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

Abstract

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

Description

Technical Field

[0001] The present invention relates to a compound for regulating 15-PGDH activity and a preparation method thereof, and 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 use thereof for preparing a drug, and belongs to the field of pharmaceutical chemistry. Background Art

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

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

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

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

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

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

[0008] The present invention also provides a compound represented by formula (I), 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 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 1 Substitution, the R 1 are each independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkyl, C1-C6 haloalkyl, 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] R A is selected from hydrogen, deuterium, tritium, halogen, amine, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl,

[0013] R 0 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imine, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy,

[0014] o is selected from 0, 1, 2, 3, 4,

[0015] represents an aromatic ring, is a single bond or a double bond,

[0016] X and Y are each independently selected from C or N, and at least one of X and Y is N,

[0017] U, V, and W are each independently selected from N, CR 2 , CR 3 R 4 NR 5 , O, S, wherein the R 2 , R 3 , R 4 , R 5Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, 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, or the above R 3 , R 4 Together with the carbon atom to which it is connected, it forms C=O, C=NR W , the R W is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or 3-12 membered cycloalkyl,

[0018] The aromatic heterocycle, alicyclic heterocycle, unsaturated alicyclic heterocycle, cyclopentane, and heterocycloalkyl groups each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, and S. 0 , R 2 , R 3 , R 4 , R 5 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.

[0019] In certain embodiments of the present invention, the Selected from the following groups,

[0020]

[0021] Wherein R 2a , R 2b , R 2c , R 3a , R 3b , R 3c , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, 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, or the above R 3a With R 4a , R 3b With R 4b , R 3c With R4c Each together forms =O or an imine group (for example, the R 2a , R 2b , R 2c , R 3a , R 3b , R 3c , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c Each independently can be selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, -NH2, carboxyl, -CONH2, -NHCOOH, 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 said R 3a With R 4a , R 3b With R 4b , R 3c With R 4c can independently form =O, =NH);

[0022] Furthermore, in certain specific embodiments of the present invention, the Selected from,

[0023] Wherein R 2a , R 2b , R 2c Consistent with the above definition.

[0024] Furthermore, in certain specific embodiments of the present invention, the Selected from, Wherein R 2a , R 2b , R 2c , R 3a , R 3b , R 3c , R 4a , R 4b , R 4c Consistent with the above definition.

[0025] In certain embodiments of the present invention, 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 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring; preferably, the aromatic ring and the aromatic heterocycle are monocyclic or bicyclic, the unsaturated alicyclic ring is a monocyclic ring, and the aromatic heterocycle and the unsaturated alicyclic ring each independently contain 1-3 heteroatoms, and the heteroatoms are independently selected from N, O, and S; more preferably, the ring A is selected from a benzene ring, a naphthalene ring, a 5-10 membered aromatic heterocycle containing 1-3 heteroatoms, a 6-membered unsaturated alicyclic ring containing 1-3 heteroatoms (preferably 1-2 heteroatoms), or an 8-14 membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic ring containing 1-3 heteroatoms (preferably 1-2 heteroatoms), and the heteroatoms are independently selected from N, O, and S.

[0026] In certain embodiments of the present invention, the R A Selected from hydrogen, deuterium, tritium, cyano, fluorine, chlorine, bromine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, isopropenyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably selected from hydrogen, deuterium, tritium, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, isopropenyl; more preferably selected from -NH2.

[0027] In certain embodiments of the present invention, the R is selected from C1 to C 10 Alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, etc.), 3-12-membered cycloalkyl (e.g., 3-10-membered cycloalkyl, 3-8-membered cycloalkyl, etc.), 3-12-membered heterocycloalkyl containing 1-2 heteroatoms (e.g., 3-10-membered heterocycloalkyl containing 1-2 heteroatoms, 3-8-membered heterocycloalkyl containing 1-2 heteroatoms, etc.), wherein the heteroatoms may be, for example, N, O, S, wherein R is replaced by 0 or 1 R 1 Substitution, the R 1 Consistent with the above definition; further, in certain specific embodiments of the present invention, the R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, tert-butylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,

[0028] Where R is 0 or 1 R1 Substitution, the R 1 Consistent with the above definition.

[0029] The present invention also provides a compound represented by formula (II), or a pharmaceutically acceptable salt thereof, or a solvate thereof (such as a hydrate), or a prodrug thereof,

[0030]

[0031] 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,

[0032] 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 1 Substitution, the R 1 are each independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkyl, C1-C6 haloalkyl, 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,

[0033] R A is selected from hydrogen, deuterium, tritium, halogen, amine, cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C1-C6 haloalkyl, 3-8 membered cycloalkyl,

[0034] R 0 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imine, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy,

[0035] o is selected from 0, 1, 2, 3, 4,

[0036] is a single bond or a double bond, U is independently selected from CR 2 or N, V, W are each independently selected from N, CR 2 , CR 3 R4 NR 5 , O or S, where each R 2 , R 3 , R 4 , R 5 Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, 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, or the above R 3 , R 4 Together with the carbon atom to which it is connected, it forms C=O, C=NR W , the R W is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or 3-12 membered cycloalkyl,

[0037] Wherein, the aromatic heterocycle, alicyclic heterocycle, unsaturated alicyclic heterocycle, cyclopentane, and heterocycloalkyl each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, and S.

[0038] The R 0 , R 2 , R 3 , R 4 , R 5 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.

[0039] In certain embodiments of the present invention, the Selected from

[0040] Wherein R 2a , R 2b , R 2c , R 3a , R 3c , R 4a , R 4c , R 5a , R 5c Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, 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, or the above R 3a With R 4a , R 3b With R4b , R 3c With R 4c Each together forms =O or an imine group (for example, the R 2a , R 2b , R 2c , R 3a , R 3c , R 4a , R 4c , R 5a , R 5c Each independently can be selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, -NH2, carboxyl, -CONH2, -NHCOOH, 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 said R 3a With R 4a , R 3b With R 4b , R 3c With R 4c can independently form =O, =NH);

[0041] Furthermore, in certain specific embodiments of the present invention, the Selected from Wherein R 2a , R 2b , R 2c Consistent with the above definition, in some embodiments, the R 2a , R 2b , R 2c Each is independently selected from hydrogen, deuterium, tritium, C1-C6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl);

[0042] Furthermore, in certain specific embodiments of the present invention, the Selected from Wherein R 2a , R 2c , R 3a , R 3c , R 4a , R 4c Consistent with the above definition, in some embodiments, the R 2a , R 2c , R 3a , R 3c , R 4a , R 4cEach is independently selected from hydrogen, deuterium, tritium, C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). When it is a substituted or unsubstituted aromatic structure, it has better PGDH inhibitory activity and better intracellular PGE2 upregulation activity.

[0043] In certain embodiments of the present invention, 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 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring; preferably, the aromatic ring and the aromatic heterocycle are monocyclic or bicyclic, the unsaturated alicyclic ring is a monocyclic ring, and the aromatic heterocycle and the unsaturated alicyclic ring each independently contain 1-3 heteroatoms, and the heteroatoms are independently selected from N, O, and S; more preferably, the ring A is selected from a benzene ring, a naphthalene ring, a 5-10 membered aromatic heterocycle containing 1-3 heteroatoms, a 6-membered unsaturated alicyclic ring containing 1-3 heteroatoms (preferably 1-2 heteroatoms), or an 8-14 membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic ring containing 1-3 heteroatoms (preferably 1-2 heteroatoms), and the heteroatoms are independently selected from N, O, and S.

[0044] In certain embodiments of the present invention, the R A Selected from hydrogen, deuterium, tritium, cyano, fluorine, chlorine, bromine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, isopropenyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably selected from hydrogen, deuterium, tritium, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, isopropenyl; more preferably selected from -NH2.

[0045] In certain embodiments of the present invention, the R is selected from C1 to C 10 Alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, etc.), 3-12-membered cycloalkyl (e.g., 3-10-membered cycloalkyl, 3-8-membered cycloalkyl, etc.), 3-12-membered heterocycloalkyl containing 1-2 heteroatoms (e.g., 3-10-membered heterocycloalkyl containing 1-2 heteroatoms, 3-8-membered heterocycloalkyl containing 1-2 heteroatoms, etc.), wherein the heteroatoms may be, for example, N, O, S, wherein R is replaced by 0 or 1 R 1 Substitution, the R 1Consistent with the above definition; further, in certain specific embodiments of the present invention, the R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, tert-butylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,

[0046] Where R is 0 or 1 R 1 Substitution, the R 1 Consistent with the above definition.

[0047] In certain specific embodiments of the present invention, the compound represented by formula (II) provided by the present invention has a structure represented by formula (II-a):

[0048]

[0049] Among them, ring A, o, R 2a , R 2c , R 0 , R A , R is consistent with the above definition; in some specific embodiments, the R 2a , R 2c Each is independently selected from hydrogen, deuterium, tritium, and C1-C6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl).

[0050] In certain specific embodiments of the present invention, the compound represented by formula (II) provided by the present invention has a structure represented by formula (II-b):

[0051]

[0052] Among them, ring A, o, R 0 , R 3a , R 3c , R 4a , R 4c , R A , R is consistent with the above definition; in some specific embodiments, the R 3a , R 3c , R 4a , R 4c Each is independently selected from hydrogen, deuterium, tritium, and C1-C6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl).

[0053] The present invention also provides a compound represented by formula (III), or a pharmaceutically acceptable salt thereof, or a solvate thereof (such as a hydrate), or a prodrug thereof,

[0054]

[0055] 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,

[0056] 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 1 Substitution, the R 1 are each independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkyl, C1-C6 haloalkyl, 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,

[0057] R A is selected from hydrogen, deuterium, tritium, halogen, amine, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl,

[0058] R 0 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imine, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy,

[0059] o is selected from 0, 1, 2, 3, 4,

[0060] is a single bond or a double bond, W is independently selected from CR 2 or N, U, and V are each independently selected from N, CR 2 , CR 3 R 4 NR 5 , O or S, where each R 2 , R 3 , R 4 , R 5Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, 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, or the above R 3 , R 4 Together with the carbon atom to which it is connected, it forms C=O, C=NR W , the R W is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or 3-12 membered cycloalkyl,

[0061] Wherein, the aromatic heterocycle, alicyclic heterocycle, unsaturated alicyclic heterocycle, cyclopentane, and heterocycloalkyl each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, and S.

[0062] The R 0 , R 2 , R 3 , R 4 , R 5 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.

[0063] In certain specific embodiments of the present invention, the Selected from

[0064] Wherein R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, 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, or the above R 3a With R 4a , R 3b With R 4b , R 3c With R 4c Each together forms =O or an imine group (for example, the R 2a , R2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b Each independently can be selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, -NH2, carboxyl, -CONH2, -NHCOOH, 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 said R 3a With R 4a , R 3b With R 4b , R 3c With R 4c can independently form =O, =NH);

[0065] Furthermore, in certain specific embodiments of the present invention, the Selected from Wherein R 2a , R 2b , R 2c Consistent with the above definition, in some embodiments, the R 2a , R 2b , R 2c Each is independently selected from hydrogen, deuterium, tritium, C1-C6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl);

[0066] Furthermore, in certain specific embodiments of the present invention, the Selected from Wherein R 2a , R 2b , R 3a , R 3b , R 4a , R 4b Consistent with the above definition, in some embodiments, the R 2a , R 2b , R 3a , R 3b , R 4a , R 4b Each is independently selected from hydrogen, deuterium, tritium, C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl). When it is a substituted or unsubstituted aromatic structure, it has better PGDH inhibitory activity and better intracellular PGE2 upregulation activity.

[0067] In certain embodiments of the present invention, 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 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring; preferably, the aromatic ring and the aromatic heterocycle are monocyclic or bicyclic, the unsaturated alicyclic ring is a monocyclic ring, and the aromatic heterocycle and the unsaturated alicyclic ring each independently contain 1-3 heteroatoms, and the heteroatoms are independently selected from N, O, and S; more preferably, the ring A is selected from a benzene ring, a naphthalene ring, a 5-10 membered aromatic heterocycle containing 1-3 heteroatoms, a 6-membered unsaturated alicyclic ring containing 1-3 heteroatoms (preferably 1-2 heteroatoms), or an 8-14 membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic ring containing 1-3 heteroatoms (preferably 1-2 heteroatoms), and the heteroatoms are independently selected from N, O, and S.

[0068] In certain embodiments of the present invention, the R A Selected from hydrogen, deuterium, tritium, cyano, fluorine, chlorine, bromine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, isopropenyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably selected from hydrogen, deuterium, tritium, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, isopropenyl; more preferably selected from -NH2.

[0069] In certain embodiments of the present invention, the R is selected from C1 to C 10 Alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, etc.), 3-12-membered cycloalkyl (e.g., 3-10-membered cycloalkyl, 3-8-membered cycloalkyl, etc.), 3-12-membered heterocycloalkyl containing 1-2 heteroatoms (e.g., 3-10-membered heterocycloalkyl containing 1-2 heteroatoms, 3-8-membered heterocycloalkyl containing 1-2 heteroatoms, etc.), wherein the heteroatoms may be, for example, N, O, S, wherein R is replaced by 0 or 1 R 1 Substitution, the R 1 Consistent with the above definition; further, in certain specific embodiments of the present invention, the R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, tert-butylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,

[0070] Where R is 0 or 1 R 1 Substitution, the R 1 Consistent with the above definition.

[0071] In certain specific embodiments of the present invention, the compound represented by formula (III) provided by the present invention has a structure represented by formula (III-a):

[0072]

[0073] Among them, ring A, o, R 0 , R 2a , R 2b , R A , R is consistent with the above definition; in some specific embodiments, the R 2a , R 2b Each is independently selected from hydrogen, deuterium, tritium, and C1-C6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl).

[0074] In certain specific embodiments of the present invention, the compound represented by formula (III) provided by the present invention has a structure represented by formula (III-b):

[0075]

[0076] Among them, ring A, o, R 0 , R 3a , R 3b , R 4a , R 4b , R A , R is consistent with the above definition; in some specific embodiments, the R 3a , R 3b , R 4a , R 4b Each is independently selected from hydrogen, deuterium, tritium, and C1-C6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl).

[0077] The compounds of formula (I), formula (II), formula (II-a), formula (II-b), formula (III), formula (III-a), formula (III-b), or pharmaceutically acceptable salts thereof, or solvates thereof (e.g., hydrates), or prodrugs thereof provided by the present invention, in some specific embodiments, the R 0each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano, =O, =NH, =CH2CH3, =NCH(CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy; preferably, R 0 Each is independently selected from deuterium, tritium, fluorine, cyano, =O, -NH2, -N(CH3)2, -C(O)OCH2CH3, carboxyl, -COCH3, methyl, ethyl, n-propyl, isopropyl.

[0078] The compounds of formula (I), formula (II), formula (II-a), formula (II-b), formula (III), formula (III-a), and formula (III-b) provided by the present invention, or pharmaceutically acceptable salts thereof, or solvates thereof (e.g., hydrates), or prodrugs thereof, in some specific embodiments, the ring A is selected from a benzene ring, a naphthalene ring, a 5-10-membered aromatic heterocycle containing 1 to 3 heteroatoms, a 6-membered unsaturated alicyclic ring containing 1 to 2 heteroatoms, or an 8-14-membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic ring containing 1 to 2 heteroatoms, and the heteroatoms are independently selected from N, O, and S;

[0079] Further, the ring A is selected from

[0080]

[0081] Select from

[0082]

[0083]

[0084] More preferably

[0085] The compounds of formula (I), formula (II), formula (II-a), formula (II-b), formula (III), formula (III-a), and formula (III-b) provided by the present invention, or pharmaceutically acceptable salts thereof, or solvates thereof (e.g., hydrates), or prodrugs thereof, in some specific embodiments, the R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, tert-butylmethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, benzyl, thephenylmethyl, methoxycarbonylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Preferably, the group consisting of isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, 2-methylbutyl, 2-hydroxyethyl, benzyl, methoxycarbonylethyl, More preferred is n-butyl, cyclopentyl and cyclohexyl.

[0086] The compounds of formula (I), formula (II), formula (II-a), formula (II-b), formula (III), formula (III-a), formula (III-b), or pharmaceutically acceptable salts thereof, or solvates thereof (e.g., hydrates), or prodrugs thereof provided by the present invention, in some specific embodiments, the R A is selected from hydrogen, deuterium, tritium, cyano, bromine, -NH2, methyl, cyclopropyl, isopropenyl (preferably -NH2, hydrogen, deuterium, tritium, methyl, isopropenyl, more preferably -NH2), said o is selected from 0, 1 or 2, said R 0 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imine, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy (for example, R 0 Each is independently selected from deuterium, tritium, methyl, =O, carboxyl, etc.), wherein R is selected from isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, 2-methylbutyl, 2-hydroxyethyl, benzyl, methoxycarbonylethyl, (preferably, for example, n-butyl, cyclopentyl, and cyclohexyl), the ring A is selected from a benzene ring, a naphthalene ring, a 5-10-membered aromatic heterocyclic ring containing 1-2 heteroatoms, a 6-membered unsaturated aliphatic heterocyclic ring containing 1 heteroatom, or an 8-14-membered cyclic ring consisting of a benzene ring and an unsaturated aliphatic heterocyclic ring containing 1-2 heteroatoms, wherein the heteroatoms are independently selected from N, O, and S (for example, the ring A is selected from

[0087] The compound represented by formula (II) of the present invention has better PGDH inhibitory activity and better intracellular up-regulation activity of PGE2 relative to formula (III). The compound represented by formula (II-a) of the present invention has better PGDH inhibitory activity and better intracellular up-regulation activity of PGE2 relative to formula (III-a).

[0088] In some specific embodiments of the present invention, the present invention provides the following compounds, or pharmaceutically acceptable salts thereof, or solvates thereof (eg hydrates), or prodrugs thereof:

[0089]

[0090]

[0091] In other aspects, the present invention also provides the following compounds, or pharmaceutically acceptable salts thereof, or solvates thereof (such as hydrates), or prodrugs thereof,

[0092]

[0093] The present invention also covers solutions obtained by any combination, deletion or replacement of the above-mentioned embodiments.

[0094] Another aspect of the present invention is to provide a pharmaceutical composition comprising at least one of the aforementioned compounds, its tautomers or mixtures thereof, or its pharmaceutically acceptable salts, or its solvates, or its prodrugs, and at least one pharmaceutically acceptable excipient.

[0095] Another aspect of the present invention is to provide a compound as mentioned above, or a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a pharmaceutical composition for the preparation of a drug. Wherein, the drug is a 15-PGDH inhibitor, which can be used to treat diseases associated with an increase in the level of unwanted 15-PGDH activity. Alternatively, the present application provides a compound as mentioned above, or a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a pharmaceutical composition thereof for use as a drug. Alternatively, the present application provides a method for treating or preventing a 15-PGDH-related disease, comprising administering the compound as mentioned above, or a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a pharmaceutical composition thereof to a subject in need. The 15-PGDH-related disease herein refers to a disease or complication thereof that achieves clinically beneficial effects such as alleviation, improvement, cessation of progression, alleviation, or no longer deterioration by inhibiting 15-PGDH activity.

[0096] In certain specific embodiments, the medicament is used to treat or prevent fibrosis, oral ulcers, gum disease, colitis, ulcerative colitis, gastroduodenal ulcers, inflammatory diseases, vascular insufficiency, Raynaud's disease, Buerger's disease, neuropathy, pulmonary hypertension, cardiovascular disease and kidney disease, cardiovascular disease, trauma, skin injury, autoimmune disease, graft-versus-host disease, osteoporosis, ear disease, eye disease, neutropenia, diabetes, underactive bladder, or to promote hair growth, pigmentation, tissue repair, tissue regeneration, implants in stem cell transplantation or bone marrow transplantation or organ transplantation, neurogenesis and nerve cell death, muscle regeneration and cervical ripening, or to enhance resistance to the toxicity of chemotherapy and the toxicity of immunosuppressants.

[0097] definition

[0098] Unless stated otherwise, the following terms used in the specification and claims have the following meanings.

[0099] "Chained hydrocarbon group" refers to a group consisting of only carbon and hydrogen atoms connected in a chain of aliphatic groups. The hydrocarbon group may be a saturated hydrocarbon group or an unsaturated hydrocarbon group; the chain may be a straight chain or a 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, including a saturated hydrocarbon group and an unsaturated hydrocarbon group.

[0100] "Alkyl" refers to a saturated aliphatic chain hydrocarbon group, including straight-chain alkyl and branched-chain alkyl. For example, the C1-C6 alkyl used in the present invention refers to a straight-chain alkyl or branched-chain alkyl consisting of 1 to 6 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, etc.

[0101] "Alkoxy" refers to -O-alkyl; the C1-C6 alkoxy used in the present invention refers to a straight chain alkoxy or branched chain alkoxy consisting of 1 to 6 carbon atoms. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentyl, tert-pentyl, n-hexyl, and the like.

[0102] "Ring" refers to any cyclic covalently closed structure, including, for example, carbocycle (e.g., aromatic ring or alicyclic ring), heterocycle (e.g., aromatic heterocycle or alicyclic heterocycle). Carbocycle refers to a ring consisting of only carbon atoms, and heterocycle refers to a closed structure formed by covalent bonding of carbon atoms and heteroatoms. Depending on the number of rings, a "ring" can be a monocyclic, bicyclic, tricyclic or polycyclic ring. When the ring is bicyclic, tricyclic or polycyclic, the relationship between the rings may include fused rings, spirocyclic rings, and bridged rings.

[0103] "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.

[0104] "Member" refers to the number of atoms constituting the ring. Typical 5-membered rings include, but are not limited to, cyclopentane, pyrrole, imidazole, thiazole, furan, and thiophene; typical 6-membered rings include, but are not limited to, cyclohexane, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, and the like.

[0105] "Alicyclic ring" or "alicyclic group" refers to a saturated or partially unsaturated aliphatic carbocyclic group. Saturated aliphatic carbocyclic rings are called, for example, saturated alicyclic rings, and may also be called "cycloalkyl"; partially unsaturated carbocyclic rings may be called, for example, unsaturated alicyclic rings. Alicyclic rings may be monocyclic, spirocyclic, fused or bridged rings, for example, a 3- to 8-membered alicyclic ring refers to an aliphatic carbocyclic group consisting of 3 to 8 backbone carbon atoms. Typical alicyclic structures include, but are not limited to:

[0106]

[0107] wait.

[0108] "Aliphatic heterocycle" or "aliphatic heterocyclic group" refers to a non-aromatic cyclic group formed by replacing carbon atoms in an alicyclic ring with one or more heteroatoms. Aliphatic heterocycles or aliphatic heterocyclic groups may include saturated aliphatic heterocycles and unsaturated aliphatic heterocycles. For example, a 3-12-membered aliphatic heterocyclic group refers to a non-aromatic cyclic group composed of 3-12 skeleton atoms and containing one or more heteroatoms, and may be a saturated aliphatic heterocyclic group or an unsaturated aliphatic heterocyclic group.

[0109] "Saturated alicyclic" is also called "cycloalkyl", which is an aliphatic cyclic group composed of saturated carbon atoms as the skeleton. The 3- to 8-membered cycloalkyl used in the present invention refers to a cyclic alkyl group composed of 3 to 8 carbon atoms. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2,1,1]hexyl, cycloheptyl, etc.

[0110] "Saturated heterocyclic ring" is also called "heterocycloalkyl", which means that the carbon atoms constituting the ring skeleton in the heterocyclic ring are all saturated. For example, the 3-12-membered heterocycloalkyl used in the present invention refers to a non-aromatic cyclic group formed by 3-12 atoms constituting the ring skeleton, wherein the atoms constituting the ring skeleton are composed of saturated carbon atoms and heteroatoms. Typical saturated heterocyclic rings include but are not limited to:

[0111] 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 some embodiments of the present invention, "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 invention refers to a non-aromatic cyclic group composed of 3-12 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:

[0113] wait.

[0114] "Aromatic ring" or "aryl group" 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 bicyclic ring, a tricyclic ring or a 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. The 6-10 membered aromatic ring or 6-10 membered aryl group used in the present invention refers to an aromatic ring group composed of 6 to 10 backbone carbon atoms.

[0115] "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:

[0116] wait.

[0117] The 5- to 10-membered aromatic heterocycle or 5- to 10-membered heteroaryl group used in the present invention refers to a heteroatom-containing aromatic ring group consisting of 5 to 10 skeleton atoms.

[0118] "Cyclic ring" refers to a cyclic structure formed by sharing two adjacent ring atoms between rings. Cyclic rings can be bicyclic, tricyclic or polycyclic.

[0119] In the present invention, "a ring consisting of an aromatic ring and an unsaturated alicyclic ring" refers to a ring structure formed by the aromatic ring and the unsaturated alicyclic ring sharing two adjacent ring atoms; "a ring consisting of an aromatic heterocyclic ring and an unsaturated alicyclic ring" refers to a ring structure formed by the aromatic heterocyclic ring and the unsaturated alicyclic ring sharing two adjacent ring atoms. In the present invention, "a 7- to 12-membered ring consisting of an aromatic heterocyclic ring and an unsaturated alicyclic ring" refers to a ring structure with 7 to 12 skeleton ring atoms formed by the unsaturated alicyclic ring and the aromatic heterocyclic ring sharing two adjacent ring atoms. In the present invention, "a 7- to 12-membered ring consisting of an aromatic ring and an unsaturated alicyclic ring" refers to a ring structure with 7 to 12 skeleton ring atoms formed by the unsaturated alicyclic ring and the aromatic ring sharing two adjacent ring atoms.

[0120] Common cyclic rings formed by aromatic rings and unsaturated heterocyclic rings include but are not limited to:

[0121] Common cyclic rings formed by aromatic heterocycles and unsaturated aliphatic heterocycles include but are not limited to:

[0122] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0123] "Haloalkyl" means that at least one hydrogen in the alkyl group is replaced by a halogen atom. The C1-C6 haloalkyl used in the present invention refers to a straight-chain alkyl or branched alkyl composed of 1 to 6 carbon atoms, and at least one hydrogen on the alkyl group is arbitrarily replaced by a halogen atom.

[0124] "Haloalkoxy" refers to an alkoxy group in which at least one hydrogen is replaced by a halogen atom. The C1-C6 haloalkoxy group used in the present invention refers to a straight-chain alkyl group or a branched-chain alkyl group consisting of 1 to 6 carbon atoms, and at least one hydrogen on the alkyl group is arbitrarily replaced by a halogen atom.

[0125] "Amine" or "amine" refers to a group having -NR S R T The chemical structure of S , R T Each is independently selected from hydrogen, deuterium, tritium, alkyl, cycloalkyl, common "amino groups" include but are not limited to -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2.

[0126] "Iminyl" or "imine" refers to a group having =NR W The chemical structure of W Selected from hydrogen, deuterium, tritium, C1-C6 alkyl or 3-12 membered cycloalkyl, common imino groups include but are not limited to =NH, =NCH3, =CH2CH3, =NCH(CH3)2.

[0127] "Carbonyl" refers to a group having -COR Z The chemical structure of Z Selected from alkyl, cycloalkyl, heterocycloalkyl, common carbonyl groups include but are not limited to -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2.

[0128] "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 , RV 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.

[0129] An "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 Each can be independently selected from alkyl (e.g., C1-C6 alkyl), cycloalkyl (e.g., 3- to 8-membered cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl). Common ester groups include, but are not limited to, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2.

[0130] "Substitution" refers to one or more hydrogen atoms in a group being replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without making too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond. Each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, alkylthio, aryloxy, nitro, acyl, halogen, haloalkyl, amino, etc. .

[0131] "Inhibitor" refers to a substance that reduces the activity of an enzyme.

[0132] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0133] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0134] "Pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0135] 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.

[0136] "Tautomers" or "tautomeric forms" refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, where the proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons. Non-limiting examples of tautomers include, but are not limited to,

[0137] "Stereoisomers" refer to isomers caused by the same order of connection between atoms or atomic groups in a molecule, but different arrangements of atoms in space. It can include two major categories: cis-trans isomers and chiral isomers. Chiral isomers can be divided into two major categories: enantiomers and diastereomers.

[0138] "Stereoisomers" refer to isomers caused by the same order of connection between atoms or atomic groups in a molecule, but different arrangements of atoms in space. It can be divided into several major categories: conformational isomers, cis-trans isomers, and chiral isomers. Chiral isomers can be divided into two major categories: enantiomers and diastereomers. The spatial arrangement of atoms in the structure of a compound in "stereoisomers" is usually represented by a wedge-shaped covalent bond (bold wedge-shaped bond) Dashed wedge key ) represents, wherein the bold wedge-shaped bonds indicate the direction outward from the paper, and the dashed wedge-shaped bonds indicate the direction inward from the paper. "Enantiomers" refer to compounds with the same molecular formula and functional groups, which have isomerism caused by different configurations of atoms in space, and the compounds form stereoisomers that are mirror images of each other and cannot be superimposed.

[0139] "Diastereoisomers" refer to compounds with the same molecular formula and functional groups, which are stereoisomers caused by different spatial configurations of atoms. At the same time, the compounds are not stereoisomers that are in a real-life mirror-image relationship with each other.

[0140] In the present invention, the straight covalent bond "—" in the compound structure can represent being in the same plane as the paper. In the present invention, when stereoisomers exist in the atoms connected by the straight covalent bond, the straight covalent bond represents that the arrangement of the atoms connected thereto can include being in the same plane as the paper, facing outward from the paper, facing inward from the paper, or a mixture of various arrangements.

[0141] Unless otherwise specified, the terms "comprise, comprises and comprising" or their equivalents (contain, contains, containing, include, includes, including) used herein are open-ended expressions and mean that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0142] Unless otherwise indicated, all numbers used herein expressing the amounts of ingredients, measurements or reaction conditions are to be understood as being modified in all cases by the term "about". When connected with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

[0143] 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.

[0144] Obviously, according to the above contents of the present invention, in accordance with the common technical knowledge and means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0145] The abbreviations in the present invention have the following meanings:

[0146] DETAILED DESCRIPTION

[0147] Synthesis method

[0148] The present invention also provides a method for synthesizing the above-mentioned compound. The method for synthesizing the present invention is mainly based on the preparation method reported in chemical literature or uses commercially available chemical reagents as starting materials for related synthesis.

[0149] Method 1

[0150]

[0151] Here are the steps:

[0152] a) reacting 2,6-dichloropyrimidine-4-carbonitrile in aqueous ammonia to obtain 2-chloro-6-aminopyrimidine-4-carbonitrile represented by formula (i);

[0153] b) coupling reaction of a 6-amino-2-chloropyrimidine-4-carbonitrile compound with the compound represented by formula (a) to obtain a compound represented by formula (i);

[0154] c) subjecting the compound represented by formula (i) to a bromination reaction under the action of a brominating agent (such as NBS, etc.) to obtain a compound represented by formula (ii);

[0155] d) subjecting the compound represented by formula (ii) to a ring-closing reaction with bromoacetaldehyde ethylene acetal to obtain a compound represented by formula (iii);

[0156] e) reacting the compound represented by formula (iii) with the compound represented by formula (b) in the presence of a sulfiding agent such as sodium hydrosulfide to obtain a compound represented by formula (iv);

[0157] f) reacting the compound represented by formula (iv) with a suitable oxidant (such as hydrogen peroxide) to obtain a compound represented by formula (v);

[0158] g) Finally, the compound represented by formula (v) is subjected to a ring-closing reaction to obtain the target compound of the present invention represented by formula (x).

[0159] The aforementioned 2,6-dichloropyrimidine-4-carbonitrile, the compounds represented by formula (a) and formula (b) can be commercially available products, or can be prepared by a person skilled in the art through a preparation method disclosed in the prior art. The compound represented by formula (a) in the present invention can also be a pinacol boroester compound formed by esterification with pinacol.

[0160] In method 1, ring A, R 0 The definitions of , o, and R are consistent with those of the present invention. In certain embodiments, for example, the ring A may be selected from

[0161] R can be selected from C1~C 10 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, wherein R is replaced by 0 or 1 R 1 substituted, said R1 is independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkyl, C1-C6 haloalkyl, 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 , Rb , R X , R Y Each independently selected from C1-C6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl (for example, the R can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, tert-butylmethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, benzyl, thephenylmethyl, methoxycarbonylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, ); o can be selected from, for example, 0, 1, 2, 3 or 4; each R 0 can be 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 [such as the R 0 The following may be independently selected from deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano, =O, =NH, =CH2CH3, =NCH(CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, -COCH3, -COCH2CH3, -CO(CH2)2CH3, - COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, piperazinyl, N-methylpiperazinyl, morpholinyl, piperidinyl, thiomorpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, cyclopropyloxy, cyclopropylmethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.]. In the present invention, when R 0It is an ester group (for example, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, etc.), and can also be hydrolyzed in a strong base to make R 0 Become the corresponding carboxyl or phenolic hydroxyl.

[0162] Method 2

[0163]

[0164] Here are the steps:

[0165] a1) subjecting 2,6-dichloropyrimidine-4-carbonitrile to a nucleophilic substitution reaction with a compound of formula (c) to obtain a compound of formula (i-1), wherein M is hydrogen or a hydroxyl protecting group (e.g., tert-butyldimethylsilyl, tetrahydropyranyl, etc.) as required for the reaction;

[0166] b1) coupling the compound represented by formula (i-1) with the compound represented by formula (a) to obtain the compound represented by formula (ii-1);

[0167] c1) subjecting the compound represented by formula (ii-1) to bromination reaction with a brominating agent (such as NBS, etc.) to obtain the compound represented by formula (iii-1);

[0168] d1) subjecting the compound represented by formula (iii-1) to a ring-closing reaction to obtain a compound represented by formula (iv-1);

[0169] e1) reacting the compound represented by formula (iv-1) with the compound represented by formula (b) in the presence of a sulfiding agent such as sodium hydrosulfide to obtain a compound represented by formula (v-1);

[0170] f1) reacting the compound represented by formula (v-1) with a suitable oxidant (such as hydrogen peroxide) to obtain a compound represented by formula (vi);

[0171] g1) then subjecting the compound represented by formula (vi) to a ring-closure reaction to obtain certain target compounds of the present invention represented by formula (x-1);

[0172] h1) The compound represented by formula (x-1) is subjected to an oxidation reaction under the action of an oxidant (such as DDQ) to obtain certain target compounds of the present invention represented by formula (x-2).

[0173] The aforementioned 2,6-dichloropyrimidine-4-carbonitrile, the compounds represented by formula (a), formula (b), and formula (c) can be commercially available products, or can be prepared by a person skilled in the art using a preparation method disclosed in the prior art. The compound represented by formula (a) in the present invention can also be a pinacol boroester compound formed by esterification with pinacol.

[0174] In method 2, ring A, R 0 ,o,R,R 2a , R 2c , R 3a , R 3c , R 4a , R 4c The definition of is consistent with the above description of the present invention. In certain embodiments, for example, the ring A can be selected from

[0175] R can be selected from C1~C 10 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, wherein R is replaced by 0 or 1 R 1 substituted, said R1 is independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkyl, C1-C6 haloalkyl, 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 independently selected from C1-C6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl (for example, the R can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, tert-butylmethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, benzyl, thephenylmethyl, methoxycarbonylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,

[0176] ); o can be selected from, for example, 0, 1, 2, 3 or 4; each R 0can be 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 [such as the R 0 The following may be independently selected from deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano, =O, =NH, =CH2CH3, =NCH(CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, -COCH3, -COCH2CH3, -CO(CH2)2CH3, - [COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, piperazinyl, N-methylpiperazinyl, morpholinyl, piperidinyl, thiomorpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, cyclopropyloxy, cyclopropylmethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.]; R 2a , R 2c , R 3a , R 3c , R 4a , R 4c are independently selected from hydrogen, deuterium, tritium, C1-C6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, etc.); in certain embodiments, the compound represented by formula (c) can be selected from In the present invention, when R 0 It is an ester group (for example, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, etc.), and can also be hydrolyzed in a strong base to make R 0 Become the corresponding carboxyl or phenolic hydroxyl.

[0177] Method 3

[0178]

[0179] Here are the steps:

[0180] a2) subjecting 3,5-dichloropyrazine-2-carbonitrile to a nucleophilic substitution reaction with the compound represented by formula (c) to obtain a compound represented by formula (i-2), wherein M is hydrogen or a hydroxyl protecting group (such as tert-butyldimethylsilyl, tetrahydropyranyl, etc.) as required for the reaction;

[0181] b2) subjecting the compound represented by formula (i-2) to bromination reaction with a brominating agent (such as NBS, etc.) to obtain a compound represented by formula (ii-2);

[0182] c2) coupling the compound represented by formula (ii-2) with the compound represented by formula (a) to obtain the compound represented by formula (iii-2);

[0183] d2) reacting the compound represented by formula (iii-2) with the compound represented by formula (b) in the presence of a sulfiding agent such as sodium hydrosulfide to obtain a compound represented by formula (iv-2);

[0184] e2) reacting the compound represented by formula (iv-2) with a suitable oxidant (such as hydrogen peroxide) to obtain a compound represented by formula (v-2);

[0185] f2) subjecting the compound represented by formula (v-2) to a ring-closing reaction to obtain a compound represented by formula (vi-2);

[0186] g2) then subjecting the compound represented by formula (vi-2) to a ring-closure reaction again to obtain certain target compounds of the present invention represented by formula (x-3);

[0187] h2) The compound represented by formula (x-3) is oxidized under the action of an oxidant (such as DDQ) to obtain certain target compounds of the present invention represented by formula (x-4).

[0188] The aforementioned 3,5-dichloropyrazine-2-carbonitrile, the compounds represented by formula (a), formula (b), and formula (c) can be commercially available products, or can be prepared by a person skilled in the art using a preparation method disclosed in the prior art. The compound represented by formula (a) in the present invention can also be a pinacol boroester compound formed by esterification with pinacol.

[0189] In method 3, ring A, R 0 ,o,R,R 2a , R 2c , R 3a , R 3c , R 4a , R 4cThe definition of is consistent with the above description of the present invention. In certain embodiments, for example, the ring A can be selected from

[0190] R can be selected from C1~C 10 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, wherein R is replaced by 0 or 1 R 1 substituted, said R1 is independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkyl, C1-C6 haloalkyl, 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 independently selected from C1-C6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl (for example, the R can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, tert-butylmethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, benzyl, thephenylmethyl, methoxycarbonylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,

[0191] ); o can be selected from, for example, 0, 1, 2, 3 or 4; each R 0 can be 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 [such as the R 0The following may be independently selected from deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano, =O, =NH, =CH2CH3, =NCH(CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, -COCH3, -COCH2CH3, -CO(CH2)2CH3, - [COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, piperazinyl, N-methylpiperazinyl, morpholinyl, piperidinyl, thiomorpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, cyclopropyloxy, cyclopropylmethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.]; R 2a , R 2c , R 3a , R 3c , R 4a , R 4c are independently selected from hydrogen, deuterium, tritium, C1-C6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, etc.); in certain embodiments, the compound represented by formula (c) can be selected from In the present invention, when R 0 It is an ester group (for example, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, etc.), and can also be hydrolyzed in a strong base to make R 0 Become the corresponding carboxyl or phenolic hydroxyl.

[0192] Method 4

[0193]

[0194] Here are the steps:

[0195] a3) coupling reaction of 2-amino-3-bromo-6-chloropyrazine with the compound represented by formula (a) to obtain a compound represented by formula (i-3);

[0196] b3) subjecting the compound represented by formula (i-3) to bromination reaction with a brominating agent (such as NBS, etc.) to obtain a compound represented by formula (ii-3);

[0197] c3) cyanating the compound represented by formula (ii-3) to obtain the compound represented by formula (iii-3);

[0198] d3) reacting the compound represented by formula (iii-3) with bromoacetaldehyde ethylene acetal to obtain a compound represented by formula (iv-3);

[0199] e3) reacting the compound represented by formula (iv-3) with the compound represented by formula (b) in the presence of a sulfiding agent such as sodium hydrosulfide to obtain a compound represented by formula (v-3);

[0200] f3) reacting the compound represented by formula (v-3) with a suitable oxidant (such as hydrogen peroxide) to obtain a compound represented by formula (vi-3);

[0201] g3) Finally, the compound represented by formula (vi-3) is subjected to a ring-closure reaction to obtain the target compound of the present invention represented by formula (x-5).

[0202] The aforementioned method 4 can also be carried out using the following route 4-1:

[0203]

[0204] 2-amino-5-bromo-6-chloropyrazine is subjected to cyanation reaction to obtain 2-amino-6-chloropyrazine-5-carbonitrile, which is then subjected to bromination reaction under the action of a brominating agent (such as NBS, etc.) to obtain 2-amino-3-bromo-6-chloropyrazine-5-carbonitrile, which is then subjected to coupling reaction with the compound shown in formula (a) to obtain the compound shown in formula (iii-3). Then, the target compound of the present invention shown in formula (x-5) is obtained according to steps d3 to g3 in method 4.

[0205] The aforementioned 2-amino-3-bromo-6-chloropyrazine, 2-amino-5-bromo-6-chloropyrazine, compounds represented by formula (a) and formula (b) can be commercially available products, or can be prepared by a person skilled in the art using a preparation method disclosed in the prior art. The compound represented by formula (a) in the present invention can also be a pinacol boroester compound formed by esterification with pinacol.

[0206] In method 4, ring A, R 0 The definitions of , o, and R are consistent with those of the present invention. In certain embodiments, for example, the ring A may be selected from

[0207] R can be selected from C1~C 10 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, wherein R is replaced by 0 or 1 R 1 substituted, said R1 is independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkyl, C1-C6 haloalkyl, 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 independently selected from C1-C6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl (for example, the R can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, tert-butylmethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, benzyl, thephenylmethyl, methoxycarbonylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, ); o can be selected from, for example, 0, 1, 2, 3 or 4; each R 0 can be 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 [such as the R 0The following may be independently selected from deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano, =O, =NH, =CH2CH3, =NCH(CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, -COCH3, -COCH2CH3, -CO(CH2)2CH3, - COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, piperazinyl, N-methylpiperazinyl, morpholinyl, piperidinyl, thiomorpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, cyclopropyloxy, cyclopropylmethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.]. In the present invention, when R 0 It is an ester group (for example, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, etc.), and can also be hydrolyzed in a strong base to make R 0 Become the corresponding carboxyl or phenolic hydroxyl.

[0208] Method 5

[0209]

[0210] The compound represented by formula (x-2) is reacted with isopentyl nitrite and dibromomethane to obtain the compound represented by formula (y-2) in which -NH2 is converted into hydrogen, and the compound represented by formula (z-2) in which -NH2 is converted into bromine. Similarly, the compounds represented by formula (x), formula (x-1), formula (x-3), formula (x-4), and formula (x-5) are reacted with isopentyl nitrite and dibromomethane respectively to obtain the corresponding compounds in which -NH2 is converted into hydrogen and bromine.

[0211] Method 6

[0212]

[0213] The compound represented by formula (iii) is reacted in a concentrated acid solution (such as concentrated hydrochloric acid) to obtain a carboxylated compound represented by formula (iv-4), which is then esterified to obtain a compound represented by formula (v-4), which is then reacted with a compound represented by formula (b) in the presence of a sulfiding agent such as sodium hydrosulfide to obtain a compound represented by formula (vi-4), which is then reacted with a suitable oxidizing agent (such as hydrogen peroxide) to oxidize to obtain a compound represented by formula (vii-4), and then a ring-closure reaction is performed to obtain the target compound of the present invention represented by formula (x-OH).

[0214] The compound represented by formula (x-OH) is reacted with trifluoromethanesulfonic anhydride to obtain the compound represented by formula (viii-4), which is then reacted with the compound represented by formula (d) to obtain the target compound of the present invention represented by formula (xx), wherein ring A, R 0 The definitions of , o, and R are consistent with those of the present invention, wherein R A1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C1-C6 haloalkyl, 3-8 membered cycloalkyl (e.g. methyl, ethyl, isopropyl, cyclopropyl, isopropenyl, etc.). 0 It is an ester group (e.g., -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, etc.), and can also be hydrolyzed in a strong base to make R 0 Similarly, the compounds represented by formula (iv-1) and formula (iv-3) are reacted according to the above route to obtain the corresponding -NH2 converted into hydroxyl and R A1 of compounds.

[0215] Example 1: Preparation of 2-(butylsulfinyl)-5-phenylimidazo[1,2-c]thieno[2,3-e]pyrimidin-3-amine

[0216] Step 1: Preparation of 6-amino-2-chloropyrimidine-4-carbonitrile

[0217] Weigh 2,6-dichloropyrimidine-4-carbonitrile (400 mg) and dissolve it in 5 mL of acetonitrile. Add 4 mL of ammonia water and react at room temperature for 2 h. LCMS monitors the reaction to be complete and concentrate under reduced pressure to obtain the title compound. MS (ESI) m / z (M+H) + =155.0.

[0218] Step 2: Preparation of 6-amino-2-phenylpyrimidine-4-carbonitrile

[0219] Weigh 6-amino-2-chloropyrimidine-4-carbonitrile (475 mg), phenylboronic acid (564 mg), cesium carbonate (2.0 g), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (113 mg) in a 100 mL single-necked bottle, add 1,4-dioxane (15 mL) and pure water (3 mL), replace with nitrogen, and react at 100 ° C for 2 h. Monitor by LCMS, quench with water, extract with ethyl acetate, dry with anhydrous sodium sulfate, and purify with silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =197.1.

[0220] Step 3: Preparation of 6-amino-5-bromo-2-phenylpyrimidine-4-carbonitrile

[0221]

[0222] Weigh 6-amino-2-phenylpyrimidine-4-carbonitrile (120 mg) and dissolve it in dichloromethane (6 mL), add N-bromosuccinimide (142 mg) and react at 50° C. for 14 h. Monitor by LCMS and purify by Prep-TLC to obtain the title compound.

[0223] MS (ESI) m / z (M+H) + =275.0.

[0224] Step 4: Preparation of 8-bromo-5-phenylimidazo[1,2-c]pyrimidine-7-carbonitrile

[0225]

[0226] Weigh 6-amino-5-bromo-2-phenylpyrimidine-4-carbonitrile (80 mg) and dissolve it in acetonitrile (3 mL). Add bromoacetaldehyde diethyl acetal (0.22 mL) and react under microwave at 120°C for 1 h. LCMS and TLC monitor the reaction completion. Prep-TLC purification gives the title compound (99 mg). MS (ESI) m / z (M+H) + =299.0.

[0227] Step 5: Preparation of 8-(((butylthio)methyl)thio)-5-phenylimidazo[1,2-c]pyrimidine-7-carbonitrile

[0228]

[0229] Weigh 8-bromo-5-phenylimidazo[1,2-c]pyrimidine-7-carbonitrile (94 mg) and dissolve it in N,N-dimethylformamide (4 mL). Add sodium hydrosulfide (38 mg) and react at room temperature for 30 min. Then add triethylamine (88 μL) and butyl (chloromethyl) sulfane (60 μL) to the above system and react at 80°C for 1 h. Monitor by TLC and LCMS, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain the title compound.

[0230] MS (ESI) m / z (M+H) + =354.8.

[0231] Step 6: Preparation of 8-(((butylsulfinyl)methyl)thio)-5-phenylimidazo[1,2-c]pyrimidine-7-carbonitrile

[0232]

[0233] Weigh 8-(((butylthio)methyl)thio)-5-phenylimidazo[1,2-c]pyrimidine-7-carbonitrile (70 mg) and dissolve it in chloroform (4 mL). Add acetic acid (172 μL) and hydrogen peroxide (37 μL) and react at room temperature for 6 h. Monitor by TLC and LCMS, quench with saturated sodium bicarbonate solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound. MS (ESI) m / z (M+H) + =370.7. Step 7: Preparation of 2-(butylsulfinyl)-5-phenylimidazo[1,2-c]thieno[2,3-e]pyrimidin-3-amine

[0234]

[0235] Weigh 8-(((butylsulfinyl)methyl)thio)-5-phenylimidazo[1,2-c]pyrimidine-7-carbonitrile (66 mg) and dissolve it in tetrahydrofuran (4 mL). Place it at 0°C, add 1M lithium bistrimethylsilylamide (0.27 mL) and react at 0°C for 20 min. Monitor by TLC and LCMS, quench with water, extract with ethyl acetate, dry over anhydrous sodium sulfate, and separate by reverse phase preparative column.

[0236] MS (ESI) m / z (M+H) + =370.7.

[0237] 1H NMR(400MHz, DMSO-d6)δ8.03–7.97(m,3H),7.71–7.63(m,4H),6.29(s,2H),3.16(ddd,J=12.8,8.8,6.0Hz,1H), 3.04(ddd,J=12.8,8.9,6.4Hz,1H), 1.58(dt,J=14.7,7.3Hz,2H), 1.44(q,J=7.3Hz,2H), 0.89(t,J=7.3Hz,3H).

[0238] Example 2: 5-(3-amino-2-(butylsulfinyl)imidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one, Example 3: Preparation of (5-(3-amino-2-(butylsulfinyl)-7,8-dihydroimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one)

[0239]

[0240] Step 1: Preparation of 6-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2-chloropyrimidine-4-carbonitrile

[0241]

[0242] Dissolve 2,6-dichloropyrimidine-4-carbonitrile (5 g) in acetonitrile (50 mL), add dropwise 2-((tert-butyldimethylsilyl)oxy)ethane-1-amine (6.55 g) in acetonitrile (10 mL), stir at room temperature for 2 h, and monitor the reaction until complete by LCMS. Quench with water, extract with ethyl acetate several times, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by column to obtain the title compound.

[0243] MS (ESI) m / z (M+H) + =313.1.

[0244] Step 2: Preparation of 6-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2-(2-methyl-1-oxoisoindolin-5-yl)pyrimidine-4-carbonitrile

[0245]

[0246] 6-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2-chloropyrimidine-4-carbonitrile (3 g), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-isoindolin-1-one (2.9 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.39 g), sodium carbonate (1.52 g) were mixed in 1,4-dioxane and water, and reacted at 95°C for 3 h under nitrogen protection. The reaction was complete after LCMS monitoring, and the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate for several times, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the title compound. MS (ESI) m / z (M+H) + =424.1.

[0247] Step 3: Preparation of 5-bromo-6-((2-hydroxyethyl)amino)-2-(2-methyl-1-oxoisoindolin-5-yl)pyrimidine-4-carbonitrile

[0248]

[0249] 6-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2-(2-methyl-1-oxoisoindolin-5-yl)pyrimidine-4-carbonitrile (4.8 g) and N-bromosuccinimide (3.02 g) were mixed in N,N-dimethylformamide (45 mL) and reacted at 70°C for 5 h. The reaction was complete after monitoring by LCMS. Cooled to room temperature, the reaction solvent was evaporated under reduced pressure, and the residue was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the title compound. MS (ESI) m / z (M+H) + =388.0.

[0250] Step 4: Preparation of 8-bromo-5-(2-methyl-1-oxoisoindolin-5-yl)-2,3-dihydroimidazo[1,2-c]pyrimidine-7-carbonitrile

[0251]

[0252] Dissolve 5-bromo-6-((2-hydroxyethyl)amino)-2-(2-methyl-1-oxoisoindolin-5-yl)pyrimidine-4-carbonitrile (3.3 g) in chloroform (40 mL), add thionyl chloride (6 mL), react at 70°C for 4 h, and monitor the reaction to be complete by LCMS. Cool to room temperature, evaporate the reaction solvent under reduced pressure, adjust the system to weak alkalinity with saturated sodium bicarbonate solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by column to obtain the title compound. MS (ESI) m / z (M+H) + =370.0.

[0253] Step 5: Preparation of 8-(((butylthio)methyl)thio)-5-(2-methyl-1-oxoisoindolin-5-yl)-2,3-dihydroimidazo[1,2-c]pyrimidine-7-carbonitrile

[0254]

[0255] Dissolve 8-bromo-5-(2-methyl-1-oxoisoindolin-5-yl)-2,3-dihydroimidazo[1,2-c]pyrimidine-7-carbonitrile (1.8 g) in N,N-dimethylformamide (20 mL), add sodium hydrosulfide (0.82 g, Purity 70%), react at 80°C for 30 min, and LCMS monitors that bromine is completely replaced. Cool to room temperature, add 1-((chloromethyl)thio)butane (2.13 g), and continue to react at 80°C for 1 h. LCMS monitors that the reaction is complete. Cool to room temperature, concentrate, and purify with a column to obtain the title compound. MS (ESI) m / z (M+H) + =426.1.

[0256] Step 6: Preparation of 8-(((butylsulfinyl)methyl)thio)-5-(2-methyl-1-oxoisoindolin-5-yl)-2,3-dihydroimidazo[1,2-c]pyrimidine-7-carbonitrile

[0257]

[0258] Dissolve 8-(((butylthio)methyl)thio)-5-(2-methyl-1-oxoisoindolin-5-yl)-2,3-dihydroimidazo[1,2-c]pyrimidine-7-carbonitrile (2g) in chloroform, add glacial acetic acid (2.82g) and hydrogen peroxide (1.60g, Purity 30%), react at room temperature for 3h, and the reaction is complete after LCMS monitoring. Use saturated sodium bicarbonate solution to adjust the system to neutrality, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, concentrate and purify with column to obtain the title compound. MS (ESI) m / z (M+H) + =442.1.

[0259] Step 7: Preparation of 5-(3-amino-2-(butylsulfinyl)-7,8-dihydroimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one (Example 3)

[0260]

[0261] Dissolve 8-(((butylsulfinyl)methyl)thio)-5-(2-methyl-1-oxoisoindolin-5-yl)-2,3-dihydroimidazo[1,2-c]pyrimidine-7-carbonitrile (1 g) in a mixture of tetrahydrofuran / methanol / water (20 mL / 6 mL / 6 mL), add sodium hydroxide (0.27 g) in an ice-water bath, and then move to room temperature to react for 1 h. TLC monitoring shows that the raw material disappears and new spots are generated. LCMS monitoring shows that it is the target product. Use 1 M dilute hydrochloric acid to adjust the system to neutrality, concentrate, and purify by column to obtain the title compound. MS (ESI) m / z (M+H) + =442.1.

[0262] 1 H NMR(400MHz, DMSO-d6)δ7.97(s,1H),7.87-7.85(dd,J=7.9,1.4Hz,1H),7.81-7.79(d,J=7.9Hz,1H),6.00(s,2H),4.55(s,2H),4.19 -4.14(m,2H),3.96-3.91(m,2H),3.12(s,3H),3.09-2.99(m,2H),1.61-1.53(m,2H),1.46-1.39(m,2H),0.91-0.87(t,J=7.3Hz,3H).

[0263] Step 8: Preparation of 5-(3-amino-2-(butylsulfinyl)imidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one (Example 2)

[0264]

[0265] Dissolve 5-(3-amino-2-(butylsulfinyl)-7,8-dihydroimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one (60 mg) in chloroform, add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (95 mg), react at room temperature for 1 hour, add saturated sodium bicarbonate solution to quench the reaction, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and separate the crude product with a reverse phase preparative column to obtain the title compound. MS (ESI) m / z (M+H) + =440.1.

[0266] 1H NMR (400MHz, DMSO-d6) δ8.20(s,1H),8.10-8.07(m,2H),7.92-7.90(d,J=7.8Hz,1H),7.72(d,J=1.5Hz,1H),6.32(s,2H),4.6 1(s,2H),3.19-3.13(m,4H),3.08-3.01(m,1H),1.64-1.55(m,2H),1.48-1.39(p,J=7.3Hz,2H),0.91-0.88(t,J=7.3Hz,3H).

[0267] Example 4: Preparation of 2-(butylsulfinyl)-5-phenylimidazo[1,2-a]thieno[3,2-e]pyrazine-3-amine

[0268] Step 1: Preparation of 6-chloro-3-phenylpyrazin-2-amine

[0269]

[0270] Weigh 3-bromo-6-chloropyrazine-2-amine (5g), phenylboronic acid (3.5g), sodium carbonate (5.1g), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (882mg) in a 150mL single-mouth bottle, add 1,4-dioxane (40mL) and pure water (8mL), replace with nitrogen three times, and react at 100°C for 2h. LCMS monitoring, the reaction is complete, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =206.0.

[0271] Step 2: Preparation of 5-bromo-6-chloro-3-phenylpyrazin-2-amine

[0272]

[0273] Weigh 6-chloro-3-phenylpyrazine-2-amine (1.9 g) and dissolve it in N,N-dimethylformamide (30 mL), add N-bromosuccinimide (1.5 g) and react at room temperature for 12 h. Monitor by LCMS and TLC. The reaction is complete, quench with water, extract with ethyl acetate twice, wash with saturated brine twice, dry with anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain the title compound.

[0274] MS (ESI) m / z (M+H) + =283.9.

[0275] Step 3: Preparation of 5-amino-3-chloro-6-phenylpyrazine-2-carbonitrile

[0276]

[0277] Weigh 5-bromo-6-chloro-3-phenylpyrazine-2-amine (1.45 g), dissolve in N,N-dimethylformamide (20 mL), add cuprous cyanide (923 mg) and react overnight at 100°C. LCMS monitoring and TLC monitoring show that the reaction is complete, quench with water, dilute with ethyl acetate, filter with diatomaceous earth, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, and purify the title compound with silica gel column chromatography. MS (ESI) m / z (M+H) + =231.1.

[0278] Step 4: Preparation of 5-bromo-8-phenylimidazo[1,2-a]pyrazine-6-carbonitrile

[0279]

[0280] Weigh 5-amino-3-chloro-6-phenylpyrazine-2-carbonitrile (470 mg), dissolve in acetonitrile (10 mL), add bromoacetaldehyde diethyl acetal (0.92 mL) and react at 120°C in a microwave for 2 h. The reaction was complete under LCMS and TLC monitoring, and the title compound was purified by silica gel column chromatography. MS (ESI) m / z (M+H) + =299.0.

[0281] Step 5: Preparation of 5-(((butylthio)methyl)thio)-8-phenylimidazo[1,2-a]pyrazine-6-carbonitrile

[0282]

[0283] Weigh 5-bromo-8-phenylimidazo[1,2-a]pyrazine-6-carbonitrile (430 mg) and dissolve it in N,N-dimethylformamide (12 mL). Add sodium hydrosulfide (203 mg) and react at 50°C for 40 min. Then add triethylamine (0.5 mL) and butyl (chloromethyl) sulfane (0.32 mL) to the above system and react at 50°C for 1 h. Monitor by TLC and LCMS, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain the title compound.

[0284] MS (ESI) m / z (M+H) + =355.2.

[0285] Step 6: Preparation of 5-(((butylsulfinyl)methyl)thio)-8-phenylimidazo[1,2-a]pyrazine-6-carbonitrile

[0286]

[0287] Weigh 5-(((butylthio)methyl)thio)-8-phenylimidazo[1,2-a]pyrazine-6-carbonitrile (365 mg) and dissolve it in chloroform (10 mL). Add acetic acid (0.88 mL) and hydrogen peroxide (0.21 mL) and react at 50°C for 3 h. Monitor by TLC and LCMS, quench with saturated sodium bicarbonate solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound.

[0288] MS (ESI) m / z (M+H) + =371.1.

[0289] Step 7: Preparation of 2-(butylsulfinyl)-5-phenylimidazo[1,2-a]thieno[3,2-e]pyrazin-3-amine

[0290]

[0291] Weigh 5-(((butylsulfinyl)methyl)thio)-8-phenylimidazo[1,2-a]pyrazine-6-carbonitrile (200 mg) and dissolve it in tetrahydrofuran (6 mL). Add 1M lithium bis(trimethylsilyl)amide (0.81 mL) and react at room temperature for 30 min. Monitor by TLC and LCMS, quench with water, extract twice with ethyl acetate, dry over anhydrous sodium sulfate, and separate by reverse phase preparative column to obtain the title compound.

[0292] MS (ESI) m / z (M+H) + =371.1.

[0293] 1 H NMR(400MHz, DMSO-d6)δ8.03–7.97(m,3H),7.71–7.63(m,4H),6.29(s,2H),3.16(ddd,J=12.8,8.8,6.0Hz,1H), 3.04(ddd,J=12.8,8.9,6.4Hz,1H), 1.58(dt,J=14.7,7.3Hz,2H), 1.44(q,J=7.3Hz,2H), 0.89(t,J=7.3Hz,3H).

[0294] Example 5: Preparation of 6-(3-amino-2-(butylsulfinyl)imidazo[1,2-a]thieno[3,2-e]pyrazin-5-yl)-2-methylisoquinolin-1(2H)-one

[0295]

[0296] Step 1: Preparation of 5-amino-3-chloropyrazine-2-carbonitrile

[0297]

[0298] Weigh 5-bromo-6-chloropyrazin-2-amine (2 g) and dissolve it in N,N-dimethylformamide (30 mL), add cuprous cyanide (1.72 g), replace with nitrogen three times, and react at 100°C overnight. TLC and LCMS monitor the reaction to be complete, dilute with ethyl acetate, filter with celite, extract the aqueous phase with ethyl acetate twice, combine the organic phases, wash with saturated brine twice, dry with anhydrous sodium sulfate, and purify with silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =155.0.

[0299] Step 2: Preparation of 5-amino-6-bromo-3-chloropyrazine-2-carbonitrile

[0300]

[0301] Weigh 5-amino-3-chloropyrazine-2-carbonitrile (830 mg) and dissolve it in dichloromethane (30 mL). Add N-bromosuccinimide (1.44 g) and react at 50°C for 2 h. LCMS and TLC monitoring showed that the reaction was complete. Water was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (PE / EA=1 / 1) to obtain the title compound. MS (ESI) m / z (M+H) + =232.9.

[0302] Step 3: Preparation of 5-amino-3-chloro-6-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)pyrazine-2-carbonitrile

[0303]

[0304] Weigh 5-amino-6-bromo-3-chloropyrazine-2-carbonitrile (780 mg), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)isoquinolin-1(2H)-one (1.05 g), sodium carbonate (464 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (123 mg), add 1,4-dioxane (20 mL) and pure water (4 mL), replace with nitrogen three times, and react at 95°C for 12 hours. LCMS monitored the complete reaction of the raw materials, and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =312.1.

[0305] Step 4: Preparation of 5-bromo-8-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)imidazo[1,2-a]pyrazine-6-carbonitrile

[0306]

[0307] Weigh 5-amino-3-chloro-6-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)pyrazine-2-carbonitrile (850 mg) and dissolve it in acetonitrile (13 mL). Add bromoacetaldehyde diethyl acetal (2.05 mL) and react at 120°C in a microwave for 2 h. Purify by silica gel column chromatography under LCMS and TLC monitoring to obtain the crude title compound. MS (ESI) m / z (M+H) + =381.1.

[0308] Step 5: Preparation of 5-(((butylthio)methyl)thio)-8-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)imidazo[1,2-a]pyrazine-6-carbonitrile

[0309]

[0310] Weigh 5-bromo-8-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)imidazo[1,2-a]pyrazine-6-carbonitrile (400 mg) and dissolve it in N,N-dimethylformamide (12 mL). Add sodium hydrosulfide (126 mg) and react at 50°C for 20 min. Then add triethylamine (0.29 mL) and butyl(chloromethyl)sulfane (0.20 mL) to the above system and react at 50°C for 40 min. Monitor by TLC and LCMS, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and purify by Prep-TLC to obtain the crude title compound. MS (ESI) m / z (M+H) + =436.1.

[0311] Step 6: Preparation of 5-(((butylsulfinyl)methyl)thio)-8-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)imidazo[1,2-a]pyrazine-6-carbonitrile

[0312]

[0313] Weigh 5-(((butylthio)methyl)thio)-8-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)imidazo[1,2-a]pyrazine-6-carbonitrile (150 mg), dissolve in chloroform (6 mL), add acetic acid (0.29 mL), hydrogen peroxide (70 μL) and react at 50 ° C for 3 h. Monitor by TLC and LCMS, quench with saturated sodium bicarbonate solution, extract twice with dichloromethane, dry over anhydrous sodium sulfate, and purify the title compound by silica gel column chromatography. MS (ESI) m / z (M+H) + =452.2.

[0314] Step 7: Preparation of 6-(3-amino-2-(butylsulfinyl)imidazo[1,2-a]thieno[3,2-e]pyrazin-5-yl)-2-methylisoquinolin-1(2H)-one

[0315]

[0316] Weigh 5-(((butylsulfinyl)methyl)thio)-8-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)imidazo[1,2-a]pyrazine-6-carbonitrile (28 mg), dissolve in tetrahydrofuran (4 mL), add 1M lithium bis(trimethylsilyl)amide (0.1 mL) and react at 0°C for 30 min. Monitor by TLC and LCMS, quench with water, extract twice with ethyl acetate, dry over anhydrous sodium sulfate, and separate on a reverse phase preparative column to obtain the title compound. MS (ESI) m / z (M+H) + =452.2.

[0317] 1 H NMR (400MHz, DMSO-d6) δ9.36 (d, J=1.6Hz, 1H), 9.06 (dd, J=8.6, 1.7Hz, 1H), 8.58 (d, J=1.3Hz,1H),8.37(d,J=8.6Hz,1H),8.10(d,J=1.2Hz,1H),7.56(d,J=7.3Hz,1H),6 .78(d,J=7.3Hz,1H),6.73(s,2H),3.56(s,3H),3.20–3.13(m,1H),3.03(ddd,J=12. 8,9.0,6.2Hz,1H),1.69–1.54(m,2H),1.45(h,J=7.3Hz,2H),0.90(t,J=7.3Hz,3H).

[0318] Example 6: (5-(3-amino-2-(butylsulfinyl)-7,8-dihydroimidazo[1,2-a]thieno[3,2-e]pyrazin-5-yl)-2-methylisoindolin-1-one), Example 7: Preparation of 5-(3-amino-2-(butylsulfinyl)imidazo[1,2-a]thieno[3,2-e]pyrazin-5-yl)-2-methylisoindolin-1-one

[0319]

[0320] Step 1: Preparation of 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-3-chloropyrazine-2-carbonitrile

[0321]

[0322] Weigh 3,5-dichloropyrazine-2-carbonitrile (3.0 g) and dissolve it in N,N-dimethylformamide (30 mL), add N,N-diisopropylethylamine (4.3 mL), then add 2-((tert-butyldimethylsilyl)oxy)ethane-1-amine (3.92 mL), and react at room temperature for 1 hour. The reaction is complete as monitored by LCMS and TLC, quenched with water, extracted with ethyl acetate, washed with saturated brine, and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =313.0.

[0323] Step 2: Preparation of ethyl 2-((3-bromo-6-chloro-5-cyanopyrazin-2-yl)amino)acetate

[0324]

[0325] Weigh 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-3-chloropyrazine-2-carbonitrile (2.5 g) and dissolve it in acetic acid (30 mL). Add N-bromosuccinimide (2.14 g) and react at 80°C for 2 h. The reaction was completed as monitored by LCMS and TLC. The mixture was concentrated under reduced pressure, quenched with water, extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =319.0.

[0326] Step 3: Preparation of ethyl 2-((6-chloro-5-cyano-3-(2-methyl-1-oxoisoindolin-5-yl)pyrazin-2-yl)amino)acetate

[0327]

[0328] Weigh ethyl 2-((3-bromo-6-chloro-5-cyanopyrazin-2-yl)amino)acetate (1 g), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-isoindolin-1-one (945 mg), cesium carbonate (2.05 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (115 mg) in a 100 mL single-necked bottle, add 1,4-dioxane (20 mL) and pure water (4 mL), replace with nitrogen three times, and react at 80°C for 2 h. Monitor by LCMS and TLC, directly stir the system, and purify by silica gel column chromatography to obtain the title compound.

[0329] MS (ESI) m / z (M+H) + =386.1.

[0330] Step 4: Preparation of ethyl 2-((6-(((butylthio)methyl)thio)-5-cyano-3-(2-methyl-1-oxoisoindolin-5-yl)pyrazin-2-yl)amino)acetate

[0331]

[0332] Weigh 2-((6-chloro-5-cyano-3-(2-methyl-1-oxoisoindolin-5-yl)pyrazin-2-yl)amino)ethyl acetate (700 mg) and dissolve it in N,N-dimethylformamide (15 mL). Add sodium hydrosulfide (189 mg) and react at 50°C for 25 min. Then add triethylamine (0.50 mL) and butyl (chloromethyl) sulfane (0.34 mL) to the above system and react at 50°C for 40 min. Monitor by TLC and LCMS. The reaction is complete. Add water to quench, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =486.2.

[0333] Step 5: Preparation of ethyl 2-((6-((butylsulfinyl)methyl)thio)-5-cyano-3-(2-methyl-1-oxoisoindolin-5-yl)pyrazin-2-yl)amino)acetate

[0334]

[0335] Weigh 2-((6-((butylthio)methyl)thio)-5-cyano-3-(2-methyl-1-oxoisoindolin-5-yl)pyrazin-2-yl)amino)ethyl acetate (450 mg) and dissolve it in chloroform (12 mL). Add acetic acid (0.8 mL) and hydrogen peroxide (0.17 mL) and react at 50°C for 1.5 h. Monitor by TLC and LCMS. Quench with saturated sodium bicarbonate solution at 0°C, extract twice with dichloromethane, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound. MS (ESI) m / z (M+H) + =502.2.

[0336] Step 6: Preparation of 5-(7-amino-6-(butylsulfinyl)-3-((2-hydroxyethyl)amino)thieno[2,3-b]pyrazin-2-yl)-2-methylisoindolin-1-one

[0337]

[0338] Weigh 2-((6-((butylsulfinyl)methyl)thio)-5-cyano-3-(2-methyl-1-oxoisoindolin-5-yl)pyrazin-2-yl)amino)ethyl acetate (500 mg) and dissolve it in a mixed solvent of N,N-dimethylformamide (8 mL) and methanol (4 mL), add 2M potassium hydroxide solution (1.00 mL) and react at room temperature for 1.5 h. Monitor by TLC and LCMS, quench with water, extract with dichloromethane twice, concentrate under reduced pressure, and purify the title compound by silica gel column chromatography. MS (ESI) m / z (M+H) + =460.1.

[0339] Step 7: Preparation of 5-(3-amino-2-(butylsulfinyl)-7,8-dihydroimidazo[1,2-a]thieno[3,2-e]pyrazin-5-yl)-2-methylisoindolin-1-one (Example 6)

[0340]

[0341] Weigh 5-(7-amino-6-(butylsulfinyl)-3-((2-hydroxyethyl)amino)thiophene[2,3-b]pyrazin-2-yl)-2-methylisoindolin-1-one (200 mg) and dissolve it in dichloromethane (10 mL). Place it at 0°C, add triethylamine (0.13 mL), p-toluenesulfonyl chloride (248 mg), and 4-dimethylaminopyridine (106 mg) in sequence, and react at room temperature overnight. Monitor by TLC and LCMS, quench with water, extract with dichloromethane twice, dry over anhydrous sodium sulfate, purify by Prep-TLC to obtain 74 mg of crude product, and then separate by reverse phase preparative column to obtain the title compound. MS (ESI) m / z (M+H) + =442.2.

[0342] 1 H NMR(400MHz, DMSO-d6)δ8.95(s,1H),8.90–8.82(m,1H),7.70(d,J=8.2Hz,1H),6.39(s,2H),4.51(s,2H),4.14(ddd,J=10.4,8.6,2.9H z,2H),4.05(dd,J=14.2,8.6Hz,2H),3.11–3.02(m,4H),2.88(ddd,J=12.7,8.9,6.0Hz,1H),1.61–1.37(m,4H),0.90(t,J=7.2Hz,3H).

[0343] Step 8: Preparation of 5-(3-amino-2-(butylsulfinyl)imidazo[1,2-a]thieno[3,2-e]pyrazin-5-yl)-2-methylisoindolin-1-one (Example 7)

[0344]

[0345] Dissolve 5-(3-amino-2-(butylsulfinyl)-7,8-dihydroimidazo[1,2-a]thieno[3,2-e]pyrazin-5-yl)-2-methylisoindolin-1-one (60 mg) in chloroform, add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (95 mg), react at room temperature for 1 hour, add saturated sodium bicarbonate solution to quench the reaction, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and separate the crude product with a reverse phase preparative column to obtain the title compound. MS (ESI) m / z (M+H) + =440.1.

[0346] 1 H NMR (400MHz, DMSO-d6) δ9.24(s,1H),9.17(dd,J=8.1,1.5Hz,1H),8.56(d,J=1.4Hz,1H),8.07(d,J=1.3Hz,1H),7.84(d,J=8.1Hz,1H),6.71(s,2H), 4.62(s,2H),3.19–3.12(m,4H),3.02(ddd,J=12.9,8.9,6.3Hz,1H),1.61( tp,J=13.5,7.1,6.7Hz,2H), 1.45(h,J=7.4Hz,2H), 0.90(t,J=7.3Hz,3H).

[0347] In the present invention, Example 7 can also be prepared by using the general synthesis method 4 of the present invention, with reference to a method similar to Example 4 or Example 5.

[0348] Example 26: 5-(2-(butylsulfinyl)imidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one, Example 28: Preparation of 5-(2-(butylsulfinyl)-3-bromoimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one

[0349]

[0350] 5-(3-Amino-2-(butylsulfinyl)imidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one (Example 2) (200 mg) was dissolved in dibromomethane at room temperature, and then cuprous bromide (100 mg) was added. The mixture was cooled to 0°C in an ice-water bath, and then isoamyl nitrite (82 mg) was added and the reaction was stirred for 3 h.

[0351] Prep-TLC purification gave 5-(2-(butylsulfinyl)imidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one (Example 26), MS (ESI) m / z (M+H) + =425.1, 1 H NMR(400MHz,MSO-d6)δ8.14(s,1H),8.10(s,1H),8.04-8.01(m,2H),7.90-7.88(d,J=7.7Hz,1H),7.72-7.71(d,J=1.4Hz,1H),4. 60(s,2H),3.23-3.17(m,2H),3.13(s,3H),1.65-1.55(m,1H),1.57-1.48(m,1H),1.45-1.39(m,2H),0.90-0.86(t,J=7.3Hz,3H);

[0352] 5-(2-(Butylsulfinyl)-3-bromoimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one (Example 28), MS (ESI) m / z (M+H) + =503.0, 1 H NMR(400MHz, DMSO-d6)δ8.16(s,1H),8.093-8.090(d,J=1.4Hz,1H),8.06-8.03(m,1H),7.94-7.92(d,J=8.0Hz,1H),7.79-7.78(d,J=1.4 Hz,1H),4.63(s,2H),3.28(s,2H),3.15(s,3H),1.78-1.69(m,1H),1.64-1.58(m,1H),1.49-1.44(m,2H),0.923-0.886(t,J=7.3Hz,3H).

[0353] Example 27: 5-(2-(butylsulfinyl)-3-methylimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one, Example 29: Preparation of 5-(2-(butylsulfinyl)-3-hydroxyimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one

[0354]

[0355] The preparation method of the compound represented by formula (iii) in method 1 was adopted, and the preparation method similar to steps 1 to 4 in Example 1 was referred to, and phenylboronic acid was replaced with 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-isoindolin-1-one to prepare 8-bromo-5-(2-methyl-1-oxo-isoindolin-5-yl)imidazo[1,2-c]pyrimidine-7-carbonitrile (Compound 1, MS (ESI) m / z (M+H) + =368.0). Then prepare according to the following steps,

[0356] Step 1: Preparation of 8-bromo-5-(2-methyl-1-oxoisoindolin-5-yl)imidazo[1,2-c]pyrimidine-7-carboxylic acid

[0357] 8-Bromo-5-(2-methyl-1-oxo-isoindolin-5-yl)imidazo[1,2-c]pyrimidine-7-carbonitrile (Compound 1, 6.5 g) was added to concentrated hydrochloric acid (100 mL) at room temperature and reacted at 80°C overnight. After the reaction, the solvent was removed to obtain the title compound.

[0358] MS (ESI) m / z (M+H) + =387..0.

[0359] Step 2: Preparation of methyl 8-bromo-5-(2-methyl-1-oxoisoindolin-5-yl)imidazo[1,2-c]pyrimidine-7-carboxylate

[0360] 8-Bromo-5-(2-methyl-1-oxoisoindolin-5-yl)imidazo[1,2-c]pyrimidine-7-carboxylic acid (8.5 g) was dissolved in methanol (150 mL), and concentrated sulfuric acid (2 mL) was added. The mixture was reacted at 80° C. for 16 hours. After the reaction was completed, the reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was collected, the solvent was removed, and the title compound was purified by silica gel column chromatography.

[0361] MS (ESI) m / z (M+H) + =401.0.

[0362] Step 3: Preparation of methyl 8-(((butylthio)methyl)thio)-5-(2-methyl-1-oxoisoindolin-5-yl)imidazo[1,2-c]pyrimidine-7-carboxylate

[0363] Dissolve 8-bromo-5-(2-methyl-1-oxoisoindolin-5-yl)imidazo[1,2-c]pyrimidine-7-carboxylic acid methyl ester (4.5 g) in DMF (100 mL), add sodium hydrosulfide (1.26 g), stir at room temperature for 1 hour, add DIEA (7.23 g), then add butyl (chloromethyl) sulfonamide (4.67 g), heat at 60°C for 3 hours, after the reaction is completed, pour the reaction solution into water, extract with ethyl acetate, collect the organic phase, remove the solvent, and purify by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =457.1. Step 4: Preparation of methyl 8-(((butylsulfinyl)methyl)thio)-5-(2-methyl-1-oxoisoindolin-5-yl)imidazo[1,2-c]pyrimidine-7-carboxylate

[0364] Dissolve 8-(((butylthio)methyl)thio)-5-(2-methyl-1-oxoisoindolin-5-yl)imidazo[1,2-c]pyrimidine-7carboxylic acid methyl ester (4.4 g) in chloroform (50 mL) and acetic acid (50 mL), add 30% hydrogen peroxide (2.19 g), stir at room temperature for 4 hours, after the reaction is completed, pour the reaction solution into saturated sodium bicarbonate solution, extract with ethyl acetate, collect the organic phase, remove the solvent, and purify by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =473.12.

[0365] Step 5: Preparation of 5-(2-(butylsulfinyl)-3-hydroxyimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one (Example 29)

[0366] 8-(((Butylsulfinyl)methyl)thio)-5-(2-methyl-1-oxoisoindolin-5-yl)imidazo[1,2-c]pyrimidine-7-carboxylic acid methyl ester (50 mg) was dissolved in methanol (2 mL), sodium methoxide (28.57 mg) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction, the pH was adjusted to 5-6 with dilute hydrochloric acid, methanol was removed, the product was precipitated, filtered, purified by Prep-TLC, and lyophilized to obtain the title compound.

[0367] MS (ESI) m / z (M+H) + =441.1.

[0368] 1H NMR (400MHz, DMSO-d6) δ10.39-12.90(brs,1H),8.14(s,1H),8.04-8.00(m,2H),7.89(d,J=8.0Hz,1H),7.71( d,J=1.5Hz,1H),4.59(s,2H),3.18-3.05(m,5H),1.64-1.56(m,2H),1.47-1.38(m,2H),0.88(t,J=7.3Hz,3H)

[0369] Step 6: Preparation of 5-(2-(butylsulfinyl)-3-trifluoromethanesulfonyloxyimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one

[0370] 5-(2-(Butylsulfinyl)-3-hydroxyimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one (300 mg) was added to dichloromethane, and then triethylamine (206.7 mg) was added. After cooling to 0°C under nitrogen protection, trifluoromethanesulfonic anhydride (288 mg) was added dropwise. The reaction was allowed to react for 6 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The title compound was purified by silica gel column chromatography. MS (ESI) m / z (M+H) + =573.1.

[0371] Step 7: Preparation of 5-(2-(butylsulfinyl)-3-methylimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one (Example 27)

[0372] 5-(2-(Butylsulfinyl)-3-trifluoromethanesulfonyloxyimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one (180 mg) was added to dioxane (5 mL), followed by methylboric acid (12 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7 mg), potassium carbonate (27 mg), and water (1.5 mL). The mixture was reacted at 80°C for 16 h under nitrogen protection, and the title compound was obtained by purification by Prep-TLC. MS (ESI) m / z (M+H) + =439.1.

[0373] 1H NMR (400MHz, DMSO-d6) δ8.17(s,1H),8.06-8.04(d,J=7.4Hz,2H),7.93-7.91(d,J=8.0Hz,1H),7.74(s,1H),4.62(s, 2H),3.21-3.17(m,2H),3.15(s,3H),2.54(s,3H),1.67-1.58(m,2H),1.49-1.40(m,2H),0.92-0.88(t,J=7.3Hz,3H).

[0374] Example 32: Preparation of 5-(2-(butylsulfinyl)-3-cyanoimidazolo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one

[0375]

[0376] 5-(2-(Butylsulfinyl)-3-trifluoromethanesulfonyloxyimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one (50 mg) was dissolved in N,N-dimethylformamide (3 mL), zinc cyanide (20.51 mg) and tetrakis(triphenylphosphine)palladium (10.09 mg) were added, and the mixture was reacted at 120°C under nitrogen protection for 16 h. Prep-TLC purification gave the title compound.

[0377] MS (ESI) m / z (M+H) + =450.1.

[0378] 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=8.5Hz,2H),8.06(d,J=7.7Hz,1H),7.94(d,J=7.7Hz,1H),7.82(s,1H),4.63(s,2 H),3.43-3.36(m,2H),3.15(s,3H),1.80-1.70(m,1H),1.66-1.55(m,1H),1.49-1.43(m,2H),0.91(t,J=7.3Hz,3H).

[0379] Using the corresponding commercial reagents and the products of the above-mentioned preparation examples and embodiments as raw materials, a class of compounds were prepared using a preparation method similar to the above-mentioned embodiment. The structures and characterization data of the compounds are shown in Table 1.

[0380] Table 1

[0381]

[0382]

[0383]

[0384]

[0385] Preparation Example 1: Preparation of 6-(butylsulfinyl)-2-phenylthieno[2,3-b]pyrazine-7-amine

[0386]

[0387] Step 1: Preparation of 3-chloro-6-phenylpyrazine-2-carbonitrile

[0388] Weigh 6-bromo-3-chloropyrazine-2-carbonitrile (250 mg), phenylboronic acid (154 mg), sodium carbonate (244 mg), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (42 mg) in a 100 mL single-necked bottle, add 1,4-dioxane (10 mL) and pure water (2 mL), replace with nitrogen three times, and react at 100°C for 2 h. LCMS monitoring, the reaction is complete, water is added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain the title compound (238 mg).

[0389] Step 2: Preparation of 3-(((butylthio)methyl)thio)-6-phenylpyrazine-2-carbonitrile

[0390] Weigh 3-chloro-6-phenylpyrazine-2-carbonitrile (238 mg) and dissolve it in N,N-dimethylformamide (8 mL). Add sodium hydrosulfide (133 mg) and react at room temperature for 20 minutes. Then add triethylamine (0.30 mL) and butyl (chloromethyl) sulfane (0.21 mL) to the above system and react at room temperature for 30 minutes. Monitor by TLC and LCMS, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and purify by column chromatography to obtain 267 mg of the title compound.

[0391] MS (ESI) m / z (M+H) + =316.1.

[0392] Step 3: Preparation of 3-(((butylsulfinyl)methyl)thio)-6-phenylpyrazine-2-carbonitrile

[0393] Weigh 3-(((butylthio)methyl)thio)-6-phenylpyrazine-2-carbonitrile (267 mg) and dissolve it in chloroform (8 mL). Add acetic acid (0.73 mL) and hydrogen peroxide (0.16 mL) and react at 50°C for 1.5 h. Monitor by TLC and LCMS. Quench with saturated sodium bicarbonate solution at 0°C, extract twice with dichloromethane, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound (283 mg).

[0394] MS (ESI) m / z (M+H) + =332.1.

[0395] Step 4: Preparation of 6-(butylsulfinyl)-2-phenylthieno[2,3-b]pyrazin-7-amine

[0396] 3-(((Butylsulfinyl)methyl)thio)-6-phenylpyrazine-2-carbonitrile (260 mg) was weighed and dissolved in tetrahydrofuran (8 mL), and 1 M lithium bis(trimethylsilyl)amide (1.18 mL) was added and reacted at room temperature for 30 min. TLC and LCMS monitoring, water was added to quench, and the mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by reverse phase preparative column to obtain the title compound (77.87 mg).

[0397] MS (ESI) m / z (M+H) + =332.0.

[0398] 1 H NMR(400MHz, DMSO-d6)δ9.34(s,1H),8.40–8.33(m,2H),7.62–7.49(m,3H),6.54(s,2H),3.15(ddd,J=12.9,8.7, 6.3Hz, 1H), 3.04 (ddd, J=12.8, 8.7, 6.7Hz, 1H), 1.67–1.55 (m, 2H), 1.44 (h, J=7.3Hz, 2H), 0.90 (t, J=7.3Hz, 3H).

[0399] Preparation Example 2: Preparation of 6-(butylsulfinyl)-2-(2-methylisoindolin-1-one-5-yl)thieno[2,3-b]pyrazin-7-amine

[0400]

[0401] The title compound was prepared by a similar method to Preparation Example 1, except that phenylboronic acid was replaced with 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-isoindolin-1-one. MS (ESI) m / z (M+H) + =401.1.

[0402] 1 H NMR (400MHz, DMSO-d6) δ9.41(d,J=0.8Hz,1H),8.59(dt,J=1.7,0.9Hz,1H),8.49(ddd,J=8.0,1.6,0.7Hz,1H),7.82(d,J=8.0Hz,1H ), 6.60 (s, 2H), 4.59 (s, 2H), 3.19–3.10 (m, 4H), 3.09–3.01 (m, 1H), 1.69–1.56 (m, 2H), 1.44 (h, J = 7.4Hz, 2H), 0.90 (t, J = 7.3Hz, 3H). Preparation Example 3: Preparation of 6-(butylsulfinyl)-2-(2-methylisoquinolin-(2H)1-one-6-yl)thieno[2,3-b]pyrazin-7-amine

[0403]

[0404] The title compound was prepared by a similar method to Preparation Example 1, except that phenylboronic acid was replaced with 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)isoquinolin-1(2H)-one. MS (ESI) m / z (M+H) + =413.1.

[0405] 1 H NMR (400MHz, DMSO-d6) δ9.45 (s, 1H), 8.67 (d, J = 1.8 Hz, 1H), 8.48 (dd, J = 8.6, 1. 8Hz,1H),8.35(d,J=8.5Hz,1H),7.56(d,J=7.4Hz,1H),6.70(d,J=7.3Hz,1H),6. 62(s,2H),3.55(s,3H),3.16(ddd,J=12.9,8.6,6.4Hz,1H),3.06(ddd,J=12.8,8 .6, 6.7Hz, 1H), 1.67–1.58 (m, 2H), 1.45 (h, J = 7.4Hz, 2H), 0.90 (t, J = 7.3Hz, 3H).

[0406] Preparation Example 4: Preparation of diethyl 4-(7-amino-6-(butylsulfinyl)thieno[2,3-b]pyrazin-2-yl)phenyl phosphate

[0407]

[0408] The title compound was prepared by a similar method to Preparation Example 1, except that phenylboronic acid was replaced with 4-diethylphosphophenylboronic acid. MS (ESI) m / z (M+H) +=468.1.

[0409] 1 H NMR(400MHz, DMSO-d6)δ9.40(s,1H),8.52(dd,J=8.2,3.6Hz,2H),7.94–7.83(m,2H),6.59(s,2H),4.13–4.02(m,4H),3.15(ddd,J=12.8,8 .6, 6.4Hz, 1H), 3.05 (ddd, J=12.8, 8.7, 6.8Hz, 1H), 1.66–1.58 (m, 2H), 1.44 (h, J=7.4Hz, 2H), 1.27 (t, J=7.0Hz, 6H), 0.90 (t, J=7.3Hz, 3H).

[0410] Preparation Example 5: Preparation of ethyl 4-(7-amino-6-(butylsulfinyl)thieno[2,3-b]pyrazin-2-yl)benzoate

[0411]

[0412] The title compound was prepared by a similar method to Preparation Example 1, except that phenylboronic acid was replaced by 4-ethoxycarbonylphenylboronic acid.

[0413] MS (ESI) m / z (M+H) + =404.1.

[0414] 1 H NMR (400MHz, DMSO-d6) δ9.41(s,1H),8.55–8.48(m,2H),8.16–8.07(m,2H),6.60(s,2H),4.37(q,J=7.1Hz,2H),3.15(ddd,J=12.8,8.6, 6.3Hz, 1H), 3.05 (ddd, J = 12.9, 8.7, 6.7Hz, 1H), 1.68–1.55 (m, 2H), 1.45 (p, J = 7.3Hz, 2H), 1.37 (t, J = 7.1Hz, 3H), 0.90 (t, J = 7.3Hz, 3H).

[0415] Preparation Example 6: Preparation of 4-(7-amino-6-(butylsulfinyl)thieno[2,3-b]pyrazin-2-yl)benzoic acid

[0416]

[0417] Dissolve Preparation Example 5 (50 mg) in 100 mL DCM, add 39 mg sodium hydroxide, and heat and stir overnight. Add water to quench the reaction, and extract with ethyl acetate. Purify by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =376.1.

[0418] 1 H NMR (400MHz, DMSO-d6) δ9.38(s,1H),8.44(d,J=8.4Hz,2H),8.07(d,J=8.4Hz,2H),6.58(s ,2H),3.15–3.07(m,2H),1.68–1.57(m,2H),1.44(q,J=7.4Hz,2H),0.90(t,J=7.3Hz,3H).

[0419] Preparation Example 7: Preparation of 5-(3-amino-2-(butylsulfinyl)thieno[2,3-b]pyridin-5-yl)-2-methylisoindolin-1-one

[0420] Step 1: Preparation of 5-bromo-2-(((butylthio)methyl)thio)nicotinonitrile

[0421] Weigh 5-bromo-2-chloronicotinonitrile (500 mg) and dissolve it in N,N-dimethylformamide (15 mL). Add sodium hydrosulfide (220 mg) and react at 80°C for 30 min. Then add triethylamine (0.64 mL) and butyl (chloromethyl) sulfane (0.43 mL) and react at 80°C for 40 min. Monitor by TLC and LCMS, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and purify with silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =317.1.

[0422] Step 2: Preparation of 5-bromo-2-(((butylsulfinyl)methyl)thio)nicotinonitrile

[0423] Weigh 5-bromo-2-(((butylthio)methyl)thio)nicotinonitrile (700 mg) and dissolve it in chloroform (15 mL). Add acetic acid (1.9 mL) and hydrogen peroxide (0.41 mL) and react at room temperature for 3 h. Monitor by TLC and LCMS. Quench with saturated sodium bicarbonate solution at 0°C, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound. MS (ESI) m / z (M+H) + =333.0.

[0424] Step 3: Preparation of 5-bromo-2-(butylsulfinyl)thieno[2,3-b]pyridin-3-amine

[0425] Weigh 5-bromo-2-(((butylsulfinyl)methyl)thio)nicotinonitrile (740 mg) and dissolve it in a mixed solvent of N,N-dimethylformamide (14 mL) and methanol (7 mL), add 2 mol / L potassium hydroxide solution (1.1 mL) and react at room temperature for 1 h. Monitor by TLC and LCMS, quench with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =333.0.

[0426] Step 4: Preparation of 5-(3-amino-2-(butylsulfinyl)thieno[2,3-b]pyridin-5-yl)-2-methylisoindolin-1-one

[0427] Weigh 5-bromo-2-(butylsulfinyl)thiophene[2,3-b]pyridine-3-amine (50 mg), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (46 mg), cesium carbonate (98 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (6 mg) in a 5 mL microwave tube, add 1,4-dioxane (2.5 mL) hexacyclic ring and pure water (0.5 mL), replace with nitrogen three times, and react at 100 ° C for 4 hours. TLC and LCMS monitoring, the reaction is complete, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by reverse phase preparative column to obtain the title compound. MS (ESI) m / z (M+H) + =400.1.

[0428] 1 H NMR (400MHz, DMSO-d6) δ9.02(d,J=2.2Hz,1H),8.87(d,J=2.2Hz,1H),8.02(d,J=1.4Hz,1H),7.91(dd,J=7.9,1.5Hz,1H),7.82(d,J=7.9Hz,1H),6 .57(s,2H),4.57(s,2H),3.18–3.10(m,4H),3.00(ddd,J=12.7,9.1,6.1 Hz, 1H), 1.66–1.51 (m, 2H), 1.44 (h, J = 7.3Hz, 2H), 0.89 (t, J = 7.3Hz, 3H).

[0429] Preparation Example 8: Preparation of 5-(3-amino-2-(butylsulfinyl)thieno[3,2-b]pyridin-5-yl)-2-methylisoindolin-1-one

[0430] Step 1: Preparation of 3-chloro-6-(2-methyl-1-oxoisoindolin-5-yl)pyridinecarbonitrile

[0431] Weigh 6-bromo-3-chloropyridinecarbonitrile (300 mg), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (417 mg), cesium carbonate (589 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (51 mg) in a 100 mL single-mouth bottle, add 1,4-dioxane (10 mL) and pure water (2 mL), replace with nitrogen three times, and react at 90°C for 2 h. TLC and LCMS monitoring, the reaction is complete, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =284.1.

[0432] Step 2: Preparation of 3-(((butylthio)methyl)thio)-6-(2-methyl-1-oxoisoindolin-5-yl)pyridinecarbonitrile

[0433] Weigh 3-chloro-6-(2-methyl-1-oxoisoindolin-5-yl)pyridinecarbonitrile (200 mg) and dissolve it in N,N-dimethylformamide (10 mL). Add sodium hydrosulfide (68 mg) and react at 45°C for 30 min. Then add triethylamine (0.19 mL) and butyl (chloromethyl) sulfane (0.13 mL) to the above system and react at 45°C for 40 min. Monitor by TLC and LCMS, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =384.1.

[0434] Step 3: Preparation of 3-((butylsulfinyl)methyl)thio)-6-(2-methyl-1-oxoisoindolin-5-yl)pyridinecarbonitrile

[0435] Weigh 3-(((butylthio)methyl)thio)-6-(2-methyl-1-oxoisoindolin-5-yl)pyridinecarbonitrile (253 mg) and dissolve it in chloroform (8 mL). Add acetic acid (0.57 mL) and hydrogen peroxide (0.12 mL) and react at room temperature for 4 h. Monitor by TLC and LCMS. Quench with saturated sodium bicarbonate solution at 0°C, extract with dichloromethane, dry with anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =400.1.

[0436] Step 4: Preparation of 5-(3-amino-2-(butylsulfinyl)thieno[3,2-b]pyridin-5-yl)-2-methylisoindolin-1-one

[0437] Weigh 3-(((butylsulfinyl)methyl)thio)-6-(2-methyl-1-oxoisoindolin-5-yl)pyridinecarbonitrile (140 mg) and dissolve it in a mixed solvent of N,N-dimethylformamide (6 mL) and methanol (3 mL), add 2M potassium hydroxide solution (0.18 mL) and react at room temperature for 1 h. Monitor by TLC and LCMS, quench with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate with a reverse phase preparative column to obtain the title compound. MS (ESI) m / z (M+H) + =400.2.

[0438] 1 H NMR (400MHz, DMSO-d6) δ8.57(d,J=1.5Hz,1H),8.52(d,J=8.6Hz,1H),8.48–8.43(m,1H),8.19(d,J=8.6Hz,1H),7.78(d,J=8.0Hz,1H),6.42( s,2H),4.57(s,2H),3.18–3.09(m,4H),3.02(ddd,J=12.8,9.0,6.4Hz,1H),1.67–1.52(m,2H),1.44(h,J=7.3Hz,2H),0.89(t,J=7.3Hz,3H).

[0439] Comparative Example 1: Preparation of 5-(3-amino-2-(butylsulfonyl)-7,8-dihydroimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one

[0440]

[0441] 5-(3-Amino-2-(butylsulfinyl)-7,8-dihydroimidazo[1,2-c]thieno[2,3-e]pyrimidin-5-yl)-2-methylisoindolin-1-one (Example 3, 40 mg) was dissolved in acetonitrile (2 mL), potassium permanganate (16 mg) was added, and the mixture was reacted at room temperature for 1 h. 1 mL of ethanol was added to quench the reaction, and the mixture was filtered. The filtrate was concentrated and separated using a reverse phase preparative column to obtain the title compound (3.96 mg).

[0442] MS (ESI) m / z (M+H) + =458.1.

[0443] 1H NMR(400MHz, DMSO-d6)δ7.96(s,1H),7.87-7.85(d,J=7.9Hz,1H),7.80-7.78(d,J=7.9Hz,1H),6.22(s,2H),4.54(s,2H),4.08-4.04(t, J=9.7Hz,2H),3.94-3.88(t,J=9.3Hz,2H),3.30(m,2H),3.11(s,3H),1.66-1.58(m,2H),1.4-1.32(m,2H),0.87-0.84(t,J=7.3Hz,3H). Comparative Example 2: Preparation of 5-(3-amino-2-(butylsulfonyl)imidazo[1,2-a]thieno[3,2-e]pyrazin-5-yl)-2-methylisoindolin-1-one

[0444]

[0445] The preparation method of the compound represented by formula (v-3) in method 4 is adopted, and the preparation method similar to steps 1 to 6 in example 4 or example 5 is referred to, and the phenylboric acid or 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)isoquinolin-1(2H)-one in the step is replaced by 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindol-1-one to prepare 5-(((butylsulfinyl)methyl)thio)-8-(2-methyl-1-oxoisoindol-5-yl)imidazo[1,2-a]pyrazine-6-carbonitrile.

[0446] MS (ESI) m / z (M+H) + =440.1.

[0447] 5-(((butylsulfinyl)methyl)thio)-8-(2-methyl-1-oxoisoindolin-5-yl)imidazo[1,2-a]pyrazine-6-carbonitrile (150 mg) was dissolved in dichloromethane (6 mL), and m-chloroperbenzoic acid (89 mg) was added. The mixture was reacted at room temperature for 1 h. The reaction was completed as monitored by LCMS and TLC. 5-(((butylsulfinyl)methyl)thio)-8-(2-methyl-1-oxoisoindolin-5-yl)imidazo[1,2-a]pyrazine-6-carbonitrile (176 mg) was obtained by purification by Prep-TLC. MS (ESI) m / z (M+H) + =456.1.

[0448] Weigh 5-(((butylsulfonyl)methyl)thio)-8-(2-methyl-1-oxoisoindolin-5-yl)imidazo[1,2-a]pyrazine-6-carbonitrile (88 mg) and dissolve it in tetrahydrofuran (4 mL). Add lithium bis(trimethylsilyl)amide (0.29 mL) and react at room temperature for 30 min. The reaction was completed as monitored by LCMS and TLC. Water was added to quench the reaction, and the mixture was extracted twice with dichloromethane. The mixture was dried over anhydrous sodium sulfate and separated by reverse phase preparative column to obtain the title compound (2.01 mg). MS (ESI) m / z (M+H) + =456.1.

[0449] 1 H NMR (400MHz, DMSO-d6) δ9.26(s,1H),9.21–9.16(m,1H),8.63(d,J=1.2Hz,1H),8.09(d,J=1.2Hz,1H),7.85(d,J=8.1Hz,1H) ,6.98(s,2H),4.63(s,2H),3.43–3.37(m,2H),3.14(s,3H),1.74–1.65(m,2H),1.39(p,J=7.4Hz,2H),0.86(t,J=7.4Hz,3H).

[0450] Comparative Example 3: Preparation of 5-(3-amino-2-(butylsulfonyl)-7,8-dihydroimidazo[1,2-a]thieno[3,2-e]pyrazin-5-yl)-2-methylisoindolin-1-one

[0451]

[0452] Weigh 2-((6-((butylthio)methyl)thio)-5-cyano-3-(2-methyl-1-oxoisoindolin-5-yl)pyrazin-2-yl)amino)ethyl acetate (500 mg), dissolve in methanol (15 mL), add potassium carbonate (313 mg) and react at room temperature for 1 h. LCMS and TLC monitoring, quench with water, extract with ethyl acetate twice, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain 3-((butylthio)methyl)thio)-5-((2-hydroxyethyl)amino)-6-(2-methyl-1-oxoisoindolin-5-yl)pyrazine-2-carbonitrile (215 mg). MS (ESI) m / z (M+H) + =444.1.

[0453] 3-((butylsulfanyl)methyl)sulfanyl)-5-((2-hydroxyethyl)amino)-6-(2-methyl-1-oxoisoindolin-5-yl)pyrazine-2-carbonitrile (185 mg) was weighed and dissolved in dichloromethane (8 mL), and m-chloroperbenzoic acid (212 mg) was added and reacted at room temperature for 8 h. The reaction was completed as monitored by LCMS and TLC, and 3-(((butylsulfanyl)methyl)sulfanyl)-5-((2-hydroxyethyl)amino)-6-(2-methyl-1-oxoisoindolin-5-yl)pyrazine-2-carbonitrile (45 mg) was obtained by purification by Prep-TLC. MS (ESI) m / z (M+H) + =476.1.

[0454] 3-(((Butylsulfonyl)methyl)thio)-5-((2-hydroxyethyl)amino)-6-(2-methyl-1-oxoisoindolin-5-yl)pyrazine-2-carbonitrile (45 mg) was dissolved in a mixed solvent of N,N-dimethylformamide (4 mL) and methanol (2 mL), and a 2M potassium hydroxide solution (92 μL) was added to react at room temperature for 1 h. TLC and LCMS monitoring, quenching with water, extraction with ethyl acetate twice, washing with saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain 5-(7-amino-6-(butylsulfonyl)-3-((2-hydroxyethyl)amino)thieno[2,3-b]pyrazin-2-yl)-2-methylisoindolin-1-one (45 mg). MS (ESI) m / z (M+H) + =476.1.

[0455] Weigh 5-(7-amino-6-(butylsulfonyl)-3-((2-hydroxyethyl)amino)thiophene[2,3-b]pyrazin-2-yl)-2-methylisoindolin-1-one (45 mg) and dissolve it in 3 mL of dichloromethane. Place it at 0°C, add triethylamine (26 μL), p-toluenesulfonyl chloride (55 mg), and 4-dimethylaminopyridine (24 mg) in sequence and react at room temperature for 48 hours. Monitor by TLC and LCMS, quench with water, extract with dichloromethane twice, dry over anhydrous sodium sulfate, and separate by reverse phase preparative column to obtain the title compound (8.78 mg). MS (ESI) m / z (M+H) + =458.2.

[0456] 1H NMR (400MHz, DMSO-d6) δ8.95(s,1H),8.87(dd,J=8.1,1.4Hz,1H),7.71(d,J=8.1Hz,1H),6.57(s,2H),4.52(s,2H),4.15(dd,J=12.5,9. 4Hz, 2H), 4.07–3.99 (m, 2H), 3.25 (dd, J = 6.4, 4.1Hz, 2H), 3.10 (s, 3H), 1.67–1.61 (m, 2H), 1.37 (q, J = 7.4Hz, 2H), 0.86 (t, J = 7.3Hz, 3H).

[0457] Biological tests

[0458] Test Example 1: 15-PGDH kinase activity detection

[0459] 1. Experimental materials:

[0460]

[0461] 2. Experimental methods:

[0462] a. Prepare a solution containing 50 mM Tris-HCl, 0.01% Tween 20, pH 7.5 with ultrapure water as a reaction buffer;

[0463] b. Prepare a 10mM stock solution of the test compound with DMSO, then dilute the stock solution of the test compound with the reaction buffer to obtain a 4000nM test compound solution 1, and then continuously dilute the test compound solution 1 by three times as a gradient difference to 9 concentrations of test compound solutions 2 to 10. Take 5μL of each concentration of the test compound solution 1 to 10 and add them to the 384-well plate as the experimental wells;

[0464] c. Add 5uL of reaction buffer to the 384-well plate as positive control wells and blank control wells.

[0465] d. Prepare a 15-PGDH protein solution with a concentration of 5 ng / μL using reaction buffer, add 5 μL of 15-PGDH protein solution to the experimental wells and positive control wells, and add 5 μL of reaction buffer to the blank control wells, and then centrifuge the plate at 2000 rpm for 30 seconds;

[0466] e. Use reaction buffer to prepare 5 mM β-NAD and 2 mM PGF2α respectively, mix them in a volume ratio of 1:1 to obtain a substrate mixture, take 10 μL of the substrate mixture and add it to the experimental well, positive control well and blank control well to start the reaction;

[0467] f. Use a multifunctional microplate reader to continuously detect the fluorescence signal value of each well (Ex / Em=340 / 450).

[0468] 3. Data Analysis:

[0469] a) Use the "kinetic calculations-slope calculation method" in PHERAstar Data analysis software to analyze the continuous fluorescence signal value and obtain the slope of each experimental well;

[0470] b) Calculate the inhibition rate using the following formula:

[0471] 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%.

[0472] 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.

[0473] 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 %.

[0474] 4. Experimental results:

[0475] The inhibitory activity of the compounds of the present invention on 15-PGDH enzyme is shown in Table 2 below.

[0476] Table 2

[0477] serial number <![CDATA[IC 50 (nM)]]> serial number <![CDATA[IC 50 (nM)]]> serial number <![CDATA[IC 50 (nM)]]> Example 1 A Embodiment 15 C Embodiment 27 C Example 2 A+ Example 16 C Embodiment 28 E Example 3 D Embodiment 17 C Embodiment 29 >1000 Example 5 B Embodiment 18 E Embodiment 30 E Example 6 C Embodiment 19 A+ Comparative Example 1 >1000 Example 7 B Embodiment 21 D Comparative Example 2 >1000 Example 9 A Embodiment 22 A+ Comparative Example 3 >1000 Example 10 B Embodiment 23 C Preparation Example 1 C Embodiment 11 C Embodiment 24 E Preparation Example 4 C Embodiment 13 A Embodiment 25 A+ Preparation Example 5 C Embodiment 14 B Embodiment 26 C Preparation Example 7 E

[0478] In the table, "A+" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is less than 2 nM; "A" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than or equal to 2nM and less than or equal to 5nM; "B" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than 5 nM and less than or equal to 10 nM; "C" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than 10nM and less than or equal to 20nM; "D" represents the IC of 15-PGDH enzyme inhibition activity 50 The range is greater than 20nM and less than or equal to 30nM; "E" represents the IC of 15-PGDH enzyme inhibition activity 50The range is greater than 30nM and less than or equal to 100nM.

[0479] The experiment found that the IC50 value of the inhibitory activity of the compounds of the present invention on 15-PGDH enzyme is less than 100nM. The IC50 value of the inhibitory activity of some compounds of the present invention on 15-PGDH enzyme is less than 100nM. 50 The value is greater than or equal to 20nM and less than 50nM. The IC values ​​of some compounds of the present invention for 15-PGDH enzyme inhibition activity are 50 The value is greater than or equal to 10 nM and less than 20 nM. The IC values ​​of some compounds of the present invention for 15-PGDH enzyme inhibition activity are 50 The value is greater than or equal to 5 nM and less than 10 nM. The IC values ​​of some compounds of the present invention for 15-PGDH enzyme inhibition activity are 50 The value is greater than or equal to 2nM and less than 5nM. The IC values ​​of some compounds of the present invention for 15-PGDH enzyme inhibition activity are 50 The value was less than 2 nM.

[0480] Test Example 2: Intracellular PGE2 upregulation activity assay

[0481] 1. Experimental materials:

[0482]

[0483] 2. Experimental methods:

[0484] a) A549 cells were seeded in 24-well plates, and after the cells adhered, IL-1β was added for 16 h to induce COX2 expression and PGE2 production.

[0485] b) The test compound solution was prepared in culture medium and graded diluted to 7 concentrations including 0.64 nM, 3.2 nM, 16 nM, 80 nM, 400 nM, 2000 nM and 10000 nM. A positive control group and a negative control group were set up. The cell supernatant was collected after 8 hours of action. The positive control group was not treated with the compound after IL-1β induction, and the negative control group was not stimulated with IL-1β and not treated with the compound.

[0486] c) The PGE2 content of the sample was determined using the Prostaglandin E2 Kit, and the fluorescence signal was detected by a multifunctional microplate reader (Ex / Em=337 / 620, 337 / 665).

[0487] 3. Data Analysis:

[0488] a) Use the PGE2 standard in the "Prostaglandin E2 Kit" to draw a standard curve and substitute the sample fluorescence signal to obtain the PGE2 concentration.

[0489] b) Calculate the PGE2 upregulation rate % using the following formula:

[0490] PGE2 upregulation ratio % = PGE2 concentration in sample group / PGE2 concentration in positive control group × 100%.

[0491] 4. Experimental Results

[0492] The up-regulation ratio of the compound of the present invention on PGE2 in A549 cells can reach >100%, and the compound of the present invention has the activity of up-regulating PGE2 in cells.

Claims

1. A compound represented by formula (I), 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 1 Substitution, the R 1 are each independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkyl, C1-C6 haloalkyl, 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, R A is selected from hydrogen, deuterium, tritium, halogen, amine, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl, R 0 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imine, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, o is selected from 0, 1, 2, 3, 4, represents an aromatic ring, is a single bond or a double bond, X and Y are each independently selected from C or N, and at least one of X and Y is N, U, V, and W are each independently selected from N, CR 2 , CR 3 R 4 NR 5 , O, S, wherein the R 2 , R 3 , R 4 , R 5 Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, 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, or the above R 3 , R 4 Together with the carbon atom to which it is connected, it forms C=O, C=NR W , the R W is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or 3-12 membered cycloalkyl, in, The aromatic heterocycle, alicyclic heterocycle, unsaturated alicyclic heterocycle, cyclopentane, and heterocycloalkyl group each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, and S. The R 0 , R 2 , R 3 , R 4 , R 5 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, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: Said Selected from Wherein R 2a , R 2b , R 2c , R 3a , R 3b , R 3c , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, 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, or the above R 3a With R 4a , R 3b With R 4b , R 3c With R 4c Each together forms =O or an imine group; preferably, the Selected from 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: The compound is a compound represented by formula (II), 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 1 Substitution, the R 1 are each independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkyl, C1-C6 haloalkyl, 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, R A is selected from hydrogen, deuterium, tritium, halogen, amine, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl, R 0 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imine, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, o is selected from 0, 1, 2, 3, 4, is a single bond or a double bond, U is independently selected from CR 2 or N, V, W are each independently selected from N, CR 2 , CR 3 R 4 NR 5 , O or S, where each R 2 , R 3 , R 4 , R 5 Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, 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, or the above R 3 , R 4 Together with the carbon atom to which it is connected, it forms C=O, C=NR W , the R W is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or 3-12 membered cycloalkyl, Wherein, the aromatic heterocycle, alicyclic heterocycle, unsaturated alicyclic heterocycle, cyclopentane, and heterocycloalkyl each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, and S. The R 0 , R 2 , R 3 , R 4 , R 5 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.

4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: Said Selected from Wherein R 2a , R 2b , R 2c , R 3a , R 3c , R 4a , R 4c , R 5a , R 5c Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, 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, or the above R 3a With R 4a , R 3b With R 4b , R 3c With R 4c Each together forms a =O or imine group; Preferably, the Selected from Or preferably, the Selected from 5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: The compound is a compound represented by formula (II-a), 6. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: The compound is a compound represented by formula (II-b), 7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: The compound is a compound represented by formula (III), 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 1 Substitution, the R 1 are each independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, halogen, cyano, -C(O)OR a 、-OC(O)R b 、-C(O)NHR X 、-NHC(O)R Y , =O, C1-C6 alkyl, C1-C6 haloalkyl, 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, R A is selected from hydrogen, deuterium, tritium, halogen, amine, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl, R 0 Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, =O, imine, amine, ester, aldehyde, carboxyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, o is selected from 0, 1, 2, 3, 4, is a single bond or a double bond, W is independently selected from CR 2 or N, U, and V are each independently selected from N, CR 2 , CR 3 R 4 NR 5 , O or S, where each R 2 , R 3 , R 4 , R 5 Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, 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, or the above R 3 , R 4 Together with the carbon atom to which it is connected, it forms C=O, C=NR W , the R W is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or 3-12 membered cycloalkyl, Wherein, the aromatic heterocycle, alicyclic heterocycle, unsaturated alicyclic heterocycle, cyclopentane, and heterocycloalkyl each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, and S. The R 0 , R 2 , R 3 , R 4 , R 5 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.

8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: Said Selected from Wherein R 2a , R 2b , R 2c , R 3a , R 3bc , R 4a , R 4bc , R 5a , R 5b Each is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, 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, or the above R 3a With R 4a , R 3b With R 4b , R 3c With R 4c Each together forms a =O or imine group; Preferably, the Selected from Or preferably, the Selected from 9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: The compound is a compound represented by formula (III-a), 10. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: The compound is a compound represented by formula (III-b), 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: The ring A is selected from a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocycle, a 3- to 8-membered unsaturated aliphatic heterocycle, a 7- to 14-membered cyclic ring consisting of an aromatic ring and an unsaturated aliphatic heterocycle, and a 7- to 14-membered cyclic ring consisting of an aromatic heterocycle and an unsaturated aliphatic heterocycle; The ring A is preferably selected from a benzene ring, a naphthalene ring, a 5-10-membered aromatic heterocyclic ring containing 1-3 heteroatoms, a 6-membered unsaturated aliphatic heterocyclic ring containing 1-2 heteroatoms, or an 8-14-membered cyclic ring consisting of a benzene ring and an unsaturated aliphatic heterocyclic ring containing 1-2 heteroatoms, wherein the heteroatoms are independently selected from N, O, and S; The ring A is more preferably selected from 12. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: The R A Selected from hydrogen, deuterium, tritium, cyano, fluorine, chlorine, bromine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, isopropenyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably selected from hydrogen, deuterium, tritium, cyano, fluorine, chlorine, bromine, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, isopropenyl.

13. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: The R is selected from C1 to C 10 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl containing 1-2 heteroatoms, the heteroatoms are independently selected from N, O, S, wherein R is replaced by 0 or 1 R 1 replace; Preferably, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, tert-butylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Where R is 0 or 1 R 1 replace; More preferably, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, tert-butylmethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, benzyl, thephenylmethyl, methoxycarbonylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 14. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: The R 0 each independently selected from deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, =O, =NH, =CH2CH3, =NCH(CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2 , aldehyde, carboxyl, -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy.

15. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, characterized in that: The R A is selected from hydrogen, deuterium, tritium, cyano, bromine, -NH2, methyl, cyclopropyl, isopropenyl, said o is selected from 0, 1 or 2, said R 0 Each is 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, and R is selected from isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, 2-methylbutyl, 2-hydroxyethyl, benzyl, methoxycarbonylethyl, The ring A is selected from a benzene ring, a naphthalene ring, a 5-10 membered aromatic heterocycle containing 1-2 heteroatoms, a 6-membered unsaturated aliphatic heterocycle containing 1 heteroatom, or an 8-14 membered cyclic ring consisting of a benzene ring and an unsaturated aliphatic heterocycle containing 1-2 heteroatoms, wherein the heteroatoms are independently selected from N, O, and S.

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

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

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