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

Abstract

This application relates to a compound of formula (I) that has the ability to regulate 15-PGDH activity and its use in the pharmaceutical field. This application also provides methods for preparing the compound of the application, compositions containing the compound of the application, and pharmaceutical uses of the compound as a 15-PGDH inhibitor. #imgabs0#

Description

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 drugs, belonging to the field of medicinal chemistry. Background Art

[0002] 15-hydroxyprostaglandin dehydrogenase (15-PGDH) belongs to the evolutionary conservative superfamily of short-chain dehydrogenase / reductase (SDR), and according to the recently approved human enzyme nomenclature, it is named SDR36C1. According to existing research results, most of the in vivo activity can be attributed to the type I 15-PGDH encoded by the HPGD gene. 15-PGDH plays an important role in the inactivation of active prostaglandins (PGD2, PGE1, PGE2, PGF2α, PGI2, etc.), hydroxyeicosatetraenoic acid (HETE) and inflammation-resolving lipid mediators (RvD1, RvD2, RvE1, MaR1, LXA4, etc.) (hereinafter referred to as 15-PGDH substrates) (for example, by catalyzing the oxidation reaction of the 15-hydroxyl group of PGF2α and converting it into 15-keto-PGF2α). These 15-PGDH substrates exert their function through the specific receptors present on target cells. Among them, prostaglandins PGE1, PGE2, PGF2α, PGI2, etc. are often used to evaluate the activity of 15-PGDH. For example, the activity of PGDH is evaluated by testing the ketone metabolite of the 15-hydroxyl group of PGF2α (Journal of Clinical Endocrinology and Metabolism, Vol. 84, No. 1, 291-299).

[0003] Receptors for 15-PGDH substrates are widely and differentially distributed in vivo, and the diversity of receptor types, signaling pathways, and expression distribution contributes to diverse in vivo functions. For example, PGE1 acts on blood vessels and platelets, increasing bleeding flow through vasodilation and platelet aggregation inhibition. Therefore, it is commonly used to treat conditions 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, on the other hand, suppresses inflammation by enhancing the barrier function of pulmonary vessels. Furthermore, PGE2 has vasodilatory effects and possesses multiple functions, including those related to blood pressure, pain, bone formation and cell growth, stem cell differentiation, 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 the migration / activation of neutrophils and accelerate the apoptosis of neutrophils. In addition, they are indispensable in the process of increasing the phagocytic activity of macrophages and effectively removing the apoptotic neutrophils / tissue fragments remaining in the inflammatory site. These functions promote inflammation and maintain homeostasis in the organism. It is reported that these inflammation-resolving lipid mediators show medicinal efficacy in various types of pathological models (such as mouse lung inflammation model, colitis model and liver injury model).

[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. 15-PGDH inhibitors can be used to prevent or treat diseases related to 15-PGDH and / or 15-PGDH substrates, and / or when it is necessary to increase the substrate level of 15-PGDH in a subject.

[0006] As mentioned above, some substrates of 15-PGDH have the effects of anti-fibrosis, anti-inflammation, blood flow improvement, growth promotion, promotion of stem cell increase, promotion of smooth muscle contraction / relaxation, influence on immunosuppression and bone metabolism, etc. 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 exacerbation of 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 bone Pelvic pain 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 alkylating agents, DNA synthesis inhibitors, DNA gyrase inhibitors, anti-metabolites and other anticancer chemotherapy agents, cellular humoral immunotherapy, or 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 leukemia), leukemia, stomatitis ... growth), osteoporosis, ear diseases (such as hearing loss, tinnitus, vertigo and balance disorders), eye diseases (such as glaucoma and dry eyes), diabetes, underactive bladder, neutropenia, nervous system diseases caused by stem cell, bone marrow or organ transplantation (such as mental neurological diseases, neuropathy, neurotoxic diseases, neuropathic pain and neurodegenerative diseases), muscle regeneration diseases (such as muscle atrophy, muscular dystrophy and muscle damage); in addition, 15-PGDH inhibitors can also be used to promote cervical ripening.

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

[0008] One aspect of the present application is to provide 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:

[0009]

[0010] Ring A is selected from aromatic rings, aromatic heterocycles, and unsaturated aliphatic heterocycles,

[0011] Ring B is a 5- to 12-membered saturated aliphatic heterocyclic ring or a ring formed by combining a 5- to 12-membered saturated aliphatic heterocyclic ring and a benzene ring.

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

[0013] R 1 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imino, amine, ester, aldehyde, carboxyl, amide, C3-C8 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, 3-8 membered saturated heterocyclic ring,

[0014] Or when o is selected from 2 or 3, any two R 1 Together with the atoms of the ring A to which it is connected, it forms a 3-8 membered alicyclic group or a 3-8 membered alicyclic heterocyclic group;

[0015] wherein the aromatic heterocycle, saturated aliphatic heterocycle, unsaturated aliphatic heterocycle, and aliphatic heterocyclic group each independently contain 1 to 3 heteroatoms, the heteroatoms being independently selected from N, O, and S, and ring B contains at least 1 nitrogen atom;

[0016] The ring B, 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 alkoxy, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0017] Furthermore, the ring B is preferably a monocyclic ring, a fused ring or a spirocyclic ring.

[0018] In some embodiments, Ring A is selected from an aromatic ring, an aromatic heterocycle, an unsaturated aliphatic heterocycle,

[0019] Ring B is a 5- to 12-membered saturated aliphatic heterocyclic ring or a ring formed by combining a 5- to 12-membered saturated aliphatic heterocyclic ring and a benzene ring.

[0020] o is selected from 0, 1, 2, 3,

[0021] R 1 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imino, amine, ester, aldehyde, carboxyl, amide, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered saturated heterocyclic ring,

[0022] Or when o is selected from 2 or 3, any two R 1 Together with the atoms of the ring A to which it is connected, it forms a 3-8 membered alicyclic group or a 3-8 membered alicyclic heterocyclic group;

[0023] wherein the aromatic heterocycle, saturated aliphatic heterocycle, unsaturated aliphatic heterocycle, and aliphatic heterocyclic group each independently contain 1 to 3 heteroatoms, the heteroatoms being independently selected from N, O, and S, and ring B contains at least 1 nitrogen atom;

[0024] The ring B, R 1 Optionally substituted by one or more groups independently selected from deuterium, tritium, nitro, hydroxyl, -NH2, thiol, halogen, cyano, ester, carboxyl, amide, =O, =NH, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0025] Furthermore, the ring B is preferably a monocyclic ring, a fused ring or a spirocyclic ring.

[0026] Furthermore, in certain embodiments of the present application, the aforementioned ring B is selected from

[0027] Wherein X is selected from covalent bond, O, S, NH, (CH2) n , SO2, Y is selected from covalent bonds, S, NH, (CH2) n , SO2;

[0028] m is selected from 0, 1, 2, 3; R 2 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, cyano, halogen, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; and n is selected from 1, 2, or 3.

[0029] Alternatively, in certain embodiments of the present application, the aforementioned ring B is selected from Among them, m, R 2 The definition is consistent with the previous definition in this application.

[0030] Further, in certain embodiments, the ring B is selected from Among them, m, R 2 The definition is consistent with the previous definition in this application.

[0031] Further, in certain embodiments, the ring B is selected from Among them, m, R 2 The definition is consistent with the previous definition in this application.

[0032] Furthermore, in certain specific embodiments of the present application, the aforementioned R 2 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, cyano, fluorine, chlorine, bromine, amino, ester, aldehyde, carboxyl, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclobutyl, cyclopropyl, phenyl, and pyridyl.

[0033] Furthermore, the ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, and a 6-8 membered unsaturated aliphatic heterocycle; preferably, the aromatic ring and aromatic heterocycle are monocyclic or fused rings, the unsaturated aliphatic heterocycle is a monocyclic ring, and the aromatic heterocycle and unsaturated aliphatic heterocycle each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, and S.

[0034] In an embodiment of the present application, the present application also provides a compound as shown in formula (II), its stereoisomer, its tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (such as a hydrate), or a prodrug thereof,

[0035]

[0036] Among them, ring A, R 1 , o is consistent with the aforementioned definition in this application;

[0037] wherein X is selected from a covalent bond, S, NH, CH2, (CH2)2 or (CH2)3; R 3 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, cyano, halogen, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; p is selected from 0, 1;

[0038] Preferably, the R 3 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, cyano, fluorine, chlorine, bromine, amino, ester, aldehyde, carboxyl, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclobutyl, cyclopropyl, phenyl, and pyridyl.

[0039] Further, in the embodiment of the present application, said p is 0;

[0040] Furthermore, in an embodiment of the present application, p is 0 and X is CH2.

[0041] In an embodiment of the present application, the ring A described in the present application is selected from a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocycle, and a 6- to 8-membered unsaturated aliphatic heterocycle.

[0042] Furthermore, the aromatic ring and aromatic heterocycle are preferably monocyclic or fused rings, the unsaturated aliphatic heterocycle is preferably monocyclic, and the aromatic heterocycle and unsaturated aliphatic heterocycle each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, and S.

[0043] In certain embodiments of the present application, the ring A is selected from

[0044] In certain specific embodiments of the present application, the ring A is preferably selected from The ring A is more preferably selected from

[0045] In certain embodiments of the present application, the R 1 R is independently selected from deuterium, tritium, nitro, hydroxyl, sulfhydryl, halogen, cyano, =0, imino, amine, ester, aldehyde, carboxyl, amide, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dioxhexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentyl, tert-pentoxy, n-hexyl, or any two R 1 The atoms of the ring A to which it is connected together form a dioxanyl, dioxolane, dioxinyl, dioxolenyl, dihydropyridinyl, 3-pyrrolinyl, 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 alkoxy, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0046] Preferably, the R 1R is independently selected from deuterium, tritium, nitro, hydroxyl, sulfhydryl, halogen, cyano, =0, imino, amine, ester, aldehyde, carboxyl, amide, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dioxhexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentyl, tert-pentoxy, n-hexyl, or any two R 1 The atoms of the ring A to which it is connected together form a dioxanyl group or a dioxolane group, 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 alkoxy, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl.

[0047] In certain specific embodiments of the present application, the R 1 Each R is independently preferably selected from deuterium, tritium, nitro, hydroxyl, mercapto, cyano, =O, =NH, -NH2, -N(CH3)2, -NHCH3, =NCH3, ester, aldehyde, carboxyl, amide, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, methyl, ethyl, isopropyl, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, morpholinyl, piperidinyl, N-methylpiperazinyl, p-methylpiperidinyl, piperazinyl, methoxy, ethoxy, isopropoxy, halogen; or two R 1 Together with the atoms of the ring A to which it is attached, it forms 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxinyl, 1,3-dioxinyl, 1,3-dioxolanyl, N-methyl-2-pyridone, N-methyl-3-pyrrolidine-2-one;

[0048] Preferably, the R 1 Each R is independently preferably selected from deuterium, tritium, nitro, hydroxyl, mercapto, cyano, =O, =NH, -NH2, -N(CH3)2, -NHCH3, =NCH3, ester, aldehyde, carboxyl, amide, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, methyl, ethyl, isopropyl, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, morpholinyl, piperidinyl, N-methylpiperazinyl, p-methylpiperidinyl, piperazinyl, methoxy, ethoxy, isopropoxy, halogen; or two R 1 Together with the atoms of the ring A to which it is connected, it forms a 1,4-dioxanyl group, a 1,3-dioxanyl group, or a 1,3-dioxolane group.

[0049] In certain preferred embodiments, the two R 1 The group structure formed by the atoms of the ring A to which it is connected is as follows: The structure of 1,4-dioxane is The 1,3-dioxolane structure is The 1,4-dioxinyl structure can be The 1,3-dioxinyl structure is The structure of 1,3-dioxolyl is The N-methyl-2-pyridone structure can be The structure of N-methyl-3-pyrrolidine-2-one is

[0050] In some embodiments, the present application provides a compound represented by formula (I), its stereoisomer or mixture form, or its pharmaceutically acceptable salt, or its solvate (such as hydrate), or its prodrug,

[0051]

[0052] in:

[0053] Ring A is selected from a 6- to 10-membered aromatic ring (e.g., a 6-membered aromatic ring, a 10-membered aromatic ring), a 5- to 10-membered aromatic heterocycle (e.g., a 5-membered aromatic heterocycle, a 6-membered aromatic heterocycle, a 9-membered aromatic heterocycle, a 10-membered aromatic heterocycle), or a 5- to 7-membered unsaturated aliphatic heterocycle (preferably a 6-membered unsaturated aliphatic heterocycle, such as heterocyclohexene or heterocyclohexadiene containing 1-2 heteroatoms selected from N, O, or S).

[0054] Ring B is a 5- to 9-membered saturated alicyclic heterocyclic ring (e.g., a 5-membered heterocycloalkyl group, a 6-membered heterocycloalkyl group, a 7-membered heterocycloalkyl group, or an 8-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, or S), or a ring formed by combining a 5- to 7-membered saturated alicyclic heterocyclic ring (e.g., a 5-membered heterocycloalkyl group, a 6-membered heterocycloalkyl group, or a 7-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, or S) with a benzene ring.

[0055] o is selected from 0, 1, 2,

[0056] R 1 Each independently selected from deuterium, tritium, hydroxyl, halogen, cyano, =O, imino, amine, amide, C5-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, 5-7 membered saturated heterocyclic ring; or, any two R 1 Together with the atoms of the ring A to which it is connected, it forms a 5- to 6-membered alicyclic group or a 5- to 6-membered alicyclic heterocyclic group;

[0057] wherein the aromatic heterocycle, saturated aliphatic heterocycle, unsaturated aliphatic heterocycle, and aliphatic heterocyclic group each independently contain 1 to 3 heteroatoms, the heteroatoms being independently selected from N, O, and S, and ring B contains at least 1 nitrogen atom;

[0058] The ring B is a monocyclic, fused or spirocyclic ring, and is optionally substituted by one or more independently selected from deuterium, tritium, hydroxyl, halogen (e.g., fluorine, chlorine, bromine), =O, C1-C6 alkyl, C1-C6 alkoxy, C3-C5 cycloalkyl (e.g., one or more selected from halogen, =O, C1-C6 alkyl);

[0059] The R 1 Optionally substituted by one or more groups independently selected from deuterium, tritium, C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl.

[0060] In some embodiments, Ring A is selected from a benzene ring, naphthalene, thiophene, benzoxazole, pyridine, pyrimidine, thiazole, pyrazole, pyrrole, imidazole, quinoline, isoquinoline, benzimidazole, indazole, pyrazolopyridine, oxazole, isoxazole, quinoxaline, indole, imidazopyridine, benzothiazole, pyrrolopyridine, azacyclohexene.

[0061] In some preferred embodiments, ring A is selected from benzene, naphthalene, thiophene, benzoxazole, pyridine, pyrimidine, thiazole, pyrazole, quinoline, isoquinoline, benzimidazole, indazole, pyrazolopyridine, isoxazole, quinoxaline, indole, imidazopyridine, benzothiazole, pyrrolopyridine, and azacyclohexene.

[0062] In some embodiments, ring B is piperidine, halopiperidine or dihalopiperidine (e.g., fluoropiperidine, difluoropiperidine, chloropiperidine, dichloropiperidine, bromopiperidine, dibromopiperidine, etc.), C1-C6 alkylpiperidine or di(C1-C6 alkyl)piperidine (e.g., C1-C5 alkylpiperidine, di(C1-C5 alkyl)piperidine, C1-C4 alkylpiperidine, di(C1-C4 alkyl)piperidine, C1-C3 alkylpiperidine, di(C1-C3 alkyl)piperidine, methylpiperidine, dimethylpiperidine, ethylpiperidine, diethylpiperidine, propylpiperidine, dipropylpiperidine), cycloheximide, thiomorpholine, morpholine, C1-C6 alkylmorpholine or di(C1-C6 alkyl)morpholine (e.g., C1-C5 alkylmorpholine, di(C1-C5 alkyl)morpholine, C1-C morpholine, methylmorpholine, dimethylmorpholine, ethylmorpholine, diethylmorpholine, propylmorpholine, dipropylmorpholine), pyrrolidine, halogenated pyrrolidine or dihalogenated pyrrolidine (e.g., fluoropyrrolidine, difluoropyrrolidine, chloropyrrolidine, dichloropyrrolidine, bromopyrrolidine, dibromopyrrolidine), piperazine, C1-C6 alkylpiperazine or di(C1-C6 alkyl)piperazine (e.g., C1-C5 alkylpiperazine, C1-C4 alkylpiperazine, C1-C3 alkylpiperazine, N-methylpiperazine, N-ethylpiperazine, N-propylpiperazine), 1,1-thiomorpholine dioxide, 1-thiomorpholine oxide, tetrahydroisoquinoline, azaspirooctane, oxazaspiroheptane. In some embodiments, ring B is, for example, piperidine, halopiperidine or dihalopiperidine (e.g., fluoropiperidine, difluoropiperidine, chloropiperidine, dichloropiperidine, bromopiperidine, dibromopiperidine, etc.), C1-C6 alkylpiperidine or di(C1-C6 alkyl)piperidine (e.g., C1-C5 alkylpiperidine, di(C1-C5 alkyl)piperidine, C1-C4 alkylpiperidine, di(C1-C4 alkyl)piperidine, C1-C3 alkylpiperidine, di(C1-C3 alkyl)piperidine, methylpiperidine, dimethylpiperidine, ethylpiperidine, diethylpiperidine, propylpiperidine, dipropylpiperidine), cycloheximide.

[0063] In some embodiments, o is selected from 0, 1, 2;

[0064] R 1are each independently selected from deuterium, tritium, halogen (e.g., fluorine, chlorine, bromine), cyano, =O, imino, amine, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, methyl, ethyl, propyl), C2-C6 alkenyl (e.g., C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl, methyl, vinyl, 1-propenyl, 2-propenyl, isopropenyl), C1-C6 alkoxy (e.g., C1-C5 alkoxy, C1-C4 alkoxy, C1-C3 alkoxy, methoxy, ethoxy, propoxy), 6-membered saturated aliphatic heterocycle (e.g., morpholine, dioxane, piperazine, thiomorpholine), amide; or, two R 1 Together with the atoms of the ring A to which it is attached, it forms a 5-6 membered alicyclic group containing 1-2 heteroatoms selected from N or O (e.g., dioxinyl (dioxinyl), dioxolyl, dihydropyrrolyl, dihydropyridinyl);

[0065] R 1 Optionally substituted by one or more groups independently selected from deuterium, tritium, C1-C6 alkyl (eg, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, methyl, ethyl, propyl).

[0066] In some embodiments, o is selected from 0, 1, 2;

[0067] R 1 Each is independently selected from deuterium, tritium, fluorine, chlorine, bromine, cyano, =O, imino, amino, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, 6-membered saturated heterocyclic ring (such as morpholine, piperazine); or, two R 1 The atoms of the ring A to which it is connected together form a 5-6 membered alicyclic group containing 1-2 heteroatoms selected from N or O (for example, dioxenyl, dioxolyl); the 6-membered saturated alicyclic group and the 5-6 membered alicyclic group are optionally substituted by one or more independently selected from deuterium, tritium, C1-C6 alkyl (for example, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, methyl, ethyl, propyl).

[0068] The present application also relates to any combination of the above embodiments or some features thereof.

[0069] In some specific embodiments of the present application, the present application is as follows: the compound, its stereoisomer, its tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate, or its prodrug:

[0070]

[0071]

[0072]

[0073] Another aspect of the present application is to provide a pharmaceutical composition comprising at least one of the aforementioned compounds, their stereoisomers, their tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates, or their prodrugs, and at least one pharmaceutically acceptable excipient.

[0074] Another aspect of the present application is to provide a compound, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, a solvate, 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, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, a solvate, 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, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, a solvate, 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.

[0075] In certain specific embodiments, the medicament, inhibitor 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 disease, trauma, skin lesions, 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 radiation exposure, the toxicity of chemotherapy, or the toxicity of immunosuppressants.

[0076] definition

[0077] 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.

[0078] "Alkyl" refers to a saturated aliphatic hydrocarbon group. The alkyl portion can be either straight-chain or branched. As used herein, C1-C6 alkyl refers to a straight-chain or branched alkyl group consisting of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, 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, and n-hexyl.

[0079] "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, 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.

[0080] "Alkenyl" refers to an aliphatic chain hydrocarbon group containing a carbon-carbon double bond. The alkenyl moiety can be straight or branched; as used herein, C2-C6 alkenyl refers to a straight or branched alkenyl group consisting of 2 to 6 carbon atoms (e.g., 2, 3, 4, 5, 6, or a range consisting of any two of the foregoing values). Typical alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, and 3-butenyl.

[0081] "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 consisting solely of carbon atoms, and a heterocycle refers to a closed structure formed by covalent bonding of carbon atoms and heteroatoms. A ring may be a monocyclic, bicyclic, tricyclic, or polycyclic ring. When a ring is bicyclic, tricyclic, or polycyclic, the relationship between the rings may include a fused ring, a spirocyclic ring, or a bridged ring. For example, a bicyclic ring may include a spirocyclic ring, a fused ring, or a bridged ring; a tricyclic ring may include three spirocyclic rings, three fused rings, or a spirocyclic ring combined with a monocyclic ring.

[0082] The term "fused" in the present application refers to two adjacent ring atoms being shared between rings. For example, fused ring refers to a cyclic structure formed by two monocyclic rings sharing two adjacent atoms.

[0083] "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.

[0084] "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.

[0085] "Alicyclic ring" or "alicyclic group" refers to a saturated or partially unsaturated carbon ring. A saturated carbon ring may be referred to as a saturated alicyclic ring, and a partially unsaturated carbon ring may be referred to as an unsaturated alicyclic ring. An alicyclic ring may be composed of 3 to 10 atoms and may be monocyclic or polycyclic. For example, the C3 to C8 alicyclic group used in this application refers to an alicyclic group composed of 3 to 8 backbone atoms. Typical alicyclic structures include, but are not limited to: wait.

[0086] "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 can include saturated aliphatic heterocycles and unsaturated aliphatic heterocycles. For example, a 3- to 8-membered aliphatic heterocyclic group as used herein refers to a non-aromatic cyclic group composed of 3-8 backbone atoms and containing one or more heteroatoms, and can be a saturated aliphatic heterocyclic group or an unsaturated aliphatic heterocyclic group.

[0087] "Saturated heterocyclic ring" or "saturated heterocyclic group" means that the carbon atoms constituting the ring backbone of the heterocyclic ring are all saturated. For example, as used in this application, a 5-12-membered saturated heterocyclic ring refers to a non-aromatic cyclic group formed by 5-12 atoms constituting the ring backbone, wherein the atoms constituting the ring backbone are composed of saturated carbon atoms and heteroatoms. Typical saturated heterocyclic rings include, but are not limited to: wait.

[0088] As used in this application, "a ring formed by combining a 5- to 12-membered saturated aliphatic heterocycle and a benzene ring" refers to a saturated aliphatic heterocycle composed of 5 to 12 atoms and a benzene ring to form a ring structure. For example, wait.

[0089] The term "unsaturated heterocyclic ring" as used herein refers to a ring containing unsaturated carbon atoms in its backbone. As used herein, a 6- to 8-membered unsaturated heterocyclic ring refers to a non-aromatic cyclic group consisting of 6-8 backbone atoms, wherein the atoms constituting the backbone of the ring include saturated carbon atoms, unsaturated carbon atoms, and heteroatoms. Typical unsaturated heterocyclic rings include, but are not limited to: wait.

[0090] "Cycloalkyl" refers to a saturated aliphatic carbocyclic group, also known as a saturated alicyclic ring. Cycloalkyl groups can be monocyclic, spirocyclic, fused, or bridged. As used herein, a C3-C8 cycloalkyl group refers to a cyclic alkyl group composed of 3 to 8 carbon atoms. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2,1,1]hexyl, and cycloheptyl.

[0091] "Aromatic ring" or "aryl" refers to a fully unsaturated carbon ring whose planar ring has a delocalized π electron system and contains 4n+2 π electrons, where n is an integer. An aromatic ring can be composed of six, eight, ten or more carbon atoms, and can be a monocyclic or polycyclic ring. Common aromatic rings include, but are not limited to, benzene rings, naphthalene rings, phenanthrene rings, anthracene rings, tetraphenyl rings, pyrene rings, pentaphenyl rings, and the like. As used in this application, a 6- to 10-membered aromatic ring or 6- to 10-membered aryl group refers to an aromatic ring group composed of 6 to 10 backbone carbon atoms.

[0092] "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.

[0093] 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 hetero atoms and composed of 5 to 10 backbone atoms.

[0094] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0095] "Haloalkyl" means that at least one hydrogen in an alkyl group 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, and at least one hydrogen on the alkyl group is arbitrarily replaced by a halogen atom.

[0096] "Amine" or "amine" refers to a group having -NR U R V The chemical structure of U R V Each is independently selected from hydrogen, deuterium, tritium, alkyl, and cycloalkyl.

[0097] "Iminyl" or "imine" refers to a group having ═NR W The chemical structure of W Selected from hydrogen, deuterium, tritium, alkyl, cycloalkyl.

[0098] "Amide" or "amido" refers to a group having -C(O)NR X R Y or -NR X C(O)R YThe chemical structure of X 、R Y Each is independently selected from hydrogen, deuterium, tritium, alkyl, cycloalkyl, common amide groups include but are not limited to -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3.

[0099] An "ester group" is a group having the formula -COOR 0 The chemical structure of 0 Selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.

[0100] "Substitution" refers to that one or more hydrogen atoms in a group are replaced by a corresponding number of substituents independently of each other. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without making too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond. Each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, alkylthio, aryloxy, nitro, acyl, halogen, haloalkyl, amino, etc. When two or more "substitutions" occur, the substituents can form a cyclic group together with the substituted atoms. For example, two R 1 Together with the atoms of the ring A to which it is connected, it forms a 1,4-dioxane structure: The 1,3-dioxolane structure is The 1,4-dioxinyl structure can be The 1,3-dioxinyl structure is The structure of 1,3-dioxolyl is The N-methyl-2-pyridone structure can be The structure of N-methyl-3-pyrrolidine-2-one is

[0101] "Inhibitor" refers to a substance that reduces the activity of an enzyme.

[0102] "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.

[0103] 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.

[0104] "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.

[0105] 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.

[0106] "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,

[0107] "Stereoisomers" refer to isomers that differ in the way the atoms in a molecule are arranged in space.

[0108] "Enantiomers" refer to compounds with the same molecular formula and functional groups, which exhibit isomerism due to different configurations of atoms in space. At the same time, the compounds form non-superimposable stereoisomers that are mirror images of each other.

[0109] "Diastereoisomers" refer to compounds with the same molecular formula and functional groups, which are stereoisomers caused by different spatial configurations of atoms. At the same time, the compounds are not stereoisomers that are in a mirror-image relationship with each other.

[0110] 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.

[0111] 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%.

[0112] 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.

[0113] 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.

[0114] The abbreviations in this application have the following meanings:

[0115] DETAILED DESCRIPTION

[0116] 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.

[0117] Example 1: Preparation of (7-amino-3-phenylthieno[2,3-b]pyrazin-6-yl)(piperidin-1-yl)methanone

[0118]

[0119] Step 1: Preparation of 3-chloro-5-phenylpyrazine-2-carbonitrile

[0120] 3,5-Dichloropyrazine-2-carbonitrile (2.5 g), phenylboronic acid (1.95 g), sodium carbonate (1.84 g), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.53 g) were dissolved in a mixed solvent of 1,4-dioxane (20 mL) and water (5 mL). After nitrogen substitution three times, the mixture was reacted at 80°C for 2 h. TLC confirmed the complete reaction. The mixture was cooled to room temperature and filtered. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified on a silica gel column to obtain the crude title compound (3.1 g).

[0121]

[0122] MS (ESI) m / z (M+H) +=216.0.

[0123] Step 2: Preparation of ethyl 7-amino-3-phenylthieno[2,3-b]pyrazine-6-carboxylate

[0124] 3-Chloro-5-phenylpyrazine-2-carbonitrile (80 mg) was weighed and dissolved in N,N-dimethylformamide (2 mL). Potassium carbonate (120 mg) and ethyl mercaptoacetate (54 μL) were added. The mixture was reacted at 80°C overnight. LC-MS monitored the reaction for completion. The mixture 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, concentrated under reduced pressure, and purified on a silica gel column to obtain the title compound (90 mg).

[0125]

[0126] MS (ESI) m / z (M+H)+ = 300.1.

[0127] Step 3: Preparation of (7-amino-3-phenylthieno[2,3-b]pyrazin-6-yl)(piperidin-1-yl)methanone

[0128] (1) Ethyl 7-amino-3-phenylthieno[2,3-b]pyrazine-6-carboxylate (90 mg) was weighed and dissolved in tetrahydrofuran (2 mL), methanol (0.6 mL) and water (0.6 mL). Potassium hydroxide (51 mg) was added and reacted at 70°C for 2 h. The reaction was complete after monitoring by LCMS. The mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was discarded, and the aqueous phase was adjusted to pH 2 with 2M dilute hydrochloric acid and extracted again with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain crude 7-amino-3-phenylthieno[2,3-b]pyrazine-6-carboxylic acid.

[0129] (2) The crude product obtained above was dissolved in N,N-dimethylformamide (2 mL). Diisopropylethylamine (100 μL), piperidine (37 μL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (170 mg) were added sequentially under ice-water bath. The mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS to be complete. The mixture was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase preparative reaction to obtain the title compound (9.5 mg).

[0130]

[0131] MS (ESI) m / z (M+H) + =339.1,

[0132] 1H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.25-8.23(m,2H),7.60-7.54(m,3H),6.20(s,2H),3.59-3.57(m,4H),1.64-1.57(m,6H).

[0133] Example 2 Preparation of (7-amino-3-(benzo[d]oxazol-6-yl)thiophene[2,3-b]pyrazin-6-yl)(piperidin-1-yl)methanone

[0134]

[0135] Step 1: Preparation of 3-chloro-5-methoxypyrazine-2-carbonitrile

[0136] 3,5-Dichloropyrazine-2-carbonitrile (8.0 g) was dissolved in methanol (50 mL). Sodium methoxide (2.5 g) was added at 0°C. The mixture was allowed to react at 0°C for 3 h, then heated to room temperature and stirred for 1 h. TLC indicated complete consumption of the starting material. The mixture was concentrated under reduced pressure, quenched with water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain the title compound (4.317 g).

[0137]

[0138] MS (ESI) m / z (M+H) + =170.0.

[0139] Step 2: Preparation of ethyl 7-amino-3-methoxythieno[2,3-b]pyrazine-6-carboxylate

[0140] 3-Chloro-5-methoxypyrazine-2-carbonitrile (4.317 g) was dissolved in N,N-dimethylformamide (50 mL). Potassium carbonate (7.76 g) and ethyl mercaptoacetate (3.35 mL) were added and reacted at 80°C overnight. TLC indicated complete consumption of the starting material. The reaction was quenched with water, extracted twice with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (4.5 g).

[0141]

[0142] MS (ESI) m / z (M+H) + =254.0.

[0143] Step 3: Preparation of 7-amino-3-methoxythieno[2,3-b]pyrazine-6-carboxylic acid

[0144] Ethyl 7-amino-3-methoxythieno[2,3-b]pyrazine-6-carboxylate (4.5 g) was dissolved in a mixed solvent of tetrahydrofuran (24 mL), methanol (8 mL), and water (8 mL). Potassium hydroxide (2.99 g) was added and the mixture was reacted at 80°C for 3 h. LCMS showed complete consumption of the starting material. The reaction was quenched with water and the pH was adjusted to acidic with 2 M hydrochloric acid. The mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (4.2 g).

[0145]

[0146] MS (ESI) m / z (M+H) + =226.0.

[0147] Step 4: Preparation of (7-amino-3-methoxythieno[2,3-b]pyrazin-6-yl)(piperidin-1-yl)methanone

[0148] 7-Amino-3-methoxythieno[2,3-b]pyrazine-6-carboxylic acid (4.2 g) was weighed and dissolved in N,N-dimethylformamide (40 mL). N,N-diisopropylethylamine (6.18 mL), hexahydropyridine (1.28 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.32 g) were added sequentially at 0°C. The mixture was then warmed to room temperature and reacted for 3 h. TLC indicated complete consumption of the starting material. The mixture was quenched with water, extracted twice with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain the title compound (2.1 g).

[0149]

[0150] MS (ESI) m / z (M+H) + =293.1.

[0151] Step 5: Preparation of (7-amino-3-hydroxythieno[2,3-b]pyrazin-6-yl)(piperidin-1-yl)methanone

[0152] Weigh (7-amino-3-methoxythieno[2,3-b]pyrazin-6-yl)(piperidin-1-yl)methanone (1.6 g) and dissolve it in 1,2-dichloroethane (20 mL). Slowly add a 2M solution of boron tribromide in tetrahydrofuran (2.64 mL). React at 60°C overnight. Monitor the complete consumption of the starting material by TLC. Quench the mixture with water, extract twice with dichloromethane, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound (1.03 g).

[0153]

[0154] MS (ESI) m / z (M+H)+ =279.1.

[0155] Step 6: Preparation of 7-amino-6-(piperidine-1-carbonyl)thieno[2,3-b]pyrazin-3-yl trifluoromethanesulfonate

[0156] (7-Amino-3-hydroxythieno[2,3-b]pyrazin-6-yl)(piperidin-1-yl)methanone (1.03 g) was dissolved in dichloromethane (15 mL). N,N-diisopropylethylamine (1.23 mL) and N-phenylbis(trifluoromethanesulfonyl)imide (2.64 g) were added at 0°C and reacted at 50°C for 3 h. TLC indicated complete consumption of the starting material. The mixture was quenched with water, extracted twice with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain the title compound (878 mg).

[0157]

[0158] MS (ESI) m / z (M+H) + =411.0.

[0159] Step 7: Preparation of (7-amino-3-(benzo[d]oxazol-6-yl)thienyl[2,3-b]pyrazin-6-yl)(piperidin-1-yl)methanone

[0160] 7-Amino-6-(piperidine-1-carbonyl)thieno[2,3-b]pyrazin-3-yl trifluoromethanesulfonate (23 mg), benzoxazole-6-boronic acid pinacol ester (15 mg), cesium carbonate (24 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3 mg) were dissolved in 1,4-dioxane (1.5 mL) and water (0.3 mL). The atmosphere was replaced with argon three times and the reaction was incubated at 80°C for 1.5 h. LCMS indicated complete consumption of the starting material. The mixture was quenched with water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and separated using a reverse-phase preparative column to obtain the title compound (6.7 mg).

[0161]

[0162] MS (ESI) m / z (M+H) + =380.1,

[0163] 1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.90(d,J=1.1Hz,1H),8.68(s,1H),8.34(dd,J=8.4,1.6Hz,1H),7 .98(d,J=8.5Hz,1H),6.23(s,2H),3.59(t,J=5.2Hz,4H),1.64(q,J=5.5,4.9Hz,2H),1.61–1.55(m,4H).

[0164] Example 3 (7-amino-3-phenylthieno[2,3-b]pyrazin-6-yl)(4-fluoropiperidin-1-yl)methanone

[0165]

[0166] 7-Amino-3-phenylthieno[2,3-b]pyrazine-6-carboxylic acid was prepared by referring to steps 1 to 3(1) of Example 1. 7-Amino-3-phenylthieno[2,3-b]pyrazine-6-carboxylic acid (70 mg) was weighed and dissolved in N,N-dimethylformamide (2 mL). Diisopropylethylamine (130 μL), 4-fluoropiperidine hydrochloride (47 mg), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (140 mg) were added in sequence under ice-water bath. The mixture was stirred at room temperature for 2 h. LCMS monitored the reaction to be complete. The mixture was quenched with water and extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase preparative method to obtain the title compound (12.43 mg).

[0167]

[0168] MS (ESI) m / z (M+H) + =357.1,

[0169] 1 H NMR (400MHz, DMSO-d6) δ9.34 (s, 1H), 8.25-8.23 (dd, J = 8.0, 1.5Hz, 2H), 7.60-7.54 (m, 3H) ,6.27(s,2H),5.00-4.85(m,1H),3.72-3.57(m,4H),2.02-1.90(m,2H),1.82-1.77(m,2H).

[0170] Examples 4 to 57

[0171] 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:

[0172] Table 1

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180] Biological tests

[0181] Test Example 1: 15-PGDH enzyme activity detection

[0182] 1. Experimental Materials:

[0183]

[0184] 2. Experimental methods:

[0185] a. Prepare a reaction buffer solution containing 50 mM Tris-HCl, 0.01% Tween 20, pH 7.5 with ultrapure water;

[0186] b. Prepare a 10 mM stock solution of the test compound using DMSO. Then dilute the stock solution with reaction buffer to obtain a 40,000 nM solution of test compound 1. Serially dilute solution 1 in a three-fold gradient to obtain 9 (or 11) concentrations of test compound solutions 2 to 9 (or 2 to 12). Add 5 μL of each concentration of test compound solution to a 384-well plate as an experimental well.

[0187] c. Add 5 μL of reaction buffer to the blank wells of the 384-well plate as positive control wells and blank control wells respectively.

[0188] 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.

[0189] e. Prepare 5 mM β-NAD and 2 mM PGF2α in reaction buffer, mix them at a volume ratio of 1:1 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.

[0190] f. Use a multifunctional microplate reader to continuously detect the fluorescence signal value of each well (Ex / Em=340 / 450).

[0191] 3. Data Analysis:

[0192] 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;

[0193] b) Calculate the inhibition rate using the following formula:

[0194] 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)] x 100%.

[0195] c) Calculate IC50 and draw inhibition rate-dose curve: Use GraphPad Prism 6.0 to fit the compound concentration and the corresponding inhibition rate by nonlinear regression (dose response-variable slope) to calculate the IC50 value.

[0196] The formula is as follows: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope)), where X is the log value of the compound concentration and Y is the inhibition rate.

[0197] 4. Experimental results:

[0198] The inhibitory activity of the compounds in this application on 15-PGDH enzyme is as follows:

[0199]

[0200]

[0201] In the table, “ / ” represents not detected; “A” represents the IC of 15-PGDH enzyme inhibition activity 50 The range is less than 0.5 nM; "B" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than or equal to 0.5nM and less than 3nM; "C" represents the IC of 15-PGDH enzyme inhibition activity 50The range is greater than or equal to 3nM and less than 10nM; "D" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than or equal to 10nM and less than or equal to 25nM; "E" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than or equal to 50nM and less than or equal to 1000nM; "F" represents 15-PGDH enzyme inhibitory activity greater than 1000nM and less than or equal to 5000nM, and "G" represents 15-PGDH enzyme inhibitory activity is not active (IC 50 >5000nM).

[0202] The results showed that the compound of the present application has strong inhibitory activity against 15-PGDH enzyme.

[0203] Test Example 2: Intracellular PGE2 upregulation activity assay

[0204] 1. Experimental Materials:

[0205]

[0206] 2. Experimental methods:

[0207] 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.

[0208] b) Prepare a test compound solution in culture medium and serially dilute to 3 concentrations of 10 nM, 300 nM, and 10,000 nM or to 7 concentrations of 0.64 nM, 3.2 nM, 16 nM, 80 nM, 400 nM, 2,000 nM, and 10,000 nM. Simultaneously, set up a positive control group (only IL-1β was added to the cells for induction) and a negative control group (only cells were added to the wells without any treatment). After 8 hours of action, the cell supernatant was collected. The positive control group was induced with IL-1β but not treated with the compound, and the negative control group was not stimulated with IL-1β and not treated with the compound.

[0209] 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).

[0210] 3. Data Analysis:

[0211] 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.

[0212] b) Calculate the PGE2 upregulation rate (%) using the following formula:

[0213] PGE2 upregulation ratio %=(PGE2 concentration in sample group / PGE2 concentration in positive control group)×100%.

[0214] 4. Experimental Results

[0215] The PGE2 up-regulation ratios of the compounds in some examples are shown in the table below.

[0216]

[0217] In the table, " / " represents not tested. As can be seen from the above table, the compounds of the present application can increase the PGE2 upregulation ratio in A549 cells by >100%, certain compounds of the present application can increase the PGE2 upregulation ratio in A549 cells by >200%, and certain preferred compounds of the present application can increase the PGE2 upregulation ratio in A549 cells by >300% or higher, indicating that the compounds of the present application have good activity in increasing intracellular PGE2.

[0218] 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.

[0219] 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), or a pharmaceutically acceptable salt thereof: Ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, or a 6-8 membered unsaturated aliphatic heterocycle, wherein the aromatic ring or aromatic heterocycle is a monocyclic ring or a fused ring, and the unsaturated aliphatic heterocycle is a monocyclic ring, and the aromatic heterocycle or unsaturated aliphatic heterocycle each independently contains 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, and S. Ring B is selected from in, X is selected from the group consisting of covalent bond, O, S, NH, (CH2) n or SO2; Y is selected from a covalent bond or (CH2) n ; m is selected from 0, 1 or 2; R 2 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, cyano, halogen, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy; wherein n is selected from 1 or 2; o is selected from 0, 1, 2, 3, R 1 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imino, amine, ester, aldehyde, carboxyl, amide, C3-C8 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, 3-8 membered saturated aliphatic heterocyclic ring containing 1-3 heteroatoms, each independently selected from N, O or S, Or when o is selected from 2 or 3, any two R 1 Together with the atoms of the ring A to which it is connected, it forms a 3-8 membered alicyclic group or a 3-8 membered alicyclic heterocyclic group, wherein the alicyclic heterocyclic group contains 1-3 heteroatoms independently selected from N, O or 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.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imino, amine, ester, aldehyde, carboxyl, amide, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered saturated aliphatic heterocyclic ring containing 1-3 heteroatoms, each independently selected from N, O or S, Or when o is selected from 2 or 3, any two R 1 Together with the atoms of the ring A to which it is connected, it forms a 3-8 membered alicyclic group or a 3-8 membered alicyclic heterocyclic group, wherein the alicyclic heterocyclic group contains 1-3 heteroatoms, and the heteroatoms are independently selected from N, O or 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. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein The ring B is selected from 4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein The R 2 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, cyano, fluorine, chlorine, bromine, amino, ester, aldehyde, carboxyl, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, and trichloroethyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocycle, or a 5- to 7-membered unsaturated aliphatic heterocycle, wherein the aromatic heterocycle and the unsaturated aliphatic heterocycle each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, and S. Ring B is selected from R 2 Each is independently selected from deuterium, tritium, hydroxyl, halogen, =O, C1-C6 alkyl, C1-C6 alkoxy; o is selected from 0, 1, 2, R 1 Each is independently selected from deuterium, tritium, hydroxyl, halogen, cyano, =O, imino, amine, amide, C5-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, 5-7 membered saturated aliphatic heterocyclic ring containing 1-3 heteroatoms independently selected from N, O or S; or any two R 1 Together with the atoms of the ring A to which it is connected, it forms a 5-6 membered alicyclic group or a 5-6 membered alicyclic heterocyclic group, wherein the alicyclic heterocyclic group contains 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O or S; The R 1 Optionally substituted by one or more groups independently selected from deuterium, tritium, C1-C6 alkyl, and C1-C6 alkoxy.

6. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein The compound has a structure as shown in Formula II, wherein X is selected from a covalent bond, S, CH2, (CH2)2 or (CH2)3; R 3 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, cyano, halogen, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; p is selected from 0 and 1.

7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein The R 3 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, cyano, fluorine, chlorine, bromine, amino, ester, aldehyde, carboxyl, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, and trichloroethyl.

8. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein The p is 0.

9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein The p is 0 and the X is CH2.

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein The ring A is selected from 11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 R is independently selected from deuterium, tritium, nitro, hydroxyl, sulfhydryl, halogen, cyano, =0, imino, amine, ester, aldehyde, carboxyl, amide, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dioxhexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentyl, tert-pentoxy, n-hexyl, or any two R 1 The atoms of the ring A to which it is connected together form a dioxanyl, dioxolane, dioxinyl, dioxolenyl, dihydropyridinyl, 3-pyrrolinyl, wherein R 1 Optionally substituted by one or more groups independently selected from deuterium, tritium, nitro, hydroxyl, -NH2, thiol, halogen, cyano, ester, carboxyl, amide, =O, =NH, C1-C6 alkyl, C1-C6 alkoxy.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 R is independently selected from deuterium, tritium, nitro, hydroxyl, sulfhydryl, halogen, cyano, =0, imino, amine, ester, aldehyde, carboxyl, amide, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dioxhexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentyl, tert-pentoxy, n-hexyl, or any two R 1 The atoms of the ring A to which it is connected together form a dioxanyl group or a dioxolane group, wherein R 1 Optionally substituted by one or more groups independently selected from deuterium, tritium, nitro, hydroxyl, -NH2, thiol, halogen, cyano, ester, carboxyl, amide, =O, =NH, C1-C6 alkyl, C1-C6 alkoxy.

13. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein The compound is selected from the following:

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

15. Use of the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 for preparing a medicament, wherein: The drug is a 15-PGDH enzyme inhibitor.

16. The use according to claim 15, wherein The medicament is used to treat or prevent fibrosis, oral ulcers, gum diseases, inflammatory diseases, vascular insufficiency, Raynaud's disease, Buerger's disease, neuropathy, pulmonary hypertension, kidney disease, cardiovascular disease, trauma, skin damage, autoimmune disease, graft-versus-host disease, osteoporosis, ear disease, eye disease, neutropenia, diabetes, underactive bladder, or to promote hair growth, pigmentation, tissue repair, tissue regeneration, implant promotion in stem cell transplantation, bone marrow transplantation or organ transplantation, neurogenesis and nerve cell death or muscle regeneration and cervical ripening, or to enhance resistance to the toxicity of radiation exposure, the toxicity of chemotherapy, and the toxicity of immunosuppressants.

17. The use according to claim 16, wherein The inflammatory disease is colitis or gastroduodenal ulcer.

18. The use according to claim 17, wherein The colitis is ulcerative colitis.

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