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

Abstract

A compound of formula (I), stereoisomers, tautomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, pharmaceutical compositions containing them, and their use to inhibit 15-PGDH activity, having regulated 15-PGDH activity. # imgabs0 #

Description

A compound for regulating 15-PGDH activity and preparation method thereof Technical Field

[0001] The present application relates to a compound for regulating 15-PGDH activity and a method for preparing the same, and specifically 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 its use in preparing a drug, belonging to the field of medicinal chemistry. Background Art

[0002] 15-hydroxyprostaglandin dehydrogenase (15-PGDH) belongs to the evolutionarily conserved superfamily of short-chain dehydrogenases / reductases (SDRs) and is designated SDR36C1 according to the most recently approved human enzyme nomenclature. Existing research indicates that 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 acids (HETEs), and lipid mediators of inflammation resolution (RvD1, RvD2, RvE1, MaR1, LXA4, etc.) (hereinafter referred to as 15-PGDH substrates) (e.g., by catalyzing the oxidation of the 15-hydroxyl group of PGF2α to produce 15-keto-PGF2α). These 15-PGDH substrates exert their functions through specific receptors on target cells. Among them, prostaglandins PGE1, PGE2, PGF2α, and PGI2 are commonly used to evaluate 15-PGDH activity. For example, PGDH activity is evaluated by measuring the ketone metabolite at the 15-hydroxyl group of PGF2α (Journal of Clinical Endocrinology and Metabolism, Vol. 84, No. 1, 291-299).

[0003] The receptors for 15-PGDH substrates are widely and differentially distributed throughout the body, and the diversity of receptor types, signaling, and expression distribution contributes to the diversity of its functions. For example, PGE1 acts on blood vessels and platelets, increasing blood flow through vasodilation and platelet aggregation inhibition, and is therefore commonly used to treat diseases such as chronic arterial occlusion (thromboangiitis obliterans (TAO) or arteriosclerosis obliterans (ASO)) and skin ulcers. PGF2α has uterine contraction and intraocular hypotensive effects, and its derivatives are used as therapeutic agents for glaucoma. PGD2 can inhibit inflammation by enhancing the barrier function of pulmonary vessels. In addition, PGE2 has vasodilatory effects and has multiple effects related to blood pressure, pain, bone formation and cell growth, stem cell differentiation, as well as anti-fibrosis and anti-inflammatory effects. PGI2 inhibits platelet activation and relaxes 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 neutrophil migration / activation and accelerate neutrophil apoptosis. Furthermore, they are essential for increasing the phagocytic activity of macrophages, effectively removing apoptotic neutrophils and tissue debris remaining at the site of inflammation. These functions promote inflammation and maintain homeostasis. These inflammation-resolving lipid mediators have been reported to exhibit medicinal efficacy in various pathological models, such as mouse pneumonia, colitis, and liver injury models.

[0004] Recent studies suggest that 15-PGDH inhibitors and 15-PGDH agonists may have therapeutic value. A recent study demonstrated that increased 15-PGDH expression plays a role in protecting against thrombin-mediated cell death. 15-PGDH is known to inactivate prostaglandin E2 (PGE2), a downstream product of COX-2 metabolism. PGE2 has been shown to be beneficial in various biological processes, such as maintaining hair density, promoting skin wound healing, and promoting 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. In order 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 the subject, 15-PGDH inhibitors can be used.

[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 (such as inflammatory bowel disease), and other diseases. 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, stem cell, bone marrow or organ transplantation-induced nervous system diseases (such as mental neurological diseases, neuropathy, neurotoxic diseases, neuropathic pain and neurodegenerative diseases), muscle regeneration diseases (such as muscle atrophy, muscular dystrophy and muscle damage); in addition, 15-PGDH inhibitors can also be used to promote cervical ripening.

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

[0008] Summary of the Invention

[0009] The present application provides a compound represented by formula (I), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (such as a hydrate), or a prodrug thereof:

[0010] Ring A is selected from an aromatic ring, an aromatic heterocycle, an unsaturated aliphatic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated aliphatic heterocycle, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated aliphatic heterocycle.

[0011] R is selected from C1~C 10 Chain hydrocarbon group, 3-12 membered alicyclic ring, 3-12 membered alicyclic heterocyclic ring, wherein R is replaced by 0-2 R 2 Substituted, the R 2 are each independently selected from deuterium, tritium, nitro, hydroxy, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle, wherein R a 、R b 、R X 、R Y Each is independently selected from C1-C6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl,

[0012] o is selected from 0, 1, 2, 3, 4,

[0013] R 1 each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imino, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl,

[0014] is a single bond or a double bond, and when When it is a double bond, X and Y are each independently selected from CR B or N; when When it is a single bond, X and Y are each independently selected from CR C R D NR E ,

[0015] R A 、R B 、R C 、R D 、R E Each is independently selected from hydrogen, hydroxyl, halogen, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl,

[0016] Wherein, the aromatic heterocycle, alicyclic heterocycle, unsaturated alicyclic heterocycle, cycloalkyl and heterocycloalkyl groups each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O and S.

[0017] The R 1 Optionally substituted by one or more groups independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered cycloalkyl, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle.

[0018] In certain embodiments of the present application, is a double bond, X and Y are each independently selected from CR B or N,

[0019] In certain embodiments of the present application, the is a double bond, and at least one of X and Y is selected from CR B ,

[0020] In certain preferred embodiments of the present application, the is a double bond, and the Y is selected from N, and the X is selected from CR B ,

[0021] In certain preferred embodiments of the present application, the is a double bond, and the X is selected from N, and the Y is selected from CR B ,or

[0022] In certain preferred embodiments of the present application, the is a double bond, and X and Y are both selected from CR B ,

[0023] Among them, the R B Each is independently selected from hydrogen, hydroxyl, cyano, halogen, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; preferably, the R B is selected from hydrogen, hydroxy, cyano, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl; preferably, the R B Each is independently selected from hydrogen, hydroxy, cyano, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl. In some embodiments, is a double bond, X is selected from CR B , Y is selected from CR B or N, wherein the R BEach independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (preferably, the R B Each independently is hydrogen, C1~C5 alkyl, C1~C5 haloalkyl, hydrogen, C1~C3 alkyl, C1~C3 haloalkyl, hydrogen, C1~C5 alkyl, C1~C5 fluoroalkyl, C1~C5 chloroalkyl, C1~C5 bromoalkyl, or hydrogen, C1~C3 alkyl, C1~C3 fluoroalkyl, C1~C3 chloroalkyl, C1~C3 bromoalkyl).

[0024] In certain embodiments of the present application, the is a single bond, and at least one of X and Y is selected from CR C R D ,

[0025] In certain preferred embodiments of the present application, the is a single bond, and said Y is selected from NR E , wherein X is selected from CR C R D ,

[0026] In certain preferred embodiments of the present application, the is a single bond, and X is selected from NR E , wherein Y is selected from CR C R D ,or

[0027] In certain preferred embodiments of the present application, the Is a single bond, and X, Y are selected from CR C R D ,

[0028] wherein R C 、R D 、R E Each is independently selected from hydrogen, hydroxy, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0029] Further, in certain embodiments of the present application, the R A is selected from hydrogen, hydroxy, cyano, fluorine, chlorine, bromine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl; or, R ASelected from hydrogen, hydroxyl, halogen (such as fluorine, chlorine, bromine, iodine), amino (such as -NH2), cyano, C1~C6 alkyl (preferably C1~C5 alkyl, C1~C3 alkyl), C1~C6 alkoxy (preferably C1~C5 alkoxy, C1~C3 alkoxy), C1~C6 haloalkyl (such as C1~C6 fluoroalkyl, C1~C6 chloroalkyl, C1~C6 bromoalkyl; preferably C1~C5 haloalkyl, C1~C3 haloalkyl).

[0030] Furthermore, in certain embodiments of the present application, the R is selected from C1 to C 10 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, wherein R is replaced by 0 or 1 R 2 replace.

[0031] Furthermore, in certain embodiments of the present application, the ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-8 membered unsaturated alicyclic ring, a 7-12 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, or a 7-12 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring. Alternatively, the ring A is selected from a 6-10 membered aromatic ring, a 5-8 membered aromatic heterocycle containing at least one heteroatom selected from N, O, or S, a 5-8 membered unsaturated alicyclic ring containing at least one heteroatom selected from N, O, or S, a 9-16 membered (e.g., 9-12 membered) cyclic ring consisting of the aromatic ring and the unsaturated alicyclic ring, or an 8-14 membered (e.g., 8-12 membered) cyclic ring consisting of the aromatic heterocycle and the unsaturated alicyclic ring.

[0032] The present application also provides a compound represented by formula (II), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (such as a hydrate), or a prodrug thereof:

[0033] R B each independently selected from hydrogen, hydroxy, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0034] R is selected from C1~C 10 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, wherein R is replaced by 0 or 1 R 2 Substituted, the R 2 Selected from deuterium, tritium, nitro, hydroxy, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y, =O, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle, wherein R a 、R b 、R X 、R Y Each is independently selected from C1-C6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl,

[0035] R A is selected from hydrogen, deuterium, tritium, hydroxyl, cyano, fluorine, chlorine, bromine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0036] o is selected from 0, 1, 2, 3, 4,

[0037] R 1 each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imino, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl,

[0038] Ring A is selected from an aromatic ring, an aromatic heterocycle, an unsaturated aliphatic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated aliphatic heterocycle, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated aliphatic heterocycle;

[0039] In certain embodiments of the present application, the ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-8 membered unsaturated aliphatic heterocycle, a 7-12 membered cyclic ring consisting of an aromatic ring and an unsaturated aliphatic heterocycle, and a 7-12 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated aliphatic heterocycle.

[0040] The present application also provides a compound represented by formula (III), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (such as a hydrate), or a prodrug thereof:

[0041] R B is selected from hydrogen, hydroxy, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0042] R is selected from C1~C 10Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, wherein R is replaced by 0 or 1 R 2 Substituted, the R 2 Selected from deuterium, tritium, nitro, hydroxy, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle, wherein R a 、R b 、R X 、R Y Each is independently selected from C1-C6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl,

[0043] R A is selected from hydrogen, deuterium, tritium, hydroxyl, cyano, fluorine, chlorine, bromine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0044] o is selected from 0, 1, 2, 3, 4,

[0045] R 1 each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imino, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl,

[0046] Ring A is selected from an aromatic ring, an aromatic heterocycle, an unsaturated aliphatic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated aliphatic heterocycle, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated aliphatic heterocycle.

[0047] In certain embodiments of the present application, the ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-8 membered unsaturated aliphatic heterocycle, a 7-12 membered cyclic ring consisting of an aromatic ring and an unsaturated aliphatic heterocycle, and a 7-12 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated aliphatic heterocycle.

[0048] The present application also provides a compound represented by formula (IV), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (such as a hydrate), or a prodrug thereof:

[0049] RB independently selected from hydrogen, hydroxy, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0050] R is selected from C1~C 10 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, wherein R is replaced by 0 or 1 R 2 Substituted, the R 2 Selected from deuterium, tritium, nitro, hydroxy, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle, wherein R a 、R b 、R X 、R Y Each is independently selected from C1-C6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl,

[0051] R A is selected from hydrogen, deuterium, tritium, hydroxyl, cyano, fluorine, chlorine, bromine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0052] o is selected from 0, 1, 2, 3, 4,

[0053] R 1 each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imino, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl,

[0054] Ring A is selected from an aromatic ring, an aromatic heterocycle, an unsaturated aliphatic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated aliphatic heterocycle, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated aliphatic heterocycle.

[0055] In certain embodiments of the present application, the ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-8 membered unsaturated aliphatic heterocycle, a 7-12 membered cyclic ring consisting of an aromatic ring and an unsaturated aliphatic heterocycle, and a 7-12 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated aliphatic heterocycle.

[0056] The compounds, stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, provided herein, are:

[0057] In certain embodiments, the R is selected from C1 to C 10 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, the alkyl is a straight chain alkyl or a branched chain alkyl, the cycloalkyl and heterocycloalkyl are monocyclic or bicyclic, and the heterocycloalkyl contains 1 heteroatom selected from N, O, S, wherein R is 0 or 1 R 2 Substituted, wherein the R 2 The definition of is consistent with the above;

[0058] Preferably, the R is selected from C1 to C 10 Alkyl (e.g., C1-C6 alkyl, C1-C5 alkyl), 3-8 membered cycloalkyl (e.g., 4-6 membered cycloalkyl, 5-6 membered cycloalkyl), 3-8 membered heterocycloalkyl (e.g., 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl) containing at least one heteroatom selected from N, O, or S, wherein R is replaced by 0-2 R 2 Substituted, the R 2 Each independently selected from deuterium, tritium, hydroxyl, -C(O)OR a , C1-C6 alkoxy, 3-8 membered cycloalkyl (e.g., 4-6 membered cycloalkyl, 5-6 membered cycloalkyl), 3-8 membered heterocycloalkyl (e.g., 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl) containing at least one heteroatom selected from N, O, or S, 6-10 membered aromatic ring (e.g., phenyl), 5-6 membered aromatic heterocycle containing at least one heteroatom selected from N, O, or S, wherein R a Selected from C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C3 alkyl);

[0059] Preferably, the R is selected from C1 to C 10 Alkyl (e.g., C1-C6 alkyl, C1-C5 alkyl), 4- to 6-membered cycloalkyl (e.g., 5- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl (e.g., 4- to 6-membered heterocycloalkyl) containing at least one heteroatom selected from O or S, wherein R is replaced by 0-1 R 2 Substituted, the R 2 Each independently selected from deuterium, tritium, hydroxyl, -C(O)OR a, phenyl, thienyl, furyl, pyrrolyl, thiazolyl (preferably, the R 2 Each independently selected from hydroxyl, -C(O)OR a , phenyl, thienyl), wherein R a Selected from C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C3 alkyl);

[0060] Preferably, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Where R is replaced by 0 or 1 R 2 Substituted, wherein the R 2 The definition is consistent with the above. Or preferably, R is selected from C1-C6 alkyl, 4-6 membered cycloalkyl (e.g. 5-6 membered cycloalkyl), 4-6 membered heterocycloalkyl containing 1 O atom (e.g. 4-5 membered heterocycloalkyl), wherein R is replaced by 0-1 R 2 Substituted, the R 2 Each independently selected from hydroxyl, phenyl (preferably, the R 2 is phenyl).

[0061] Furthermore, the R 2 selected from deuterium, tritium, nitro, hydroxyl, aldehyde, halogen, cyano, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethoxy, trifluoroethoxy, trifluoro-n-propoxy, -C(O)OCH3, -C(O)OC2H5, -OC(O)CH3, -OC(O)C2H5, -C(O)NHCH3, -C(O)NHC2H5, -NHC(O)CH3, -NHC(O)C2H5, =O,

[0062] The compounds, stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, provided herein, are:

[0063] In certain specific embodiments, the ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-8 membered unsaturated alicyclic ring, a 7-12 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-12 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring. The aromatic ring and the aromatic heterocycle are preferably monocyclic or cyclic, the unsaturated alicyclic ring is preferably monocyclic, and the cyclic ring is preferably bicyclic. The aromatic heterocycle, the unsaturated alicyclic heterocycle, and the cyclic ring each independently contain 1-2 heteroatoms, and the heteroatoms are independently selected from N, O, and S.

[0064] In certain preferred embodiments of the present application, Ring A is selected from phenyl, naphthyl, a 5-8 membered aromatic heterocycle containing at least one heteroatom of N, O or S, a 5-8 membered unsaturated alicyclic ring containing at least one heteroatom of N, O or S, a 9-12 membered cyclic ring consisting of a phenyl group and the 5-8 membered unsaturated alicyclic ring, and an 8-14 membered (e.g., 8-12 membered) cyclic ring consisting of the 5-8 membered aromatic heterocycle and the 5-8 membered unsaturated alicyclic ring; preferably, Ring A is selected from phenyl, naphthyl, a 5-6 membered aromatic heterocycle containing at least one heteroatom of N, O or S, a 5-6 membered unsaturated alicyclic ring containing at least one heteroatom of N, O or S, a 9-10 membered cyclic ring consisting of a phenyl group and the 5-6 membered unsaturated alicyclic ring, and an 8-10 membered cyclic ring consisting of the 5-6 membered aromatic heterocycle and the 5-6 membered unsaturated alicyclic ring;

[0065] Furthermore, the ring A is selected from

[0066] In certain specific embodiments of the present application, the ring A is preferably selected from

[0067] In certain specific embodiments of the present application, the ring A is selected from Preferably, the ring A is selected from

[0068] The compounds, stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, provided herein, are:

[0069] In certain specific embodiments, the R 1 are each independently selected from deuterium, tritium, nitro, hydroxyl, sulfhydryl, halogen, cyano, =0, imino, amine, ester, aldehyde, carboxyl, amide, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolane, dioxhexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclopropylmethoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, n-hexyloxy, wherein R 1Optionally substituted by one or more independently selected from deuterium, tritium, nitro, hydroxyl, -NH2, thiol, halogen, cyano, ester, carboxyl, amide, =O, =NH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-8 membered cycloalkyl, 5-10 membered alicyclic ring, 6-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring.

[0070] In certain embodiments, o is selected from 0, 1, 2, 3 (preferably 0, 1, 2), R 1 Each is independently selected from deuterium, tritium, hydroxyl, =O, imino, amine, ester, carboxyl, C1-C6 alkyl, 4-8 membered cycloalkyl (e.g., 5-6 membered cycloalkyl), 4-8 membered heterocycloalkyl (e.g., 5-6 membered heterocycloalkyl); preferably, o is selected from 0, 1, 2, R 1 Each is independently selected from =O, ester group, carboxyl group, C1-C6 alkyl group (preferably =O, carboxyl group, C1-C3 alkyl group).

[0071] In certain specific embodiments of the present application, the R 1 Not substituted by other groups.

[0072] The compounds, stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts, or solvates, or prodrugs thereof represented by formula (I), (II), (III), or (IV) provided herein, in some specific embodiments, said o is selected from 0, 1, or 2, and said R 1 are each independently selected from deuterium, tritium, =O, -NH2, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl (e.g., deuterium, tritium, =O, -NH2, carboxyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, n-propyl, isopropyl, morpholinyl), and R A Selected from -NH2, the ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-8 membered unsaturated alicyclic heterocycle, a 7-12 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic heterocycle, a 7-12 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic heterocycle, the aromatic ring and the aromatic heterocycle are preferably monocyclic or cyclic, the unsaturated alicyclic heterocycle is preferably monocyclic, the cyclic ring is preferably bicyclic, and the aromatic heterocycle, the unsaturated alicyclic heterocycle, and the cyclic ring each independently contain 1-2 heteroatoms, and the heteroatoms are independently selected from N, O, S (for example, ring A is selected from ), the R B Each is independently selected from hydrogen, deuterium, tritium, methyl, ethyl, isopropyl, n-propyl, and R is selected from C1 to C 10Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl and R is optionally substituted by thienyl, phenyl, hydroxyl, -COOCH3 (for example, R is selected from n-butyl, tert-butyl, isobutyl, n-pentyl, 2-methylbutyl, benzyl, hydroxyethyl, methoxycarbonylethyl, cyclopentyl, cyclohexyl, cyclobutyloxy, thienylmethyl, preferably n-butyl, cyclopentyl, cyclohexyl, 2-methylbutyl).

[0073] In some embodiments, in the compound represented by formula (I), stereoisomer, tautomer or mixture thereof, or pharmaceutically acceptable salt thereof, or solvate thereof (such as hydrate), or prodrug thereof,

[0074] The ring A is selected from a 6- to 10-membered aromatic ring, a 5- to 8-membered aromatic heterocycle containing at least one heteroatom selected from N, O, or S, a 5- to 8-membered unsaturated aliphatic heterocycle containing at least one heteroatom selected from N, O, or S, a 9- to 16-membered (e.g., 9- to 12-membered) cyclic ring formed by the aromatic ring and the unsaturated aliphatic heterocycle, and an 8- to 14-membered (e.g., 8- to 12-membered) cyclic ring formed by the aromatic heterocycle and the unsaturated aliphatic heterocycle;

[0075] The R is selected from C1 to C 10 Alkyl (e.g., C1-C6 alkyl, C1-C5 alkyl), 3-8 membered cycloalkyl (e.g., 4-6 membered cycloalkyl, 5-6 membered cycloalkyl), 3-8 membered heterocycloalkyl (e.g., 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl) containing at least one heteroatom selected from N, O, or S, wherein R is replaced by 0-2 R 2 Substituted, the R 2 Each independently selected from deuterium, tritium, hydroxyl, -C(O)OR a , C1-C6 alkoxy, 3-8 membered cycloalkyl (e.g., 4-6 membered cycloalkyl, 5-6 membered cycloalkyl), 3-8 membered heterocycloalkyl (e.g., 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl) containing at least one heteroatom selected from N, O or S, 6-10 membered aromatic ring (e.g., phenyl), 5-6 membered aromatic heterocycle containing at least one heteroatom selected from N, O or S, wherein R a Selected from C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C3 alkyl);

[0076] The o is selected from 0, 1, 2, 3 (preferably 0, 1, 2);

[0077] The R 1 Each is independently selected from deuterium, tritium, hydroxyl, =0, imino, amine, ester, carboxyl, C1-C6 alkyl, 4-8 membered cycloalkyl (e.g., 5-6 membered cycloalkyl), 4-8 membered heterocycloalkyl (e.g., 5-6 membered heterocycloalkyl);

[0078] is a double bond, X and Y are each independently selected from CR B or N, the R B Each is independently selected from hydrogen, halogen, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl (preferably, the R B are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl);

[0079] R A Selected from hydrogen, amino (e.g. -NH2), hydroxyl, halogen, cyano, C1-C6 alkyl (preferably C1-C5 alkyl), C1-C6 alkoxy (preferably C1-C5 alkoxy), C1-C6 haloalkyl (e.g. C1-C6 fluoroalkyl, C1-C6 chloroalkyl, C1-C6 bromoalkyl).

[0080] In some preferred embodiments, in the compound represented by formula (I), stereoisomer, tautomer or mixture thereof, or pharmaceutically acceptable salt thereof, or solvate thereof (e.g. hydrate), or prodrug thereof,

[0081] The ring A is selected from phenyl, naphthyl, a 5-8 membered aromatic heterocycle containing at least one heteroatom of N, O or S, a 5-8 membered unsaturated alicyclic ring containing at least one heteroatom of N, O or S, a 9-12 membered cyclic ring consisting of a phenyl group and the 5-8 membered unsaturated alicyclic ring, and an 8-14 membered (e.g., 8-12 membered) cyclic ring consisting of the 5-8 membered aromatic heterocycle and the 5-8 membered unsaturated alicyclic ring; preferably, the ring A is selected from phenyl, naphthyl, a 5-6 membered aromatic heterocycle containing at least one heteroatom of N, O or S, a 5-6 membered unsaturated alicyclic ring containing at least one heteroatom of N, O or S, a 9-10 membered cyclic ring consisting of a phenyl group and the 5-6 membered unsaturated alicyclic ring, and an 8-10 membered cyclic ring consisting of the 5-6 membered aromatic heterocycle and the 5-6 membered unsaturated alicyclic ring;

[0082] The R is selected from C1 to C 10 Alkyl (e.g., C1-C6 alkyl, C1-C5 alkyl), 4- to 6-membered cycloalkyl (e.g., 5- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl (e.g., 4- to 6-membered heterocycloalkyl) containing at least one heteroatom selected from O or S, wherein R is replaced by 0-1 R 2 Substituted, the R 2 Each independently selected from deuterium, tritium, hydroxyl, -C(O)OR a , phenyl, thienyl, furyl, pyrrolyl, thiazolyl (preferably, the R 2 Each independently selected from hydroxyl, -C(O)OR a , phenyl, thienyl), wherein R ais selected from C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C3 alkyl); for example, R is preferably selected from butyl (e.g., n-butyl), cyclopentyl, cyclohexyl, cyclobutyloxy, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, tert-butyl, 2-methylpropyl, benzyl, thienyl, methoxycarbonylethyl, hydroxyethyl, and more preferably selected from n-butyl, cyclopentyl, cyclohexyl, cyclobutyloxy, 2-methylbutyl, tert-butyl, and benzyl;

[0083] Said o is selected from 0, 1, 2;

[0084] The R 1 Each is independently selected from =O, ester group, carboxyl group, C1-C6 alkyl group, 5-6 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S (for example, 6 membered heterocycloalkyl group containing N and O atoms);

[0085] is a double bond, X is selected from CR B , Y is selected from CR B or N, wherein the R B Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (the R B Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 chloroalkyl, C1-C6 bromoalkyl);

[0086] R A Selected from hydrogen, amino (e.g. -NH2), cyano, C1~C6 alkyl (preferably C1~C5 alkyl, C1~C3 alkyl), C1~C6 alkoxy (preferably C1~C5 alkoxy, C1~C3 alkoxy), C1~C6 haloalkyl (e.g. C1~C6 fluoroalkyl, C1~C6 chloroalkyl, C1~C6 bromoalkyl).

[0087] In some preferred embodiments, in the compound represented by formula (I), stereoisomer, tautomer or mixture thereof, or pharmaceutically acceptable salt thereof, or solvate thereof (e.g. hydrate), or prodrug thereof,

[0088] The ring A is selected from Preferably, the ring A is selected from

[0089] The R is selected from C1-C6 alkyl, 4-6 membered cycloalkyl (e.g. 5-6 membered cycloalkyl), 4-6 membered heterocycloalkyl (e.g. 4-5 membered heterocycloalkyl) containing 1 O atom, wherein R is replaced by 0-1 R 2 Substituted, the R 2Each independently selected from hydroxyl, phenyl (preferably, the R 2 is phenyl); for example, R is preferably selected from n-butyl, cyclopentyl, cyclohexyl, cyclobutoxy, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, tert-butyl, 2-methylpropyl, benzyl, methoxycarbonylethyl, hydroxyethyl, more preferably from n-butyl, cyclopentyl, cyclohexyl, cyclobutoxy, 2-methylbutyl, tert-butyl, benzyl;

[0090] The o is selected from 0, 1, and 2;

[0091] The R 1 each independently selected from =O, carboxyl, C1-C3 alkyl, a 5- to 6-membered heterocycloalkyl containing at least one heteroatom selected from N, O, or S (e.g., a 5- to 6-membered heterocycloalkyl containing at least one heteroatom selected from N or O, such as a 6-membered heterocycloalkyl containing N and O atoms);

[0092] is a double bond, X is selected from CR B , Y is selected from CR B or N, wherein the R B Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl (preferably the R B each independently selected from hydrogen, C1-C5 alkyl, C1-C5 fluoroalkyl, C1-C5 chloroalkyl, C1-C5 bromoalkyl, or hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 chloroalkyl, C1-C3 bromoalkyl);

[0093] R A is selected from hydrogen, amino, cyano, C1-C6 alkyl (preferably C1-C5 alkyl, C1-C3 alkyl), C1-C6 alkoxy (preferably C1-C5 alkoxy, C1-C3 alkoxy), C1-C6 haloalkyl (preferably C1-C5 haloalkyl, C1-C3 haloalkyl); preferably R A is selected from hydrogen, -NH2, C1-C5 alkyl (preferably C1-C3 alkyl), C1-C5 alkoxy (preferably C1-C3 alkoxy); for example, R A Selected from -NH2, C1~C5 alkyl (preferably C1~C3 alkyl).

[0094] In some embodiments, each substituent in the compound of formula (II), (III) or (IV) above may have the same definition as above.

[0095] In some specific embodiments of the present application, the present application provides the following compounds, their stereoisomers, tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates, or their prodrugs:

[0096] This application also covers solutions obtained by any combination, deletion or replacement of the above embodiments.

[0097] Another aspect of the present application is to provide a pharmaceutical composition comprising at least one of the aforementioned compounds, stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, and at least one pharmaceutically acceptable excipient.

[0098] Another aspect of the present application is to provide a compound, or a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt, or a solvate, or a prodrug, 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 increased levels of unwanted 15-PGDH activity. Alternatively, the present application provides a compound, or a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt, or a solvate, or a prodrug, or a pharmaceutical composition 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, or a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt, or a solvate, or a prodrug, or a pharmaceutical composition to a subject in need. The 15-PGDH-related disease herein refers to a disease or complication thereof that achieves clinically beneficial therapeutic effects such as alleviation, improvement, cessation of progression, alleviation, or no longer worsening by inhibiting 15-PGDH activity.

[0099] In certain specific embodiments, the medicament or method 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 and renal diseases, cardiovascular diseases, trauma, skin injuries, autoimmune diseases, graft-versus-host disease, osteoporosis, ear diseases, eye diseases, neutropenia, diabetes, underactive bladder, or to promote hair growth, pigmentation, tissue repair, tissue regeneration, implantation in stem cell transplantation, 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.

[0100] definition

[0101] Unless otherwise stated, the following terms used in the specification and claims have the following meanings. A particular term should not be considered ambiguous or unclear if it is not specifically defined, but should be understood according to its ordinary meaning in the art.

[0102] "Chained hydrocarbon group" refers to a group of aliphatic groups that are connected in a chain and contain only carbon and hydrogen atoms. The hydrocarbon group can be a saturated hydrocarbon group or an unsaturated hydrocarbon group; the chain can be straight chain or branched chain. 10 The chain hydrocarbon group refers to a straight-chain hydrocarbon group or a branched hydrocarbon group consisting of 1 to 10 carbon atoms (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or a range consisting of any two of the foregoing values), including saturated hydrocarbon groups and unsaturated hydrocarbon groups.

[0103] "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 this application refers to a straight-chain alkyl or branched-chain alkyl composed of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the foregoing values). 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.

[0104] "Alkoxy" refers to an -O-alkyl group; as used herein, a C1-C6 alkoxy group refers to a straight-chain or branched alkoxy group consisting of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6, or a range consisting of any two of the foregoing values). Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, tert-pentoxy, n-hexoxy, and the like.

[0105] "Ring" refers to any cyclic covalently closed structure, including, for example, a carbocycle (e.g., an aromatic ring or an alicyclic ring) or a heterocycle (e.g., an aromatic heterocycle or an alicyclic heterocycle). A carbocycle refers to a ring composed solely of carbon atoms, and a heterocycle refers to a closed structure formed by covalently bonding carbon atoms and heteroatoms. Depending on the number of rings, a "ring" may be monocyclic, bicyclic, tricyclic, or polycyclic. When a ring is bicyclic, tricyclic, or polycyclic, the relationships between the rings may include fused, spirocyclic, or bridged.

[0106] "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.

[0107] "Member" refers to the number of atoms that make up 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, and benzene.

[0108] "Alicyclic" or "alicyclic group" refers to a saturated or partially unsaturated aliphatic carbocyclic group. A saturated aliphatic carbocyclic ring is called, for example, a saturated alicyclic ring, and may also be called a "cycloalkyl group"; a partially unsaturated carbocyclic ring may be called, for example, an unsaturated alicyclic ring. An alicyclic ring may be a monocyclic, spirocyclic, fused, or bridged ring. For example, a 3- to 8-membered alicyclic ring refers to an aliphatic carbocyclic ring group consisting of 3 to 8 backbone carbon atoms. Typical alicyclic structures include, but are not limited to: wait.

[0109] "Aliphatic heterocycle" or "aliphatic heterocyclic group" refers to a non-aromatic cyclic group formed by replacing a carbon atom 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- to 12-membered aliphatic heterocyclic group refers to a non-aromatic cyclic group containing one or more heteroatoms and composed of 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or a range consisting of any two of the foregoing) backbone atoms, and may be a saturated aliphatic heterocyclic group or an unsaturated aliphatic heterocyclic group.

[0110] A "saturated alicyclic ring," also known as a "cycloalkyl," is an aliphatic cyclic group composed of saturated carbon atoms as its backbone. As used herein, a 3- to 8-membered cycloalkyl group refers to a cyclic alkyl group composed of 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, or a range consisting of any two of the foregoing numbers). Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2,1,1]hexyl, and cycloheptyl.

[0111] "Saturated alicyclic heterocycles" also known as "heterocycloalkyl" means that the carbon atoms constituting the ring backbone of the alicyclic heterocycle are all saturated. For example, the 3-12 membered heterocycloalkyl used in this application refers to a non-aromatic cyclic group formed by 3-12 atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or a range consisting of any two of the foregoing values) forming the ring backbone, wherein the atoms constituting the ring backbone are composed of saturated carbon atoms and heteroatoms. Typical saturated alicyclic heterocycles include, but are not limited to: wait.

[0112] "Unsaturated heterocyclic ring" or "unsaturated heterocyclic group" refers to a non-aromatic cyclic structure containing some unsaturated atoms as the ring skeleton in the heterocyclic ring. For example, in certain embodiments of the present application, "unsaturated heterocyclic ring" refers to a non-aromatic cyclic structure containing unsaturated carbon atoms in the skeleton constituting the heterocyclic ring. The 3-12 membered unsaturated heterocyclic ring used in the present application refers to a non-aromatic cyclic group composed of 3-12 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or a range consisting of any two of the foregoing values) skeleton atoms, wherein the atoms constituting the ring skeleton include saturated carbon atoms, unsaturated carbon atoms and heteroatoms. Typical unsaturated heterocyclic rings include but are not limited to: wait.

[0113] "Aromatic ring" or "aryl" refers to a completely unsaturated carbon ring whose planar ring has a delocalized π electron system and contains 4n+2 π electrons, where n is an integer. The aromatic ring can be composed of six, eight, ten or more carbon atoms, and the aromatic ring can be a monocyclic ring or a polycyclic ring (such as a bicyclic ring or a tricyclic ring). Common aromatic rings include but are not limited to benzene rings, naphthalene rings, phenanthrene rings, anthracene rings, tetraphenyl rings, pyrene rings, pentaphenyl rings, etc. The 6-10 membered aromatic ring or 6-10 membered aryl used in this application refers to an aromatic ring group composed of 6 to 10 (e.g., 6, 7, 8, 9, 10 or a range consisting of any two of the foregoing values) backbone carbon atoms.

[0114] "Aromatic heterocycle" or "heteroaryl" refers to an aromatic ring structure formed by replacing one or more heteroatoms with carbon atoms in the aromatic ring. Typical aromatic heterocycles or heteroaryl groups include but are not limited to: wait.

[0115] The 5- to 10-membered aromatic heterocycle or 5- to 10-membered heteroaryl group used in the present application refers to an aromatic ring group containing heteroatoms and consisting of 5 to 10 (e.g., 5, 6, 7, 8, 9, 10, or a range consisting of any two of the foregoing) backbone atoms.

[0116] "Cyclic ring" refers to a cyclic structure in which two adjacent ring atoms are shared between the rings. Cyclic rings can be bicyclic, tricyclic or polycyclic.

[0117] In the present application, “a cyclic ring composed of an aromatic ring and an unsaturated alicyclic heterocycle” refers to a cyclic ring structure formed by an aromatic ring and an unsaturated alicyclic heterocycle sharing two adjacent ring atoms; “a cyclic ring composed of an aromatic heterocycle and an unsaturated alicyclic heterocycle” refers to a cyclic ring structure formed by an aromatic heterocycle and an unsaturated alicyclic heterocycle sharing two adjacent ring atoms. In the present application, “a cyclic ring of 7 to 12 members composed of an aromatic heterocycle and an unsaturated alicyclic heterocycle” refers to a cyclic ring structure having 7 to 12 (e.g., 7, 8, 9, 10, 11, 12, or a range consisting of any two of the aforementioned values) skeletal ring atoms, formed by an unsaturated alicyclic heterocycle and an aromatic heterocycle sharing two adjacent ring atoms. In the present application, “a cyclic ring of 7 to 12 members composed of an aromatic ring and an unsaturated alicyclic heterocycle” refers to a cyclic ring structure having 7 to 12 (e.g., 7, 8, 9, 10, 11, 12, or a range consisting of any two of the aforementioned values) skeletal ring atoms, formed by an unsaturated alicyclic heterocycle and an aromatic ring sharing two adjacent ring atoms.

[0118] Common cyclic rings formed by aromatic rings and unsaturated heterocyclic rings include but are not limited to:

[0119] Common fused rings formed by aromatic heterocycles and unsaturated aliphatic heterocycles include but are not limited to:

[0120] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0121] "Haloalkyl" refers to an alkyl group in which at least one hydrogen is replaced by a halogen atom. The C1-C6 haloalkyl group used in this application refers to a straight-chain or branched alkyl group consisting of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the foregoing values), and at least one hydrogen on the alkyl group is arbitrarily replaced by a halogen atom.

[0122] "Haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom is replaced by a halogen atom. As used herein, a C1-C6 haloalkoxy group refers to a straight-chain or branched alkoxy group consisting of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6, or a range consisting of any two of the foregoing values), and at least one hydrogen atom on the alkoxy group is arbitrarily replaced by a halogen atom.

[0123] "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, and cycloalkyl.

[0124] "Iminyl" or "imine" refers to a group having ═NR W The chemical structure ofW Selected from hydrogen, deuterium, tritium, alkyl, cycloalkyl.

[0125] "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.

[0126] "Ester group" refers to a group having the formula -C(O)OR a or -OC(O)R b The chemical structure of a 、R b Selected from alkyl, cycloalkyl, and heterocycloalkyl.

[0127] " substitution " refers to that one or more hydrogen atoms in the group are replaced by the substituent of corresponding number independently of one another. It goes without saying that substituent is only in their possible chemical position, and those skilled in the art can determine (by experiment or theory) possible or impossible substitution when not paying too much effort. For example, amino or hydroxyl with free hydrogen may be unstable when combined with the carbon atom with unsaturated (such as olefinic) key. Separately and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, alkylthio, aryloxy, nitro, acyl, halogen, haloalkyl, amino etc.

[0128] The optional groups or substituents in the general formula compounds of the present application are "each independently selected from" means that when the group or substituent appears at multiple positions at the same time, the group or substituent at each position may be the same or different. For example, if there are multiple R B When each R B They may be the same or different and may be selected from the same or different specific groups.

[0129] "Inhibitor" refers to a substance that reduces the activity of an enzyme.

[0130] "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, "optionally substituted" includes both substituted and unsubstituted. 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.

[0131] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with 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, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0132] "Pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0133] 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.

[0134] "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 via reorganization of some of the bonding electrons. Non-limiting examples of tautomers include, but are not limited to,

[0135] "Stereoisomers" refer to isomers caused by the same order of connection between atoms or atomic groups in a molecule, but different ways of arranging atoms in space. They 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 compound structure in "stereoisomers" is usually represented by a wedge-shaped covalent bond (bold wedge-shaped bond). Dashed wedge key ) are represented by, where the bold wedge-shaped bond indicates the bond faces outward from the paper, and the dotted wedge-shaped bond indicates the bond faces inward from the paper.

[0136] "Enantiomers" refer to compounds with the same molecular formula and functional groups that exhibit isomerism due to different configurations of their atoms in space, forming non-superimposable stereoisomers that are mirror images of each other. "Diastereoisomers" refer to compounds with the same molecular formula and functional groups that exhibit isomerism due to different configurations of their atoms in space, forming stereoisomers that are not mirror images of each other.

[0137] In this application, a straight covalent bond "—" in a compound structure may indicate that the bond is in the same plane as the paper. In this application, when stereoisomers exist for the atoms connected by a straight covalent bond, the straight covalent bond indicates that the arrangement of the atoms connected by the straight covalent bond may include being in the same plane as the paper, facing outward from the paper, facing inward from the paper, or a mixture of these arrangements.

[0138] Unless otherwise indicated, the terms "comprise, comprise, 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.

[0139] Unless otherwise indicated, all numbers used herein expressing amounts of ingredients, measurements, or reaction conditions are to be understood as modified in all instances by the term "about." When used in conjunction with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, and more preferably ±0.1%.

[0140] 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.

[0141] Obviously, based on the above content of this application, in accordance with the common technical knowledge and means in this field, without departing from the above basic technical ideas of this application, various other forms of modifications, replacements or changes can be made.

[0142] The abbreviations in this application have the following meanings: DETAILED DESCRIPTION

[0143] Synthesis method

[0144] The present application also provides a method for synthesizing the above-mentioned compounds. The method for synthesizing the above-mentioned compounds is mainly based on the preparation methods reported in chemical literature or is synthesized using commercially available chemical reagents as starting materials.

[0145] Method 1-1

[0146] Here are the steps:

[0147] a) reacting the compound represented by formula i or a pharmaceutically acceptable salt thereof, such as the hydrochloride, with bis(methylmercaptomethylenemalononitrile) to obtain a compound represented by formula ii;

[0148] b) undergoing a ring-closing reaction with the compound represented by formula vii to obtain the compound represented by formula iii;

[0149] c) reacting the compound represented by formula iii with a suitable oxidizing agent such as m-chloroperbenzoic acid to obtain a compound represented by formula iv;

[0150] d) reacting the compound represented by formula iv with the compound represented by formula viii in the presence of a sulfiding agent such as sodium hydrosulfide to obtain a compound represented by formula v;

[0151] e) reacting the compound represented by formula v with a suitable oxidant such as hydrogen peroxide to obtain a compound represented by formula vi;

[0152] f) Finally, the compound represented by formula vi is subjected to a ring-closure reaction to obtain the target compound of the present application represented by formula x.

[0153] The compounds represented by the aforementioned formula i, formula vii, and formula viii may be commercially available products, or may be prepared by those skilled in the art using preparation methods disclosed in the prior art.

[0154] The compound represented by formula ii in method 1-1 can also be prepared by reacting 4-amino-2-chloro-6-(methylthio)pyrimidine-5-carbonitrile with (Compound of formula a) is prepared by coupling reaction under the action of a coupling reagent (e.g. 1,1-bis(diphenylphosphino)ferrocenepalladium chloride). In certain embodiments, the compound of formula a can also be esterified with pinacol to form

[0155] In method 1-1, ring A, R 1 ,o,R,R B The definition of is consistent with that of the present application. In certain embodiments, for example, the ring A may be selected from R 1can be selected from deuterium, tritium, nitro, hydroxyl, sulfhydryl, halogen, cyano, =0, imino, amine, ester, aldehyde, carboxyl, amide, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl , isothiazolidinyl, dioxolanyl, dioxane, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclopropylmethoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, n-hexyloxy; R can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Each R B Each is independently selected from hydrogen, hydroxy, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; when R B When all are selected from hydrogen, the compound represented by formula vii may also be an acetal, such as 2-bromoethyl diethyl acetal.

[0156] Method 1-2

[0157] Here are the steps:

[0158] d-1) reacting the compound represented by formula v to obtain the compound represented by formula v-1;

[0159] e-1) reacting the compound represented by formula v-1 with a suitable oxidant such as hydrogen peroxide to obtain the compound represented by formula vi-1;

[0160] f-1) Finally, the compound represented by formula vi-1 is subjected to a ring-closure reaction to obtain the target compound of the present application represented by formula xi.

[0161] The compounds represented by the aforementioned formula i, formula vii, and formula viii may be commercially available products, or may be prepared by those skilled in the art using preparation methods disclosed in the prior art.

[0162] In method 1-2, ring A, R 1 、o、R、R B The definition is the same as that of method 1-1, by converting the cyano group of the compound represented by formula v in method 1-1 into a group Then, the oxidation of step e-1) and the reduction of step f-1) are performed to obtain the target compound of the present application shown in formula xi. A The definition is consistent, and Z is not -NH2. In certain embodiments of the present application, for example, Z can be selected from hydrogen, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0163] Method 2-1

[0164] Here are the steps:

[0165] a-2) reacting the compound represented by formula i or a pharmaceutically acceptable salt thereof, such as the hydrochloride, with ethyl 2-cyano-3,3-bis(methylthio)prop-2-enoate to obtain the compound represented by formula ii-2;

[0166] b-2) reacting with a chlorinating agent such as phosphorus oxychloride to obtain a compound represented by formula iii-2;

[0167] c-2) reacting with the compound represented by formula ix-2 to produce a compound represented by formula iv-2;

[0168] d-2) In the presence of a dehydrating agent such as phosphorus oxychloride, an intramolecular ring-closure reaction occurs to obtain a compound represented by formula v-2;

[0169] e-2) reacting the compound represented by formula v-2 with a suitable oxidizing agent such as m-chloroperbenzoic acid to obtain the compound represented by formula vi-2;

[0170] f-2) reacting the compound represented by formula vi-2 with the compound represented by formula viii in the presence of a sulfiding agent such as sodium hydrosulfide to obtain the compound represented by formula vii-2;

[0171] g-2) reacting the compound represented by formula vii-2 with a suitable oxidant such as hydrogen peroxide to obtain the compound represented by formula viii-2;

[0172] h-2) Finally, the compound represented by formula viii-2 is subjected to a ring-closure reaction to obtain the target compound of the present application represented by formula x-2.

[0173] The compounds represented by the aforementioned formula i, formula ix-2, and formula viii may be commercially available products, or may be prepared by those skilled in the art using preparation methods disclosed in the prior art.

[0174] In method 2-1, ring A, R 1 、o、R、RB The definition is the same as that of method 1-1 of this application.

[0175] The following examples illustrate the synthesis methods of the compounds and intermediates of this application. The following examples are merely examples of this application and should not be construed as limiting the scope of this application. Unless otherwise specified, the raw materials and reagents involved in this application can be obtained through commercial channels, and the specific source of the channel does not affect the implementation of the technical solution of this application.

[0176] Preparation Example 1: Preparation of tert-butyl-[2-(chloromethylsulfanyl)ethoxy]-dimethylsilane

[0177] Step 1: Preparation of 2-[tert-butyl(dimethyl)silyl]oxyethanethiol

[0178] At room temperature, 4.0 g of 2-mercaptoethanol was dissolved in 40 mL of dichloromethane, 8.36 g of imidazole was added, and 8.49 g of tert-butylchlorodimethylsilane was added dropwise to the reaction solution. The reaction system was stirred at room temperature for 16 hours. TLC (petroleum ether / ethyl acetate = 10 / 1) showed that the reaction was complete. The reaction solution was poured into water and extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain the title compound. 1 H NMR (400MHz, CDCl3-d) δ3.74 (t, J = 6.4 Hz, 2H), 2.64 (td, J = 6.4, 8.2 Hz, 2H), 1.55 (s, 1H), 0.92-0.91 (m, 9H), 0.10-0.08 (m, 6H).

[0179] Step 2: Preparation of tert-butyl-[2-(chloromethylsulfanyl)ethoxy]-dimethylsilane

[0180] At room temperature, 935 mg of sodium hydride was dissolved in 20 mL of tetrahydrofuran, and the reaction system was cooled to 0°C. 4.50 g of 2-[tert-butyl(dimethyl)silyl]oxyethanethiol was dissolved in 20 mL of tetrahydrofuran and added dropwise to the reaction system and stirred for 1 hour. 15.1 g of bromo(chloro)methane was added dropwise to the reaction system at 0°C. The reaction system was stirred at 0°C for 1 hour and then at 25°C for 16 hours. TLC (petroleum ether / ethyl acetate = 20 / 1) showed that the reaction of the starting materials was complete. The reaction solution was filtered, the filter cake was rinsed with 30.0 mL of tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain the crude product to obtain the title compound. 1H NMR (400MHz, CDCl3-d) δ4.73 (s, 2H), 3.83-3.78 (m, 2H), 2.80 (t, J = 6.4Hz, 2H), 0.82 (s, 9H), 0.00 (s, 6H).

[0181] Preparation Example 2: Preparation of chloromethylthiocyclohexane

[0182] At room temperature, 344 mg of sodium hydride was dissolved in 20.0 mL of tetrahydrofuran. The reaction system was cooled to 0°C, 1.00 g of cyclohexanethiol was added dropwise to the reaction system and stirred for 1 hour. At 0°C, 5.57 g of bromo(chloro)methane was added dropwise to the reaction system. The reaction system was stirred at 0°C for 1 hour. The reaction system was stirred at room temperature for 16 hours. GCMS showed that the raw material reaction was complete. The reaction solution was filtered, the filter cake was rinsed with 10.0 mL of tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain a crude product to obtain the title compound. 1 H NMR (400MHz, CDCl3-d) δ4.72 (s, 2H), 2.97-2.87 (m, 1H), 1.96 (br d, J = 9.4Hz, 2H), 1.74-1.69 (m, 2H), 1.34-1.27 (m, 4H), 1.26-1.20 (m, 2H).

[0183] Preparation Example 3: Preparation of chloromethylthiocyclopentane

[0184] At room temperature, dissolve 391 mg of sodium hydride in 20.0 mL of tetrahydrofuran. Cool the reaction system to 0°C, add 1.00 g of cyclopentanethiol dropwise to the reaction system, and stir for 1 hour. Add 6.33 g of bromo(chloro)methane dropwise to the reaction system at 0°C. Stir the reaction system at 0°C for 2 hours. GCMS indicates complete reaction of the starting materials. Filter the reaction solution, rinse the filter cake with 10.0 mL of tetrahydrofuran, and concentrate the filtrate under reduced pressure to obtain the crude product, the title compound. GCMS m / z = 150.1.

[0185] Preparation Example 4: Preparation of 3-(chloromethylsulfanyl)oxetane

[0186] At room temperature, 354 mg of sodium hydride was dissolved in 20.0 mL of tetrahydrofuran. The reaction system was cooled to 0°C, 0.80 g of oxetane-3-thiol was added dropwise to the reaction system and stirred for 1 hour. At 0°C, 5.74 g of bromo(chloro)methane was added dropwise to the reaction system, and the reaction system was stirred at room temperature for 16 hours. GCMS showed that the raw material reaction was complete. The reaction solution was filtered, the filter cake was rinsed with 10.0 mL of tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain a crude product to obtain the title compound. 1H NMR (400MHz, CDCl3-d) δ5.03 (t, J = 7.3Hz, 2H), 4.73-4.71 (m, 2H), 4.69-4.58 (m, 2H), 4.38-4.30 (m, 1H).

[0187] Preparation Example 5: Preparation of 2-methyl-7-methylsulfanyl-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile

[0188] Step 1: Preparation of 4-amino-6-(methylthio)-2-phenylpyrimidine-5-carbonitrile

[0189] At room temperature, 9.66 g of benzamidine hydrochloride was dissolved in 100 mL of ethanol, and 20.4 mL of N,N-diisopropylethylamine and 10.0 g of 2-[bis(methylsulfanyl)methylene]malononitrile were added. The reaction was stirred for 16 hours, and LCMS showed that the starting material had been completely consumed. After the reaction mixture was concentrated to remove ethanol, it was diluted with water and extracted twice with ethyl acetate. After the organic phases were combined, anhydrous sodium sulfate was added to dry them, and the mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1). The title compound was obtained. MS (ESI) m / z = 243.0 (M+H) + , 1 H NMR (400MHz, METHANOL-d4) δ8.50-8.39(m,2H),7.56-7.43(m,3H),2.74(s,3H).

[0190] Step 2: Preparation of 7-methylsulfanyl-5-phenyl-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine-8-carbonitrile

[0191] Dissolve 5 g of 4-amino-6-methylsulfanyl-2-phenyl-pyrimidine-5-carbonitrile in 1,4-dioxane, add 19.7 g of bromoacetone, heat to 120°C, and react for 16 hours. TLC indicates the reaction is complete. Concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product is separated using silica gel column chromatography to obtain the title compound. MS (ESI) m / z = 281.4 (M+H) + . 1 H NMR (400MHz, CDCl3-d) δ7.96 (dd, J=1.4, 8.1Hz, 2H), 7.72-7.62 (m, 3H), 7.58 (d, J=0.8Hz, 1H), 2.75 (s, 3H), 2.48 (d, J=0.8Hz, 3H).

[0192] Preparation Example 6: Preparation of 7-methylsulfanyl-5-phenyl-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine-8-carbonitrile

[0193] Dissolve 5 g of 4-amino-6-methylsulfanyl-2-phenyl-pyrimidine-5-carbonitrile in 1,4-dioxane, add 19.7 g of 3-bromo-1,1,1-trifluoroacetone, heat to 120°C, and react for 16 hours. TLC indicates completion of the reaction. Concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product is separated by silica gel column chromatography to obtain the title compound. 1 H NMR (400MHz, DMSO-d6) δ8.65 (d, J = 1.1Hz, 1H), 8.08-8.02 (m, 2H), 7.73-7.66 (m, 3H), 2.81-2.74 (m, 3H).

[0194] Preparation Example 7: Preparation of 7-methylsulfanyl-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile

[0195] Dissolve 5 g of 4-amino-6-methylsulfanyl-2-phenyl-pyrimidine-5-carbonitrile in anhydrous ethanol, add 12.7 g of 2-bromoacetaldehyde, heat to 120°C, and react for 16 hours. TLC indicates completion of the reaction. Concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product is separated by silica gel column chromatography to obtain the title compound. 1 H NMR (400MHz, CDCl3-d) δ7.92-7.85 (m, 2H), 7.74 (d, J = 1.5Hz, 1H), 7.64-7.52 (m, 4H), 2.68 (s, 3H).

[0196] Preparation Example 8: Preparation of 4-amino-6-methylsulfanyl-2-(4-pyridyl)pyrimidine-5-carbonitrile

[0197] At room temperature, add 20 g of 2-[bis(methylthio)methylene]malononitrile and 22.2 g of pyridine-4-carboximidamide hydrochloride to 200 mL of ethanol. Add 22.7 g of N,N-diisopropylethylamine to the reaction mixture. After the addition is complete, raise the temperature to 80°C and react for 12 hours. LCMS confirms the reaction is complete. After cooling the reaction mixture to room temperature, add 150 mL of water while stirring. Filter and dry the filter cake to obtain the title compound. MS (ESI) m / z = 244.2 (M+H) + , 1H NMR (400MHz, DMSO-d6) δ8.80-8.76(m,2H),8.21-8.17(m,2H),8.12-7.90(m,2H),2.70(s,3H).

[0198] Preparation Example 9: Preparation of 4-amino-6-methylsulfanyl-2-(6-morpholino-3-pyridyl)pyrimidine-5-carbonitrile

[0199] At room temperature, 12.11 g of 6-morpholinopyridine-3-carboximidamide and 8.93 g of potassium carbonate were dissolved in 120 mL of acetonitrile and 30 mL of water. 5 g of 2-[bis(methylsulfanyl)methylene]malononitrile was added, and the mixture was heated to 80°C and stirred for 16 hours. TLC (petroleum ether / ethyl acetate = 3:1) confirmed the complete reaction of the starting materials. The reaction solution was cooled to 25°C, and a solid precipitated. The solid was filtered and rinsed with ethyl acetate. The product did not dissolve, and the filtrate contained impurities, which were stored separately. The filter cake was then rinsed with a large amount of dichloromethane (2.0 L), and the filtrate was concentrated to obtain the title compound. MS (ESI) m / z = 329.0 (M+H) + , 1 H NMR (400MHz, CDCl3-d) δ9.27(d,J=2.3Hz,1H),8.44(dd,J=2.3,9.0Hz,1H),6.68(d,J=9.0Hz,1H),5.42(br s,2H),3.89-3.82(m,4H),3.72-3.66(m,4H),2.71(s,3H).

[0200] Preparation Example 10: Preparation of 4-amino-2-(1-methylpyrazol-4-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile

[0201] At room temperature, 11.3 g of 1-methylpyrazole-4-carboximidamide hydrochloride was dissolved in 100 mL of ethanol, and 15.1 g of N,N-diisopropylethylamine and 10.0 g of 2-[bis(methylsulfanyl)methylene]malononitrile were added. The reaction system was heated to 80°C and stirred for 16 hours. TLC indicated complete consumption of the starting material. The reaction solution was cooled to 25°C and concentrated under reduced pressure to remove the ethanol. 60.0 mL of water was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to obtain the title compound. 1H NMR (400MHz, DMSO-d6) δ8.25 (s, 1H), 7.90 (s, 1H), 7.59 (br d, J = 1.5Hz, 2H), 3.87-3.81 (m, 3H), 2.44 (s, 3H).

[0202] Preparation Example 11: Preparation of 3-methyl-7-methylsulfanyl-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile

[0203] Dissolve 5 g of 4-amino-6-methylsulfanyl-2-phenyl-pyrimidine-5-carbonitrile in 1,4-dioxane, add 20.1 g of 2-bromopropanal, heat to 120°C, and react for 16 hours. TLC indicates the reaction is complete. Concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product is separated using silica gel column chromatography to obtain the title compound. MS (ESI) m / z = 281.4 (M+H) + .

[0204] Preparation Example 12: Preparation of 5-(2-methyl-1-oxoisoindolin-5-yl)-7-(methylthio)imidazo[1,2-c]pyrimidine-8-carbonitrile

[0205] Step 1: Preparation of 4-amino-2-(2-methyl-1-oxoisoindolin-5-yl)-6-(methylthio)pyrimidine-5-carbonitrile

[0206] 4-Amino-2-chloro-6-(methylthio)pyrimidine-5-carbonitrile (1.50 g) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (2.04 g) were added to 1,4-dioxane (20 mL) and water (2.0 mL). Cesium carbonate (3.65 g) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (610 mg) were added at 20°C under nitrogen. The reaction was stirred at 100°C for 12 hours. The reaction was complete, and the desired product was detected. 60 mL of dimethyl sulfoxide was added to the reaction solution, which was stirred at 40°C for 0.5 hour. After complete dissolution, the solution was filtered. 200 mL of water was added to the filtrate, and the solution was stirred at 15°C for 0.5 hour, resulting in the precipitation of a solid. The mixture was filtered, the filter cake was rinsed with 50 mL of water, and the solid was dried to obtain the crude product. The crude product was again separated and purified by prep-HPLC to obtain the title compound. MS (ESI) m / z (M+H) + =312.2.

[0207] 1H NMR (400MHz, DMSO-d6) δ = 8.70-8.23 (m, 2H), 8.13-7.65 (m, 3H), 4.59-4.54 (m, 2H), 3.11 (s, 3H), 2.72 (s, 3H).

[0208] Step 2: Preparation of 5-(2-methyl-1-oxoisoindolin-5-yl)-7-(methylthio)imidazo[1,2-c]pyrimidine-8-carbonitrile

[0209] 4-Amino-2-(2-methyl-1-oxoisoindolin-5-yl)-6-(methylthio)pyrimidine-5-carbonitrile (0.10 g) and 2-bromo-1,1-diethoxyethane (2.62 g) were added to a microwave tube. Acetonitrile (20 mL) was added to the microwave tube. The reaction was allowed to proceed at 128°C for 1.5 hours under microwave irradiation. TLC (petroleum ether:ethyl acetate = 1:1) and LCMS (EC13289-64-P1C) indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The product was then purified by silica gel column chromatography to obtain the title compound.

[0210] MS (ESI) m / z (M+H) + =336.1.

[0211] Example 1: Preparation of 8-(butylsulfinyl)-5-phenylimidazo[1,2-c]thieno[3,2-e]pyrimidin-9-amine

[0212] Step 1: Preparation of 4-amino-6-(methylthio)-2-phenylpyrimidine-5-carbonitrile

[0213] At room temperature, 9.66 g of benzamidine hydrochloride was dissolved in 100 mL of ethanol, and 20.4 mL of N,N-diisopropylethylamine and 10.0 g of 2-[bis(methylsulfanyl)methylene]malononitrile were added. The reaction mixture was stirred for 16 hours, and LCMS showed complete consumption of the starting material. After the reaction mixture was concentrated to remove the ethanol, it was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain the title compound.

[0214] Step 2: Preparation of 7-methylsulfanyl-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile

[0215] 0.50 g of 4-amino-6-methylsulfanyl-2-phenyl-pyrimidine-5-carbonitrile and 1.22 g of 2-bromoethyl diethyl acetal were added to a microwave tube. 10.0 mL of ethanol was added to the microwave tube. The reaction was allowed to proceed at 120°C for 1.5 hours under microwave irradiation. TLC indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated using silica gel column chromatography to obtain the title compound. 1 H NMR (400MHz, CDCl3-d) δ7.92-7.85 (m, 2H), 7.74 (d, J = 1.5Hz, 1H), 7.64-7.52 (m, 4H), 2.68 (s, 3H).

[0216] Step 3: Preparation of 7-methylsulfonyl-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile

[0217] At room temperature, 2.50 g of 7-methylsulfanyl-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile was dissolved in 25.0 mL of chloroform, and 4.76 g (content 85.0%) of m-chloroperbenzoic acid was added in batches at room temperature. The reaction solution was stirred at room temperature for 16 hours. LCMS showed that the raw material had been completely consumed. The reaction solution was added to a saturated aqueous sodium bicarbonate solution, and the aqueous phase was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain the title compound. MS (ESI) m / z = 298.9 (M+H) + , 1 H NMR (400MHz, CDCl3-d) δ8.16 (d, J = 1.3Hz, 1H), 8.09-7.99 (m, 3H), 7.81-7.66 (m, 3H), 3.42 (s, 3H).

[0218] Step 4: Preparation of 7-(butylsulfanylmethylsulfanyl)-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile

[0219] At room temperature, 0.50 g of 7-methylsulfonyl-5-phenyl-imidazole[1,2-c]pyrimidine-8-carbonitrile was added to 5.00 mL of N,N-dimethylformamide. 131 mg of sodium hydrosulfide was then added to the reaction solution, and the temperature was raised to 80°C for 20 minutes. After TLC analysis showed that the reaction was complete, the reaction solution was cooled to room temperature, and 508 mg of triethylamine and 464 mg of 1-(chloromethylsulfinyl)butane were added to the reaction solution. The temperature was raised to 80°C for 2 hours. TLC and LCMS analysis showed that the starting material was completely consumed. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phase was concentrated to obtain the crude product. The crude product was purified by prep-TLC (petroleum ether:ethyl acetate = 1:1) to obtain the title compound. MS (ESI) m / z = 355.0 (M+H) + , 1 H NMR(400MHz, CDCl3-d)δ8.01-7.96(m,2H),7.86(d,J=1.4Hz,1H),7.74-7.63(m,4H),4.53(s,2H),2.80-2.70(m,2H),1.66(br d, J=7.1Hz, 2H), 1.49-1.38 (m, 2H), 0.93 (t, J=7.4Hz, 3H).

[0220] Step 5: Preparation of 7-(butylsulfinylmethylsulfanyl)-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile

[0221] At room temperature, add 0.33 g of 7-(butylsulfanylmethylsulfanyl)-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile to 3.30 mL of chloroform. Then, add 838 mg of acetic acid and 263 mg of hydrogen peroxide (30% content) to the reaction solution in sequence. Heat to 40°C and react for 3 hours. LCMS and TLC tests indicate that the reaction is complete. Add saturated aqueous sodium bicarbonate solution to the reaction solution, then extract twice with dichloromethane, and concentrate the organic phase to obtain a crude product. The crude product is purified by prep-TLC to obtain the title compound. MS (ESI) m / z = 371.3 (M+H) + , 1 H NMR (400MHz, CDCl3-d) δ8.01-7.96(m,2H),7.90(d,J=1.5Hz,1H),7.76-7.64(m,4H),4.47(d,J =13.3Hz,2H),3.01-2.79(m,2H),1.86-1.76(m,2H),1.57-1.45(m,2H),0.97(t,J=7.4Hz,3H).

[0222] Step 6: Preparation of 8-(butylsulfinyl)-5-phenylimidazo[1,2-c]thieno[3,2-e]pyrimidin-9-amine

[0223] 0.28 g of 7-(butylsulfinylmethylsulfanyl)-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile was dissolved in 0.60 mL of tetrahydrofuran and cooled to 0°C. 1.13 mL of lithium bis(trimethylsilyl)amide (concentration 1.00 mol / L) was slowly added dropwise to the reaction solution and replaced with nitrogen three times. After the addition was completed, the mixture was stirred at 0°C for 15 minutes. LCMS detected that the reaction was complete. After the reaction solution was returned to room temperature, 5 mL of water was added to the reaction solution, extracted twice with ethyl acetate, and the organic phase was concentrated to obtain a crude product. The obtained crude product was separated and purified by prep-HPLC to obtain Example 1 compound.

[0224] MS (ESI) m / z = 371.1 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ8.03 (d, J = 1.7Hz, 1H), 7.99-7.96 (m, 2H), 7.72-7.64 (m, 4H), 6.54 (s, 2H), 3.21-3. 15(m,1H),3.08-3.01(m,1H),1.66-1.53(m,2H),1.49-1.40(q,J=7.4Hz,2H),0.92-0.88(t,J=7.3Hz,3H).

[0225] Example 2: Preparation of 8-(butylsulfinyl)-9-methoxy-5-phenylimidazo[1,2-c]thieno[3,2-e]pyrimidine

[0226] Step 1: Preparation of 7-(butylsulfanylmethylsulfanyl)-5-phenyl-imidazo[1,2-c]pyrimidine-8-carboxylic acid methyl ester

[0227] At room temperature, 0.24 g of 7-(butylsulfanylmethylsulfanyl)-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile was added to 3.84 mL of methanolic hydrochloric acid (4 mol / L). The reaction solution was stirred at 85°C for 15 hours. LCMS and TLC (petroleum ether:ethyl acetate = 1:1) showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z = 388.2 (M+H) + .

[0228] Step 2: Preparation of 7-(butylsulfinylmethylsulfanyl)-5-phenyl-imidazo[1,2-c]pyrimidine-8-carboxylic acid methyl ester

[0229] 0.48 g of methyl 7-(butylsulfanylmethylsulfanyl)-5-phenyl-imidazo[1,2-c]pyrimidine-8-carboxylate was added to 2.3 mL of chloroform. At room temperature, 1.12 g of acetic acid and 351 mg of hydrogen peroxide (30% content) were added to the reaction solution and stirred at room temperature for 13 hours. LCMS and TLC (petroleum ether: ethyl acetate = 0:1) showed that the reaction was complete. The reaction solution was poured into an aqueous sodium sulfite solution, extracted twice with dichloromethane, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified using prep-TLC (petroleum ether: ethyl acetate = 0:1) to obtain the title compound. MS (ESI) m / z = 404.1 (M+H) + , 1 H NMR (400MHz, CDCl3-d) δ8.02(dd,J=1.6,7.9Hz,2H),7.86(d,J=1.4Hz,1H),7.77(s,1H),7.73-7.64(m,3H),4.77(d,J=13.0Hz,1H),4.26(d,J= 13.0Hz,1H),4.16(s,3H),2.97(td,J=8.1,13.0Hz,1H),2.86-2.71(m,1H),1.81(quin,J=7.7Hz,2H),1.52-1.41(m,2H),0.95(t,J=7.4Hz,3H).

[0230] Step 3: Preparation of 8-(butylsulfinyl)-9-methoxy-5-phenylimidazo[1,2-c]thieno[3,2-e]pyrimidine

[0231] 0.1 g of methyl 7-(butylsulfinylmethylsulfanyl)-5-phenyl-imidazo[1,2-c]pyrimidine-8-carboxylate was added to 1.0 mL of N,N-dimethylformamide. 41.71 mg of potassium tert-butoxide and 70.35 mg of methyl iodide were added to the system under nitrogen protection at 0°C. Stir at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction solution was quenched by adding water, extracted twice with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. The obtained crude product was separated and purified by Prep-HPLC to obtain Example 2 compound. MS (ESI) m / z = 386.0 (M+H) + , 1H NMR(400MHz, CDCl3-d)δ7.89-7.81(m,2H),7.78(s,1H),7.60(s,1H),7.59-7.51(m,3H),4.28(s,3H) ,3.21-3.12(m,1H),3.09-3.00(m,1H),1.77-1.64(m,2H),1.51-1.36(m,2H),0.88(t,J=7.3Hz,3H).

[0232] Example 3: Preparation of 2-((9-amino-5-phenylimidazo[1,2-c]thieno[3,2-e]pyrimidin-8-yl)sulfinyl)ethane-1-ol

[0233] Step 1: Preparation of 7-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfanylmethylsulfanyl]-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile

[0234] At room temperature, 3.25 g of 7-methylsulfonyl-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile was dissolved in 25 mL of N,N-dimethylformamide, 1.22 g of sodium hydrosulfide was added, and the mixture was heated to 80°C in a sealed container for 20 minutes. TLC (petroleum ether / ethyl acetate = 1 / 1) showed complete consumption of the starting material. The reaction system was cooled to room temperature, and 3.31 g of triethylamine and 3.94 g of tert-butyl-[2-(chloromethylsulfanyl)ethoxy]-dimethylsilane were added. The mixture was heated to 80°C in a sealed container for 2 hours. LCMS confirmed the reaction was complete. The reaction system was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain the title compound. MS (ESI) m / z = 457.3 (M+H) + .

[0235] Step 2: Preparation of 7-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfinylmethylsulfanyl]-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile.

[0236] 1.16 g of 7-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfanylmethylsulfanyl]-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile was dissolved in 23.2 mL of chloroform and 2.29 g of acetic acid at room temperature, and 719 mg of hydrogen peroxide was added dropwise. The temperature was raised to 40°C and stirred for 2 hours. LCMS showed that the reaction of the raw materials was complete. The reaction solution was added to 15.0 mL of saturated aqueous sodium bicarbonate solution and 20.0 mL of saturated aqueous sodium sulfite solution, extracted twice with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 0 / 1) to obtain the title compound. MS (ESI) m / z = 473.3 (M+H) + .

[0237] Step 3: Preparation of 8-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfinyl)-5-phenylimidazo[1,2-c]thieno[3,2-e]pyrimidin-9-amine

[0238] At 0°C, 0.25 g of 7-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfinylmethylsulfanyl]-5-phenyl-imidazo[1,2-c]pyrimidine-8-carbonitrile was dissolved in 5.0 mL of tetrahydrofuran, and 652 μL of lithium hexamethyldisilazide (concentration 1.0 mol / L) was added dropwise. The reaction solution was stirred at 0°C for 20 minutes. LCMS showed that the reaction was complete. The reaction solution was added to water and extracted twice with ethyl acetate. The combined organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 0 / 1) to obtain the title compound. MS (ESI) m / z = 473.5 (M+H) + , 1 H NMR(400MHz, CDCl3-d)δ7.95-7.90(m,2H),7.83(d,J=1.6Hz,1H),7.67-7.58(m,4H),6.14-5 .83(m,2H),4.18-3.90(m,2H),3.65-3.23(m,2H),0.97-0.89(m,9H),0.12(d,J=8.3Hz,6H).

[0239] Step 4: Preparation of 2-((9-amino-5-phenylimidazo[1,2-c]thieno[3,2-e]pyrimidin-8-yl)sulfinyl)ethan-1-ol.

[0240] At room temperature, 80 mg of 8-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfinyl)-5-phenylimidazo[1,2-c]thieno[3,2-e]pyrimidin-9-amine was dissolved in 0.50 mL of tetrahydrofuran, and 202 μL of tetrabutylammonium fluoride (1.0 mol / L) was added. The reaction system was stirred at 25°C for 2 hours. LCMS showed complete consumption of the starting material. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC to obtain the title compound, Example 3.

[0241] MS (ESI) m / z = 358.9 (M+H) + , 1 H NMR (400MHz, CDCl3-d) δ = 7.85 (dd, J = 1.8, 7.5Hz, 2H), 7.76 (d, J = 1.4Hz, 1H), 7.61-7.49 (m, 4H), 6.17-5.63 (m, 2H ),4.27-4.17(m,1H),4.16-4.03(m,1H),3.54(ddd,J=3.4,6.8,13.4Hz,1H),3.20(ddd,J=3.4,7.2,13.3Hz,1H).

[0242] Example 4: Preparation of 8-(butylsulfinyl)-3-methyl-5-phenylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidin-9-amine

[0243] Step 1: Preparation of 4-hydroxy-6-methylthio-2-phenyl-pyrimidine-5-carbonitrile

[0244] Add 10.0 g of ethyl 2-cyano-3,3-bis(methylthio)prop-2-enoate and 7.93 g of benzamidine hydrochloride to a 500 mL three-necked flask. At 20°C, add 100 mL of ethanol and 9.62 mL of N,N-diisopropylethylamine to the reactor. After the addition is complete, raise the temperature to 80°C and stir at this temperature for 12 hours. LCMS indicates the reaction is complete. Add 100 mL of water to the reaction solution and continue stirring at room temperature (20°C) for 0.5 hours. Filter the reaction solution under reduced pressure to obtain the title compound.

[0245] MS (ESI) m / z = 244.1 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ13.65-13.36(m,1H),8.28-8.16(m,2H),7.72-7.67(m,1H),7.63-7.57(m,2H),2.72(s,3H).

[0246] Step 2: Preparation of 4-chloro-6-methylthio-2-phenyl-pyrimidine-5-carbonitrile

[0247] Add 4.00 g of 4-hydroxy-6-methylthio-2-phenyl-pyrimidine-5-carbonitrile to 40 mL of phosphorus oxychloride at 25°C. After addition, heat to 80°C and allow to react for 12 hours. LCMS confirms complete reaction. After the reaction mixture cools to room temperature, slowly add water to quench the mixture while stirring. Add aqueous sodium bicarbonate to make the reaction mixture alkaline, then extract twice with ethyl acetate and concentrate the organic phase to yield the title compound.

[0248] MS (ESI) m / z 262.1=(M+H) + , 1 H NMR (400MHz, DMSO-d6) δ8.48-8.36(m,2H),7.42-7.37(m,1H),7.63-7.57(m,2H),2.72(s,3H).

[0249] Step 3: Preparation of N-(5-cyano-6-methylsulfanyl-2-phenyl-pyrimidin-4-yl)acetohydrazide

[0250] 3.60 g of 4-chloro-6-methylthio-2-phenyl-pyrimidine-5-carbonitrile was added to 36 mL of ethanol at room temperature of 25 ° C. 1.53 g of acetic hydrazide was added to the reaction solution. After the addition was completed, the temperature was raised to 80 ° C and reacted at this temperature for 12 hours. LCMS detection showed that the raw material disappeared. After the reaction solution returned to room temperature, 60 mL of water and 30 mL of ethyl acetate were added to the reaction solution, and the organic phase was concentrated by liquid extraction to obtain a crude product. The crude product was added with 5 mL of ethyl acetate and 30 mL of tert-methyl ether for slurry purification. The title compound was obtained. MS (ESI) m / z = 300.2 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ10.44-9.90(m,2H),8.38(br d,J=7.1Hz,2H),7.62-7.52(m,3H),2.71(s,3H),1.99(s,3H).

[0251] Step 4: Preparation of 3-methyl-7-(methylthio)-5-phenyl-[1,2,4]triazolo[4,3-c]pyrimidine-8-carbonitrile

[0252] At room temperature (25°C), add 1.38g of nitrogen-(5-cyano-6-methylsulfanyl-2-phenyl-pyrimidin-4-yl)acetohydrazide to 13.8mL of acetonitrile. Then, slowly add 642μL of N,N-diisopropylethylamine and 214μL of phosphorus oxychloride dropwise to the reaction solution. After the addition is complete, raise the temperature to 90°C and allow the reaction to proceed at this temperature for 12 hours. TLC and LCMS confirm the complete reaction of the starting materials. After the reaction solution cools to room temperature, slowly add the reaction solution to water to quench the reaction while stirring. Add aqueous sodium bicarbonate solution to make the reaction solution alkaline, then extract twice with ethyl acetate, and concentrate the organic phase. The resulting crude product is separated and purified using a chromatography column (petroleum ether / ethyl acetate = 50 / 1 to 0 / 1). This yields the title compound.

[0253] MS (ESI) m / z = 282.1 (M+H) + , 1 H NMR (400MHz, CDCl3-d) δ8.78-8.72(m,2H),7.75-7.61(m,3H),2.85(s,3H),2.70(s,3H).

[0254] Step 5: Preparation of 3-methyl-7-(methylsulfonyl)-5-phenyl-[1,2,4]triazolo[4,3-c]pyrimidine-8-carbonitrile

[0255] Dissolve 0.6 g of 3-methyl-7-(methylthio)-5-phenyl-[1,2,4]triazolo[4,3-c]pyrimidine-8-carbonitrile in 6 mL of chloroform at 25°C. Slowly add 1.15 g of m-chloroperbenzoic acid to the reaction mixture under nitrogen. After addition, allow to react at 25°C for 3 hours. LCMS confirms the reaction is complete. Add the reaction mixture to 20 mL of saturated sodium bicarbonate solution, extract twice with dichloromethane, combine the concentrated organic phases, and quench with sodium sulfite solution to yield the title compound.

[0256] MS (ESI) m / z = 314.1 (M+H) + .

[0257] Step 6: Preparation of 7-(((butylthio)methyl)thio)-3-methyl-5-phenyl-[1,2,4]triazolo[4,3-c]pyrimidine-8-carbonitrile

[0258] At room temperature (25°C), 1.00 g of 3-methyl-7-(methylsulfonyl)-5-phenyl-[1,2,4]triazolo[4,3-c]pyrimidine-8-carbonitrile was added to 10 mL of N,N-dimethylformamide. 250 mg of sodium hydrosulfide was then added to the reaction solution, which was heated to 80°C and allowed to react for 20 minutes. After TLC analysis, the reaction solution was cooled to room temperature, and 1.33 mL of triethylamine and 885 mg of 1-(chloromethylthio)butane were added. After the addition was complete, the temperature was raised to 80°C and allowed to react for 2 hours. TLC and LCMS analysis confirmed the reaction was complete. After the reaction solution cooled to room temperature, water (30 mL) was added, and the solution was extracted twice with ethyl acetate. The organic phase was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain the title compound. MS (ESI) m / z = 370.4 (M+H) + , 1 H NMR (400MHz, CDCl3-d) δ8.80-8.68(m,2H),7.75-7.61(m,3H),4.60(s,2H),2.82-2.73(m,2H),2.72-2.63(m,3H),1.65(br d,J=7.3Hz,2H),1.52-1.37(m,2H),1.04-0.89(m,3H).

[0259] Step 7: Preparation of 7-(((butylsulfinyl)methyl)thio)-3-methyl-5-phenyl-[1,2,4]triazolo[4,3-c]pyrimidine-8-carbonitrile

[0260] At room temperature (25°C), add 0.52 g of 7-(((butylthio)methyl)thio)-3-methyl-5-phenyl-[1,2,4]triazolo[4,3-c]pyrimidine-8-carbonitrile to 5.2 mL of chloroform. Then, add 1.21 mL of glacial acetic acid and 338 μL of hydrogen peroxide to the reaction solution. After the addition is complete, raise the temperature to 40°C and allow the reaction to react at this temperature for 3 hours. LCMS and TLC confirm the reaction is complete. After cooling the reaction solution to room temperature, add saturated aqueous sodium bicarbonate (15 mL) to the reaction solution, extract twice with dichloromethane, and concentrate the organic phase to obtain a crude product. The crude product is purified by prep-TLC to obtain the title compound.

[0261] MS (ESI) m / z 386.3 = (M + H) + . 1H NMR(400MHz, CDCl3-d)δ8.66-8.60(m,2H),7.67-7.53(m,3H),4.75-4.39(m,2H),2.94-2.7 1(m,2H),2.62(s,3H),1.75(quin,J=7.6Hz,2H),1.46-1.37(m,2H),0.89(t,J=7.3Hz,3H).

[0262] Step 8: Preparation of 8-(butylsulfinyl)-3-methyl-5-phenylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidin-9-amine

[0263] Dissolve 0.2 g of 7-(((butylsulfinyl)methyl)thio)-3-methyl-5-phenyl-[1,2,4]triazolo[4,3-c]pyrimidine-8-carbonitrile in 2.0 mL of tetrahydrofuran and cool to 0°C. At this temperature, slowly add 78 μL of lithium bis(trimethylsilyl)amide in tetrahydrofuran (THF) dropwise to the reaction mixture, and replace the atmosphere with nitrogen three times. After addition, stir at 0°C for 2 hours. LCMS confirms the reaction is complete. After returning the reaction mixture to room temperature, water (10 mL) is added, and the mixture is extracted twice with ethyl acetate. The organic phase is concentrated to obtain the crude product. The crude product is purified by prep-HPLC (column: Waters xbridge 150*25 mm 10 μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 32%-62%, 10 min) to obtain the title compound.

[0264] MS (ESI) m / z 386.2 = (M+H) + , 1 H NMR(400MHz, CDCl3-d)δ8.67-8.54(m,2H),7.68-7.56(m,3H),6.12-5.38(m,2H),3.4 3-3.09(m,2H),2.72(s,3H),1.89-1.78(m,2H),1.58-1.51(m,2H),1.04-0.93(m,3H).

[0265] Using the corresponding commercial reagents and the products of the above preparation examples and examples as raw materials, a class of compounds were prepared using a preparation method similar to the above examples. The structures and characterization data of the compounds are shown in Table 1:

[0266] Table 1

[0267] Biological tests

[0268] Test Example 1: 15-PGDH kinase activity detection

[0269] 1. Experimental Materials:

[0270] 2. Experimental methods:

[0271] a. Prepare a reaction buffer solution containing 50 mM Tris-HCl, 0.01% Tween 20, pH 7.5 with ultrapure water;

[0272] b. Prepare a 10 mM stock solution of the test compound in DMSO. Then dilute the stock solution with reaction buffer to obtain a 4000 nM solution of test compound 1. Serially dilute solution 1 in a three-fold gradient to obtain nine concentrations of test compound solutions 2 to 10. Add 5 μL of each of test compound solutions 1 to 10 to a 384-well plate as an experimental well.

[0273] c. Add 5 μL of reaction buffer to the 384-well plate as positive control wells and blank control wells.

[0274] d. Prepare a 15-PGDH protein solution at 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. Add 5 μL of reaction buffer to the blank control wells, and then centrifuge the plate at 2000 rpm for 30 seconds.

[0275] e. Prepare 5 mM β-NAD and 2 mM PGF2α in reaction buffer, mix them in a 1:1 volume ratio to prepare a substrate mixture, add 10 μL of the substrate mixture to the experimental wells, positive control wells, and blank control wells to start the reaction;

[0276] f. Use a multifunctional microplate reader to continuously detect the fluorescence signal value of each well (Ex / Em=340 / 450).

[0277] 3. Data Analysis:

[0278] a) Analyze the continuous fluorescence signal values ​​using the "kinetic calculations-slope calculation method" in PHERAstar Data analysis software to obtain the slope of each experimental well;

[0279] b) Calculate the inhibition rate using the following formula:

[0280] 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%.

[0281] c) Calculate IC50 and plot inhibition rate-dose curve: Use GraphPad Prism 6.0 to fit compound concentration and corresponding inhibition rate using nonlinear regression (dose response - variable slope) to calculate the IC50 value. The formula is as follows:

[0282] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)), where X is the log value of compound concentration and Y is the inhibition rate.

[0283] 4. Experimental results:

[0284] The compounds in this application have the following inhibitory activities on 15-PGDH enzyme:

[0285] In the table, “A+” represents the IC50 of 15-PGDH enzyme inhibition activity. 50 The range is less than 1.5 nM; "A" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than or equal to 1.5 nM and less than 4 nM; "B" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than or equal to 4 nM and less than 10 nM; "C" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than or equal to 10nM and less than 15nM. "D" represents the IC of 15-PGDH enzyme inhibition activity. 50 The range is greater than or equal to 15nM and less than 30nM. "E" represents the IC of 15-PGDH enzyme inhibition activity. 50 The range is greater than 30 nM.

[0286] The experiments found that the IC50 value of the compounds of the present application for the 15-PGDH enzyme inhibitory activity is less than 100nM. The IC50 value of some compounds of the present application for the 15-PGDH enzyme inhibitory activity is less than 100nM. 50 The IC values ​​of some compounds in this application for 15-PGDH enzyme inhibition are greater than or equal to 20 nM and less than 50 nM. 50 The IC values ​​of some compounds of the present invention for 15-PGDH enzyme inhibition are greater than or equal to 10 nM and less than 20 nM. 50 The IC values ​​of certain compounds of the present invention for 15-PGDH enzyme inhibition are greater than or equal to 3 nM and less than 10 nM. 50 The IC values ​​of certain compounds of the present invention for 15-PGDH enzyme inhibition are greater than or equal to 1.5 nM and less than 3 nM. 50The value was less than 1.5 nM.

[0287] Test Example 2: Intracellular PGE2 upregulation activity assay

[0288] 1. Experimental Materials:

[0289] 2. Experimental methods:

[0290] a) A549 cells were seeded in 24-well plates and stimulated with IL-1β for 16 h after cell attachment to induce COX2 expression and PGE2 production.

[0291] b) Prepare the test compound solution in F12k Kaighn's Modification medium and serially dilute to 7 concentrations, including 0.64 nM, 3.2 nM, 16 nM, 80 nM, 400 nM, 2000 nM, and 10000 nM. Set up a positive control group and a negative control group. Collect the cell supernatant after 8 hours. The positive control group is induced with IL-1β but not treated with the compound. The negative control group is not stimulated with IL-1β and not treated with the compound.

[0292] c) The PGE2 content of the sample was determined using a Prostaglandin E2 Kit, and the fluorescence signal was detected by a multifunctional microplate reader (Ex / Em=337 / 620, 337 / 665).

[0293] 3. Data Analysis:

[0294] a) Use the PGE2 standard in the "Prostaglandin E2 Kit" to draw a standard curve and substitute the sample fluorescence signal to calculate the PGE2 concentration.

[0295] b) Calculate the PGE2 upregulation rate (%) using the following formula:

[0296] PGE2 upregulation ratio % = PGE2 concentration in sample group / PGE2 concentration in positive control group × 100%.

[0297] 4. Experimental Results

[0298] The compounds of the present application, especially the compounds prepared in Examples 1-26, can achieve an upregulation ratio of PGE2 in A549 cells of >100%. The compounds of the present application, especially the compounds prepared in Examples 1-26, have good activity in upregulating intracellular PGE2.

[0299] For the purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present application. All statements regarding the dates of these documents or the representations of their contents are based on information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications become part of the common general knowledge in the art in any country.

[0300] 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 fall within the scope of protection of the present application.

Claims

1. A compound represented by formula (I), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof: Ring A is selected from an aromatic ring, an aromatic heterocycle, an unsaturated aliphatic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated aliphatic heterocycle, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated aliphatic heterocycle. R is selected from C1~C 10 Chain hydrocarbon group, 3-12 membered alicyclic ring, 3-12 membered alicyclic heterocyclic ring, wherein R is replaced by 0-2 R 2 Substituted, the R 2 are each independently selected from deuterium, tritium, nitro, hydroxy, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle, wherein R a 、R b 、R X 、R Y Each is independently selected from C1-C6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, o is selected from 0, 1, 2, 3, 4, R 1 each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imino, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, is a single bond or a double bond, and when When it is a double bond, X and Y are each independently selected from CR B or N; when When it is a single bond, X and Y are each independently selected from CR C R D NR E , R A 、R B 、R C 、R D 、R E Each is independently selected from hydrogen, hydroxyl, halogen, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl; The aromatic heterocycle, aliphatic heterocycle, unsaturated aliphatic heterocycle, cycloalkyl, and heterocycloalkyl groups each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, and S; The R 1 Optionally substituted by one or more groups independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered cycloalkyl, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle.

2. The compound according to claim 1, its stereoisomer, tautomer or mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: described is a double bond, and at least one of X and Y is selected from CR B ; Alternatively, X is selected from N, and Y is selected from CR B , where R B Selected from hydrogen, hydroxy, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Alternatively, the Y is selected from N, and the X is selected from CR B , where R B Selected from hydrogen, hydroxy, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Alternatively, X and Y are both selected from CR B , where R B Each is independently selected from hydrogen, hydroxy, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

3. The compound according to claim 1, its stereoisomer, tautomer or mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: described is a single bond, and at least one of X and Y is selected from CR C R D ; Alternatively, X is NR E , Y is CR C R D , where R C 、R D 、R E each independently selected from hydrogen, hydroxy, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Alternatively, X is CR C R D , Y is NR E , where R C 、R D 、R E each independently selected from hydrogen, hydroxy, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Alternatively, both X and Y are CR C R D , where R C 、R D Each is independently selected from hydrogen, hydroxy, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

4. The compound, stereoisomer, tautomer or mixture thereof, or pharmaceutically acceptable salt, or solvate, or prodrug thereof according to any one of claims 1 to 3, wherein: The R A Selected from hydrogen, hydroxy, cyano, fluorine, chlorine, bromine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl.

5. The compound, stereoisomer, tautomer or mixture thereof, or pharmaceutically acceptable salt, or solvate, or prodrug thereof according to any one of claims 1 to 4, wherein: The R is selected from C1 to C 10 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, wherein R is replaced by 0 or 1 R 2 replace.

6. The compound according to claim 4, its stereoisomer, tautomer or mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: The compound is represented by formula (II), formula (III) or formula (IV): R B each independently selected from hydrogen, hydroxy, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, R is selected from C1~C 10 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, wherein R is replaced by 0 or 1 R 2 Substituted, the R 2 Selected from deuterium, tritium, nitro, hydroxy, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle, wherein R a 、R b 、R X 、R Y Each is independently selected from C1-C6 alkyl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocycloalkyl.

7. The compound, stereoisomer, tautomer or mixture thereof, or pharmaceutically acceptable salt, or solvate, or prodrug thereof according to any one of claims 1 to 6, wherein: The R is selected from C1 to C 10 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, the alkyl is a straight chain alkyl or a branched chain alkyl, the cycloalkyl and heterocycloalkyl are monocyclic or bicyclic, and the heterocycloalkyl contains 1 heteroatom selected from N, O, S, wherein R is 0 or 1 R 2 replace; Preferably, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, cyclopentyl, Propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Where R is replaced by 0 or 1 R 2 replace; The R 2 Selected from deuterium, tritium, nitro, hydroxy, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle, wherein R a 、R b 、R X 、R Y Each is independently selected from C1-C6 alkyl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocycloalkyl.

8. The compound according to claim 7, its stereoisomer, tautomer or mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: The R 2 is selected from deuterium, tritium, nitro, hydroxyl, aldehyde, halogen, cyano, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethoxy, trifluoroethoxy, trifluoro-n-propoxy, -C(O)OCH3, -C(O)OC2H5, -OC(O)CH3, -OC(O)C2H5, -C(O)NHCH3, -C(O)NHC2H5, -NHC(O)CH3, -NHC(O)C2H5, =O, 9. The compound, stereoisomer, tautomer or mixture thereof, or pharmaceutically acceptable salt, or solvate, or prodrug thereof according to any one of claims 1 to 8, wherein: The ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-8 membered unsaturated alicyclic ring, a 7-12 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-12 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring; preferably, the aromatic ring and the aromatic heterocycle are monocyclic or cyclic, the unsaturated alicyclic ring is monocyclic, and the cyclic ring is bicyclic, and the aromatic heterocycle, the unsaturated alicyclic heterocycle, and the cyclic ring each independently contain 1-2 heteroatoms, and the heteroatoms are independently selected from N, O, and S.

10. The compound according to claim 9, its stereoisomer, tautomer or mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: Ring A is selected from 11. The compound, stereoisomer, tautomer or mixture thereof, or pharmaceutically acceptable salt, or solvate, or prodrug thereof according to any one of claims 1 to 10, wherein: R 1 are each independently selected from deuterium, tritium, nitro, hydroxyl, sulfhydryl, halogen, cyano, =0, imino, amine, ester, aldehyde, carboxyl, amide, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolane, dioxhexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclopropylmethoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, n-hexyloxy, wherein R 1 Optionally substituted by one or more independently selected from deuterium, tritium, nitro, hydroxyl, -NH2, thiol, halogen, cyano, ester, carboxyl, amide, =O, =NH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-8 membered cycloalkyl, 5-10 membered alicyclic ring, 6-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring.

12. The compound according to claim 1, its stereoisomer, tautomer or mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein The ring A is selected from phenyl, naphthyl, a 5-8 membered aromatic heterocycle containing at least one heteroatom of N, O or S, a 5-8 membered unsaturated alicyclic ring containing at least one heteroatom of N, O or S, a 9-12 membered cyclic ring formed by a phenyl group and the 5-8 membered unsaturated alicyclic ring, and an 8-14 membered cyclic ring formed by the 5-8 membered aromatic heterocycle and the 5-8 membered unsaturated alicyclic ring; The R is selected from C1 to C 10 Alkyl, 4-6 membered cycloalkyl, 3-6 membered heterocycloalkyl containing at least one heteroatom selected from O or S, wherein R is replaced by 0-1 R 2 Substituted, the R 2 Each independently selected from deuterium, tritium, hydroxyl, -C(O)OR a , phenyl, thienyl, furyl, pyrrole yl, thiazolyl; Said o is selected from 0, 1, 2; The R 1 Each is independently selected from =O, ester group, carboxyl group, C1-C6 alkyl group, 5-6 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S; is a double bond, X is selected from CR B , Y is selected from CR B or N, where The R B Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl; R A Selected from hydrogen, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; Preferably, wherein The ring A is selected from The R is selected from C1-C6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl containing 1 O atom, wherein R is replaced by 0-1 R 2 Substituted, the R 2 Each independently selected from hydroxyl, phenyl; Said o is selected from 0, 1, 2; The R 1 Each is independently selected from =O, carboxyl, C1-C3 alkyl, 5-6 membered heterocycloalkyl containing at least one heteroatom selected from N, O or S; is a double bond, X is selected from CR B , Y is selected from CR B or N, wherein the R B Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl; R A Selected from hydrogen, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl.

13. The compound, stereoisomer, tautomer or mixture thereof, or pharmaceutically acceptable salt, or solvate, or prodrug thereof according to any one of claims 1 to 12, wherein: Selected from the following compounds:

14. A pharmaceutical composition comprising at least one compound, stereoisomer, tautomer or mixture thereof according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, and at least one pharmaceutically acceptable excipient.

15. A compound according to any one of claims 1 to 13, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt, or a solvate, or a prodrug thereof, or a pharmaceutical composition according to claim 14 for use as a medicament; Preferably, the drug 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 injury, autoimmune disease, graft-versus-host disease, osteoporosis, ear disease, eye disease, neutropenia, diabetes, underactive bladder, or for promoting hair growth, pigmentation, tissue repair, tissue regeneration, implant promotion in stem cell transplantation, 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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