Thiophenecarboxamide compound and application thereof

Abstract

The invention discloses a thiophenecarboxamide compound as shown in a formula (I), or an isotope label, an optical isomer and a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, X1, X2, X3, X4, X5, j and k are defined in the specification. The compound provided by the invention, or the isotope marker, the optical isomer, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition containing the same shows excellent Vanin-1 inhibitory activity, and can be used for preventing and / or treating Vanin-1 mediated diseases or symptoms, such as autoimmune diseases, inflammatory diseases, metabolic diseases, infection-based diseases and the like.

Description

Technical Field

[0001] The present invention relates to a novel thiophenecarboxamide compound having Vanin-1 inhibitory activity, and a pharmaceutical composition containing the same and its medical use. Background Art

[0002] Vanin-1 is a molecular chaperone encoded by the PTGES3 gene, which is widely distributed in eukaryotes as a highly conserved protein. Vanin-1 can bind to the Hsp90 protein and promote the stability of the Hsp90 protein and various biological function molecular aggregates, such as estrogen receptor, androgen receptor, and telomerase. It has been found that the substrate of Vanin-1 is pantetheine, and Vanin-1 catalyzes its hydrolysis to produce pantothenic acid and cysteamine (Pitari G et al., Pantetheinase activity of membrane-bound vanin-1: lack of free cysteamine in tissues of vanin-1 deficient mice. FEBS Lett. 2000; 483: 149-154). These products affect various biological processes. Pantothenic acid participates in the anabolic process of coenzyme A, regulates the metabolic processes of fatty acid synthesis and pyruvate oxidation, and cysteamine affects the cellular redox state. Its deficiency leads to resistance to oxidative tissue damage caused by γ-radiation or administration of paraquat, and can prevent or eliminate tissue inflammation (Berruyer C et al., Vanin-1- / - mice exhibit a glutathione mediated tissue resistance to oxidative stress. Mol Cell Biol. 2004; 24: 7214-7224). Vanin-1 deficiency can effectively resist IBD in mouse models (including DSS (dextran sodium sulfate) and TNBS (trinitrobenzenesulfonate) colitis) (Berruyer C, et al., Vanin-1 licenses inflammatory mediator production by gut epithelial cells and controls colitis by antagonizing peroxisome proliferator-activated receptor γ activity. J Exp Med. 2006; 203: 2817-2827). Prior arts such as WO2018011681, WO2016193844, and WO2020114947 have disclosed a series of Vanin-1 inhibitors for treating various diseases, such as Crohn's disease and ulcerative colitis. In addition, it has been found that Vanin-1 is highly expressed in various tumors, including lung cancer, prostate cancer, breast cancer, leukemia, etc. The high expression of Vanin-1 can promote tumor cell migration, upregulate the level and biological activity of androgen receptor, and promote tumorigenesis.

[0003] However, overall, there is still a lack of small molecule compounds that act as effective Vanin-1 inhibitors, and there is also a lack of relatively mature small molecule compound drugs related thereto.

[0004] The technical problem to be solved by the present invention is to provide a novel compound that can be used as a Vanin-1 inhibitor, and this novel compound can effectively prevent and / or treat diseases related to or mediated by Vanin-1. Summary of the Invention

[0005] The present invention prepared a series of thiophenecarboxamide compounds by chemical synthesis methods, and surprisingly found that they have a high affinity for Vanin-1, can efficiently inhibit the catalytic activity of Vanin-1 on the pantetheine substrate, and interfere with the synthetic metabolism process of pantethine and coenzyme A. Based on this action pathway, this series of thiophenecarboxamide compounds have a therapeutic effect on Vanin-1-mediated diseases, especially inflammatory diseases such as inflammatory bowel disease, and have the prospect of being developed into drugs for treating inflammatory diseases in the future.

[0006] On the one hand, the present invention provides a compound represented by formula (I), or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt,

[0007]

[0008] Wherein,

[0009] X1, X2, X3, and X4 are each independently selected from CR5 or N;

[0010] X5 is selected from O, S, or CH2;

[0011] R1 is selected from H or C 1-6 alkyl;

[0012] R2 is selected from -(CH2)i-X6;

[0013] Or,

[0014] R1 and R2 together with the nitrogen atom to which they are attached form a 5-membered or 6-membered heterocyclic group; wherein the heterocyclic group is optionally substituted with a group selected from C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl), C 5-8 carbocyclic group, C 6-14 aryl, 5-membered or 6-membered heteroaryl, 5-membered or 6-membered heterocyclic group;

[0015] Each R3 is independently selected from H, C 1-6Alkyl, halogen, hydroxy, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl);

[0016] Each R4 is independently selected from H, C 1-6 Alkyl, halogen, hydroxy, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl);

[0017] Each R5 is independently selected from H, C 1-6 Alkyl, halogen, hydroxy, C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl);

[0018] X6 is selected from C 1-6 Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 Alkyl), C 5-8 Carbocyclic group, C 6-14 Aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group; wherein the carbocyclic group, aryl, heteroaryl, heterocyclic group is optionally substituted with a group selected from C 6-14 Aralkyl, NR6R6’, -C(O)NH2, -S(O)2NH2;

[0019] R6 and R6’ are each independently selected from H, C 1-6 Alkyl, or R6 and R6’ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group;

[0020] i is 0, 1, 2, 3, 4 or 5;

[0021] j is 2;

[0022] k is 0 or 1.

[0023] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein or its isotope-labeled compound, optical isomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0024] In another aspect, the present invention provides a method for preventing and / or treating Vanin-1-mediated diseases, comprising administering to a patient in need a therapeutically effective amount of a compound represented by the general formula (I), or an isotope-labeled compound thereof, an optical isomer, a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same.

[0025] In another aspect, the present invention provides the use of a compound represented by the general formula (I) described herein, or an isotope-labeled compound thereof, an optical isomer, a pharmaceutically acceptable salt, in the preparation of a drug for preventing and / or treating Vanin-1-mediated diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention, but do not constitute a limitation to the present invention. In the drawings:

[0027] Figure 1 Shows the results of the acute-phase body weight and DAI score of mice with DSS-induced inflammatory bowel disease after treatment with the compounds of the present invention.

[0028] Figure 2 Shows the results of the acute-phase colon length measurement of mice with DSS-induced inflammatory bowel disease after treatment with the compounds of the present invention.

[0029] Figure 3 Shows the expression levels of inflammatory factors IL-1β, TNF-α, IL-10, IFN-γ in the acute phase of mice with DSS-induced inflammatory bowel disease after treatment with the compounds of the present invention.

[0030] Figure 4 Shows the results of the recovery-phase body weight of mice with DSS-induced inflammatory bowel disease after treatment with the compounds of the present invention. # represents mouse death, and each # represents one mouse.

[0031] Figure 5A and Figure 5B Shows the results of the recovery-phase colon length measurement of mice with DSS-induced inflammatory bowel disease after treatment with the compounds of the present invention.

[0032] Figure 6 Shows the expression levels of inflammatory factors IL-1β, IL-6, TNF-α, IFN-γ in the recovery phase of mice with DSS-induced inflammatory bowel disease after treatment with the compounds of the present invention.

[0033] Figure 7 shows the comparison of colon tissue repair and inflammation status of mice with DSS-induced inflammatory bowel disease after treatment with the compounds of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0034] DEFINITIONS

[0035] As used in the specification of the present invention, the following words and phrases are generally considered to have the meanings set forth below, unless otherwise specified in the context in which such words or phrases are used.

[0036] As used herein, the term "about" means an approximation of the nominal value it refers to, ±10%. In one embodiment, the term "about" means an approximation of the nominal value it refers to, ±5%. In another embodiment, the term "about" means an approximation of the nominal value it refers to, ±2%. This level of approximation is appropriate unless the value is required to have a more stringent range.

[0037] As used herein, the term "alkyl" refers to a monovalent group of a straight-chain or branched-chain saturated hydrocarbon chain consisting only of carbon and hydrogen atoms. In one embodiment, the alkyl contains 1 to 6 carbon atoms. In another embodiment, the alkyl contains 1 to 4 carbon atoms. In a further embodiment, the alkyl contains 1 to 3 carbon atoms. Exemplary of this term are groups such as methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc.

[0038] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0039] As used herein, the term "alkoxy" refers to an "alkyl-O-" group, where the alkyl is as defined herein. Exemplary of this term are groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0040] As used herein, the terms "carbocyclic", "carbocyclic group" refer to a 5- to 8-membered monocyclic saturated or partially unsaturated group having 5 to 8 carbon atoms as ring atoms. The carbocyclic or carbocyclic group can be saturated or partially unsaturated and can be fused to another saturated, partially unsaturated, or aromatic ring, provided that the ring atom connected to the target molecule is not an aromatic carbon. Examples of the carbocyclic or carbocyclic group include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, etc.

[0041] As used herein, the term "aryl" refers to an aromatic carbocyclic group having from 6 to 14 carbon atoms (more typically from 6 to 10 carbon atoms, or 6 carbon atoms) in a single ring (e.g., phenyl), a polycyclic ring (e.g., biphenyl), or multiple fused (condensed) rings (e.g., naphthyl, fluorenyl, and anthracenyl). Exemplary of this term are groups such as phenyl, fluorenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthalene (if the point of attachment is through an aryl group), and the like.

[0042] As used herein, the term "heteroaryl" refers to a monocyclic aromatic ring group containing 5 to 6 ring atoms in the ring, wherein in addition to carbon atoms, the ring atoms further contain at least one heteroatom selected from oxygen, nitrogen, and / or sulfur. Exemplary heteroaryls include, but are not limited to: pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl.

[0043] As used herein, the term "heterocyclic group" refers to a monocyclic saturated or partially unsaturated group having 5 to 6 ring atoms in the ring, wherein in addition to carbon atoms, the ring atoms further contain at least one heteroatom selected from oxygen, nitrogen, and / or sulfur. Examples of heterocyclic groups include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridyl, and the like.

[0044] As used herein, the term "therapeutically effective amount" means an amount sufficient to (i) prevent or treat a specific disease or disorder, (ii) alleviate, ameliorate, or eliminate one or more symptoms of a specific disease or disorder, or (iii) prevent or delay the onset of one or more symptoms of a disease or disorder described herein, when administered to a mammal in need of such treatment. The therapeutically effective amounts described herein include amounts sufficient to detectably modulate the activity of Vanin-1, inhibit the activity of Vanin-1, or alleviate the symptoms of a disease associated with Vanin-1 activity. The therapeutically effective amount will vary depending on the subject being treated and the disease condition, the weight and age of the subject, the severity of the disease condition, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art.

[0045] As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a given compound and that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, metaphosphates, carbonates, bisulfates, hydrogen phosphates, dihydrogen phosphates, bicarbonates, and the like. Salts derived from organic acids include formates, acetates, propionates, glycolates, pyruvates, oxalates, malates, malonates, succinates, maleates, fumarates, tartrates, citrates, benzoates, cinnamates, mandelates, mesylates, trifluoromethanesulfonates, ethanesulfonates, p-toluenesulfonates, trifluoroacetates, gluconates, salicylates, ascorbates, glucuronates, aspartates, glutamates, stearates, p-hydroxybenzoates, phenylacetates, pantothenates, 2-hydroxyethanesulfonates, sulfamates, alginates, camphorates, camphorsulfonates, nicotinates, palmitates, adipates, laurates, lactates, o-aminobenzoates, naphthylates, and the like.

[0046] As used herein, "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes both the case where the event or circumstance occurs and the case where it does not occur.

[0047] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated therewith.

[0048] Any general formula or structure given herein, including General Formula I or any general formula disclosed herein, is also intended to represent both the unlabeled form and the isotopically labeled form of the compound. Compounds of these forms may also be referred to as "isotope labels" or "isotope-enriched analogs". Isotopically labeled compounds have the structures depicted herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18F, 36 Cl, 123 I and 125 I. The various isotopically labeled compounds of the present invention, such as those incorporating a radioactive isotope (e.g., 3 H, 13 C and 14 C). Such compounds are synthesized by means well-known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0049] Compound

[0050] In one embodiment, the present invention provides a compound of formula (I), or its isotopically labeled form, optical isomer, pharmaceutically acceptable salt,

[0051]

[0052] wherein,

[0053] X1, X2, X3, X4 are each independently selected from CR4 or N;

[0054] X5 is selected from O or S;

[0055] R1 is selected from H or C 1-6 alkyl;

[0056] R2 is selected from -(CH2)i-X6;

[0057] Alternatively,

[0058] R1 and R2 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group; wherein said heterocyclic group is optionally substituted with a group selected from: C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxy, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl), C 5-8 carbocyclic group, C 6-14 aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group;

[0059] each R3 is independently selected from H, C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxy, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0060] each R4 is independently selected from H, C 1-6 alkyl, halogen, hydroxy, C 1-6Alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0061] Each R5 is independently selected from H, C 1-6 alkyl, halogen, hydroxyl, C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0062] X6 is selected from C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl), C 5-8 carbocyclic group, C 6-14 aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic group; wherein the carbocyclic group, aryl, heteroaryl, and heterocyclic group are optionally substituted with a group selected from C 6-14 aralkyl, NR6R6’, -C(O)NH2, -S(O)2NH2;

[0063] R6, R6’ are each independently selected from H, C 1-6 alkyl, or R6, R6’ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group;

[0064] i is 0, 1, 2, 3, 4 or 5;

[0065] j is 2;

[0066] k is 0 or 1.

[0067] Preferably, X5 is selected from O or S.

[0068] Preferably, k is 1.

[0069] Preferably, R3 is H.

[0070] In one embodiment, the compounds described herein have the structure shown in formula (II),

[0071]

[0072] wherein, X1 is selected from C or N;

[0073] l is 3 or 4;

[0074] R1 is selected from H or C 1-6 alkyl;

[0075] R2 is selected from -(CH2) i -X6;

[0076] Or,

[0077] R1, R2 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group; wherein said heterocyclic group is optionally substituted with a group selected from C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxy, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl), C 5-8 carbocyclic group, C 6-14 aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group;

[0078] Each R3 is independently selected from H, C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxy, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0079] Each R4 is independently selected from H, C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxy, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0080] Each R5 is independently selected from H, C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxy, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0081] X6 is selected from C 1-6 alkoxy, cyano, amino, carboxy, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl), C 5-8 carbocyclic group, C 6-14 aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic group; wherein said carbocyclic group, aryl, heteroaryl, and heterocyclic group are optionally substituted with a group selected from the following: C 6-14 aralkyl, NR6R6’, -C(O)NH2, -S(O)2NH2;

[0082] R6, R6’ are each independently selected from H, C 1-6 alkyl, or R6, R6’ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group;

[0083] i is 0, 1, 2, 3, 4 or 5;

[0084] j is 2;

[0085] k is 1;

[0086] l is 3 or 4.

[0087] In one embodiment, the compounds described herein are compounds of formula (II-A) or formula (II-B),

[0088]

[0089] or their isotopically labeled compounds, optical isomers, pharmaceutically acceptable salts,

[0090] wherein,

[0091] R1 is selected from H or C 1-6 alkyl;

[0092] R2 is selected from -(CH2) i -X6;

[0093] Or,

[0094] R1, R2 and the nitrogen atom to which they are attached together form a 5- or 6-membered heterocyclic group; wherein the heterocyclic group is optionally substituted with a group selected from C 1-6 alkyl, halogen, hydroxyl, C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl), C 5-8 carbocyclic group, C 6-14 aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group;

[0095] Each R4 is independently selected from H, C 1-6 alkyl, halogen, hydroxyl, C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0096] Each R5 is independently selected from H, C 1-6 alkyl, halogen, hydroxyl, C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl);

[0097] X6 is selected from C 1-6alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl), C 5-8 carbocyclic group, C 6-14 aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic group; wherein the carbocyclic group, aryl, heteroaryl, and heterocyclic group are optionally substituted with a group selected from C 6-14 aralkyl, NR6R6’, -C(O)NH2, -S(O)2NH2;

[0098] R6 and R6’ are each independently selected from H, C 1-6 alkyl, or R6 and R6’ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group;

[0099] i is 0, 1, 2, 3, 4 or 5.

[0100] In one embodiment, the compounds described herein are compounds of formula (II-A), or formula (II-B), or their isotopically labeled compounds, optical isomers, pharmaceutically acceptable salts,

[0101] wherein,

[0102] R1 is selected from H;

[0103] R2 is selected from wherein the above groups are optionally substituted with a group selected from C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl), C 5-6 carbocyclic group, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group;

[0104] i is selected from 0, 1, 2, 3, 4 or 5.

[0105] In one embodiment, the compounds described herein are compounds of formula (II-A), or formula (II-B), or their isotopically labeled compounds, optical isomers, pharmaceutically acceptable salts,

[0106] wherein,

[0107] R1 and R2 together with the nitrogen atom to which they are attached form wherein the above groups are optionally substituted with a group selected from C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6(alkyl), C 5-6 substituted by a group of a carbocyclic group, phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic group;

[0108] X6 is selected from C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 (alkyl), C 5-6 carbocyclic group, phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic group; wherein the above groups are optionally substituted by a group selected from benzyl, NR6R6’, -C(O)NH2, -S(O)2NH2; R6 and R6’ are each independently selected from H or C 1-6 (alkyl);

[0109] i is selected from 0, 1, 2, 3, 4 or 5.

[0110] In one embodiment, the compounds described herein, or their isotopically labeled forms, optical isomers, pharmaceutically acceptable salts, wherein the compounds have

[0111]

[0112] the structure shown.

[0113] Pharmaceutical Composition and Administration

[0114] The pharmaceutical composition provided by the present invention comprises the compound of the present invention or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are known to those skilled in the art and include diluents, lubricants, disintegrants, binders, buffers, preservatives, stabilizers, wetting agents, glidants, emulsifiers, coloring agents, flavoring agents, sweetening agents, etc. According to the different routes of drug administration, such as oral administration, parenteral administration, and rectal administration, etc., the pharmaceutical composition of the present invention can be made in solid form (including but not limited to tablets, capsules, pills, granules, powders, dusting powders, suppositories) or in liquid form (including but not limited to solutions, suspensions, emulsions, tinctures, syrups). When the pharmaceutical composition of the present invention is in solid form, the pharmaceutically acceptable carrier usually comprises one or more of the following: a) diluents, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose, etc.; b) lubricants, such as silica, talc, stearic acid, polyethylene glycol, etc.; c) binders, such as magnesium aluminosilicate, gelatinized starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, etc.; d) disintegrants, such as starch, alginic acid, agar, corn starch; e) stabilizers, such as antioxidants like ascorbic acid; f) glidants, such as silica; g) flavoring agents, such as mint, methyl salicylate; sweetening agents, such as sucrose, saccharin. When the pharmaceutical composition of the present invention is in liquid form, the pharmaceutically acceptable carrier usually comprises one or more of the following: a) diluents, such as water for injection, normal saline, Ringer's solution, polyethylene glycol, glycerol, propylene glycol, etc.; b) antioxidants, such as ascorbic acid or sodium bisulfite; c) buffers, such as acetates, phosphates, etc.

[0115] In one embodiment, the pharmaceutical composition of the present invention can be administered orally. Oral administration can be achieved by swallowing or by buccal or sublingual administration. In another embodiment, the compound of the present invention can be administered parenterally. Suitable ways of parenteral administration include but are not limited to intravenous, intraarterial, intraperitoneal, intracardiac, intraurethral, intracranial, intramuscular, and subcutaneous administrations, etc. In another embodiment, the compound of the present invention can also be administered topically. Suitable ways of topical administration include but are not limited to transdermal topical administration, intranasal inhalation, rectal administration, vaginal administration, ophthalmic administration, otic administration, etc.

[0116] The effective dose of the pharmaceutical composition of the present invention depends on at least a variety of factors, including the nature, severity, route of administration, pharmaceutical dosage form of the disorder being treated, and the age, weight, medical condition, etc. of the patient, which will be ultimately determined by a clinician. It is expected that the dose of the compound of the present invention can be in the range of about 0.01 to about 100 mg per kilogram of body weight per day; typically about 0.1 to about 50 mg per kilogram of body weight per day; more typically, about 0.5 to about 30 mg per kilogram of body weight per day. In one embodiment, the daily dose of the compound of the present invention can be about 0.01 to about 10 mg per kilogram of body weight, or about 0.1 to about 10 mg per kilogram of body weight, or about 0.1 to about 5 mg per kilogram of body weight, or about 0.1 to about 1 mg per kilogram of body weight, or about 0.1 to about 0.5 mg per kilogram of body weight, and can be administered in the form of a single dose or multiple doses.

[0117] Indications

[0118] The compound of general formula (I) of the present invention or its isotope-labeled compound, optical isomer, pharmaceutically acceptable salt, or a pharmaceutical composition containing the same is a Vanin-1 inhibitor and can be used for the prevention and / or treatment of diseases and / or disorders related to or mediated by Vanin-1, including but not limited to the prevention and / or treatment of autoimmune diseases, inflammatory diseases, metabolic diseases, and infection-based diseases.

[0119] In one embodiment, the compound of general formula (I) of the present invention or its isotope-labeled compound, optical isomer, pharmaceutically acceptable salt, or a pharmaceutical composition containing the same can be used for the prevention and / or treatment of Crohn's disease, ulcerative colitis, atopic dermatitis, psoriasis, systemic sclerosis, non-alcoholic steatohepatitis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, cystic fibrosis, atherosclerosis, gingivitis, interstitial cystitis, pain associated with irritable bowel syndrome, acute lung injury, irritable bowel syndrome, inflammatory bowel disease, proctitis, celiac disease, eosinophilic gastroenteritis, allergic urticaria, angioedema, glomerular injury, spinal cord injury, graft-versus-host disease, hyperlipidemia, metabolic syndrome, etc.

[0120] Preferably, the compound of general formula (I) of the present invention or its isotope-labeled compound, optical isomer, pharmaceutically acceptable salt, or a pharmaceutical composition containing the same can be used for the prevention and / or treatment of Crohn's disease, ulcerative colitis, systemic sclerosis, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, scleroderma, etc.

[0121] More preferably, the compound represented by the general formula (I) of the present invention, or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, or the pharmaceutical composition containing the same can be used for preventing and / or treating Crohn's disease and / or ulcerative colitis.

[0122] General Synthetic Method

[0123] The compounds of the present invention can be prepared using the methods disclosed herein and their modified routes, as well as methods well-known in the art. Typical embodiments of the compounds according to the present invention can be synthesized using the following general reaction procedures. It is obvious from the description herein that corresponding different products can be obtained by using other materials with similar structures to replace the reaction raw materials. The reaction raw materials are typically obtained from commercial sources or synthesized using disclosed methods.

[0124] Reaction Scheme I

[0125]

[0126] The compound represented by formula (I-a) is subjected to a coupling reaction with the compound represented by formula (I-b) under suitable conditions, and then a hydrolysis reaction occurs under basic conditions to generate the compound represented by formula (I-c). For example, the suitable conditions for the coupling reaction between the compound represented by formula (I-a) and the compound represented by formula (I-b) include, but are not limited to, reacting under a metal palladium catalyst and a phosphine ligand compound, and under basic conditions. The metal palladium catalyst is a common metal palladium catalyst for Buchwald-Hartwig coupling reaction, including, but not limited to, tris(dibenzylideneacetone)dipalladium, 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II), bis(benzonitrile)dichloropalladium(II), palladium acetate, tetrakis(triphenylphosphine)palladium, etc. The phosphine ligand compounds include, but are not limited to, 1,1'-bis(diphenylphosphino)ferrocene, tris(o-tolyl)phosphine, 2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, 1,1'-binaphthalene-2,2'-bis(diphenylphosphine), etc. The basic conditions for the hydrolysis reaction include inorganic bases and / or organic bases. The inorganic bases include, but are not limited to, alkali metal or alkaline earth metal hydroxides (such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonates or bicarbonates (such as lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, cesium carbonate, barium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, etc.); the organic bases include, but are not limited to, ammonia, dimethylamine, trimethylamine, diethylamine, triethylamine, diisopropylethylamine, pyrrole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, piperidine, piperazine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.

[0127] Among them, the variables X1, X2, X3, X4, X5, R1, R2, and n are as defined herein.

[0128] Reaction Process II

[0129]

[0130] The compound represented by formula (I-c) is subjected to a condensation reaction with the compound represented by formula (I-d) under suitable conditions. For example, a condensing agent (such as 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI HCl), ethyl 2-oximinocyanoacetate, etc.) and a base (such as N-methylmorpholine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, etc.) are added to a mixture of the compounds represented by formula (I-c) and formula (I-d) in an inert solvent (such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane), and the reaction gives the compound represented by formula (I).

[0131] Examples

[0132] The following examples are provided to illustrate the preparation of the compounds of the present invention, but do not limit the present invention in any way.

[0133] The abbreviations used in the examples of the present invention have the following meanings:

[0134] BINAP 1,1'-Binaphthalene-2,2'-bis(diphenylphosphine) <![CDATA[Cs2CO3]]> Cesium Carbonate DCM Dichloromethane DMAP 4-Dimethylaminopyridine DMSO Dimethyl Sulfoxide EA Ethyl Acetate EDC·HCl 1-Ethyl-(3-dimethylaminopropyl)carbodiimide Hydrochloride HCl Hydrogen Chloride h Hour LiOH Lithium Hydroxide MeOH Methanol mg Milligram mL Milliliter mmol Millimole <![CDATA[Pd2(DBA)3]]> Tris(dibenzylideneacetone)dipalladium PE Petroleum Ether TLC Thin Layer Chromatography THF Tetrahydrofuran

[0135] Synthesis of Compound III-A in Example 1

[0136]

[0137] 1. Preparation of Intermediate 1-c

[0138] Under nitrogen protection, ethyl 5-bromothiophene-2-carboxylate (1-a, 3.11 g, 13.2 mmol), 3,4-dihydro-2H-benzo[b][1,4]thiazine (1-b, 1 g, 6.6 mmol), Cs2CO3 (3.23 g, 9.9 mmol), Pd2(DBA)3 (300 mg, 0.33 mmol) and BINAP (526 mg, 0.98 mmol) were dissolved in 20 mL of 1,4-dioxane and stirred at 100 °C for 12 h. TLC monitoring showed that most of 1-b had reacted completely. The solvent was removed by distillation under reduced pressure, and the residue was separated by silica gel column chromatography (PE:EA = 6:1, V / V) to obtain a mixture of coupling reaction products, which was directly used in the next reaction without further purification. The obtained product mixture and LiOH (1.58 g, 66 mmol) were all dissolved in 20 mL of THF / 20 mL of H2O and reacted at 80 °C for 24 h. After TLC detection showed the reaction was complete, the reaction solution was poured into 200 mL of 1N HCl, extracted twice with EA, the organic phases were combined, EA was removed by rotary evaporation, and the residue was separated by silica gel column chromatography (DCM:MeOH = 10:1, V / V) to obtain a pale yellow solid 5-(2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)thiophene-2-carboxylic acid 1-c (1 g), with a two-step yield of 54.6%.

[0139] 1 H NMR (500 MHz, DMSO) δ 7.50 (d, J = 4.1 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.28–7.13 (m, 1H), 7.09 (dd, J = 11.1, 4.1 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.55 (d, J = 4.1 Hz, 1H), 4.16–3.62 (m, 2H), 3.29–2.82 (m, 2H).

[0140] 13 C NMR (125 MHz, DMSO) δ 162.90, 159.42, 140.51, 133.75, 127.57, 125.01, 124.88, 124.04, 122.85, 121.15, 111.71, 50.03, 25.50.

[0141] 2. Preparation of Compound III-A

[0142] 1-c (1 g, 3.6 mmol), 2-(cyclohex-1-en-1-yl)ethanamine (1-d, 900 mg, 7.2 mmol), EDC·HCl (1.38 g, 7.2 mmol) and DMAP (878 mg, 7.2 mmol) were dissolved in 40 mL of DCM and stirred at room temperature for 12 h. The residue was separated by silica gel column chromatography (PE:EA = 2:1, V / V) to give white solid 1 (1 g) with a yield of 72.2%.

[0143] 1 H NMR (500 MHz, CDCl3) δ 7.22 (t, J = 10.5 Hz, 1H), 7.19–7.08 (m, 2H), 6.98 (dd, J = 11.1, 4.0 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 6.44 (d, J = 4.0 Hz, 1H), 5.88 (s, 1H), 5.51 (s, 1H), 4.07–3.80 (m, 2H), 3.45 (dd, J = 12.4, 6.6 Hz, 2H), 3.27–2.98 (m, 2H), 2.20 (t, J = 6.7 Hz, 2H), 1.98 (d, J = 28.1 Hz, 4H), 1.71–1.48 (m, 4H).

[0144] 13 C NMR (125 MHz, CDCl3) δ 161.86, 157.65, 141.03, 134.74, 128.32, 127.74, 125.13, 123.83, 123.55, 122.98, 121.81, 114.44, 51.58, 37.66, 37.51, 27.90, 26.01, 25.29, 22.84, 22.38。

[0145] Preparation of Compound III-B in Example 2

[0146]

[0147] 2,3-Dihydro-1H-pyrido[2,3-b][1,4]thiazine was used instead of intermediate 1-b, and the preparation was carried out in a similar manner to Example 1 to obtain Compound III-B.

[0148] Preparation of Compound III-C in Example 3

[0149]

[0150] 1-Benzylpiperidin-4-amine was used instead of intermediate 1-d, and the preparation was carried out in a similar manner to Example 1 to obtain Compound III-C.

[0151] Preparation of Compound III-D in Example 4

[0152]

[0153] Using 4-(aminomethyl)-N,N-dimethylaniline to replace Intermediate 1-d, the preparation was carried out in a similar method to Example 1 to obtain Compound 4.

[0154] Preparation of Compound III-E in Example 5

[0155]

[0156] Using 4-(aminomethyl)-N,N-dimethylaniline to replace Intermediate 1-d, the preparation was carried out in a similar method to Example 1 to obtain Compound III-E.

[0157] Preparation of Compound III-F in Example 6

[0158]

[0159] Using 1-phenylpiperazine to replace Intermediate 1-d, the preparation was carried out in a similar method to Example 1 to obtain Compound III-F.

[0160] Preparation of Compound III-G in Example 7

[0161]

[0162] Using 7-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine to replace Intermediate 1-b and benzylamine to replace Intermediate 1-d, the preparation was carried out in a similar method to Example 1 to obtain Compound III-G.

[0163] Preparation of Compound III-H in Example 8

[0164]

[0165] Using cyclohexylamine to replace Intermediate 1-d, the preparation was carried out in a similar method to Example 1 to obtain Compound III-G.

[0166] Preparation of Compound III-I in Example 9

[0167]

[0168] Using 4-(2-aminoethyl)benzenesulfonamide to replace Intermediate 1-d, the preparation was carried out in a similar method to Example 1 to obtain Compound III-I.

[0169] Preparation of Compound III-J in Example 10

[0170]

[0171] Using aniline to replace intermediate 1-d, the preparation was carried out by a method similar to that of Example 1 to obtain compound III-J.

[0172] Biological activity test

[0173] 1. Inhibitory experiment on the activity of human recombinant Vanin-1

[0174] Select pantethiol of Vanin-1 as its classical endogenous physiological substrate (final concentration 5 μM), select 80 ng / mL of human recombinant Vanin-1 protein concentration within its catalytic linear range as the optimal concentration, and the incubation metabolism time is 30 min within the linear range time. The concentration of the test compound as an inhibitor is set between 0 - 1000 nM (5, 10, 20, 50, 100, 500, 1000 nM); fitting the inhibition curve of its inhibition of Vanin-1, the compound of the present invention inhibits the hydrolysis metabolism of pantethiol catalyzed by Vanin-1 to VB5 and cysteamine in a concentration-dependent manner. The IC 50 value is shown in Table 1. The results show that the compound of the present invention has a good inhibitory effect on Vanin-1.

[0175] Table 1

[0176] Example Number <![CDATA[Human recombinant Vanin-1 IC 50 (nM)]]> 1 A 2 A 3 A 4 A 5 A 6 C 7 B 8 B 9 B 10 C RR6 B

[0177] Note: A ≤ 50 nM, 50 nM < B ≤ 500 nM, 500 nM < C ≤ 5000 nM;

[0178] RR6 (CAS No.: 1351758-37-6) is a competitive Vanin-1 inhibitor and is used as a positive control here.

[0179] 2. Pharmacodynamic evaluation for the acute phase of DSS-induced inflammatory bowel disease

[0180] 2.1 Materials

[0181] Male C57BL / 6J mice at 6 - 8 weeks old, 20 - 22 g per mouse, were purchased from Liaoning Changsheng Biotechnology Co., Ltd. All mice were given sterile water and standard feed and were raised in an SPF laboratory. Dextran sulfate sodium (DSS) was purchased from Dalian Meilun Biotechnology Co., Ltd.

[0182] 2.2 Model construction and administration

[0183] All mice were adaptively fed for 1 week before the start of the experiment and randomly divided into a normal control group, a model control group, and a treatment group, with 6 mice in each group. Mice in the model group and the treatment group were given 3% DSS aqueous solution to drink freely for 7 days to induce colitis. Mice in the treatment group were given compound III-A orally (10 mg / kg / day) while drinking 3% DSS aqueous solution freely, and the normal control group and the model control group were given an equal volume of solvent by gavage during the same period. The body weight of the mice was monitored daily, and the disease activity index (DAI) of the fecal intestinal function index was scored. Modeling and administration were terminated on the 7th day, and the mice were euthanized the next day after fasting to collect physiological and biochemical indexes to evaluate the pharmacodynamic efficacy of compound III-A in the treatment of inflammatory bowel disease.

[0184] 2.3 Evaluation

[0185] As Figure 1 can be seen, the changes in body weight and DAI scores of mice in the treatment group during the modeling period were significantly lower than those in the model control group, revealing that compound III-A can effectively relieve the physiological function and activity status of mice during inflammatory bowel disease. The colon length of the treated mice was measured, and the results are as Figure 2 shown. The colon length of mice in the treatment group was about 1.8 cm longer than that of mice in the modeling group, almost approaching the colon length of mice in the normal control group. The fecal morphology of the colon in the treatment group was intact, revealing that compound III-A can significantly improve diarrhea and intestinal epithelial mucosal injury in mice during the course of inflammatory bowel disease. Further molecular mechanism results showed that multiple inflammatory factors in the colon of mice in the treatment group, such as IL-6, TNF-α, IL-10, and IFN-γ, were significantly lower than those in the model control group, indicating that the compound of the present invention can significantly improve the inflammatory level of the mouse colon, thereby reducing tissue damage caused by inflammatory factors during the course of inflammatory bowel disease ( Figure 3 ). In summary, the compound of the present invention can significantly improve the level of inflammatory factors in the colon during the course of inflammatory bowel disease, relieve colon tissue damage, and thereby improve symptoms such as diarrhea under inflammatory bowel disease, and has an excellent therapeutic effect on inflammatory bowel disease.

[0186] 3. Pharmacodynamic evaluation for the recovery period of DSS-induced inflammatory bowel disease

[0187] 3.1 Materials

[0188] Male C57BL / 6J mice, 6 - 8 weeks old, weighing 20 - 24 g each, were purchased from Liaoning Changsheng Biotechnology Co., Ltd. All mice were given sterile water and standard feed and raised in an SPF laboratory. Dextran sulfate sodium (DSS) was purchased from Dalian Meilun Biotechnology Co., Ltd.

[0189] 3.2 Model construction and administration

[0190] All mice were adaptively housed for 1 week before the start of the experiment and randomly divided into a normal control group, a model control group, and a treatment group, with 6 mice in each group. For the recovery-phase model, colitis was first induced, and then drug treatment was given to observe the recovery of colitis in mice under drug treatment. Details are as follows: Mice in the model group and the treatment group were given a 4% DSS aqueous solution to drink freely for 7 days to induce colitis. Mice in the treatment group and the model group started to be given normal drinking water on the 8th day; meanwhile, the treatment group started to be given compound III-A (10 mg / kg / day) on the 8th day, and the model group was given a blank solvent in parallel. Subsequently, until the 15th day, the body weight and activity of the mice were monitored daily, and the death of the mice was recorded. Finally, the mice were euthanized, the colon tissues of the mice were collected, and the levels of inflammatory factors in the colon tissues were detected by PCR. At the same time, the colon tissues were fixed for H&E and PAS staining to perform pathological analysis of the inflammatory recovery of the intestinal tract.

[0191] 3.3 Evaluation

[0192] In the treatment group, the hair of the mice gradually returned to normal during the recovery period, and was dark and shiny. Compared with the model control group where the mice were listless, the food intake of the mice in the treatment group was much higher than that of the model control group. In addition, body weight monitoring showed that after DSS was withdrawn, the body weight of the mice in the model control group continued to decline, and the final average body weight decreased by about 40%. While the body weight of the treatment group gradually leveled off and then increased day by day. One mouse in the model control group died on the seventh and eighth days after DSS was withdrawn, and no mouse in the treatment group died ( Figure 4 ). The colon length of the treatment group was much higher than that of the model control group, and the ileocecal valve and feces in the colon were almost close to those of the normal control group, indicating a return to the normal level ( Figure 5A and Figure 5B ). It shows that the compound of the present invention has a significant therapeutic effect on the recovery period of mice with inflammatory bowel disease and can accelerate the recovery and improvement of the state of the mice. The measurement results of inflammatory factors in the colon tissues are as Figure 6 shown. The inflammatory factors IL-1β, IL-6, TNF-α, and IFN-γ in the treatment group of mice all returned to near-normal levels, while the colon tissues of the model control group were still at a relatively high inflammatory level. The histopathological sections also indicated that the colon villi and morphology of the mice in the treatment group returned to normal, and there was no obvious inflammatory infiltration. The colon villi of the mice in the model control group were still severely damaged, and there was significant inflammatory infiltration ( Figure 7A and Figure 7B ). The above results show that the compound of the present invention can significantly improve the repair of colon tissues and the inflammatory state of patients with inflammatory bowel disease and has a good therapeutic effect during the recovery period of the disease.

[0193] In the description of this specification, the descriptions with reference to the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples", etc. mean that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0194] It should be noted that the above embodiments all belong to the same inventive concept. The descriptions of each embodiment have their own focuses. For the parts not described in detail in individual embodiments, reference may be made to the descriptions in other embodiments. The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A thiophenecarboxamide compound represented by formula (I), or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, wherein, X1, X2, X3, and X4 are each independently selected from CR5 or N; X5 is selected from O, S, or CH2; R1 is selected from H or C 1-6 alkyl; R2 is selected from -(CH2) i -X6; alternatively, R1, R2 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group; wherein the heterocyclic group is optionally substituted with a group selected from C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxy, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl), C 5-8 carbocyclic group, C 6-14 aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group; Each R3 is independently selected from H, C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl); Each R4 is independently selected from H, C 1-6 alkyl, halogen, hydroxyl, C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl); Each R5 is independently selected from H, C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl); X6 is selected from C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl), C 5-8 carbocyclic group, C 6-14 aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group; wherein the carbocyclic group, aryl, heteroaryl, heterocyclic group is optionally substituted with a group selected from C 6-14 aralkyl, NR6R6 ’ , -C(O)NH2, -S(O)2NH2; R6 and R6' are each independently selected from H, C 1-6 alkyl, or R6 and R6' together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group; i is 0, 1, 2, 3, 4, or 5; j is 2; k is 0 or 1.

2. The compound according to claim 1, or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, wherein, X5 is selected from O or S.

3. The compound according to claim 1, or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, wherein, k is 1.

4. The compound according to claim 1, or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, wherein, R3 is H.

5. The compound according to any one of the preceding claims 1-4, or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, wherein, the compound has the structure shown in formula (II): wherein, X1 is selected from C or N; l is 3 or 4.

6. The compound according to claim 5, or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, wherein, R1 is selected from H or C 1-6 alkyl; R2 is selected from -(CH2) i -X6; alternatively, R1, R2 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group; wherein said heterocyclic group is optionally substituted with a group selected from C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxy, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl), C 5-6 carbocyclic group, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group.

7. The compound according to claim 6, or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, wherein, R1 is selected from H; R2 is selected from wherein the above groups are optionally substituted with groups selected from C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxyl, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl), C 5-6 carbocyclic group, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group 8. The compound according to claim 6, or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, wherein, R1, R2 together with the nitrogen atom to which they are attached form wherein said group is optionally substituted with a group selected from C 1-6 alkyl, halogen, hydroxy, C 1-6 alkoxy, cyano, amino, carboxy, -CONH2, -CONHCH3, -CON(CH3)2, -S(C 1-6 alkyl), C 5-6 carbocyclic group, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclic group.

9. The compound according to claim 6, or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, wherein the compound has the structure shown in formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (III-G), formula (III-H), formula (III-I), or formula (III-J):

10. A pharmaceutical composition comprising the compound according to any one of claims 1-9, or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

11. The compound according to any one of claims 1-9, or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 10, which is a Vanin-1 inhibitor.

12. The compound according to any one of claims 1-9, or its isotope-labeled substance, optical isomer, pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 10, for preventing and / or treating Vanin-1-mediated diseases.

13. The use according to claim 12, wherein the diseases are selected from autoimmune diseases, inflammatory diseases, metabolic diseases, and infection-based diseases.

14. Use according to claim 13, wherein the disease is selected from Crohn's disease, ulcerative colitis, atopic dermatitis, psoriasis, systemic sclerosis, non-alcoholic steatohepatitis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, cystic fibrosis, atherosclerosis, gingivitis, interstitial cystitis, pain associated with irritable bowel syndrome, acute lung injury, irritable bowel syndrome, inflammatory bowel disease, proctitis, celiac disease, eosinophilic gastroenteritis, allergic urticaria, angioedema, glomerular injury, spinal cord injury, graft-versus-host disease, hyperlipidemia, metabolic syndrome.

15. Use according to claim 14, wherein the disease is selected from Crohn's disease, ulcerative colitis, systemic sclerosis, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, scleroderma, etc.

16. Use according to claim 15, wherein the disease is selected from Crohn's disease and / or ulcerative colitis.

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