Heterocyclic compound and application thereof

Abstract

The invention discloses a heterocyclic compound and application thereof. The invention provides a compound as shown in a formula I, and a tautomer, a stereoisomer, a hydrate, a solvate, a salt or a prodrug thereof. The compounds are useful in the treatment of diseases.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically, it relates to a heterocyclic compound and its uses. Background Technology

[0002] Inflammation is a fundamental pathological process, primarily a defensive response, that occurs in biological tissues in response to stimuli such as trauma or infection. Local manifestations of inflammation include redness, swelling, heat, pain, and functional impairment, and systemic reactions such as fever and changes in peripheral blood leukocyte counts may also occur. Inflammation is a significant cause of many diseases, including cardiovascular disease, diabetes, cerebrovascular disease, Alzheimer's disease, and cancer. Increasing research has revealed the important role of neuroinflammation in ischemic stroke. The mechanism of secondary injury after cerebral ischemia may be due to the production of intracranial inflammation following ischemic stroke; the inflammatory response accelerates the formation of ischemic damage and affects neuronal death and neural tissue regeneration. The neuroinflammatory response after cerebral ischemia is characterized by microglial activation, astrocyte activation, and an increase in inflammasomes. Microglia are rapidly activated within minutes of the acute phase of ischemic stroke, peaking 2-3 days after ischemia and persisting for several weeks. After a stroke, about 40% of patients will suffer from serious sequelae, causing them great pain. However, there are currently no drugs that can promote the repair of nerve function after a stroke.

[0003] Neuropathic pain (NP) is chronic pain directly caused by damage or disease of the somatic sensory nervous system. It often manifests as spontaneous pain, hyperalgesia, and angina, typically lasting longer than 3 months and causing significant disability, requiring multidisciplinary intervention. Any disease or injury affecting neural pathways from the peripheral nerves to the central brain can lead to neuropathic pain, such as peripheral neuropathy, central nervous system neuropathy, metabolic / nutritional disorders, infection / inflammation, etc. Pain mechanisms include peripheral sensitization, central sensitization, and ion channel abnormalities. However, existing drugs often have problems such as central nervous system side effects, drug tolerance, and limited efficacy, necessitating the development of a new generation of analgesics with better efficacy, fewer side effects, and no drug tolerance. Pregabalin is a commonly used clinical treatment for neuropathic pain, but long-term use can lead to analgesia tolerance. (+)-Kantol has good analgesic effects, and long-term oral administration is necessary for neuropathic pain; however, its low oral bioavailability limits its clinical application. Therefore, there is an urgent clinical need to develop drugs for treating inflammation or inflammation-related diseases, as well as for treating neuropathic pain. Summary of the Invention

[0004] The purpose of this invention is to provide a class of compounds or derivatives thereof that can be used to treat inflammation or related diseases, as well as pain and related diseases, such as neuropathic pain.

[0005] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0006] In a first aspect, the present invention provides compounds of Formula I, their tautomers, stereoisomers, hydrates, solvates, salts, or prodrugs:

[0007]

[0008] Among them, 3-12 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or 8-14 membered fused heteroaryl;

[0009] R x It is a bond or a C1-C6 alkylene group;

[0010] Ring B is a 3-12 membered cycloalkyl, a 4-10 membered heterocycloalkyl, a 6-10 membered aryl, a 5-10 membered heteroaryl, or an 8-14 membered fused heteroaryl;

[0011] The ring A is optionally substituted by one or more substituents Ra; when there are multiple Ra, the Ra may be the same or different;

[0012] The ring B is optionally substituted by one or more substituents Rb; when there are multiple Rb, the Rb may be the same or different;

[0013] Ra and Rb are each independently selected from: H, halogen, hydroxyl, nitro, cyano, amino, C1-C6 ester group, phosphate group, phosphate ester group, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamine, aryl, heteroaryl;

[0014] The Ra and Rb are optionally substituted with halogen, hydroxyl, amino, nitro, cyano, C1-C3 alkyl, or -PO(OH)2.

[0015] In another preferred embodiment, R x For the bond -CH2-, -CH2CH2-, -CH2CH2CH2-.

[0016] In another preferred embodiment, Ra and Rb are each independently selected from: H, halogen, -OH, -NH2, -NO2, -CN, -SF5, -SH, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -COO-C1-C6 alkyl, -CO-C1-C6 alkyl, -OC(O)-C1-C6 alkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2;

[0017] The Ra and Rb are optionally substituted with halogen, hydroxyl, amino, nitro, cyano, C1-C3 alkyl, or -PO(OH)2.

[0018] In another preferred embodiment, ring A is selected from benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, quinoline, isoquinoline, benzopyran, acridine, indole, purine, and carbazole.

[0019] In another preferred embodiment, the ring A is replaced by one, two, or three Ra.

[0020] In another preferred embodiment, Ra is selected from: halogen, hydroxyl, nitro, cyano, amino, phosphate, ester, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamine, aryl, and heteroaryl. When the substituent is aryl or heteroaryl, the substituent and ring A can also form a fused ring.

[0021] The halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0022] In another preferred embodiment, the ring B is a 3-12 membered cycloalkyl or a 4-10 membered heterocycloalkyl.

[0023] In another preferred embodiment, ring B is a single ring, a double ring, a triple ring, a spiral ring, or a bridge ring.

[0024] In another preferred embodiment, ring B is a benzene ring, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, benzocyclobutane, benzocyclopentane, benzocyclohexane, etc.

[0025] In another preferred embodiment, It has the following structure and its isomers:

[0026]

[0027] In another preferred embodiment, ring B is a 4-10 membered heterocyclic alkyl group; the 4-10 membered heterocyclic alkyl group has 1, 2 or 3 heteroatoms, the heteroatoms being N, O or S; for example, the number of heteroatoms is 1 or 2, for example, the heteroatoms are O or S.

[0028] In another preferred embodiment, the 6-10 aryl group is:

[0029] In another preferred embodiment, the ring B is not substituted or is substituted by one, two or three substituents Rb, wherein the substituents Rb are preferably alkyl, more preferably C1-C6 alkyl; for example, methyl, ethyl, propyl.

[0030] In another preferred embodiment, the compound represented by formula I has the structure of formula Ia:

[0031]

[0032] Among them, X1, X2, X3, X4, and X5 are each independently N or CRa;

[0033] Ring B may be optionally replaced by one or more Rb;

[0034] The definitions of Ra and Rb are as described in the first aspect;

[0035] In each individual CRa, Ra may be the same or different.

[0036] In another preferred embodiment, Ra is hydrogen, halogen, hydroxyl, nitro, cyano, amino, phosphate, ester, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamine, aryl, or heteroaryl.

[0037] In another preferred embodiment, Ra is H, -CX3, -CHX2, -CH2X, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamine, ester, amino, halogen, -NO2, -CN; wherein X is a halogen, preferably fluorine.

[0038] In another preferred embodiment, the compound represented by formula I has the structure of formula Ib:

[0039]

[0040] In this embodiment, ring B is optionally substituted by one or more substituents Rb;

[0041] R1 and R2 are each independently represented by Ra;

[0042] The definitions of rings B, Ra, and Rb are as described in the first aspect;

[0043] In another preferred embodiment, ring B is a 3-12 membered cycloalkyl, a 4-10 membered heterocycloalkyl, a 6-10 membered aryl, or a 6-10 membered heteroaryl; it is optionally substituted by one or more substituents selected from the following: halogen, hydroxyl, nitro, cyano, amino, phosphate, ester, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamine, aryl, or heteroaryl. When substituted by multiple substituents, the substituents may be the same or different.

[0044] In another preferred embodiment, R1 and R2 are each independently: halogen, hydroxyl, nitro, cyano, amino, phosphate, ester, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamine, aryl, heteroaryl.

[0045] In another preferred embodiment, R1 is selected from: -CX3, -CHX2, -CH2X, C1-C3 alkyl, halogen, -NO2, -CN, -COOMe; X is a halogen, preferably fluorine.

[0046] In another preferred embodiment, R2 is selected from: -OR b , amino, C1-C3 alkylamine, ester, of which R b It can be hydrogen, phosphoric acid (-H2PO3), straight-chain or branched alkyl.

[0047] In another preferred embodiment, R1 is a halogen, -NO2, -CN, -C1-C6 haloalkyl, or -COOC1-C6 alkyl.

[0048] In another preferred embodiment, R1 is -F, -CF3, -CHF2, -CH2F, -NO2, -CN, or -COOCH3.

[0049] In another preferred embodiment, R2 is -OH, -NH2, -SH, -F, -Cl, -Br, -OCOCH3, -OCH3, -O-PO(OH)2, or -O-CH2-PO(OH)2.

[0050] In another preferred embodiment, the compound represented by Formula I has the structure of Formula Ic:

[0051]

[0052] Where Y represents N, O, or S;

[0053] Ring B may be optionally replaced by one or more Rb;

[0054] R1 and R2 are each independently represented by Ra;

[0055] The definitions of rings B, Ra, and Rb are as described in claim 1.

[0056] In another preferred embodiment, ring B is a 3-12 membered cycloalkyl, a 4-10 membered heterocycloalkyl, a 6-10 membered aryl, or a 6-10 membered heteroaryl; it is optionally substituted by one or more substituents selected from the following: halogen, hydroxyl, nitro, cyano, amino, phosphate, ester, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamine, aryl, or heteroaryl. When substituted by multiple substituents, the substituents may be the same or different.

[0057] In another preferred embodiment, R1 and R2 are each independently: halogen, hydroxyl, nitro, cyano, amino, phosphate, ester, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamine, aryl, heteroaryl.

[0058] In another preferred embodiment, R1 is selected from: -CX3, -CHX2, -CH2X, C1-C3 alkyl, halogen, -NO2, -CN, -COOMe; wherein X is a halogen, preferably fluorine.

[0059] In another preferred embodiment, R2 is selected from: -OR 21 , amino, ester, C1-C3 alkylamine, of which R 21 It is -H, -H2PO3, straight-chain or branched alkyl.

[0060] In another preferred embodiment, R1 is a halogen, -NO2, -CN, -C1-C6 haloalkyl, or -COOC1-C6 alkyl.

[0061] In another preferred embodiment, R1 is -F, -CF3, -CHF2, -CH2F, -NO2, -CN, or -COOCH3.

[0062] In another preferred embodiment, R2 is -OH, -NH2, -SH, -F, -Cl, -Br, -OCOCH3, -OCH3, -O-PO(OH)2, or -O-CH2-PO(OH)2.

[0063] In another preferred embodiment, the ring A is replaced by 1, 2 or 3 identical or different Ra.

[0064] In another preferred embodiment, ring A is replaced by R1 and R2.

[0065] In another preferred embodiment, the ring B is replaced by 1, 2 or 3 identical or different Rb.

[0066] In another preferred embodiment, Rb is methyl, ethyl, or propyl.

[0067] In another preferred embodiment, the compound represented by Formula I has the structure of Formula Id:

[0068]

[0069] R1 and R2 are defined as Ra in the first aspect.

[0070] In another preferred embodiment, R1 and R2 are each independently: halogen, hydroxyl, nitro, cyano, amino, phosphate, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamine, aryl, heteroaryl, -COOR 22 , where R 22 It can be a straight-chain or branched alkyl group. R1 and R2 may be the same or different.

[0071] In another preferred embodiment, R1 is selected from: -CX3, -CHX2, -CH2X, C1-C3 alkyl, halogen, -NO2, -CN, -COOMe, where X is a halogen.

[0072] In another preferred embodiment, R2 is selected from: -OR 21 , amino, ester, C1-C3 alkylamine, of which R 21 It is hydrogen, -H2PO3, straight-chain or branched alkyl.

[0073] In another preferred embodiment, R1 is a halogen, -NO2, -CN, C1-C6 haloalkyl, or -COOC1-C6 alkyl.

[0074] In another preferred embodiment, R1 is -F, -CF3, -CHF2, -CH2F, -NO2, -CN, or -COOCH3.

[0075] In another preferred embodiment, R2 is -OH, -NH2, -SH, -F, -Cl, -Br, -OCOCH3, -OCH3, -O-PO(OH)2, or -O-CH2-PO(OH)2.

[0076] In a preferred embodiment, Having structure

[0077] In a preferred embodiment, the compound, its tautomers, stereoisomers, hydrates, solvates, salts, or prodrugs have a structure of formula Id-1 or Id-2.

[0078]

[0079] In another preferred embodiment, Having structure

[0080] In another preferred embodiment, Having structure

[0081] In another preferred embodiment, the compound represented by Formula I comprises:

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089] In a second aspect, the present invention provides a pharmaceutical composition comprising: a compound of formula I as described in the first aspect of the present invention, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug; and a pharmaceutically acceptable carrier.

[0090] A third aspect of the invention provides the use of compounds of Formula I as described in the first aspect of the invention, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the use of pharmaceutical compositions as described in the second aspect of the invention in the preparation of medicaments for treating inflammation and related diseases, or pain and related diseases.

[0091] In another preferred embodiment, the pain and related diseases are neuropathic pain.

[0092] Terms and Definitions

[0093] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures shall fall within the scope of this application specification.

[0094] Unless otherwise defined, all technical terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains.

[0095] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg, "Advanced Organic Chemistry 4th Edition," Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR, UV / VIS spectroscopy, and pharmacological methods, are used. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art, based on the descriptions in the various summary and more specific references cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0096] When a substituent is described using a conventional chemical formula written from left to right, that substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2. As used herein, Indicates the linking site of a group. As used herein, "R1", "R1", and "R" indicate the linking site of the group. 1 The meanings of "" are the same and they can be used interchangeably. The same definition applies to other symbols such as R2.

[0097] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0098] The numerical ranges described in this application specification and claims, when interpreted as "integers," should be understood to include the two endpoints of the range and every integer within that range. For example, "integers from 1 to 6" should be understood to include every integer of 0, 1, 2, 3, 4, 5, and 6.

[0099] In this application, the term "halogen" refers to fluorine, chlorine, bromine, or iodine, either alone or as part of other substituents; fluorine is preferred.

[0100] As used herein, the term "amino" means -NH2, either alone or as part of other substituents.

[0101] As used herein, the term "alkyl" means, alone or as part of other substituents, a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and connected to the rest of the molecule by single bonds. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. Alkyl groups may also be isotopic isomers of naturally abundant alkyl groups rich in carbon and / or hydrogen isotopes (i.e., deuterium or tritium).

[0102] When used alone or as part of other substituents, the term "C1-C6 alkyl" should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. In particular, the group has 1, 2 or 3 carbon atoms (“C1-C3 alkyl”), such as methyl, ethyl, n-propyl or isopropyl.

[0103] When used alone or as part of other substituents, the term "cycloalkyl" or "carbocycloalkyl" refers to a cyclic alkyl group. The terms "mn-membered cycloalkyl" or "C" refer to a cyclic alkyl group. m -C n "Cycloalkyl" should be understood to mean a saturated, unsaturated, or partially saturated carbon ring having m to n atoms. For example, "3-15 membered cycloalkyl" or "C3-C15 cycloalkyl" refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6, or 3 to 5 carbon atoms, which may contain 1 to 4 rings. "3-10 membered cycloalkyl" contains 3 to 10 carbon atoms. Cycloalkyl groups include monocyclic, bicyclic, tricyclic, spirocyclic, or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as decahydronaphthalene. Cycloalkyl groups may be substituted with one or more substituents. In some embodiments, the cycloalkyl group may be a cycloalkyl group fused with an aryl or heteroaryl ring.

[0104] When used alone or as part of other substituents, the terms "heterocyclic alkyl," "heterocyclic group," or "heterocycle" refer to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are substituted with heteroatoms, such as, but not limited to, N, O, S, and P. The terms "mn-membered heterocyclic alkyl" or "C m -C n "Heterocyclic alkyl" should be understood to mean a saturated, unsaturated, or partially saturated ring having m to n atoms, wherein the heterocyclic atoms are selected from N, O, S, and P, preferably from N, O, or S. For example, the terms "4-8 membered heterocyclic alkyl" or "C4-C8 heterocyclic alkyl" should be understood to mean a saturated, unsaturated, or partially saturated ring having 4 to 8 atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, S, and P, preferably from N, O, or S. "9-11 membered heterocyclic alkyl" means a saturated, unsaturated, or partially saturated ring having 9 to 11 atoms. In some embodiments, the heterocyclic alkyl may be a heterocyclic alkyl fused with an aryl or heteroaryl group. When prefixes such as 9-11 or 9-11 are used to denote a heterocyclic alkyl, the number of carbon atoms also implies the inclusion of heteroatoms. This includes monocyclic, bicyclic, tricyclic, spirocyclic, or bridged rings.

[0105] When used alone or as part of other substituents, the term "heterocyclic aromatic ring" refers to a monocyclic or polycyclic aromatic ring system in some embodiments, where one to three atoms in the ring system are heteroatoms, i.e., elements other than carbon, including but not limited to N, O, S, or P. Examples include furanyl, imidazolyl, dihydroindolyl, pyrrolyl, pyrimidinyl, tetrazolyl, thiophene, pyridinyl, pyrrolithyl, N-methylpyrrolithyl, quinolinyl, and isoquinolinyl. The heterocyclic aromatic ring may optionally be fused with a benzene ring and may be monocyclic, bicyclic, tricyclic, spirocyclic, or bridged rings.

[0106] When used alone or as part of other substituents, the terms "9-11 heterocyclic" or "C9-C11 heterocyclic" should be understood as a monovalent monocyclic, bicyclic, or tricyclic aromatic ring group having 9 to 11 ring atoms and containing 1 to 3 heteroatoms independently selected from N, O, and S; and should be understood as a monovalent monocyclic, bicyclic, or tricyclic aromatic ring group having 9, 10, or 11 ring atoms, heteroatoms independently selected from N, O, and S, and, in each case, may be benzofused. When used alone or as part of other substituents, it may be linked by carbon or nitrogen, wherein the -CH2- group is optionally replaced by -C(O)-; and wherein, unless otherwise stated to the contrary, the cyclic nitrogen atom or cyclic sulfur atom is optionally oxidized to form an N-oxide or S-oxide, or the cyclic nitrogen atom is optionally quaternized; wherein the -NH in the ring is optionally replaced by an acetyl, formyl, methyl, or methanesulfonyl group; and the ring is optionally replaced by one or more halogens. It should be understood that when the total number of S and O atoms in a heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclic group is bicyclic or tricyclic, at least one ring may be optionally a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is monocyclic, it is definitely not aromatic.

[0107] When used alone or as part of other substituents, "haloalkyl" refers to a saturated aliphatic hydrocarbon group (such as -C) that comprises a specific number of carbon atoms and is branched or straight-chained and substituted with one or more halogens. v X w Where v = 1 to 3, w = 1 to (2v+1)). Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0108] The compounds described herein include intermediates that can be used to prepare the compounds described herein, which contain reactive functional groups (e.g., but not limited to carboxyl, hydroxyl, and amino moieties), and also their protected derivatives (compounds). A “protected derivative (compound)” is a compound in which one or more reactive sites are closed by one or more protecting groups (also called protecting groups). Suitable carboxyl moieties include benzyl, tert-butyl, etc., and isotopes, etc. Suitable amino and amide protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable hydroxyl protecting groups include benzyl, etc. Other suitable protecting groups are well known to those skilled in the art.

[0109] In this application, "optional" or "optionally" means that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or not substituted, and the description includes both substituted and unsubstituted aryl groups.

[0110] In this application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, to the extent of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0111] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are also considered in this invention. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or can be used for the identification, characterization, or purification of the compounds of this invention.

[0112] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0113] Depending on the choice of raw materials and methods, the compounds of the present invention can exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral centers (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0114] When the bonds of the chiral carbon in the formulas of this invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. The absolute configuration of a stereocenter is indicated by wedge-shaped and dashed bonds.

[0115] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this invention can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form; attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0116] In this application, "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0117] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is permitted by the relevant government regulatory authority to be acceptable for human or animal use.

[0118] The term "solvent" refers to a compound of the present invention or a salt thereof comprising a stoichiometric or nonstoichiometric solvent bound by intermolecular noncovalent forces, and a hydrate when the solvent is water.

[0119] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of the present invention are prepared by modifying functional groups in the compound; this modification can be performed conventionally or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group within the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group.

[0120] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0121] The reaction temperature and time for each step can be selected appropriately based on the solvent, starting materials, and reagents. After each reaction step is completed, the target compound can be separated and purified from the reaction system using common methods such as filtration, extraction, recrystallization, washing, and silica gel column chromatography. Alternatively, the target compound can proceed directly to the next reaction step without separation or purification, provided it does not affect the subsequent reaction.

[0122] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention. All reagents and raw materials used in the present invention are commercially available.

[0123] The beneficial effects of this invention are:

[0124] This invention provides compounds of Formula I, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, which have good inhibitory effects on neuropathic pain, can effectively increase the pain threshold in animals, reduce the degree of neuropathic pain, and have few side effects and are not prone to drug resistance, making them very suitable for current clinical drug needs. Detailed Implementation

[0125] The present invention will be further described in detail below through specific embodiments. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as a limitation on the scope of protection of the present invention. Based on a full understanding of the present invention, experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or according to the conditions recommended by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present invention, and such modifications should be considered to be included within the scope of protection of the present invention.

[0126] Example 1: Synthesis of Compound 1

[0127] Synthesis route:

[0128]

[0129] 2.1 g (10 mmol) of 2-hydroxy-6-trifluoromethylnicotinic acid and 8 mmol of dextroborneol were dissolved in 25 mL of toluene, and 1 mmol of p-toluenesulfonic acid was added. The mixture was reacted at 140 °C for 6 h. After the reaction was complete, the filtrate was collected, evaporated to dryness, dissolved in ethyl acetate (EA), washed three times with saturated brine (50 mL), and the organic layer was collected, dried, and concentrated under reduced pressure to obtain the crude product. The crude product was then slurried with methanol to obtain a white powder.

[0130] 1H NMR (700MHz, CDCl3) δ11.59(s,1H),8.42(d,J=7.8Hz,1H),7.34(d,J=7.8Hz,1H),5.25–5.16(m,1H),2.57–2.47(m,1H),2.05–2.00(m,1H),1.8 9–1.83(m,1H),1.81(t,J=4.5Hz,1H),1.52–1.45(m,1H),1.36–1.30(m,1H),1.17(dd,J=14.1,3.5Hz,1H),0.99(s,3H),0.95(d,J=5.7Hz,6H).

[0131] Example 2: Synthesis of Compound 2

[0132] Synthesis route:

[0133]

[0134] 2.1 g (10 mmol) of 2-hydroxy-6-trifluoromethylnicotinic acid and 8 mmol of loratadine were dissolved in 25 mL of toluene, and 1 mmol of p-toluenesulfonic acid was added. The mixture was reacted at 140 °C for 6 h. After the reaction was complete, the filtrate was collected, evaporated to dryness, dissolved in ethyl acetate (EA), washed three times with saturated brine (50 mL), and the organic layer was collected, dried, and concentrated under reduced pressure to obtain the crude product. The crude product was then pulped to obtain a white powder.

[0135] 1 H NMR (700MHz, CDCl3) δ11.58(s,1H),8.42(d,J=7.8Hz,1H),7.34(d,J=7.8Hz,1H),5.20(d,J=9.9Hz,1H),2.58–2.47(m,1H),2.07–1.98(m,1H),1 .89–1.82(m,1H),1.81(t,J=4.5Hz,1H),1.51–1.44(m,1H),1.36–1.30( m, 1H), 1.16 (dd, J = 14.1, 3.4Hz, 1H), 0.99 (s, 3H), 0.94 (d, J = 5.5Hz, 6H).

[0136] Example 3: Synthesis of Compound 3

[0137] Synthesis route:

[0138]

[0139] 2.1 g (10 mmol) of 2-hydroxy-6-trifluoromethylnicotinic acid and 8 mmol of 1-adamantanol were dissolved in 25 mL of toluene, and 1 mmol of p-toluenesulfonic acid was added. The mixture was reacted at 140 °C for 6 h. After the reaction was complete, the filtrate was collected, evaporated to dryness, dissolved in ethyl acetate (EA), washed three times with saturated brine (50 mL), and the organic layer was collected, dried, and concentrated under reduced pressure to obtain the crude product. The crude product was then pulped to obtain a white powder.

[0140] MS: 342.2 [M+H] +

[0141] Example 4 Synthesis of Compound 5

[0142] Synthesis route:

[0143]

[0144] 2.1 g (10 mmol) of 2-hydroxy-6-trifluoromethylnicotinic acid and 8 mmol of 2-methylcyclohexanol were dissolved in 25 mL of toluene, and 1 mmol of p-toluenesulfonic acid was added. The mixture was reacted at 140 °C for 6 h. After the reaction was complete, the filtrate was collected, evaporated to dryness, dissolved in ethyl acetate (EA), washed three times with saturated brine (50 mL), and the organic layer was collected, dried, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-pressure pretreatment to obtain a pale yellow solid.

[0145] MS: 304.2 [M+H] +

[0146] Example 5 Synthesis of Compound 82

[0147] Synthesis route:

[0148]

[0149] 2.1 g (10 mmol) of 2-hydroxy-6-trifluoromethylnicotinic acid was dissolved in 25 mL of tetrahydrofuran. 0.8 g (60%, 20 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 15 min. Then, 3.0 g (15 mmol) of diisopropylphosphonic chloride was added dropwise. The reaction was allowed to proceed at room temperature for 4 h, followed by quenching with water. Extraction was performed with ethyl acetate, and the mixture was concentrated to dryness under reduced pressure. The solution was then dissolved in 100 mL of dichloromethane. 15.3 g (0.1 mol) of trimethylbromosilane and 1.49 g (10 mmol) of sodium iodide were added, and the mixture was reacted at 50 °C for 2 h. After the reaction was complete, 100 mL of water was added to quench the reaction. The mixture was extracted and separated. Dichloromethane was removed from the organic phase under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase rapid preparative liquid chromatography (mobile phase A: 0.1% TFA / water, mobile phase B: acetonitrile; 0%-80%, 40 min), and then lyophilized to obtain a yellow solid.

[0150] MS: 422.1 [MH]-

[0151] Example 6 Synthesis of Compound 83

[0152] Synthesis route:

[0153]

[0154] 2.1 g (10 mmol) of 2-hydroxy-6-trifluoromethylnicotinic acid was dissolved in 25 mL of tetrahydrofuran. 0.8 g (60%, 20 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 15 min. Then, 3.9 g (15 mmol) of di-tert-butylchloromethyl phosphate was added dropwise. The reaction was allowed to proceed at room temperature for 4 h, followed by quenching with water. Extraction with ethyl acetate was performed, and the mixture was concentrated to dryness under reduced pressure. The solution was then dissolved in 100 mL of dichloromethane, and 20 mL of trifluoroacetic acid was added. The reaction was allowed to proceed at room temperature for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase rapid preparative liquid chromatography (mobile phase A: 0.1% TFA / water, mobile phase B: acetonitrile; 0%-80%, 40 min), and lyophilized to obtain a white solid.

[0155] MS: 454.2 [M+H] +

[0156] Example 7 Synthesis of other compounds

[0157] The preparation methods of other compounds of the present invention are the same as those in Examples 1-6 above.

[0158] The following table lists some of the compounds as examples:

[0159]

[0160]

[0161]

[0162]

[0163] Test case

[0164] Neuropathic pain model:

[0165] A neuropathological pain model was established using chronic sciatic nerve compression (CCI). C57 mice were anesthetized using a Reward inhalation anesthesia machine. After the righting reflex disappeared, the mice were immobilized in a lateral recumbent position. Following anesthesia, the skin was bluntly incised with the tip of sterile scissors, and the biceps femoris muscle was bluntly dissected to expose the main trunk of the sciatic nerve. Chromium catgut soaked in physiological saline was used to lightly ligate the nerve trunk three times at 1 mm intervals (the pressure was sufficient to cause a slight indentation of the nerve or mild leg twitching). The muscle was gently closed, and the skin was sutured. Postoperatively, the animals' mobility was monitored to avoid excessively tight ligation that could lead to limb paralysis. Precise ligation pressure is crucial; excessive compression can block nerve conduction and cause motor dysfunction. Animals were randomly divided into 14 groups of 8 mice each: a normal control group, a solvent-treated model group, and a drug-treated group. Mice in the solvent group were given a solvent of 5% DMSO + 95% water. Mice in the drug treatment group were given a drug solution prepared as follows: the corresponding compound was dissolved in DMSO and then diluted with purified water to form a solution with DMSO at a volume ratio of 5% and purified water at a volume ratio of 95%. The dosage for both the solvent and drug treatment groups was 3 mg / kg, administered via gavage.

[0166] Spared Nerve Injury Model:

[0167] C57 mice were anesthetized using a Reward inhalation anesthesia machine. After the righting reflex disappeared, the mice were fixed in a lateral recumbent position. The sciatic nerve and its branches were exposed by incising the hind limb skin and bluntly dissecting the muscles. Subsequently, two selected nerves were double-ligated and distally severed, while avoiding damage to the preserved nerve branches. The tibial nerve was preserved, and the common peroneal nerve and sural nerve were damaged. The skin was sutured, and the animals' mobility was monitored postoperatively to avoid excessively tight ligation that could lead to limb paralysis. The animals were randomly divided into 8 groups of 8 mice each: a normal control group, a model given solvent group, and a drug administration group. Mice in the model given solvent group were fed a solvent of 5% DMSO + 95% water. Mice in the drug administration group were given the drug prepared as follows: the corresponding compound was dissolved in DMSO and then diluted with purified water to prepare a drug solution with a DMSO volume ratio of 5% and a purified water volume ratio of 95%. The dosage for each mouse in the solvent group and the drug administration group was 3 mg / kg, administered by gavage.

[0168] Behavioral testing:

[0169] The mechanical withdrawal threshold (PWT) of mice was measured using von Frey fibers to average the mechanical pain sensitivity of the mice. Baseline pain thresholds were measured in all groups of mice two days before surgery, and animals with baseline pain thresholds between 0.6 and 2 g were selected for model establishment. In the drug-treated groups, PWT was measured before drug administration and at 0.5, 2, and 4 hours after drug administration.

[0170] Methods for determining the paw withdrawal threshold (PWT):

[0171] The 50% withdrawal threshold was calculated using von Frey fibers. The 50% withdrawal threshold is the mechanical force required to elicit a 50% withdrawal response after repeated mechanical stimulation. This experiment used contact stimulation and employed an up-and-down method to determine the 50% withdrawal threshold in the mouse hind paw. Contact forces of 0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1.0, 1.4, and 2.0 g were applied sequentially to stimulate the mid-sole of the hind paw. An acrylic box (45cm × 5cm × 11cm) was placed on a metal mesh. After the mice had acclimatized in the acrylic box for 30 minutes, the soles of the rat hind paws were vertically stimulated with von Frey fibers for <4 seconds. A positive response was indicated by the mouse lifting or licking its paw; otherwise, a negative response was indicated. Begin with a stimulation force of 0.4g. If there is no withdrawal response, proceed to the next stimulation force of 0.6g for the hind toe. If a withdrawal response occurs, proceed to the next stimulation force of 0.16g, and so on. Each time a different response occurs (from withdrawal to no withdrawal or from no withdrawal to withdrawal), repeat the stimulation sequence 4 times, for a total of 6 times, thus completing the 50% withdrawal threshold determination. If the required force exceeds 2.0g or is less than 0.02g, the threshold for that side is directly recorded as 2.0 or 0.02, with a 30-second interval between each stimulation.

[0172] Throughout the experiment, consistent measurement methods were maintained, such as force direction, applied force rate, and fiber bending degree, as well as force stability and force removal rate. Additionally, the criteria for judging the mice's responses were kept as consistent as possible.

[0173] The 50% foot withdrawal threshold is calculated using the following formula: 50% foot withdrawal threshold = 10log(X) + kδ (X is the intensity of the last stimulus; k is the coefficient for different stimulus methods, which can be found in the coefficient table; δ is the average of the intervals between adjacent stimulus intensities)

[0174] CCI mouse model pharmacological effects

[0175] compound Dosage (IG) 2h results normal group / 0.843±0.258 solvent group / 0.248±0.117 1 3mpk 1.059±0.429 2 3mpk 0.950±0.352 3 3mpk 0.510±0.000 6 3mpk 0.286±0.125 8 3mpk 0.640±0.148 9 3mpk 0.430±0.137 10 3mpk 0.695±0.203 11 3mpk 0.350±0.150 12 3mpk 0.342±0.153

[0176] SNI mouse model pharmacological effects

[0177] compound Dosage (IG) 2h results normal group / 1.490 solvent group / 0.196 1 3mpk 0.470±0.106 4 3mpk 0.372±0.152 5 3mpk 0.355±0.181 7 3mpk 0.283±0.151 8 3mpk 0.693±0.201 11 3mpk 0.395±0.277

[0178] Experimental results show that the compounds in this invention have a good therapeutic effect on neuropathic pain.

[0179] The above description, in conjunction with specific embodiments, provides a further detailed explanation of this application and should not be construed as limiting the specific implementation of this application to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of this application, and all such modifications or substitutions should be considered within the scope of protection of this application.

Claims

1. A compound, its tautomers, stereoisomers, hydrates, solvates, salts, or prodrugs, characterized in that, The structural formula of the compound is shown in Figure I: Wherein, ring A is a 3-12 membered cycloalkyl, a 4-10 membered heterocycloalkyl, a 6-10 membered aryl, a 5-10 membered heteroaryl, or an 8-14 membered fused heteroaryl; R x It is a bond or a C1-C6 alkylene group; Ring B is a 3-12 membered cycloalkyl, a 4-10 membered heterocycloalkyl, a 6-10 membered aryl, a 5-10 membered heteroaryl, or an 8-14 membered fused heteroaryl; The ring A is optionally substituted by one or more substituents Ra; when there are multiple Ra, the Ra may be the same or different; The ring B is optionally substituted by one or more substituents Rb; when there are multiple Rb, the Rb may be the same or different; Ra and Rb are each independently selected from: H, halogen, hydroxyl, nitro, cyano, amino, C1-C6 ester group, phosphate group, phosphate ester group, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamine, aryl, heteroaryl; The Ra and Rb are optionally substituted with halogen, hydroxyl, amino, nitro, cyano, C1-C3 alkyl, or -PO(OH)2.

2. The compound, its tautomers, stereoisomers, hydrates, solvates, salts, or prodrugs according to claim 1, characterized in that, Ring A is selected from benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, quinoline, isoquinoline, benzopyran, acridine, indole, purine, and carbazole.

3. The compound, its tautomers, stereoisomers, hydrates, solvates, salts, or prodrugs according to claim 1, characterized in that, Having the structure of formula Ia Among them, X1, X2, X3, X4, and X5 are each independently N or CR. a ; Ring B may be optionally replaced by one or more Rb; The definitions of Ra and Rb are as described in claim 1; Each independent CR a In the middle, R a Same or different.

4. The compound, its tautomers, stereoisomers, hydrates, solvates, salts, or prodrugs according to claim 1, characterized in that, Having Ib structure In this context, ring B can be optionally replaced by one or more Rb; R1 and R2 are each independently represented by Ra; The definitions of rings B, Ra, and Rb are as described in claim 1; Preferably, R1 is a halogen, -NO2, -CN, -C1-C6 haloalkyl, or -COOC1-C6 alkyl. Preferably, R1 is -F, -CF3, -CHF2, -CH2F, -NO2, -CN, or -COOCH3; Preferably, R2 is -OH, -NH2, -OCOCH3, -OCH3, -O-PO(OH)2, or -O-CH2-PO(OH)2.

5. The compound, its tautomers, stereoisomers, hydrates, solvates, salts, or prodrugs according to claim 1, characterized in that, With Ic structure Where Y represents N, O, or S; Ring B may be optionally replaced by one or more Rb; R1 and R2 are each independently represented by Ra; The definitions of rings B, Ra, and Rb are as described in claim 1; Preferably, R1 is a halogen, -NO2, -CN, -C1-C6 haloalkyl, or -COOC1-C6 alkyl. Preferably, R1 is -F, -CF3, -CHF2, -CH2F, -NO2, -CN, or -COOCH3; Preferably, R2 is -OH, -NH2, -SH, -OCOCH3, -OCH3, -O-PO(OH)2, or -O-CH2-PO(OH)2.

6. The compound, its tautomer, stereoisomer, hydrate, solvate, salt, or prodrug according to any one of claims 1-5, characterized in that, The ring B is a 3-12 membered cycloalkyl or a 4-10 membered heterocycloalkyl; Preferably, ring B is a single ring, a double ring, a triple ring, a spiral ring, or a bridge ring; Preferably, ring B is a benzene ring, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, benzocyclobutane, benzocyclopentane, or benzocyclohexane. Preferably, It has the following structure and its isomers:

7. The compound, its tautomers, stereoisomers, hydrates, solvates, salts, or prodrugs according to claim 1, characterized in that, Having Id structure Wherein, R1 and R2 are as defined by Ra in claim 1; Preferably, R1 is a halogen, -NO2, -CN, -C1-C6 haloalkyl, or -COOC1-C6 alkyl. Preferably, R1 is -F, -CF3, -CHF2, -CH2F, -NO2, -CN, or -COOCH3; Preferably, R2 is -OH, -NH2, -SH, -OCOCH3, -OCH3, -O-PO(OH)2, or -O-CH2-PO(OH)2; Preferably, Having structure 8. The compound, its tautomers, stereoisomers, hydrates, solvates, salts, or prodrugs according to claim 1, characterized in that, Selected from the following compounds:

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: the compound of any one of claims 1 to 9, its tautomers, stereoisomers, hydrates, solvates, salts or prodrugs; and a pharmaceutically acceptable carrier.

10. The use of the compound, tautomer, stereoisomer, hydrate, solvate, salt or prodrug of any one of claims 1 to 8; or the use of the pharmaceutical composition of claim 9 in the preparation of a medicament for treating inflammation and related diseases, or pain and related diseases; Preferably, the pain and related diseases are neuropathic pain.

Images