Compound for regulating and controlling activity of 15-PGDH and preparation method thereof

Abstract

The invention relates to a compound capable of regulating and controlling activity of 15-PGDH and application of the compound in the field of pharmacy. The invention further provides a method for preparing the compound, a composition containing the compound and pharmaceutical application of the compound serving as a 15-PGDH inhibitor.

Description

Technical Field

[0001] The present invention relates to a compound for regulating 15-PGDH activity and a preparation method thereof, and in particular to a compound for regulating 15-PGDH activity that can be used as a drug, and a pharmacologically acceptable salt thereof, a composition containing the compound or its salt and use thereof for preparing a drug, and belongs to the field of pharmaceutical chemistry. Background Art

[0002] 15-hydroxyprostaglandin dehydrogenase (15-PGDH) belongs to the evolutionary conservative superfamily of short-chain dehydrogenase / reductase (SDR), and is named SDR36C1 according to the latest approved human enzyme nomenclature. According to existing research results, most of the in vivo activity can be attributed to type I 15-PGDH encoded by the HPGD gene. 15-PGDH plays an important role in the inactivation of active prostaglandins (PGD2, PGE1, PGE2, PGF2α, PGI2, etc.), hydroxyeicosatetraenoic acid (HETEs) and inflammatory resolution lipid mediators (RvD1, RvD2, RvE1, MaR1, LXA4, etc.) (hereinafter referred to as 15-PGDH substrates) (for example, by catalyzing the oxidation reaction of the 15-hydroxyl group of PGF2α to generate 15-keto-PGF2α). These 15-PGDH substrates exert their functions through specific receptors on target cells. Among them, prostaglandins PGE1, PGE2, PGF2α, PGI2, etc. are often used to evaluate the activity of 15-PGDH. For example, the activity of PGDH is evaluated by measuring the ketone metabolite of the 15-hydroxyl group of PGF2α (Journal of Clinical Endocrinology and Metabolism, Vol84, No.1, 291-299).

[0003] The receptors of 15-PGDH substrates have a wide and diverse distribution in the body, and the diversity of receptor types, signal transduction and expression distribution together create a diversity of functions in the body. For example, PGE1 acts on blood vessels and platelets, and increases blood flow through vasodilation and platelet aggregation inhibition, so it is often used to treat chronic arterial occlusion (thromboangiitis obliterans (TAO) or arteriosclerosis obliterans (ASO)), skin ulcers and other diseases; PGF2α has uterine contraction and intraocular pressure lowering effects, and its derivatives are used as therapeutic agents for glaucoma; and PGD2 can inhibit inflammation by enhancing the barrier function of pulmonary blood vessels. In addition, PGE2 has a vasodilatory effect, and also has multiple effects involving blood pressure, pain, bone formation and cell growth, stem cell differentiation, as well as anti-fibrosis and anti-inflammatory effects. PGI2 has an inhibitory effect on platelet activation and a relaxant effect on vascular smooth muscle, and its derivatives are used as therapeutic agents for chronic arterial occlusion and primary pulmonary hypertension. Inflammation-resolving lipid mediators (RvD1, RvD2, RvE1, MaR1, LXA4, etc.) inhibit the migration / activation of neutrophils and accelerate the apoptosis of neutrophils. In addition, they are indispensable in increasing the phagocytic activity of macrophages to effectively remove apoptotic neutrophils / tissue fragments remaining in the inflammatory site. These functions can promote inflammation and maintain homeostasis in the organism. It is reported that these inflammation-resolving lipid mediators can exhibit medicinal effects in various types of pathological models (such as mouse pneumonia models, colitis models, and liver injury models).

[0004] Recent studies have shown that 15-PGDH inhibitors and 15-PGDH agonists may have therapeutic value. A recent study showed that increased expression of 15-PGDH in the protection of thrombin-mediated cell death. It is well known that 15-PGDH leads to the inactivation of prostaglandin E2 (PGE2), a downstream product of COX-2 metabolism. PGE2 has been shown to be beneficial in a variety of biological processes, such as maintaining hair density, promoting skin wound healing, and bone formation.

[0005] 15-PGDH is an important enzyme in the inactivation of 15-PGDH substrates and is involved in a wide range of in vivo effects. 15-PGDH inhibitors can be used to prevent or treat diseases related to 15-PGDH and / or 15-PGDH substrates, and / or when it is necessary to increase the substrate level of 15-PGDH in a subject.

[0006] As mentioned above, some substrates of 15-PGDH have the effects of anti-fibrosis, anti-inflammation, blood flow improvement, growth promotion, promotion of stem cell increase, promotion of smooth muscle contraction / relaxation, influence on bone metabolism and immunosuppression. Therefore, 15-PGDH inhibitors can effectively treat or prevent fibrosis (such as pulmonary fibrosis (idiopathic pulmonary fibrosis, etc.), liver fibrosis, kidney fibrosis, myocardial fibrosis, scleroderma and myelofibrosis), inflammatory diseases (such as chronic obstructive pulmonary disease (COPD), acute lung injury, sepsis, asthma and lung disease, inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), peptic ulcer (such as NSAID-induced ulcer), autoinflammatory diseases (such as Behcet's disease), vasculitis syndrome, acute liver injury, acute kidney injury, non-alcoholic fatty liver disease (NASH), atopic dermatitis, psoriasis, interstitial cystitis, prostatitis syndrome (such as chronic prostatitis / chronic pelvic pain syndrome) syndrome), cardiovascular diseases (such as pulmonary hypertension, angina pectoris, myocardial infarction, heart failure, ischemic heart disease, chronic kidney disease, renal failure, stroke and peripheral circulatory disorders), trauma (such as diabetic ulcers, burns, pressure ulcers, acute mucosal injury (including Stevens-Johnson syndrome and mucosal injury associated with anticancer chemotherapy agents such as alkylating agents, DNA synthesis inhibitors, DNA gyrase inhibitors, antimetabolites, mucosal injury associated with cellular or humoral immunotherapy, mucosal injury associated with graft-versus-host disease, such as mucositis or stomatitis), autoimmune diseases (such as multiple sclerosis or rheumatoid arthritis), graft-versus-host disease (GVHD), hair growth (hair growth) disorders, osteoporosis, ear diseases (such as hearing loss, tinnitus, vertigo and balance disorders), eye diseases (such as glaucoma and dry eyes), diabetes, underactive bladder, neutropenia, nervous system diseases caused by stem cell, bone marrow or organ transplantation (such as mental neurological diseases, neuropathy, neurotoxic diseases, neuropathic pain and neurodegenerative diseases), muscle regeneration diseases (such as muscle atrophy, muscular dystrophy and muscle injury); in addition, 15-PGDH inhibitors can also be used to promote cervical ripening.

[0007] The compounds and pharmaceutically acceptable salts thereof provided by the present invention further meet the demand for small molecules that inhibit the activity of 15-PGDH. Summary of the invention

[0008] The present invention also provides a compound represented by formula (I), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (such as a hydrate), or its prodrug,

[0009]

[0010] X, Y, and Z are each independently selected from C or N,

[0011] A is selected from CR 1 or N,

[0012] U is selected from C or N, and when U is selected from C, for The -V- is selected from -CR a R b -、-NR c 、-O-、-N=CR 1c -*, -CR 2c =N-*,-CR 3c =CR 4c -, the * represents connection with the group W; when U is selected from N, for The =V is selected from =N, =CR 1d -、=CR 2d CR 3d R 4d -、=NCR 5d R 6d ,

[0013] R A is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, amine, cyano, hydroxyl, amide, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl,

[0014] W is selected from NR W , O, S, R W is selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl,

[0015] Among them, the R 1 , R 2 , R 3 , R a , R b , R c , R 1c , R 2c , R 3c , R 4c , R 1d , R 2d , R 3d , R 4d , R 5d , R 6d Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy.

[0016] In some embodiments of the present invention, the R 1 , R 2 , R 3 , R a , R b , R c , R 1c , R 2c , R 3c , R 4c , R 1d , R 2d , R 3d , R 4d , R 5d , R 6d Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, carbonyl, -COC H3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy.

[0017] In some embodiments of the present invention, the U is selected from C, and the V is selected from CR a R b NR c 、O、N=CR 1c , CR 3c =CR 4c , or both U and V are N; preferably, U is selected from C, and V is selected from CR a R b , CR 3c =CR 4c , or both U and V are N, where R a , R b , R c , R 1c , R 3c , R4c Consistent with the above definition.

[0018] In some embodiments of the present invention, Selected from Select from Where R a , R b , R c , R 1c , R 3c , R 4c Consistent with the above definition.

[0019] In some embodiments of the present invention, W is selected from NR W or O, preferably NR W , wherein R W Selected from hydrogen, deuterium, tritium, C1-C6 alkyl (e.g. C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl), 3-12 membered cycloalkyl (e.g. 3-10 membered cycloalkyl, 3-9 membered cycloalkyl, 3-8 membered cycloalkyl, 3-7 membered cycloalkyl, 3-6 membered cycloalkyl, 3-5 membered cycloalkyl).

[0020] In some embodiments of the present invention, the A is preferably CR 1 , the R 1 Consistent with the above definition.

[0021] In some embodiments of the present invention, X, Y, and Z are each independently selected from C or N, and X and Y are not N at the same time, and Y and Z are not N at the same time; further, in some specific embodiments of the present invention, Y and Z are both C; in some specific embodiments of the present invention, X is C; in some specific embodiments of the present invention, X and Z are both N, and Y is C. Preferably, in some specific embodiments of the present invention, at most one of X, Y, and Z is N; more preferably, Y and Z are both C, and X is C or N; particularly preferably, X, Y, and Z are all C.

[0022] In some embodiments of the present invention, the R A Selected from C1~C6 alkyl (for example, C1~C5 alkyl, C1~C4 alkyl, C1~C3 alkyl), C1~C6 haloalkyl (for example, C1~C5 haloalkyl, C1~C4 haloalkyl, C1~C3 haloalkyl), halogen, amine, cyano, amide, 3~12 membered cycloalkyl (for example, 3~10 membered cycloalkyl, 3~9 membered cycloalkyl, 3~8 membered cycloalkyl, 3~7 membered cycloalkyl, 3~6 membered cycloalkyl, 3~5 membered cycloalkyl).

[0023] In some embodiments of the present invention, W is selected from NR W; X, Y, Z are each independently selected from C or N, and X and Y are not N at the same time, and Y and Z are not N at the same time; R A is selected from C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl), C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl), halogen, amine, cyano, amide, 3-12 membered cycloalkyl (e.g., 3-10 membered cycloalkyl, 3-9 membered cycloalkyl, 3-8 membered cycloalkyl, 3-7 membered cycloalkyl, 3-6 membered cycloalkyl, 3-5 membered cycloalkyl); U is selected from C, and V is selected from CR a R b , CR 3c =CR 4c , or both U and V are N,

[0024] Wherein R W is selected from hydrogen, deuterium, tritium, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl), 3-12-membered cycloalkyl (e.g., 3-10-membered cycloalkyl, 3-9-membered cycloalkyl, 3-8-membered cycloalkyl, 3-7-membered cycloalkyl, 3-6-membered cycloalkyl, 3-5-membered cycloalkyl), said R a , R b , R 3c , R 4c Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy.

[0025] The present invention also provides a compound represented by formula (II), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (such as a hydrate), or its prodrug,

[0026]

[0027] X, Y, and Z are each independently selected from C or N, and X and Y are not N at the same time, and Y and Z are not N at the same time,

[0028] A is selected from CR 1 or N, preferably CR 1 ,

[0029] V is selected from CR a R b or CR 3c =CR 4c ,

[0030] R Ais selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, amine, cyano, hydroxyl, amide, 3-12 membered cycloalkyl,

[0031] R W is selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl,

[0032] Where R 1 , R 2 , R 3 , R a , R b , R 3c , R 4c Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy.

[0033] In some embodiments of the present invention, at most one of X, Y and Z is N, and the other two are C; preferably, Y and Z are both C, and X is selected from C or N.

[0034] In some embodiments of the present invention, the R W Selected from hydrogen, deuterium, tritium, C1-C6 alkyl (e.g. C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl), 3-12 membered cycloalkyl (e.g. 3-10 membered cycloalkyl, 3-9 membered cycloalkyl, 3-8 membered cycloalkyl, 3-7 membered cycloalkyl, 3-6 membered cycloalkyl, 3-5 membered cycloalkyl).

[0035] In certain embodiments of the present invention, the R A Selected from C1~C6 alkyl (for example, C1~C5 alkyl, C1~C4 alkyl, C1~C3 alkyl), C1~C6 haloalkyl (for example, C1~C5 haloalkyl, C1~C4 haloalkyl, C1~C3 haloalkyl), halogen, amine, cyano, amide, 3~12 membered cycloalkyl (for example, 3~10 membered cycloalkyl, 3~9 membered cycloalkyl, 3~8 membered cycloalkyl, 3~7 membered cycloalkyl, 3~6 membered cycloalkyl, 3~5 membered cycloalkyl).

[0036] In some embodiments of the present invention, the R 1 , R 2 , R 3 , R a , R b , R 3c , R 4cEach is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, carbonyl, -COC H3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy.

[0037] The present invention also provides a compound represented by formula (III), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (such as a hydrate), or its prodrug,

[0038]

[0039] Any one of X, Y and Z is N, and the other two are C; preferably, Y and Z are both C, and X is selected from C or N,

[0040] R A is selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, amine, cyano, hydroxyl, amide, 3-12 membered cycloalkyl,

[0041] R W is selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl,

[0042] Where R 1 , R 2 , R 3 , R a , R b Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy.

[0043] In some embodiments of the present invention, the R W Selected from hydrogen, deuterium, tritium, C1-C6 alkyl (e.g. C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl), 3-12 membered cycloalkyl (e.g. 3-10 membered cycloalkyl, 3-9 membered cycloalkyl, 3-8 membered cycloalkyl, 3-7 membered cycloalkyl, 3-6 membered cycloalkyl, 3-5 membered cycloalkyl).

[0044] In some embodiments of the present invention, the R A Selected from C1~C6 alkyl (for example, C1~C5 alkyl, C1~C4 alkyl, C1~C3 alkyl), C1~C6 haloalkyl (for example, C1~C5 haloalkyl, C1~C4 haloalkyl, C1~C3 haloalkyl), halogen, amine, cyano, amide, 3~12 membered cycloalkyl (for example, 3~10 membered cycloalkyl, 3~9 membered cycloalkyl, 3~8 membered cycloalkyl, 3~7 membered cycloalkyl, 3~6 membered cycloalkyl, 3~5 membered cycloalkyl).

[0045] In some embodiments of the present invention, the R 1 , R 2 , R 3 , R a , R b Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, carbonyl, -COC H3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy.

[0046] The compounds of formula (I), formula (II), formula (III), their stereoisomers, their tautomers or their mixtures, or their pharmaceutically acceptable salts, or their solvates (such as hydrates), or their prodrugs provided by the present invention, in some specific embodiments, the R ASelected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, fluorine, chlorine, bromine, iodine, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, cyano, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, preferably methyl, trifluoromethyl, iodine, -NH2, -CONH2, cyano, cyclopropyl, more preferably -NH2, cyano.

[0047] The compounds of formula (I), formula (II), formula (III), their stereoisomers, their tautomers or their mixtures, or their pharmaceutically acceptable salts, or their solvates (such as hydrates), or their prodrugs provided by the present invention, in some specific embodiments, the R a , R b Each is independently selected from hydrogen, deuterium, tritium, methyl, ethyl, n-propyl, isopropyl, preferably hydrogen, deuterium, tritium.

[0048] The compounds of formula (I), formula (II), formula (III), their stereoisomers, their tautomers or their mixtures, or their pharmaceutically acceptable salts, or their solvates (such as hydrates), or their prodrugs provided by the present invention, in some specific embodiments, the R W It is selected from hydrogen, deuterium, tritium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, preferably hydrogen, deuterium, tritium, methyl, ethyl, isopropyl and cyclopropyl, more preferably methyl, ethyl, isopropyl and cyclopropyl.

[0049] The compounds of formula (I), formula (II), and formula (III) provided by the present invention, their stereoisomers, their tautomers, or their mixtures, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs, in some specific embodiments, said Y and Z are both C, said X is selected from C or N, and R A R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, fluorine, chlorine, bromine, iodine, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, cyano, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl (preferably methyl, trifluoromethyl, iodine, -NH2, -CONH2, cyano, cyclopropyl, more preferably -NH2, cyano);W is selected from C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl), 3-12-membered cycloalkyl (e.g., 3-10-membered cycloalkyl, 3-9-membered cycloalkyl, 3-8-membered cycloalkyl, 3-7-membered cycloalkyl, 3-6-membered cycloalkyl, 3-5-membered cycloalkyl, specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, preferably hydrogen, deuterium, tritium, methyl, ethyl, isopropyl, cyclopropyl, preferably methyl, ethyl, isopropyl, cyclopropyl; the R a , R b Each is independently selected from hydrogen, deuterium, tritium, methyl, ethyl, n-propyl, isopropyl (preferably selected from hydrogen, deuterium, tritium).

[0050] The present invention also covers solutions obtained by any combination, deletion or substitution of the above-mentioned embodiments.

[0051] In some specific embodiments of the present invention, the present invention provides the following compounds, their pharmaceutically acceptable salts, or solvates (eg, hydrates), or prodrugs thereof:

[0052]

[0053] Another aspect of the present invention is to provide a pharmaceutical composition comprising at least one of the aforementioned compounds, its tautomers or mixtures thereof, or its pharmaceutically acceptable salts, or its solvates, or its prodrugs, and at least one pharmaceutically acceptable excipient.

[0054] Another aspect of the present invention is to provide a compound as mentioned above, or a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a pharmaceutical composition for the preparation of a drug. Wherein, the drug is a 15-PGDH inhibitor, which can be used to treat diseases associated with an increase in the level of unwanted 15-PGDH activity. Alternatively, the present application provides a compound as mentioned above, or a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a pharmaceutical composition thereof for use as a drug. Alternatively, the present application provides a method for treating or preventing a 15-PGDH-related disease, comprising administering the compound as mentioned above, or a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a pharmaceutical composition thereof to a subject in need. The 15-PGDH-related disease herein refers to a disease or complication thereof that achieves clinically beneficial effects such as alleviation, improvement, cessation of progression, alleviation, or no longer deterioration by inhibiting 15-PGDH activity.

[0055] In certain specific embodiments, the medicament is used to treat or prevent fibrosis, oral ulcers, gum disease, colitis, ulcerative colitis, gastroduodenal ulcers, inflammatory diseases, vascular insufficiency, Raynaud's disease, Buerger's disease, neuropathy, pulmonary hypertension, cardiovascular disease and kidney disease, cardiovascular disease, trauma, skin injury, autoimmune disease, graft-versus-host disease, osteoporosis, ear disease, eye disease, neutropenia, diabetes, underactive bladder, or to promote hair growth, pigmentation, tissue repair, tissue regeneration, implants in stem cell transplantation or bone marrow transplantation or organ transplantation, neurogenesis and nerve cell death, muscle regeneration and cervical ripening, or to enhance resistance to the toxicity of chemotherapy and the toxicity of immunosuppressants.

[0056] definition

[0057] Unless stated otherwise, the following terms used in the specification and claims have the following meanings.

[0058] "Alkyl" refers to a saturated aliphatic chain hydrocarbon group, including straight-chain alkyl and branched-chain alkyl. For example, the C1-C6 alkyl used in the present invention refers to a straight-chain alkyl or branched-chain alkyl consisting of 1 to 6 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, etc.

[0059] "Alkoxy" refers to -O-alkyl; the C1-C6 alkoxy used in the present invention refers to a straight chain alkoxy or branched chain alkoxy consisting of 1 to 6 carbon atoms. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentyl, tert-pentyl, n-hexyl, and the like.

[0060] "Ring" refers to any cyclic covalently closed structure, including, for example, carbocycle (e.g., aromatic ring or alicyclic ring), heterocycle (e.g., aromatic heterocycle or alicyclic heterocycle). Carbocycle refers to a ring consisting of only carbon atoms, and heterocycle refers to a closed structure formed by covalent bonding of carbon atoms and heteroatoms. Depending on the number of rings, a "ring" can be a monocyclic, bicyclic, tricyclic or polycyclic ring. When the ring is bicyclic, tricyclic or polycyclic, the relationship between the rings may include fused rings, spirocyclic rings, and bridged rings.

[0061] "Heteroatom" refers to any atom other than a carbon atom that can be covalently bonded to a carbon atom. Common heteroatoms include, but are not limited to, O, S, N, P, Si, etc.

[0062] "Member" refers to the number of atoms constituting the ring. Typical 5-membered rings include, but are not limited to, cyclopentane, pyrrole, imidazole, thiazole, furan, and thiophene; typical 6-membered rings include, but are not limited to, cyclohexane, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, and the like.

[0063] "Alicyclic ring" or "alicyclic group" refers to a saturated or partially unsaturated aliphatic carbocyclic group. Saturated aliphatic carbocyclic rings are called, for example, saturated alicyclic rings, and may also be called "cycloalkyl"; partially unsaturated carbocyclic rings may be called, for example, unsaturated alicyclic rings. Alicyclic rings may be monocyclic, spirocyclic, fused or bridged rings, for example, a 3- to 8-membered alicyclic ring refers to an aliphatic carbocyclic group consisting of 3 to 8 backbone carbon atoms. Typical alicyclic structures include, but are not limited to:

[0064]

[0065] wait.

[0066] "Aliphatic heterocycle" or "aliphatic heterocyclic group" refers to a non-aromatic cyclic group formed by replacing carbon atoms in an alicyclic ring with one or more heteroatoms. Aliphatic heterocycles or aliphatic heterocyclic groups may include saturated aliphatic heterocycles and unsaturated aliphatic heterocycles. For example, a 3-12-membered aliphatic heterocyclic group refers to a non-aromatic cyclic group composed of 3-12 skeleton atoms and containing one or more heteroatoms, and may be a saturated aliphatic heterocyclic group or an unsaturated aliphatic heterocyclic group.

[0067] "Saturated alicyclic" is also called "cycloalkyl", which is an aliphatic cyclic group composed of saturated carbon atoms as the skeleton. The 3- to 8-membered cycloalkyl used in the present invention refers to a cyclic alkyl group composed of 3 to 8 carbon atoms. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2,1,1]hexyl, cycloheptyl, etc.

[0068] "Saturated heterocyclic ring" is also called "heterocycloalkyl", which means that the carbon atoms constituting the ring skeleton in the heterocyclic ring are all saturated. For example, the 3-12-membered heterocycloalkyl used in the present invention refers to a non-aromatic cyclic group formed by 3-12 atoms constituting the ring skeleton, wherein the atoms constituting the ring skeleton are composed of saturated carbon atoms and heteroatoms. Typical saturated heterocyclic rings include but are not limited to:

[0069] wait.

[0070] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0071] "Haloalkyl" means that at least one hydrogen in the alkyl group is replaced by a halogen atom. The C1-C6 haloalkyl used in the present invention refers to a straight-chain alkyl or branched alkyl composed of 1 to 6 carbon atoms, and at least one hydrogen on the alkyl group is arbitrarily replaced by a halogen atom.

[0072] "Haloalkoxy" refers to an alkoxy group in which at least one hydrogen is replaced by a halogen atom. The C1-C6 haloalkoxy group used in the present invention refers to a straight-chain alkyl group or a branched-chain alkyl group consisting of 1 to 6 carbon atoms, and at least one hydrogen on the alkyl group is arbitrarily replaced by a halogen atom.

[0073] "Amine" or "amine" refers to a group having -NR S R T The chemical structure of S , R T Each is independently selected from hydrogen, deuterium, tritium, alkyl, cycloalkyl, common "amino groups" include but are not limited to -NH2 (also known as amino), -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2.

[0074] "Iminyl" or "imine" refers to a group having =NR t The chemical structure of t Selected from hydrogen, deuterium, tritium, C1-C6 alkyl or 3-12 membered cycloalkyl, common imino groups include but are not limited to =NH, =NCH3, =CH2CH3, =NCH(CH3)2.

[0075] "Carbonyl" refers to a group having -COR Z The chemical structure of Z Selected from alkyl, cycloalkyl, heterocycloalkyl, common carbonyl groups include but are not limited to -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2.

[0076] "Amide" or "amido" refers to a group having -C(O)NR U R V or -NR U C(O)R V The chemical structure of U , R V Each is independently selected from hydrogen, deuterium, tritium, alkyl, cycloalkyl, heterocycloalkyl, common amide groups include but are not limited to -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3.

[0077] An "ester group" refers to a group having the formula -C(O)OR X or -OC(O)R Y The chemical structure of X , RY Selected from alkyl, cycloalkyl, heterocycloalkyl, common ester groups include but are not limited to -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2.

[0078] "Substitution" refers to one or more hydrogen atoms in a group being replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without making too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond. Each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, alkylthio, aryloxy, nitro, acyl, halogen, haloalkyl, amino, etc. .

[0079] "Inhibitor" refers to a substance that reduces the activity of an enzyme.

[0080] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0081] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0082] "Pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0083] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0084] "Tautomers" or "tautomeric forms" refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, where the proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons. Non-limiting examples of tautomers include, but are not limited to,

[0085] "Stereoisomers" refer to isomers caused by the same order of connection between atoms or atomic groups in a molecule, but different arrangements of atoms in space. It can include two major categories: cis-trans isomers and chiral isomers. Chiral isomers can be divided into two major categories: enantiomers and diastereomers.

[0086] "Stereoisomers" refer to isomers caused by the same order of connection between atoms or atomic groups in a molecule, but different arrangements of atoms in space. It can be divided into several major categories: conformational isomers, cis-trans isomers, and chiral isomers. Chiral isomers can be divided into two major categories: enantiomers and diastereomers. The spatial arrangement of atoms in the structure of a compound in "stereoisomers" is usually represented by a wedge-shaped covalent bond (bold wedge-shaped bond) Dashed wedge key Indicates that the bold wedge-shaped keys are facing outward from the paper, and the dotted wedge-shaped keys are facing inward from the paper.

[0087] In the present invention, the straight covalent bond "—" in the compound structure can represent being in the same plane as the paper. In the present invention, when stereoisomers exist in the atoms connected by the straight covalent bond, the straight covalent bond represents that the arrangement of the atoms connected thereto can include being in the same plane as the paper, facing outward from the paper, facing inward from the paper, or a mixture of various arrangements.

[0088] "Enantiomers" refer to compounds with the same molecular formula and functional groups, which exhibit isomerism due to different configurations of atoms in space. At the same time, the compounds form stereoisomers that are mirror images of each other and cannot be superimposed.

[0089] "Diastereoisomers" refer to compounds with the same molecular formula and functional groups, which are stereoisomers caused by different spatial configurations of atoms. At the same time, the compounds are not stereoisomers that are in a real-life mirror-image relationship with each other.

[0090] Unless otherwise specified, the terms "comprise, comprises and comprising" or their equivalents (contain, contains, containing, include, includes, including) used herein are open-ended expressions and mean that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0091] Unless otherwise indicated, all numbers used herein expressing the amounts of ingredients, measurements or reaction conditions are to be understood as being modified in all cases by the term "about". When connected with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

[0092] Unless the context clearly indicates otherwise, singular terms herein include plural referents and vice versa. Similarly, the word "or" herein is intended to include "and" unless the context clearly indicates otherwise.

[0093] Obviously, according to the above contents of the present invention, in accordance with the common technical knowledge and means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0094] The abbreviations in the present invention have the following meanings:

[0095]

[0096] DETAILED DESCRIPTION

[0097] Synthesis method

[0098] The present invention also provides a method for synthesizing the above-mentioned compound. The method for synthesizing the present invention is mainly based on the preparation method reported in chemical literature or uses commercially available chemical reagents as starting materials for related synthesis.

[0099] Method I

[0100]

[0101] The steps are as follows: a compound represented by formula (i) or a pharmaceutically acceptable salt thereof, such as hydrochloride, is subjected to coupling reaction with a compound represented by formula (ii) in the presence of a coupling catalyst (such as [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium, etc.) to obtain a compound represented by formula (I). 1 is bromine or chlorine, said r 1 is hydrogen or F, and X, Y, Z, R A , A, U, V, W, R2 , R 3 , The definition is consistent with the above description of the present invention. In some synthesis methods, the compound shown in formula ii can also be a boronic acid structure that is not esterified with pinacol, that is, the structure of the compound shown in formula ii can also be

[0102] Method II

[0103]

[0104] The steps are as follows: a compound represented by formula (i-1) or a pharmaceutically acceptable salt thereof, such as hydrochloride, is subjected to coupling reaction with a compound represented by formula (ii-1) in the presence of a coupling catalyst (such as [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium, etc.) to obtain a compound represented by formula (I). 1 is bromine or chlorine, said r 1 is hydrogen or F, and X, Y, Z, R A , A, U, V, W, R 2 , R 3 , The definition is consistent with the above description of the present invention.

[0105] Method III

[0106]

[0107] The steps are as follows: a compound represented by formula (i-2) or a pharmaceutically acceptable salt thereof, such as a hydrochloride, is subjected to a coupling reaction with a compound represented by formula (ii) under the action of a coupling catalyst (such as [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium, etc.) to obtain a compound represented by formula (Ia); the compound represented by formula (Ia) is subjected to ester hydrolysis under the action of a base (such as potassium hydroxide, lithium hydroxide, etc.) to obtain a compound represented by formula (Ib); and then the compound is subjected to a condensation reaction with a compound represented by formula (i1-4) to obtain a compound represented by formula (I). Wherein, the X 1 is bromine or chlorine, said r 1 is hydrogen or F, and X, Y, Z, R A , A, U, V, W, R 2 , R 3 , The definition is consistent with the above description of the present invention. In the method III of the present invention, the compound represented by formula (Ia) can also be prepared by reacting the compound represented by formula (i-2) with biboric acid pinacol ester, and then reacting with the compound represented by formula (ii-1) in the presence of a coupling catalyst (e.g., [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium, etc.) to produce a coupling reaction.

[0108] In the present invention, the compounds represented by formula i, i-1, i-2, ii, ii-1, and i1-4 can be commercially available products, or can be prepared by a person skilled in the art using a preparation method disclosed in the prior art. A When is -NH2, the compound represented by formula i can be prepared by the following method:

[0109] Method i1

[0110]

[0111] The compound represented by formula i1-1 is subjected to a ring-closing reaction with ethyl 2-mercaptoacetate to obtain a compound represented by formula i1-2, which is then hydrolyzed to obtain a compound represented by formula i1-3, which is then subjected to a condensation reaction with a compound represented by formula i1-4 to obtain a compound represented by formula i. 1 、r 1 The definition is consistent with the above description of the present invention.

[0112] For example, when R A When is I, the compound shown in formula I can be prepared by the following method:

[0113] Method i2

[0114]

[0115] The compound of formula i1-2 is iodinated to obtain the compound of formula i2-2, which is hydrolyzed to obtain the compound of formula i2-3, which is then condensed with the compound of formula i1-4 to obtain the compound of formula i. 1 、r 1 The definition is consistent with the above description of the present invention.

[0116] In the preparation method of the present invention, when R A When I is I, conventional means in the art can be used, and I can be converted into, for example, hydrogen, CF3, CN, amide, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, etc. through further reaction.

[0117] For example, the compound represented by formula i-1 can be prepared by the following method:

[0118] Method i3

[0119]

[0120] The compound represented by formula i is reacted with pinacol diboron to obtain the compound represented by formula i-1. 1 , R A 、r 1 The definition is consistent with the above description of the present invention.

[0121] The following examples illustrate the synthesis methods of the compounds and intermediates of the present invention. The following examples are only examples of the present invention and should not be used as limitations on the scope of the present invention. Unless otherwise specified, the raw materials and reagents involved in the present invention can be obtained through commercial channels, and the specific channel sources do not affect the implementation of the technical solution of the present invention.

[0122] Preparation Example 1: Preparation of (3-amino-7-bromobenzo[b]thiophen-2-yl)(piperidin-1-yl)methanone

[0123]

[0124] Step 1: Preparation of ethyl 3-amino-7-bromobenzo[b]thiophene-2-carboxylate

[0125]

[0126] 3-Bromo-2-fluorobenzonitrile (1 g) and ethyl 2-mercaptoacetate (0.6 g) were dissolved in N,N-dimethylformamide (25 mL), and potassium carbonate (2.1 g, 15 mmol) was added, and the mixture was reacted at 90°C for 3 hours. After the disappearance of the raw material by LCMS monitoring, water was added to quench the reaction, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1.5 g of the target compound. MS (ESI) m / z (M+H) + =300.1.

[0127] Step 2: Preparation of 3-amino-7-bromobenzothiophene-2-carboxylic acid

[0128]

[0129] Dissolve 3-amino-7-bromobenzo[b]thiophene-2-carboxylic acid ethyl ester (1.5 g) and potassium hydroxide (0.84 g) in a mixed solution of ethanol and water (30 mL, V:V=1:1) and react at 80°C for 2 hours. After the disappearance of the raw material monitored by LCMS, the ethanol was concentrated under reduced pressure and dried, and acetic acid was used to adjust the acid to a weak acid to precipitate a light yellow solid, which was filtered to obtain 1.2 g of the target compound. MS (ESI) m / z (M+H) + =272.1.

[0130] Step 3: Preparation of (3-amino-7-bromobenzo[b]thiophen-2-yl)(piperidin-1-yl)methanone

[0131]

[0132] 3-Amino-7-bromobenzothiophene-2-carboxylic acid (1.2 g) was dissolved in dimethylformamide (30 mL), HATU (2.53 g), piperidine (0.753 g) and N,N-diisopropylethylamine (1.71 g) and reacted at room temperature for 0.5 hours. After the disappearance of the raw material monitored by LCMS, the reaction was quenched with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1.29 g of the target compound. MS (ESI) m / z (M+H) + =339.1.

[0133] Preparation Example 2: Preparation of (3-amino-7-chlorothieno[3,2-c]pyridin-2-yl)(piperidin-1-yl)methanone

[0134]

[0135] The title compound was obtained by a method similar to that in Preparation Example 1, using 4,5-dichloronicotinonitrile as the starting material.

[0136] MS (ESI) m / z (M+H) + =296.1.

[0137] Preparation Example 3: (3-amino-7-chlorothieno[2,3-c]pyridin-2-yl)(piperidin-1-yl)methanone

[0138]

[0139] Step 1: Preparation of 3-chloro-4-cyanopyridine-1-oxide

[0140]

[0141] 3-Chloro-4-cyanopyridine (1.0 g) and m-chloroperbenzoic acid (2.49 g) were dissolved in dichloromethane (30 mL) and stirred at room temperature overnight. After the raw material disappeared as monitored by LCMS, an aqueous sodium bisulfite solution was added to quench the reaction, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1.0 g of the target compound.

[0142] MS (ESI) m / z (M+H) + =155.1.

[0143] Step 2: Preparation of 3-amino-2-(ethoxycarbonyl)thiophene[2,3-c]pyridine-6-oxide

[0144]

[0145] 3-Chloro-4-cyanopyridine-1-oxide (1.0 g) and ethyl mercaptoacetate (0.78 g) were dissolved in N,N-dimethylformamide (25 mL), potassium carbonate (2.68 g) was added, and the mixture was reacted in an oil bath at 100°C for 3 hours. Water was added to quench the reaction, and the mixture was extracted four times with ethyl acetate. The organic phases were combined, backwashed with sodium chloride solution four times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 0.86 g of the target compound. MS (ESI) m / z (M+H) + =239.2.

[0146] Step 3: Preparation of ethyl 3-amino-7-chlorothieno[2,3-c]pyridine-2-carboxylate

[0147]

[0148] 3-Amino-2-(ethoxycarbonyl)thiophene[2,3-c]pyridine-6-oxide (0.5 g) was dissolved in toluene (15 mL), phosphorus oxychloride (1.0 mL) was added, and the mixture was reacted in an oil bath at 100°C for 1 hour. After the disappearance of the raw material by LCMS monitoring, the phosphorus oxychloride was removed by concentration under reduced pressure, and the mixture was adjusted to alkalinity with saturated sodium bicarbonate solution. The residue was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 0.412 g of the target compound. MS (ESI) m / z (M+H) + =257.1.

[0149] Step 4: Preparation of 3-amino-7-chlorothieno[2,3-c]pyridine-2-carboxylic acid

[0150]

[0151] Dissolve 3-amino-7-chlorothieno[2,3-c]pyridine-2-carboxylic acid ethyl ester (0.3 g) and potassium hydroxide (0.28 g) in a mixed solution of ethanol and water (30 mL, V:V = 1:1) and react at 80°C for 2 hours. After the disappearance of the raw material monitored by LCMS, the ethanol was concentrated under reduced pressure and dried, and acetic acid was used to adjust the acid to a weak acid to precipitate a light yellow solid, which was filtered to obtain 0.21 g of the target compound. MS (ESI) m / z (M+H) + =229.0.

[0152] Step 5: Preparation of (3-amino-7-chlorothieno[2,3-c]pyridin-2-yl)(piperidin-1-yl)methanone

[0153]

[0154] 3-Amino-7-chlorothieno[2,3-c]pyridine-2-carboxylic acid (0.2 g) was dissolved in dimethylformamide (5 mL), HATU (0.5 g), piperidine (0.15 g) and N,N-diisopropylethylamine (0.4 g) and reacted at room temperature for 0.5 hours. After the disappearance of the raw material monitored by LCMS, the reaction was quenched with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the target compound. MS (ESI) m / z (M+H) + =296.1.

[0155] Preparation Example 4: (3-amino-7-chlorothieno[3,2-b]pyridin-2-yl)(piperidin-1-yl)methanone

[0156]

[0157] The title compound was obtained by using a method similar to that in Preparation Example 3, with 3-chloro-2-cyanopyridine as the starting material and replacing phosphorus oxychloride in Step 3 of Preparation Example 3 with thionyl chloride. MS (ESI) m / z (M+H) + =296.1.

[0158] Preparation Example 5: Preparation of 7-bromo-2-(piperidine-1-carbonyl)benzo[b]thiophene-3-carbonitrile

[0159]

[0160] Step 1: Preparation of ethyl 7-bromo-3-iodobenzo[b]thiophene-2-carboxylate

[0161]

[0162] Weigh 3-amino-7-bromobenzo[b]thiophene-2-carboxylic acid ethyl ester (2.1 g), dissolve cuprous iodide (2.0 g) in 20 mL acetonitrile, place in a 60°C oil bath, add tert-butyl nitrite (1.25 mL) dropwise and react at 60°C for 3 h. Monitor the reaction to be complete by TLC, dilute with EA, filter on diatomaceous earth, quench with water, extract twice with ethyl acetate, dry with anhydrous sodium sulfate, and purify with column chromatography to obtain the title compound (960 mg). MS (ESI) m / z (M+H) + =410.9.

[0163] Step 2: Preparation of 7-bromo-3-iodobenzo[b]thiophene-2-carboxylic acid

[0164]

[0165] Weigh 7-bromo-3-iodobenzo[b]thiophene-2-carboxylic acid ethyl ester (960 mg) and dissolve it in a mixed solvent of tetrahydrofuran (12 mL), methanol (4 mL) and water (4 mL), add potassium hydroxide (394 mg), and react at 80°C for 2 h. After the raw material is consumed as monitored by LCMS and TLC, add water to quench, adjust the pH value to acidic with 2M hydrochloric acid, extract with ethyl acetate 3 times, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound (800 mg). MS (ESI) m / z (M+H) - =336.8.

[0166] Step 3: Preparation of (7-bromo-3-iodobenzo[b]thiophen-2-yl)(piperidin-1-yl)methanone

[0167]

[0168] Weigh 7-bromo-3-iodobenzo[b]thiophene-2-carboxylic acid (800 mg) and dissolve it in N,N-dimethylformamide (15 mL). Add N,N-diisopropylethylamine (0.69 mL), hexahydropyridine (0.29 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.2 g) in sequence at 0°C, and then warm to room temperature for 2 hours. TLC shows that the raw material is consumed, and water is added to quench, extract with ethyl acetate twice, wash with saturated brine twice, dry over anhydrous sodium sulfate, and purify with column chromatography to obtain the title compound (653 mg). MS (ESI) m / z (M+H) + =449.9.

[0169] Step 4: Preparation of 7-bromo-2-(piperidine-1-carbonyl)benzo[b]thiophene-3-carbonitrile

[0170]

[0171] Weigh (7-bromo-3-iodobenzo[b]thiophen-2-yl)(piperidin-1-yl)methanone (638 mg), dissolve in N,N-dimethylformamide (10 mL), add cuprous cyanide (256 mg), replace with argon three times, react at 100°C for 6 h. Quench with water, extract twice with ethyl acetate, wash twice with saturated brine, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain the title compound (380 mg).

[0172] MS (ESI) m / z (M+H) + =349.0.

[0173] Preparation Example 6: Preparation of (3-trifluoromethyl-7-bromobenzo[b]thiophen-2-yl)(4,4-difluoropiperidin-1-yl)methanone

[0174]

[0175] Dissolve (7-bromo-3-iodobenzo[b]thiophen-2-yl)(piperidin-1-yl)methanone (659 mg) in N,N-dimethylformamide (10 mL), add methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (41 mL), cuprous iodide (40 mg), replace with argon three times, and react at 90°C for 4 hours. Quench with water, extract twice with ethyl acetate, wash twice with saturated brine, dry over anhydrous sodium sulfate, and separate with reverse phase preparative column to obtain the title compound. MS (ESI) m / z (M+H) + =392.0.

[0176] Preparation Example 7: Preparation of (3-amino-7-bromobenzo[b]thiophen-2-yl)(4,4-difluoropiperidin-1-yl)methanone

[0177]

[0178] Using a method similar to step 3 of Preparation Example 1, 3-amino-7-bromobenzothiophene-2-carboxylic acid was reacted with 4,4-difluoropiperidine in DMF and DIEA to obtain the title compound. MS (ESI) m / z (M+H) + =375.0.

[0179] Preparation Example 8: Preparation of 7-bromo-2-(piperidine-1-carbonyl)benzo[b]thiophene-3-carbonitrile

[0180]

[0181] Using a method similar to steps 3 and 4 of Preparation Example 3, replacing hexahydropyridine with 4,4-difluoropiperidine, the title compound was obtained. MS (ESI) m / z (M+H) + =385.0.

[0182] Preparation Example 9: Preparation of 6-boronic acid pinacol ester benzo[d]isoxazol-3(2H)-one

[0183]

[0184] 6-Bromobenzo[d]isoxazol-3(2H)-one (500 mg), bipyraclostrobin (378 mg), potassium acetate (190 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (37 mg) were placed in a 100 mL single-mouth bottle, 1,4-dioxane (10 mL) was added, nitrogen was replaced three times, and the reaction was carried out at 100°C for 2 h. LCMS monitoring, the system was stirred, and the title compound (377 mg) was purified by column chromatography. MS (ESI) m / z (M+H) + =262.1.

[0185] Preparation Example 10: Preparation of 6-boronic acid pinacol ester-1,2-dihydro-3H-indazol-3-one

[0186]

[0187] Using a method similar to Preparation Example 7, 6-bromo-1,2-dihydro-3H-indazol-3-one was reacted with diboronic acid pinacol ester in potassium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and 1,4-dioxane to obtain the title compound. MS (ESI) m / z (M+H) + =261.1.

[0188] Preparation Example 11: Preparation of 6-methyl-3-boronic acid pinacol ester-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0189]

[0190] Using a method similar to Preparation Example 7, 3-bromo-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one was reacted with diboronic acid pinacol ester in potassium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and 1,4-dioxane to obtain the title compound. MS (ESI) m / z (M+H)+ = 275.2.

[0191] Preparation Example 12: Preparation of 2,3,3-trimethyl-5-boronic acid pinacol ester-isoindolin-1-one

[0192]

[0193] Using a method similar to Preparation Example 7, 2,3,3-trimethyl-5-bromo-isoindolin-1-one was reacted with diboronic acid pinacol ester in potassium acetate, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, and 1,4-dioxane to obtain the title compound. MS (ESI) m / z (M+H) + =302.2.

[0194] Preparation Example 13: Preparation of 7-boronic acid pinacol ester-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one

[0195]

[0196] Using a method similar to Preparation Example 7, 7-bromo-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one was reacted with diboronic acid pinacol ester in potassium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and 1,4-dioxane to obtain the title compound. MS (ESI) m / z (M+H) +=262.1.

[0197] Preparation Example 14: Preparation of 6-methyl-2-boronic acid pinacol ester-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0198]

[0199] Using a method similar to Preparation Example 7, 2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one was reacted with diboronic acid pinacol ester in potassium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and 1,4-dioxane to obtain the title compound. MS (ESI) m / z (M+H)+ = 275.2.

[0200] Preparation Example 15: Preparation of 2-methyl-6-boronic acid pinacol ester-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one

[0201]

[0202] Using a method similar to Preparation Example 7, 6-chloro-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one was reacted with diboronic acid pinacol ester in potassium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and 1,4-dioxane to obtain the title compound. MS (ESI) m / z (M+H)+ = 275.2.

[0203] Preparation Example 16: Preparation of 2-(piperidine-1-carbonyl)-7-boronic acid pinacol ester-benzo[b]thiophene-3-carbonitrile

[0204]

[0205] 7-Bromo-2-(piperidine-1-carbonyl)benzo[b]thiophene-3-carbonitrile (345 mg), biboronic acid pinacol ester (378 mg), potassium acetate (190 mg), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (37 mg) were placed in a 100 mL single-mouth bottle, 1,4-dioxane (10 mL) was added, nitrogen was replaced three times, and the reaction was carried out at 100°C for 2 hours. LCMS monitoring, the system was stirred, and the title compound (377 mg) was purified by column chromatography. MS (ESI) m / z (M+H) + = 397.2.

[0206] Preparation Example 17: (3-amino-7-boronic acid pinacol ester benzo[b]thiophen-2-yl)(piperidin-1-yl)methanone

[0207]

[0208] (3-amino-7-bromobenzo[b]thiophene-2-yl)(piperidin-1-yl)methanone (500 mg), biboronic acid pinacol ester (778 mg), potassium acetate (290 mg), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (37 mg) were placed in a 100 mL single-necked bottle, 1,4-dioxane (10 mL) was added, nitrogen was replaced three times, and the reaction was carried out at 100°C for 2 h. LCMS monitoring, the system was stirred, and the title compound (377 mg) was purified by column chromatography. MS (ESI) m / z (M+H) + = 387.2.

[0209] Example 1: Preparation of 5-(3-amino-2-(piperidine-1-carbonyl)benzo[b]thiophen-7-yl)isoindolin-1-one

[0210]

[0211] (3-amino-7-bromobenzo[b]thiophene-2-yl)(piperidin-1-yl)methanone (100 mg), 1-oxoisoindolin-5-ylboronic acid (163.8 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (24.3 mg) and potassium carbonate (124.2 mg) were dissolved in a mixed solution (10 mL) of dioxane and water in a volume ratio of 4:1, and reacted at 85°C for 1 hour. After the disappearance of the raw material monitored by LCMS, the reaction was quenched with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 36 mg of the target compound.

[0212] MS (ESI) m / z (M+H) + =392.2.

[0213] 1 H NMR(400MHz, DMSO-d6)δ8.57(s,1H),8.00(dd,J=6.2,3.0Hz,1H),7.80(s,1H),7.77-7.69(m,2H),7. 49-7.43(m,2H),6.27(s,2H),4.40(s,2H),3.49(s,4H),1.53(d,J=5.4Hz,2H),1.45(d,J=7.6Hz,4H).

[0214] Example 2: Preparation of 5-(3-amino-2-(piperidine-1-carbonyl)benzo[b]thiophen-7-yl)isobenzofuran-1(3H)-one

[0215]

[0216] (3-amino-7-bromobenzo[b]thiophen-2-yl)(piperidin-1-yl)methanone (100 mg), 1-oxo-1,3-dihydroisobenzofuran-5-boronic acid pinacol ester (163.8 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (24.3 mg) and potassium carbonate (124.2 mg) were dissolved in a mixed solution (10 mL) of dioxane and water in a volume ratio of 4:1, and reacted at 85°C for 1 hour. After the disappearance of the raw material monitored by LCMS, the reaction was quenched with water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 36 mg of the target compound.

[0217] MS (ESI) m / z (M+H) + =393.1.

[0218] 1 HNMR(400MHz,DMSO-d6)δ8.04(dd,J=5.4,3.8Hz,1H),7.97-7.87(m,2H),7.83(dd,J=7.9,1.6Hz,1H),7.57- 7.41(m,2H),6.28(s,2H),5.44(s,2H),3.49(d,J=5.4Hz,4H),1.53(d,J=5.7Hz,2H),1.45(q,J=5.5Hz,4H).

[0219] Example 3: Preparation of 7-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2-(piperidine-1-carbonyl)benzo[b]thiophene-3-carbonitrile

[0220]

[0221] 2-(Piperidine-1-carbonyl)-7-boronic acid pinacol ester benzo[b]thiophene-3-carbonitrile (40 mg), 3-bromo-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (25 mg), cesium carbonate (43 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (4 mg) were weighed into a 5 mL microwave tube, 1,4-dioxane (2 mL) and pure water (0.4 mL) were added, nitrogen was replaced three times, and the reaction was carried out at 100°C for 2 h. LCMS monitoring showed that the reaction was complete, water was added to quench, ethyl acetate was extracted twice, and the mixture was concentrated under reduced pressure. The title compound (12.14 mg) was separated by reverse phase preparative column.

[0222] MS (ESI) m / z (M+H) + =417.1.

[0223] 1HNMR(400MHz,DMSO-d6)δ9.03(d,J=2.0Hz,1H),8.45(d,J=2.0Hz,1H),8.08(dd,J=7.5,1.6 Hz,1H),7.88–7.79(m,2H),4.60(s,2H),3.64–3.46(m,4H),3.17(s,3H),1.64–1.57(m,6H).

[0224] Comparative Example 36: Preparation of 7-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-2-(piperidine-1-carbonyl)benzo[b]thiophene-3-carbonitrile

[0225]

[0226] Step 1: Preparation of ethyl 3-amino-7-(2-methyl-1-oxoisoindolin-5-yl)benzo[b]thiophene-2-carboxylate

[0227]

[0228] Weigh 3-amino-7-bromobenzo[b]thiophene-2-carboxylic acid ethyl ester (600 mg), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindol-1-one (603 mg), cesium carbonate (850 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (74 mg), add 1,4-dioxane (20 mL) and pure water (4 mL), replace with argon three times, and react at 80°C for 2 hours. LCMS monitors the reaction of the raw materials, quench with water, extract with ethyl acetate, dry with anhydrous sodium sulfate, and purify with column chromatography to obtain the title compound (500 mg).

[0229] MS (ESI) m / z (M+H) + =367.1.

[0230] Step 2: Preparation of 3-amino-7-(2-methyl-1-oxoisoindolin-5-yl)benzo[b]thiophene-2-carboxylic acid

[0231]

[0232] Weigh 3-amino-7-(2-methyl-1-oxoisoindol-5-yl)benzo[b]thiophene-2-carboxylic acid ethyl ester (500 mg) and dissolve it in a mixed solvent of tetrahydrofuran (15 mL), methanol (5 mL) and water (5 mL), add potassium hydroxide (230 mg) and react at 90°C for 6 hours. LCMS monitors the reaction of the raw material, quench with water, adjust the pH to acidic with 2M hydrochloric acid, extract twice with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound (200 mg).

[0233] MS (ESI) m / z (M+H) + =339.0.

[0234] Step 3: Preparation of 5-(3-amino-2-(4,4-difluoropiperidine-1-carbonyl)benzo[b]thiophen-7-yl)-2-methylisoindol-1-one

[0235]

[0236] Weigh 3-amino-7-(2-methyl-1-oxoisoindol-5-yl)benzo[b]thiophene-2-carboxylic acid (50 mg) and dissolve it in N,N-dimethylformamide (2 mL). Add N,N-diisopropylethylamine (74 μL), 4,4-difluoropiperidine hydrochloride (35 mg), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (85 mg) in sequence and react at room temperature for 2 h. TLC and LCMS monitor the complete reaction of the raw materials. Quench with water, extract twice with ethyl acetate, wash twice with saturated brine, dry over anhydrous sodium sulfate, purify by Prep-TLC to obtain 41 mg, and separate by reverse phase preparative column to obtain the title compound (8.97 mg).

[0237] MS (ESI) m / z (M+H) + =442.1.

[0238] 1 H NMR(400MHz,DMSO-d6)δ8.10(p,J=3.6Hz,1H),7.88(d,J=1.4Hz,1H),7.83–

[0239] 7.74(m,2H),7.57–7.53(m,2H),6.45(s,2H),4.55(s,2H),3.68(t,J=5.8Hz,4H),3.11(s,

[0240] 3H), 2.04 (tt, J = 13.7, 5.7Hz, 4H).

[0241] Using the corresponding commercial reagents and the products of the above-mentioned preparation examples and embodiments as raw materials, a class of compounds were prepared using a preparation method similar to the above-mentioned embodiment. The structures and characterization data of the compounds are shown in Table 1.

[0242] Table 1

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249] Example 24: Preparation of 5-(7-amino-6-(piperidine-1-carbonyl)thieno[3,2-d]pyrimidin-4-yl)-2-methylisoindolin-1-one

[0250] Step 1: Preparation of 5-(6-chloro-5-methoxypyrimidin-4-yl)-2-methylisoindolin-1-one

[0251]

[0252] 4,6-dichloro-5-methoxypyrimidine (2g), 2-methyl-5-boronic acid pinacol ester isoindolyl-1-one (3.38g), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (0.46g), sodium carbonate (1.78g) were mixed in 1,4-dioxane (25mL) and water (5mL), and reacted at 80°C for 3h under nitrogen protection. The reaction was complete after LCMS monitoring. Cooled to room temperature, added water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated and purified by column to obtain the title compound (1.3g). MS (ESI) m / z (M+H) + =290.1.

[0253] Step 2: Preparation of 5-methoxy-6-(2-methyl-1-oxoisoindol-5-yl)pyrimidine-4-carbonitrile

[0254]

[0255] 5-(6-chloro-5-methoxypyrimidin-4-yl)-2-methylisoindolin-1-one (1.3 g), tetrakistriphenylphosphine palladium (0.26 g), zinc cyanide (0.79 g) were mixed in DMF (15 mL), and the mixture was reacted at 110° C. for 3 h under nitrogen protection. The reaction was complete after LCMS monitoring. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the title compound (0.6 g).

[0256] MS (ESI) m / z (M+H) + =281.1.

[0257] Step 3: Preparation of 4-cyano-6-(2-methyl-1-oxoisoindolin-5-yl)pyrimidin-5-yl 4-methylbenzenesulfonate

[0258]

[0259] 5-Methoxy-6-(2-methyl-1-oxoisoindol-5-yl)pyrimidine-4-carbonitrile (600 mg) and lithium chloride (180 mg) were mixed in DMF (10 mL), reacted at 110°C for 2 h, cooled to room temperature, added water, and adjusted the pH to 2 with dilute hydrochloric acid. After concentration, the crude product of 5-hydroxy-6-(2-methyl-1-oxoisoindol-5-yl)pyrimidine-4-carbonitrile was obtained. The crude product was dissolved in dichloromethane (20 mL), and pyridine (332 mg) and p-toluenesulfonyl chloride (650 mg) were added in sequence. The reaction was carried out at room temperature for 2 h. The reaction was completed after LCMS monitoring. The solvent was evaporated under reduced pressure, and the residue was purified by column to obtain the title compound (400 mg). MS (ESI) m / z (M+H) + =421.0.

[0260] Step 4: Preparation of ethyl 7-amino-4-(2-methyl-1-oxoisoindolin-5-yl)thieno[3,2-d]pyrimidine-6-carboxylate

[0261]

[0262] Dissolve 4-cyano-6-(2-methyl-1-oxoisoindolin-5-yl)pyrimidin-5-yl 4-methylbenzenesulfonate (100 mg) in N,N-dimethylformamide (2 mL), add sodium hydrosulfide (27 mg), react at room temperature for 2 hours, and the reaction is complete after LCMS monitoring. Add triethylamine (73 mg) and ethyl 2-chloroacetate (59 mg), continue to react at room temperature for 2 hours, and LCMS monitoring shows that the product is generated. Quench with water, extract with ethyl acetate, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and purify the residue by column to obtain the title compound (50 mg).

[0263] MS (ESI) m / z (M+H) + =369.0.

[0264] 1 H NMR (400MHz, DMSO-d6) δ9.39(s,1H),8.37(s,1H),8.27(dd,J=7.9,1.6Hz,1H),7.94(d,J=7 .9Hz,1H),7.07(s,2H),4.63(s,2H),4.35(q,J=7.1Hz,2H),3.13(s,3H),1.38-1.32(m,3H).

[0265] Step 5: Preparation of 5-(7-amino-6-(piperidine-1-carbonyl)thieno[3,2-d]pyrimidin-4-yl)-2-methylisoindolin-1-one

[0266]

[0267] Dissolve 7-amino-4-(2-methyl-1-oxoisoindolin-5-yl)thieno[3,2-d]pyrimidine-6-carboxylic acid ethyl ester (50 mg) in a mixed solvent of ethanol (2 mL) and water (2 mL), react at 60°C for 3 h, and monitor the complete removal of the ester group by LCMS. Cool to room temperature, adjust the pH to 2 with dilute hydrochloric acid, evaporate the solvent under reduced pressure, and dissolve the residue in N,N-dimethylformamide. Add N,N-diisopropylethylamine (55 mg), piperidine (18 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (80 mg), and react at room temperature for 2 h. Monitor the complete reaction by LCMS. Add water, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate, and separate the crude product by reverse preparative separation to obtain the title compound (6.34 mg).

[0268] MS (ESI) m / z (M+H) + =408.1.

[0269] 1 H NMR (400MHz, DMSO-d6) δ9.33 (s, 1H), 8.35 (s, 1H), 8.26-8.24 (d, J = 7.9Hz, 1H), 7.93-7.91 (d ,J=7.9Hz,1H),6.13(s,2H),4.62(s,2H),3.58-3.56(m,4H),3.13(s,3H),1.65-1.53(m,6H).

[0270] The embodiments of the present invention can also use the following preparation method to convert I into, for example, hydrogen, CF3, CN, amide, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, etc. The following is a specific example.

[0271] Example 16: Preparation of 5-(3-iodo-2-(piperidine-1-carbonyl)benzothiophen-7-yl)-2-methylisoindol-1-one

[0272]

[0273] Step 1: Preparation of ethyl 3-amino-7-(2-methyl-1-oxoisoindolin-5-yl)benzo[b]thiophene-2-carboxylate

[0274]

[0275] Weigh 3-amino-7-bromobenzo[b]thiophene-2-carboxylic acid ethyl ester (2.5 g), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (2.5 g), cesium carbonate (5.4 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (300 mg), add 1,4-dioxane (40 mL), water (8 mL), replace with argon three times, and react at 80°C for 2 h. LCMS monitored the complete reaction of the raw material, quenched with water, extracted with ethyl acetate twice, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title compound (1.6 g). MS (ESI) m / z (M+H) + =367.1.

[0276] Step 2: Preparation of ethyl 3-iodo-7-(2-methyl-1-oxoisoindolin-5-yl)benzo[b]thiophene-2-carboxylate

[0277]

[0278] Weigh 3-amino-7-(2-methyl-1-oxoisoindolin-5-yl)benzo[b]thiophene-2-carboxylic acid ethyl ester (681 mg), dissolve cuprous iodide (530 mg) in 15 mL acetonitrile, place in a 60°C oil bath, drop tert-butyl nitrite (0.33 mL) and react at 60°C for 3 h. Monitor the reaction until complete by TLC, dilute with EA, filter on diatomaceous earth, quench with water, extract twice with ethyl acetate, dry with anhydrous sodium sulfate, and purify with column chromatography to obtain the title compound (570 mg). MS (ESI) m / z (M+H) + =478.0.

[0279] Step 3: Preparation of 3-iodo-7-(2-methyl-1-oxoisoindolin-5-yl)benzo[b]thiophene-2-carboxylic acid

[0280]

[0281] Weigh 3-iodo-7-(2-methyl-1-oxoisoindolin-5-yl)benzo[b]thiophene-2-carboxylic acid ethyl ester (600 mg), dissolve in a mixed solvent of tetrahydrofuran (9 mL), methanol (3 mL), and water (3 mL), add potassium hydroxide (212 mg), and react at 80°C for 2 h. LCMS shows that the raw material is consumed, quench with water, adjust the pH value to acidic with 2M hydrochloric acid, extract with ethyl acetate 3 times, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound (440 mg). MS (ESI) m / z (M+H) + =449.9.

[0282] Step 4: Preparation of 5-(3-iodo-2-(piperidine-1-carbonyl)benzothiophen-7-yl)-2-methylisoindol-1-one

[0283]

[0284] Weigh 3-iodo-7-(2-methyl-1-oxoisoindolin-5-yl)benzo[b]thiophene-2-carboxylic acid (440 mg) and dissolve it in N,N-dimethylformamide (10 mL). Add N,N-diisopropylethylamine (0.323 mL), hexahydropyridine (0.15 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (559 mg) in sequence at 0°C, and then warm to room temperature for 2 hours. TLC shows that the raw material is consumed, and water is added to quench, extract twice with ethyl acetate, wash twice with saturated brine, dry over anhydrous sodium sulfate, and purify with column chromatography to obtain the title compound (195 mg). MS (ESI) m / z (M+H) + =517.1.

[0285] Example 17: Preparation of 2-methyl-5-(2-(piperidine-1-carbonyl)-3-(trifluoromethyl)benzothiophen-7-yl)isoindol-1-one

[0286]

[0287] 5-(3-iodo-2-(piperidine-1-carbonyl)benzothiophene-7-yl)-2-methylisoindol-1-one (Example 16, 55 mg) was weighed and dissolved in N,N-dimethylformamide (2 mL), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (41 μL) and cuprous iodide (4 mg) were added. The argon gas was replaced three times and reacted at 90°C for 4 h. The mixture was quenched with water, extracted twice with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and separated by preparative column to obtain the title compound (10.35 mg).

[0288] MS (ESI) m / z (M+H) + =459.1.

[0289] 1 H NMR (400MHz, DMSO-d6) δ7.97(dq,J=8.1,1.4Hz,1H),7.94(t,J=1.2Hz,1H),7.87–7.80(m,2H),7.77(t,J=7.7Hz,1H),7.70(dd,J =7.4,1.1Hz,1H),4.57(s,2H),3.62(t,J=5.4Hz,2H),3.24(t,J=5.6Hz,2H),3.12(s,3H),1.63–1.52(m,4H),1.45–1.40(m,2H).

[0290] Example 18: Preparation of 7-(2-methyl-1-oxoisoindol-5-yl)-2-(piperidine-1-carbonyl)benzo[b]thiophene-3-carbonitrile

[0291]

[0292] 5-(3-iodo-2-(piperidine-1-carbonyl)benzothiophene-7-yl)-2-methylisoindol-1-one (Example 16, 55 mg) was weighed and dissolved in N,N-dimethylformamide (2 mL), and cuprous cyanide (29 mg) was added. The gas was replaced with argon three times and reacted at 100°C for 4 h. Water was added to quench the mixture, and the mixture was extracted twice with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and separated by reverse phase preparative column to obtain the title compound (5.71 mg).

[0293] MS (ESI) m / z (M+H) + =416.1.

[0294] 1 H NMR(400MHz, DMSO-d6)δ8.03(dd,J=8.0,1.1Hz,1H),7.95(t,J=1.1Hz,1H),7.87–7.82(m,2H),7.80(d,J=7.9Hz ,1H),7.74(dd,J=7.4,1.2Hz,1H),4.57(s,2H),3.70–3.56(m,2H),3.47(m,2H),3.12(s,3H),1.60–1.56(m,6H).

[0295] Example 25: Preparation of 5-(3-cyclopropyl-2-(piperidine-1-carbonyl)benzothiophen-7-yl)-2-methylisoindol-1-one

[0296]

[0297] Weigh 5-(3-iodo-2-(piperidine-1-carbonyl)benzothiophene-7-yl)-2-methylisoindol-1-one (Example 16, 30 mg), cyclopropylboric acid (10 mg), cesium carbonate (38 mg), tetrakis(triphenylphosphine)palladium (7 mg) and dissolve in 2 mL of toluene and 0.5 mL of water, replace with argon three times, and react at 100°C for 6 h. TLC and LCMS monitor the complete reaction of the raw materials. Quench with water, extract with ethyl acetate three times, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate with a reverse phase preparative column to obtain the title compound (9.74 mg).

[0298] MS (ESI) m / z (M+H) + =431.2.

[0299] 1 H NMR (400MHz, DMSO-d6) δ8.03(dd,J=7.9,1.2Hz,1H),7.89(d,J=1.3Hz,1H),7.83–7.76(m,2H),7.63(t,J=7.6Hz,1H),7.55(dd,J=7.4,1.1Hz, 1H),4.55(s,2H),3.63(m,2H),3.33(m,2H)3.11(s,3H),2.03(tt,J=8. 5,5.4Hz,1H),1.64–1.44(m,6H),1.02–0.97(m,2H),0.67–0.61(m,2H)

[0300] Example 26: Preparation of 2-methyl-5-(3-methyl-2-(piperidine-1-carbonyl)benzothiophen-7-yl)isoindol-1-one

[0301]

[0302] 5-(3-iodo-2-(piperidine-1-carbonyl)benzothiophene-7-yl)-2-methylisoindol-1-one (Example 23, 30 mg), methylboronic acid (7 mg), cesium carbonate (38 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2 mg) were weighed and dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), replaced with argon three times, and reacted at 100°C for 2 h. TLC and LCMS monitored the complete reaction of the raw materials. Water was added to quench, extracted with ethyl acetate three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by reverse phase preparative column to obtain the title compound (10.41 mg).

[0303] MS (ESI) m / z (M+H) + =405.2.

[0304] 1H NMR (400MHz, DMSO-d6) δ7.94–7.86(m,2H),7.81(s,2H),7.63(t,J=7.7Hz,1H),7.56(d,J= 7.3Hz,1H),4.56(s,2H),3.63–3.48(m,4H),3.12(s,3H),2.39(s,3H),1.67–1.41(m,6H).

[0305] Example 27: Preparation of 7-(2-methyl-1-oxoisoindol-5-yl)-2-(piperidine-1-carbonyl)benzo[b]thiophene-3-carbonitrile

[0306]

[0307] 7-(2-methyl-1-oxoisoindol-5-yl)-2-(piperidine-1-carbonyl)benzo[b]thiophene-3-carbonitrile (Example 24, 55 mg) was weighed and dissolved in 6 mL of sulfuric acid and reacted at room temperature overnight. The reaction was monitored by LCMS, and ice water was added to quench the reaction. The pH value was adjusted to weak alkalinity with sodium carbonate, and the mixture was extracted with ethyl acetate twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound (23.35 mg) was separated by reverse phase preparative column.

[0308] MS (ESI) m / z (M+H) + =434.2.

[0309] 1 H NMR(400MHz, DMSO-d6)δ8.06(dd,J=8.0,1.1Hz,1H),7.91(s,1H),7.86–7.75(m,3H),7.72–7.62(m,2H ),7.59(dd,J=7.4,1.2Hz,1H),4.57(s,2H),3.56(m,2H),3.33(m,2H),3.12(s,3H),1.64–1.45(m,6H).

[0310] Comparative Example 1

[0311]

[0312] The compound comparative example 1 was prepared by referring to the method disclosed in the prior art. MS (ESI) m / z (M+H) + =428.1.

[0313] 1H NMR (400MHz, DMSO-d6) δ9.01(d,J=1.9Hz,1H),8.44(d,J=1.9Hz,1H),8.06(t,J=4.6Hz,1H),7.9 5(s,1H),7.65(d,J=4.6Hz,2H),4.60(s,2H),3.75-3.81(m,4H),3.17(s,3H),2.05-2.17(m,4H).

[0314] Comparative Example 2

[0315]

[0316] The compound comparative example 2 was prepared by referring to the method disclosed in the prior art. MS (ESI) m / z (M+H) + =414.1.

[0317] 1 H NMR(400MHz, DMSO-d6)δ9.12(s,1H),9.03(d,J=1.9Hz,1H),8.42(d,J=1.9Hz,1H),8.03-8.0 9(m,1H),7.95(s,1H),7.63-7.69(m,2H),4.52(s,2H),3.77-3.81(m,4H),2.05-2.12(m,4H).

[0318] Biological tests

[0319] Test Example 1: 15-PGDH kinase activity detection

[0320] 1. Experimental materials:

[0321]

[0322] 2. Experimental methods:

[0323] a. Prepare a solution containing 50 mM Tris-HCl, 0.01% Tween 20, pH 7.5 with ultrapure water as a reaction buffer;

[0324] b. Prepare a 10mM stock solution of the test compound with DMSO, then dilute the stock solution of the test compound with the reaction buffer to obtain a 4000nM test compound solution 1, and then continuously dilute the test compound solution 1 by three times as a gradient difference to 9 concentrations of test compound solutions 2 to 10. Take 5μL of each concentration of the test compound solution 1 to 10 and add them to the 384-well plate as the experimental wells;

[0325] c. Add 5uL of reaction buffer to the 384-well plate as positive control wells and blank control wells.

[0326] d. Prepare a 15-PGDH protein solution with a concentration of 5 ng / μL using reaction buffer, add 5 μL of 15-PGDH protein solution to the experimental wells and positive control wells, and add 5 μL of reaction buffer to the blank control wells, and then centrifuge the plate at 2000 rpm for 30 seconds;

[0327] e. Use reaction buffer to prepare 5 mM β-NAD and 2 mM PGF2α respectively, mix them in a volume ratio of 1:1 to obtain a substrate mixture, take 10 μL of the substrate mixture and add it to the experimental well, positive control well and blank control well to start the reaction;

[0328] f. Use a multifunctional microplate reader to continuously detect the fluorescence signal value of each well (Ex / Em=340 / 450).

[0329] 3. Data Analysis:

[0330] a) Use the "kinetic calculations-slope calculation method" in PHERAstar Data analysis software to analyze the continuous fluorescence signal value and obtain the slope of each experimental well;

[0331] b) Calculate the inhibition rate using the following formula:

[0332] Inhibition rate %=[1-(slope of experimental well-signal value of positive control well) / (signal value of blank control well-average signal value of positive control well)]×100%.

[0333] c) Calculate IC50 and draw inhibition rate-dose curve: Use GraphPad Prism 6.0 to fit the compound concentration and the corresponding inhibition rate by nonlinear regression (dose response-variable slope) to calculate the IC50 value.

[0334] The formula is as follows: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope)), where X is the log value of the compound concentration and Y is the inhibition rate %.

[0335] 4. Experimental results:

[0336] The inhibitory activity of the compounds of the present invention on 15-PGDH enzyme is shown in Table 3 below.

[0337] Table 3

[0338] serial number <![CDATA[IC 50 (nM)]]> serial number <![CDATA[IC 50 (nM)]]> serial number <![CDATA[IC 50 (nM)]]> Example 1 B Embodiment 14 C Embodiment 28 B Example 2 E Embodiment 15 A+ Embodiment 29 A Example 3 C Example 16 D Embodiment 30 B Example 4 E Embodiment 18 A+ Comparative Example 31 F Example 5 E Embodiment 21 B Comparative Example 32 F Example 6 E Embodiment 23 A Comparative Example 33 G Example 7 C Embodiment 24 D Comparative Example 34 G Example 8 B Embodiment 25 C Comparative Example 35 G Example 10 A Embodiment 26 C Example 12 A Embodiment 27 C

[0339] In the table, "A+" represents the IC of 15-PGDH enzyme inhibition activity50 The range is less than 1 nM; "A" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than or equal to 1nM and less than or equal to 3nM; "B" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than 3 nM and less than or equal to 10 nM; "C" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than 10nM and less than or equal to 20nM; "D" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than 20nM and less than or equal to 30nM; "E" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than 30nM and less than or equal to 100nM; "F" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than 100 nM and less than or equal to 500 nM; "G" represents the IC of 15-PGDH enzyme inhibition activity 50 Range greater than 1000 nM or inactive.

[0340] The experiment found that the IC50 value of the inhibitory activity of the compounds of the present invention on 15-PGDH enzyme is less than or equal to 100nM, and the IC50 value of the inhibitory activity of some compounds of the present invention on 15-PGDH enzyme is less than or equal to 100nM. 50 The value is greater than 20 nM and less than or equal to 30 nM. The IC values ​​of some compounds of the present invention for 15-PGDH enzyme inhibition activity are 50 The value is greater than 10 nM and less than or equal to 20 nM. The IC values ​​of some compounds of the present invention for 15-PGDH enzyme inhibition activity are 50 The value is greater than or equal to 3 nM and less than or equal to 10 nM. The IC values ​​of some compounds of the present invention for the 15-PGDH enzyme inhibitory activity are 50 The value is greater than or equal to 1 nM and less than or equal to 3 nM. The IC values ​​of some compounds of the present invention for the 15-PGDH enzyme inhibitory activity are 50 The value is less than 1 nM.

[0341] The inhibitory activity of certain compounds of the present invention on 15-PGDH enzyme is increased by 9 times compared with Comparative Example 2 and by 3 times compared with Comparative Example 1; the inhibitory activity of certain preferred compounds of the present invention on 15-PGDH enzyme is increased by 25 times compared with Comparative Example 2 and by 8 times compared with Comparative Example 1.

[0342] Test Example 2: Intracellular PGE2 upregulation activity assay

[0343] 1. Experimental materials:

[0344]

[0345] 2. Experimental methods:

[0346] a) A549 cells were seeded in 24-well plates, and after the cells adhered, IL-1β was added for 16 h to induce COX2 expression and PGE2 production.

[0347] b) The test compound solution was prepared in culture medium and graded diluted to 7 concentrations including 0.64 nM, 3.2 nM, 16 nM, 80 nM, 400 nM, 2000 nM and 10000 nM. A positive control group and a negative control group were set up. The cell supernatant was collected after 8 hours of action. The positive control group was not treated with the compound after IL-1β induction, and the negative control group was not stimulated with IL-1β and not treated with the compound.

[0348] c) The PGE2 content of the sample was determined using the Prostaglandin E2Kit kit, and the fluorescence signal was detected by a multifunctional microplate reader (Ex / Em=337 / 620, 337 / 665).

[0349] 3. Data Analysis:

[0350] a) Use the PGE2 standard in the "Prostaglandin E2Kit" to draw a standard curve and substitute the sample fluorescence signal to obtain the PGE2 concentration.

[0351] b) Calculate the PGE2 upregulation rate % using the following formula:

[0352] PGE2 upregulation ratio % = PGE2 concentration in sample group / PGE2 concentration in positive control group × 100%.

[0353] 4. Experimental Results

[0354] The up-regulation ratio of the compound of the present invention on PGE2 in A549 cells can reach >100%, and the compound of the present invention can have the activity of up-regulating PGE2 in cells.

[0355] Test Example 3: In vivo pharmacokinetic study in ICR mice

[0356] 1. Experimental Animals

[0357] Species: ICR mice, SPF grade. Source: Hunan Slake Jingda Experimental Animal Co., Ltd. Quantity: 3 mice / dosage form or dose.

[0358] 2. Preparation of test samples

[0359] Accurately weigh an appropriate amount of the test sample, add 5% DMSO, 10% polyethylene glycol-15 hydroxystearate, and 85% saline (all by volume) in sequence, vortex or ultrasonicate to mix thoroughly to obtain a dosing solution with a test sample concentration of 0.2 mg / mL for intravenous administration.

[0360] Accurately weigh an appropriate amount of the test sample, add 10% DMSO, 10% polyethylene glycol-15-hydroxystearate, and 80% saline (all by volume) in sequence, vortex or ultrasonicate to mix thoroughly to obtain a dosing solution with a test sample concentration of 0.5 mg / mL for oral gavage administration.

[0361] 3. Experimental design

[0362]

[0363] 4. Dosage method

[0364] Weigh before administration and calculate the dosage based on body weight. Administer by intravenous injection or oral gavage.

[0365] 5. Blood collection time

[0366] 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after intravenous administration.

[0367] 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after oral gavage administration.

[0368] 6. Sample collection and disposal

[0369] Blood was collected through the submandibular vein or other appropriate methods. About 0.10 mL of each sample was collected and placed in an anticoagulant tube containing EDTA-K2. The whole blood sample was centrifuged at 6800g for 6 minutes to separate the plasma. The upper plasma sample was collected into a sample tube and stored at -40 to -20°C for analysis.

[0370] 7. Bioanalysis and data processing

[0371] When testing the blood drug concentration of the test product and drawing the plasma drug concentration-time curve, BLQ (lowest detection limit) is recorded as 0. When calculating pharmacokinetic parameters, the concentration before administration is calculated as 0; the BLQ before Cmax (including "No peak") is calculated as 0; the BLQ after Cmax (including "No peak") is not included in the calculation. WinNonlin is used to calculate pharmacokinetic parameters such as AUC (0-t), T1 / 2, Cmax, etc. through the blood drug concentration data at different time points.

[0372] The compounds of the present invention (especially the compounds prepared in the examples) have more excellent pharmacokinetic properties, especially in terms of oral bioavailability and in vivo exposure, and have better performance. For example, the in vivo exposure of the compounds of the present invention (especially the compounds prepared in the examples) far exceeds the existing level, and the intravenous exposure (for example, AUC (0-t)) can be increased by more than about 4 times, and the oral exposure can be increased by about 100 times; the oral bioavailability of the compounds of the present invention (especially the compounds prepared in the examples) can be increased by more than about 10 times relative to existing compounds (the compounds prepared in some examples can be increased by more than about 20 times); the half-life of the compounds of the present invention (especially the compounds prepared in the examples) is longer, increased by more than about 4 times (the compounds prepared in some examples can be increased by more than about 9 times).

[0373] For the purpose of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements about the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission of the correctness of the dates of these documents or the contents of these documents. Moreover, any reference to these publications in this document does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

[0374] Those skilled in the art will recognize that the scope of the present application is not limited to the various specific implementation plans and examples described above, but that various modifications, replacements, or recombinations can be made without departing from the spirit of the present application, and these adjusted solutions all fall within the scope of protection of the present application.

Claims

1. A compound represented by formula (I), its stereoisomer, its tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, X, Y, and Z are each independently selected from C or N, A is selected from CR 1 or N, U is selected from C or N, and when U is selected from C, for The -V- is selected from -CR a R b -、-NR c -、-O-、-N=CR 1c -*, -CR 2c =N-*,-CR 3c =CR 4c -, the * represents connection with the group W; when U is selected from N, for The =V- is selected from =N-, =CR 1d -、=CR 2d CR 3d R 4d -、=NCR 5d R 6d -, R A is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, amine, cyano, hydroxyl, amide, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, W is selected from NR Ww , O, S, R Ww is selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, in, The R 1 , R 2 , R 3 , R a , R b , R c , R 1c , R 2c , R 3c , R 4c , R 1d , R 2d , R 3d , R 4d , R 5d , R 6d Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy.

2. The compound according to claim 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: The U is selected from C, and the V is selected from CR a R b NR c 、O、N=CR 1c , CR 3c =CR 4c , or both U and V are N; preferably, U is selected from C, and V is selected from CR a R b , CR 3c =CR 4c , or U and V are both N.

3. The compound according to claim 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: Selected from Select from 4. The compound according to claim 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: The W is selected from NR W or O, preferably NR W .

5. The compound according to claim 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: The A is selected from CR 1 .

6. The compound according to claim 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: The R 1 , R 2 , R 3 , R a , R b , R c , R 1c , R 2c , R 3c , R 4c , R 1d , R 2d , R 3d , R 4d , R 5d , R 6d Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, carbonyl, -COC H3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy.

7. The compound according to claim 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: X and Y are not N at the same time, and Y and Z are not N at the same time.

8. The compound according to any one of claims 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: The compound is a compound represented by formula (II), X, Y, and Z are each independently selected from C or N, and X and Y are not N at the same time, and Y and Z are not N at the same time, A is selected from CR 1 or N, preferably CR 1 , V is selected from CR a R b or CR 3c =CR 4c , R A is selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, amine, cyano, hydroxyl, amide, 3-12 membered cycloalkyl, R W is selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, Where R 1 , R 2 , R 3 , R a , R b , R 3c , R 4c Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy.

9. The compound according to claim 8, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: At most one of X, Y, and Z is N.

10. The compound according to claim 8, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: The R 1 , R 2 , R 3 , R a , R b , R 3c , R 4c Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, carbonyl, -COC H3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy.

11. The compound according to claim 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: The compound is a compound represented by formula (III), Any one of X, Y and Z is N, and the other two are C; preferably, Y and Z are both C, and X is selected from C or N, R A is selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, amine, cyano, hydroxyl, amide, 3-12 membered cycloalkyl, R W is selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, Where R 1 , R 2 , R 3 , R a , R b Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy.

12. The compound according to claim 11, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: The R 1 , R 2 , R 3 , R a , R b Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, carbonyl, -COC H3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy.

13. The compound according to any one of claims 1 to 12, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: The R a , R b Each is independently selected from hydrogen, deuterium, tritium, methyl, ethyl, n-propyl, isopropyl, preferably hydrogen, deuterium, tritium.

14. The compound according to any one of claims 1 to 13, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: The R W is selected from hydrogen, deuterium, tritium, C1-C6 alkyl, 3-12 membered cycloalkyl; preferably, R W is selected from hydrogen, deuterium, tritium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, more preferably, said R W Selected from hydrogen, deuterium, tritium, methyl, ethyl, isopropyl, cyclopropyl.

15. The compound according to any one of claims 1 to 13, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, characterized in that: The R A is selected from C1-C6 alkyl, C1-C6 haloalkyl, halogen, amine, cyano, amide, 3-12 membered cycloalkyl; preferably, R A is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, fluorine, chlorine, bromine, iodine, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, cyano, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; more preferably, said R A Selected from methyl, trifluoromethyl, iodine, -NH2, -CONH2, cyano, cyclopropyl.

16. The compound according to any one of claims 1 to 15, its pharmaceutically acceptable salt, or solvate, or prodrug thereof, characterized in that: Selected from the following compounds, 17. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 16, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, and at least one pharmaceutically acceptable excipient.

18. Use of a compound according to any one of claims 1 to 16, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or a pharmaceutical composition according to claim 17 for the preparation of a medicament; preferably, the medicament is a 15-PGDH enzyme inhibitor; more preferably, the medicament is used for the treatment or prevention of fibrosis, oral ulcers, gum diseases, colitis, ulcerative colitis, gastroduodenal ulcers, inflammatory diseases, vascular insufficiency, Raynaud's disease, Buerger's disease, neuropathy, pulmonary hypertension, cardiovascular disease and kidney disease, cardiovascular disease, trauma, skin lesions, autoimmune diseases, graft-versus-host disease, osteoporosis, ear diseases, eye diseases, neutropenia, diabetes, underactive bladder, or for promoting hair growth, pigmentation, tissue repair, tissue regeneration, implant promotion in stem cell transplantation or bone marrow transplantation or organ transplantation, neurogenesis and nerve cell death or muscle regeneration and cervical ripening, or for resistance to chemotherapeutic toxicity, immunosuppressant toxicity.

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