. Non-limiting examples of "bridged ring alkyl" groups include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicycloo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, Bridged ring alkyl groups can be substituted or unsubstituted.

[0063] "Heterocyclyl," "heterocycloalkyl," "heterocycle," or "heterocyclic" are used interchangeably herein and refer to non-aromatic heterocyclic radicals wherein one or more ring-forming atoms are selected from nitrogen, oxygen, or S(O) r containing 0, 1, or multiple double bonds, including monocyclic, polycyclic, fused, bridged, and spiro rings, preferably having 3 to 8 membered monocyclic or 5 to 18 membered bicyclic or tricyclic rings, which can contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Heterocyclyl groups can be substituted or unsubstituted.

[0064] Examples of "monocyclic heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, azetidinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidinyl, Monocyclic heterocyclyl groups can be substituted or unsubstituted.

[0065] "Spiroheterocyclyl" refers to a polycyclic radical of 5 to 18 membered, two or more ring structures, and single rings sharing one atom with each other, containing 0, 1, or multiple double bonds, but no ring has a fully conjugated system of π electrons, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) r containing 0, 1, or multiple double bonds, including monocyclic, polycyclic, fused, bridged, and spiro rings, preferably having 3 to 8 membered monocyclic or 5 to 18 membered bicyclic or tricyclic rings, which can contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Heterocyclyl groups can be substituted or unsubstituted. Spiroheterocyclyl groups can be substituted or unsubstituted.

[0066] "Fused heterocyclyl" refers to a polycyclic radical of two or more ring structures sharing a pair of atoms with each other, one or more rings can contain 0, 1, or multiple double bonds, but no ring has a fully conjugated system of π electrons, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) rheteroatoms, the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Depending on the number of rings making up the fused heterocyclyl group, it can be a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl group, preferably a bicyclic or tricyclic, more preferably a 5 membered / 5 membered or 5 membered / 6 membered bicyclic fused heterocyclyl group. Non-limiting examples of "fused heterocyclyl groups" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-lH-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][l,4]dioxine, The single fused heterocyclyl group can be substituted or unsubstituted.

[0067] "bridged heterocyclyl" refers to a polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two atoms not directly attached to each other, one or more rings can contain 0, 1 or more double bonds, but no ring has a fully conjugated π-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r heteroatoms, the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Depending on the number of rings making up the fused heterocyclyl group, it can be a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl group, preferably a bicyclic or tricyclic, more preferably a 5 membered / 5 membered or 5 membered / 6 membered bicyclic fused heterocyclyl group. Non-limiting examples of "fused heterocyclyl groups" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-lH-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][l,4]dioxine,

[0068] "aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings can be connected together in a fused manner. The term "aryl" includes mono- or bicyclic aromatic groups such as the aromatic groups of phenyl, naphthyl, tetrahydronaphthyl. Preferably the aryl group is a C6-Ci2 10 aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. The aryl group can be substituted or unsubstituted.

[0069] "Heteroaryl" means an aromatic 5- to 6-membered monocyclic ring or 8- to 10-membered bicyclic ring, which can contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-l,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzoimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzoisothiazolyl, benzoaxazolyl, benzoisoxazolyl, isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridyl, pyrid-2(lH)-ononyl, pyrimidinyl, pyrazin-2(lH)-ononyl, pyrimidin-4(3H)-ononyl, pyrimidin-2(lH)-ononyl, pyridazin-3(2H)-ononyl, lH-indolyl, lH-benzo[d]imidazolyl, lH-pyrrolo[2,3-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridinyl, furan[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, benzofuranyl, benzo[b]thiophenyl, lH-pyrrolo[3,2-b]pyridinyl, 2H-pyrrolo[3,4-c]pyridinyl, Heteroaryl can be substituted or unsubstituted.

[0070] "Fused ring" means a polycyclic group in which two or more cyclic structures share a pair of atoms with each other, at least one of which rings has a fully conjugated pi-electron aromatic system, while one or more rings can contain 0, 1, or multiple double bonds, but at least one ring does not have a fully conjugated pi-electron aromatic system, where the ring atoms are selected from 0, 1, or multiple heteroatoms selected from nitrogen, oxygen, or S(O) r (wherein r is selected from 0, 1, or 2) heteroatoms, with the remaining ring atoms being carbon. Fused rings preferably include bicyclic or tricyclic fused rings, with bicyclic fused rings preferably being the fusion of an aryl or heteroaryl group with a monocyclic heterocyclyl or monocyclic cycloalkyl group. Preferred are 6- to 14-membered, more preferably 8- to 10-membered. Examples of "fused ring" include, but are not limited to:

[0071] Fused rings can be substituted or unsubstituted.

[0072] "Aryloxy" means an (aryl-O-) group. Aryl is as defined above. C6-C10 aryl is preferred. Examples include, but are not limited to, phenoxy, naphthoxy, and the like.

[0073] "Aryloxy" means an (aryl-O-) group. Aryl is as defined above. C6-C10 aryl is preferred. Examples include, but are not limited to, phenoxy, naphthoxy, and the like.

[0074] "Nitro" means a -NO2 group.

[0075] "Hydroxy" means an -OH group.

[0076] "Halo" means fluoro, chloro, bromo and iodo.

[0077] "Amino" means -NH2.

[0078] "Hydroxylamino" means -NHOH.

[0079] "Cyano" means -CN.

[0080] "Benzyl" means -CH2-phenyl.

[0081] "Carboxyl" means -C(=O)OH.

[0082] "Carboxylate" means -C(=O)O-alkyl or -C(=O)O-cycloalkyl, where alkyl and cycloalkyl are as defined above.

[0083] "Hydroxyalkyl" means hydroxy substituted alkyl, where alkyl is as defined above.

[0084] "Aminoalkyl" means amino substituted alkyl, where alkyl is as defined above.

[0085] "Haloalkyl" means halo substituted alkyl, where alkyl is as defined above.

[0086] "Haloalkoxy" means halo substituted alkoxy, where alkoxy is as defined above.

[0087] "DMSO" means dimethyl sulfoxide.

[0088] "BOC" means tert-butoxy carbonyl.

[0089] "Bn" means benzyl.

[0090] "THP" means 2-tetrahydropyranyl.

[0091] "TFA" means trifluoroacetic acid.

[0092] "Ts" means p-toluenesulfonyl.

[0093] "Bn" means benzyl.

[0094] "SEM" means (trimethylsilyl)ethoxymethyl.

[0095] A "leaving group", or leaving group, is an atom or functional group that departs from a larger molecule in a chemical reaction, and is a term used in nucleophilic substitution reactions and elimination reactions. In a nucleophilic substitution reaction, the reactant that is attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. A good leaving group is one that readily accepts electrons and bears a negative charge. The smaller the pKa of the conjugate acid of the leaving group, the more likely the leaving group is to depart from other molecules. This is because the smaller the pKa of the conjugate acid, the more the corresponding leaving group tends to exist as an anion (or a neutral leaving group) without bonding to other atoms. Common leaving groups include, but are not limited to, halogen, mesyl, -OTs, or -OH.

[0096] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of the group are each, independently, replaced with the corresponding number of substituents. It is understood that the substituents are only in their possible chemical positions and can or can not be possible to substitute (by experiment or theory) by one of skill in the art without undue effort. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bonded to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0097] "Substituted" or "substitution" as used herein, unless otherwise indicated, means that a group can be substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =0, OR 5 , -C(=O)R 5 , -C(=O)OR 5 , -NHC(=O)R 5 , -NHC(=O)OR 5 , -NR 6 R 7 , -C(=O)NR 6 R 7 , -CH2NHC(=O)OR 5 , -CH2NR 6 R 7or -S(O) r R 5 The substituents are replaced;

[0098] R 5 Each is independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 or -NR 9 C(=O)R 10 The substituents are replaced;

[0099] R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 or -NR 9 C(=O)R 10 The substituents are replaced;

[0100] Or, R 6 and R 7 The atoms bonded to them together form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further composed of one or more elements selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R. 8 -C(=O)OR 8-OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -SO2NR 9 R 10 or -NR 9 C(=O)R 10 The substituents are replaced;

[0101] R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group;

[0102] r can be 0, 1, or 2 independently.

[0103] The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformal) isomers, and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0104] Unless otherwise stated, the structures described in this invention also include all isomers of this structure (e.g., diastereomers, enantiomers, and turn-blocking isomers and geometric (conformal) isomers); for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, diastereomers, and geometric (conformal) isomers, are all within the scope of this invention.

[0105] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Medicinal salts of compounds represented by general formula (I) can be metal salts or amine salts formed with suitable acids.

[0106] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity. Attached Figure Description

[0107] Figure 1 is a chart of the body weight changes of the experimental animals in Test Example 3. DETAILED DESCRIPTION

[0108] The following examples are intended to further describe the present application and are not intended to limit the scope of the present application.

[0109] EXAMPLE

[0110] The examples below provide the preparation of representative compounds of formula (I) and related structure identification data. It must be understood that the examples below are intended to illustrate the present application and are not intended to limit the scope of the present application.

[0111] 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are reported in ppm using tetramethylsilane as internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets, if coupling constants are given, they are in Hz.

[0112] Mass spectra were recorded on a LC / MS instrument and ionization can be ESI or APCI.

[0113] Thin layer chromatography silica gel plates were Yantai Huanghai HSG F254 or Qingdao GF254 silica gel plates. The silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.2 mm in thickness. The silica gel plates used for thin layer chromatography separation and purification of products were 0.4 mm to 0.5 mm in thickness.

[0114] Column chromatography generally used Yantai Huanghai silica gel 200 to 300 mesh silica gel as the carrier.

[0115] In the following examples, all temperatures are in degrees Celsius, unless otherwise indicated. Unless otherwise indicated, all starting materials and reagents were obtained from commercial suppliers, such as Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzhan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd., and used without further purification, unless otherwise indicated. Unless otherwise indicated, the commercial suppliers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzhan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0116] CD3OD: Deuterated methanol.

[0117] CDCl3: Deuterated chloroform.

[0118] DMSO-d6: Deuterated dimethyl sulfoxide.

[0119] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0120] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0121] The compounds were purified using silica gel column chromatography and reversed-phase column chromatography. The eluent system was selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile. The volume ratio of the solvent varied depending on the polarity of the compound and could be adjusted by adding small amounts of acidic or basic reagents, such as acetic acid or triethylamine.

[0122] Example 1

[0123] 1-((1-(6-(1H-pyrazol-4-yl)naphthalen-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one

[0124] 1-((1-(6-(1H-pyrazol-4-yl)naphth-2-yl)piperidin-4-yl)methyl)pyrrolidine-2-one

[0125] first step

[0126] tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate

[0127] 4-((p-toluenesulfonyloxy)methyl)piperidine-1-carboxylic acid tert-butyl ester

[0128] 15 g (69.67 mmol) of 4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester 1a was dissolved in dichloromethane (100 mL), and p-toluenesulfonyl chloride (15.89 g, 83.61 mmol) and N,N-diisopropylethylamine (27.01 g, 209.02 mmol) were added. The mixture was reacted at room temperature for 12 hours, and water (100 mL) was added. The aqueous phase was extracted with dichloromethane (80 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was separated by silica gel column chromatography (eluent: system A) to give 10 g (10 g) of 4-((p-toluenesulfonyloxy)methyl)piperidine-1-carboxylic acid tert-butyl ester 1b), with a yield of 38.9%.

[0129] Step 2

[0130] tert-butyl 4-((2-oxopyrrolidin-1-yl)methyl)piperidine-1-carboxylate

[0131] tert-butyl 4-((2-oxopyrrolidin-1-yl)methyl)piperidine-1-carboxylate

[0132] tert-butyl 4-((2-oxopyrrolidin-1-yl)methyl)piperidine-1-carboxylate

[0133] tert-butyl 4-((2-oxopyrrolidin-1-yl)methyl)piperidine-1-carboxylate

[0134] tert-butyl 4-((2-oxopyrrolidin-1-yl)methyl)piperidine-1-carboxylate

[0135] tert-butyl 4-((2-oxopyrrolidin-1-yl)methyl)piperidine-1-carboxylate

[0136] tert-butyl 4-((2-oxopyrrolidin-1-yl)methyl)piperidine-1-carboxylate

[0137] tert-butyl 4-((2-oxopyrrolidin-1-yl)methyl)piperidine-1-carboxylate

[0138] tert-butyl 4-((2-oxopyrrolidin-1-yl)methyl)piperidine-1-carboxylate

[0139] tert-butyl 4-((2-oxopyrrolidin-1-yl)methyl)piperidine-1-carboxylate

[0140] To a flask, 1-(piperidin-4-yl-methyl)pyrrolidin-2-one hydrochloride 1e (3.4 g, 15.54 mmol), 2,6-dibromonaphthalene 1f (4.88 g, 17.10 mmol), sodium tert-butoxide (7.46 g, 77.72 mmol), tris(dibenzylideneacetone)dipalladium (1.42 g, 1.55 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (967.92 mg, 1.55 mmol) were added sequentially into toluene (45 mL), and the reaction was stirred at 100 °C for 7 h. The reaction mixture was distilled under reduced pressure, and the residue was separated by column chromatography on silica gel (eluent: B system) to give 1-((1-(6-bromonaphthalen-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one 1g (1.3 g) in 22.0% yield.

[0141] MS m / z (ESI): [M+H] + = 387.1.

[0142] Fifth step

[0143] 1-((1-(6-(1H-pyrazol-4-yl)naphthalen-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one

[0144] 1-((1-(6-(1H-pyrazol-4-yl)naphthalen-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one

[0145] To a flask, 1-((1-(6-bromonaphthalen-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one 1g (2.05 g, 5.29 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1h (1.34 g, 6.88 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (392.62 mg, 529.29 µmol), cesium carbonate (5.17 g, 15.88 mmol), 1,4-dioxane (20 mL) and water (5 mL) were added sequentially, and the reaction was stirred at 100 °C for 7 h. The reaction mixture was distilled under reduced pressure, and the residue was separated by column chromatography on silica gel (eluent: B system) to give 1-((1-(6-(1H-pyrazol-4-yl)naphthalen-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one 1 (496 mg) in 25.0% yield.

[0146] MS m / z (ESI): [M+H] + = 375.2.

[0147] 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.22 (s, 1H), 7.96-7.93 (m, 2H), 7.70-7.64 (m, 3H), 7.33 (d, J = 9.1 Hz, 1H), 7.12 (s, 1H), 3.80 (d, J = 12.2 Hz, 2H), 3.38-3.33 (m, 2H), 3.10 (d, J = 7.3 Hz, 2H), 2.72 (t, J = 11.9 Hz, 2H), 2.24 (t, J = 8.0 Hz, 2H), 1.94 (t, J = 7.6 Hz, 2H), 1.80-1.73 (m, 1H), 1.69 (d, J = 12.9 Hz, 2H), 1.44-1.17 (m, 2H) ppm.

[0148] Examples 2-5 were synthesized according to the synthetic procedure of Example 1 and the specific structures and characterization are shown in the table below:

[0149] Biological Evaluation

[0150] Test Example 1, Inhibition of CYP Enzymes in Human and Rat Liver Microsomes by Compounds of the Invention

[0151] 1. Principle of the experiment: Inhibition of 20-HETE production was evaluated by testing the inhibitory activity of the compounds on human liver microsomes (HLM). This experiment used HLM to detect the effect of the test compounds on the metabolic rate of enzyme-specific substrates at different concentrations, in order to determine the inhibitory effect of the test compounds on CYP enzymes in HLM.

[0152] 2. Experimental method: The test compound was dissolved in DMSO to 10 mM, then diluted with acetonitrile and DMSO mixed solution (3:1), and the reaction system was prepared with phosphate buffer solution. 70 μL of 1.66 mg / mL human liver microsomes (I phase, 0121A1.03) working solution was taken into different EP tubes, 1.4 μL of 7 concentrations of inhibitors (the initial concentration of the compound was 2 μM in the final 60 μL reaction system, diluted by 4 times) was added in turn, and vortexed and mixed, then 30 μL was taken into new EP tubes for parallel duplicate experiments. 15 μL of 400 μM arachidonic acid solution (Cayman, 90030) was added in parallel duplicate experiments, mixed and preheated in a water bath for 10-15 min. After preheating, 15 μL of 6 mM NADPH (Roche, 10107824001) was added to each well and mixed, and incubated in a water bath for 20 min for full reaction, then 180 μL of pre-cooled acetonitrile containing 100 ng / mL glibenclamide (internal standard) (Macklin, G832360) was added, and the reaction was terminated by shaking for 60 s. Finally, the samples were centrifuged at 10000 r / min for 10 min on a 4°C centrifuge, and the supernatant was detected by LC-MS / MS.

[0153] The curve was drawn with the concentration of the compound as the abscissa and the inhibition rate as the ordinate, and the curve was fitted according to the equation Y = Bottom + (Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)) using Graphpad Prism8 software to calculate the IC50. X represents the logarithmic concentration of the compound, and Y is the relative activity of the enzyme at the corresponding compound concentration (relative to the condition without inhibitor).

[0154] The rat liver microsomal (RLM) test method was similar, and the working solution of rat liver microsomes (I phase, 0121D1.01) was 1 mg / mL. The initial concentration of the added compound was 10 μM in the final 60 μL reaction system, and the rest of the steps were consistent with the human liver microsomal test method.

[0155] 3. Experimental results

[0156] The half-inhibitory concentration of the test compound was calculated according to the above experimental method, and the results are shown in Table 1.

[0157] Table 1. Inhibitory activity of compounds on the generation of 20-HETE in HLM

[0158] As can be seen from Table 1, the compounds of the present application can effectively inhibit the activity of CYP enzymes in human liver microsomes (HLM) or rat liver microsomes (RLM), thereby inhibiting the generation of 20-HETE.

[0159] Test 2, mouse pharmacokinetic test of the compound of the present application

[0160] 1. Experimental purpose

[0161] ICR mice were used as test animals, and LC / MS / MS method was used to determine the drug concentration in the plasma of the mice at different time points after intragastrical administration of the compound of the present application, so as to study the pharmacokinetic characteristics of the compound of the present application in mice.

[0162] 2. Experimental scheme

[0163] 2.1 Experimental drugs and animals

[0164] The compound of the present application

[0165] ICR mice, male, 20-22g, purchased from Vantian Lihua Experimental Animal Technology Co., Ltd.

[0166] 2.2 Drug preparation

[0167] An appropriate amount of compound was weighed, and an appropriate amount of DMSO, 30% HS15 and saline was added in sequence, and then ultrasonic vortex was mixed to prepare a 1mg / mL administration preparation. Among them, DMSO, 30% HS15 and saline = 5:5:90 (v:v:v).

[0168] 2.3 Drug administration

[0169] The ICR mice in each test compound intragastrical administration group (9 mice in each group) were fasted overnight and then administered (PO, the compound administration dose was 10mg / kg, and the administration volume was 10mL / kg), and then fed 4 hours after administration.

[0170] 3. Operation

[0171] About 0.1mL of blood was taken from the orbit before administration and 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration. The whole blood sample was placed in an anticoagulant tube containing EDTA-K2. The blood sample was placed on ice after collection, and the plasma was separated by centrifugation (centrifugation conditions: 10000rpm, 10 minutes). The collected plasma was stored at -40 to -20℃ before analysis.

[0172] LC-MS / MS was used to determine the content of the test compound in the plasma of the mice after intragastrical administration.

[0173] 4. Pharmacokinetic parameter results

[0174] The pharmacokinetic parameters of the compound of the present application are shown in Table 2.

[0175] Table 2. Mouse pharmacokinetic parameters of the compound of the present application

[0176] Conclusion: The blood concentration and area under the curve of the compound of the present application are higher, and the compound has good pharmacokinetic properties.

[0177] Test Example 3, pharmacodynamic test of the compound of the present application on DIO mice

[0178] The test is divided into low-dose treatment group of test compound 1, medium-dose treatment group of test compound 1, high-dose treatment group of test compound 1 and solvent control group, 10 in each group, oral gavage for 28 days, according to the change of animal weight to evaluate the efficacy, according to the animal state and death to evaluate the safety.

[0179] DIO mice, male, 45-55g, high-fat modeling for more than 16 weeks, purchased from Hangzhou Qizhen Experimental Animal Technology Co., Ltd. The animal experiment is approved by the experimental animal welfare ethics committee. The animals are fed in the experimental environment for at least 14 days before the experiment begins. The experimental animals are fed in a constant temperature and humidity intelligent independent ventilation cage (IVC), the temperature of the feeding room is 20-26℃, the humidity is 40-70%, the animals can freely take food and water. The experimental animals are labeled by ear tag method.

[0180] According to the body weight, they are randomly divided into 4 groups, which are low-dose treatment group of test compound 1 (group 2), medium-dose treatment group of test compound 1 (group 3), high-dose treatment group of test compound 1 (group 4) and solvent control group (group 1), 10 in each group. Oral gavage once a day, a total of 28 days of administration, record the animal body weight every day. The body weight change of experimental animals is shown in Figure 1.

[0181] Conclusion: The compound of the present application has a significant effect of reducing body weight on DIO mouse model. During the test, the state of the test animals is good, and there is no animal death, indicating that the compound of the present application has good safety after administration.

[0182] Unless specifically limited, the terms used in the present application have the meanings generally understood by those skilled in the art.

[0183] The embodiments described in the present application are for illustrative purposes only and are not intended to limit the scope of protection of the present application. Those skilled in the art can make various other replacements, changes and improvements within the scope of the present application, therefore, the present application is not limited to the above embodiments, but is limited by the claims.

Claims

1. A compound of Formula (I) or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof: ###00001### (I) ​ wherein: Ring A is selected from a bicyclic aryl, a bicyclic heteroaryl, or a bicyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of a monocyclic aryl or monocyclic heteroaryl with a monocyclic heterocyclyl or monocyclic cycloalkyl; Ring B is selected from a 5-10 membered heteroaryl or a 5-10 membered heterocyclyl; Ring C is selected from a 5-10 membered heteroaryl or a 4-10 membered heterocyclyl; L is selected from -(CR a R b ) p -, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -C(O)O-, -N(R c )C(O)-, -C(O)N(R c )-, -C(O)N(R c )(CR a R b )-, -N(R c )C(O)(CR a R b )-, -C(O)(CR a R b )-, -(CR a R b )C(O)-, -O-, -N(R c )-, -S-, wherein p is selected from 0, 1 or 2, R a , R b and R c are each independently selected from a hydrogen atom or a C 1-6 alkyl group; Y is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -SF5, -OR 4 , -OC(=O)R 4 , -C(=O)R 4 , -C(=O)OR 4 , -N(R 5 )C(=O)R 6 , -N(R 5 )C(=O)OR 6 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -S(=O) r NR 5 R 6 or -S(=O) r R 4 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -OR 7 , =O, -C(=O)R 7 , -C(=O)OR 7 , -OC(=O)R 7 , -NR 8 R 9 , -C(=O)NR 8 R 9 , -S(=O)2NR 8 R 9 , -N(R 8 )C(=O)R 9 or -N(R 8 )C(=O)OR 9 ; R 1 each independently is selected from a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, a C 6-10 aryl group, or a 5-10 membered heteroaryl group; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl group is optionally further substituted with one or more substituents selected from a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, a halogen, a hydroxyl group, a cyano group, or a -NR 5 R 6 R R 2 each independently is selected from a hydrogen atom, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy; wherein said alkyl or alkoxy is optionally further substituted by one or more substituents selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, hydroxy or cyano; R 3 each independently is selected from a hydrogen atom, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy; wherein said alkyl or alkoxy is optionally further substituted by one or more substituents selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, hydroxy or cyano; and / or, two R 3 with the atom to which they are attached, form a 4-8 membered heterocyclyl, wherein the 4-8 membered heterocyclyl contains one or more N, O, or S(O) r and the 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from C 1- 6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, hydroxyl, or cyano; R 4 each independently is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =0, -C(=0)R 7 , -C(=0)OR 7 , -OC(=0)R 7 , -NR 8 R 9 , -C(=0)NR 8 R 9 , -SO2NR 8 R 9 , or -NR 8 C(=0)R 9 ; R 5 and R 6 are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein said alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =0, -C(=0)R 7 , -C(=0)OR 7 , -OC(=0)R 7 , -NR 8 R 9 , -C(=0)NR 8 R 9 , -SO2NR 8 R 9 , or -NR 8 C(=0)R 9 ; or R 5 and R 6 together with the atom to which they are attached form a 4-8 membered heterocyclyl, wherein the 4-8 membered heterocyclyl contains one or more N, O or S(O) r and the 4-8 membered heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -C(=O)R 7 , -C(=O)OR 7 , -OC(=O)R 7 , -NR 8 R 9 , -C(=O)NR 8 R 9 , -SO2NR 8 R 9 or -NR 8 C(=O)R 9 ; R 7 , R 8 and R 9 are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; q is 0, 1, 2, or 3; each r is independently 0, 1, or 2.

2. The compound according to claim 1, or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from a 4-10 membered heterocyclyl, more preferably piperidinyl.

3. The compound according to claim 1 or 2, or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof, wherein L is selected from -CH2-, -CH2CH2-, -C(O)-, -C(O)NH-, -C(O)NHCH2-, -NHC(O)-, -CH2C(O)-, or -S(O)2-.

4. The compound according to claim 3, or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof, wherein L is selected from -CH2-.

5. The compound of any one of claims 1-4 or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein selected from 6. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R 3 each is independently selected from a hydrogen atom or a C 1-6 alkyl group, preferably a hydrogen atom or a methyl group.

7. The compound according to any one of claims 1-6, or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from a 5-10 membered heteroaryl, more preferably a 5 membered heteroaryl.

8. The compound according to claim 7, wherein ring B is selected from the following groups: ###00010### or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof. ​ 9. The compound according to any one of claims 1-8, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R 2 each independently is selected from a hydrogen atom or a C 1-6 alkyl group, preferably a hydrogen atom or a methyl group.

10. The compound according to any one of claims 1-9, or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof, wherein Y is selected from a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally further substituted with one =O.

11. The compound of claim 10, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof, wherein Y is selected from the following groups:

12. The compound according to any one of claims 1-11, or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from a naphthyl, an 8-10 membered bicyclic heteroaryl, or an 8-10 membered bicyclic fused ring, wherein the bicyclic fused ring is a fused ring of a monocyclic aryl with a monocyclic cycloalkyl.

13. The compound of any one of claims 1-11 or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of:

14. The compound according to any one of claims 1-13, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R 1 each is independently selected from a hydrogen atom, a halogen, or a C 1-6 alkyl, preferably a hydrogen atom, fluorine, or methyl.

15. The compound according to any one of claims 1-14, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein the compound is:

16. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-15, or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.

17. Use of a compound according to any one of claims 1-15, or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for the manufacture of an inhibitor of 20-HETE production.

18. Use of a compound according to any one of claims 1-15, or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for the manufacture of a medicament for treating a disease associated with 20-HETE signaling pathway.

19. The use of claim 18, wherein the disease associated with 20-HETE signaling pathway is selected from obesity, metabolic syndrome, dyslipidemia, diabetes, diabetic retinopathy, diabetic cerebrovascular disease, diabetic neuropathy, insulin resistance, hyperglycemia, hyperlipidemia, diabetic nephropathy, hypertension, cataract, osteoporosis, hyperuricemia, multiple infections caused by diabetes, non-alcoholic steatohepatitis, fibrosis, heart disease, stroke, liver cirrhosis, metabolic acidosis, ketosis, cardiovascular discomfort, epilepsy, atherosclerosis, Parkinson's disease, myocardial infarction, acute renal failure, chronic kidney disease, polycystic kidney disease, tumors, end-organ damage, Alzheimer's disease; preferably wherein the diabetes is Type I diabetes, Type II diabetes, gestational diabetes, idiopathic TID, early-onset T2DM, maturity onset diabetes of the young, youth-onset atypical diabetes, malnutrition-related diabetes, latent autoimmune diabetes in adults.

20. The use of a compound of any one of claims 1-15, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 16 in the manufacture of a medicament for the treatment of obesity, metabolic syndrome, dyslipidemia, diabetes, diabetic retinopathy, diabetic cerebrovascular disease, diabetic neuropathy, insulin resistance, hyperglycemia, hyperlipidemia, diabetic nephropathy, hypertension, cataract, osteoporosis, hyperuricemia, multiple infections caused by diabetes, non-alcoholic steatohepatitis, fibrosis, heart disease, stroke, liver cirrhosis, metabolic acidosis, ketosis, cardiovascular discomfort, epilepsy, atherosclerosis, Parkinson's disease, myocardial infarction, acute renal failure, chronic kidney disease, polycystic kidney disease, tumors, end-organ damage, Alzheimer's disease; preferably wherein the diabetes is Type I diabetes, Type II diabetes, gestational diabetes, idiopathic TID, early-onset T2DM, maturity onset diabetes of the young, youth-onset atypical diabetes, malnutrition-related diabetes, latent autoimmune diabetes in adults.

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