Amidino-containing heterocyclic derivative and application thereof in medicine

Abstract

The invention relates to an amidino-containing heterocyclic derivative and application thereof in medicine, in particular to a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, pharmaceutically acceptable salt or eutectic of the compound, an intermediate and a preparation method of the compound, and application of the compound in preparation of medicine for treating pain. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and use of the compounds in preparing drugs for treating or alleviating pain. Background Art

[0002] Pain originates in nociceptors in the peripheral nervous system. These receptors convert thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are transmitted via afferent nerve fibers to their cell bodies in the dorsal root ganglia (DRG), ultimately reaching higher neural centers, causing pain sensation. The generation and conduction of action potentials in neurons, in turn, rely on voltage-gated sodium channels (VGSCSs) on the cell membrane. When the cell membrane depolarizes, sodium channels activate and open, triggering an influx of sodium ions, further depolarizing the cell membrane and generating action potentials.

[0003] VGSCSs are composed of a pore-forming α-subunit (approximately 260 kDa) and an associated smaller β-subunit (30-40 kDa). The related α-subunit family consists of 10 members, 9 of which (Nav1.1-1.9) are voltage-gated. Nav1.8 is encoded by the gene SCN10A and is preferentially expressed in peripheral sensory neurons. It has been shown to shape action potentials in these neurons. Nav1.8 transcripts and proteins have been found in dorsal root ganglion (DRG) neurons. Nav1.8 has not been detected in non-neuronal tissues (such as heart and skeletal muscle) or in the central nervous system (including the brain and spinal cord).

[0004] The key role of Nav1.8 in pain signaling has been supported by multiple lines of evidence. Based on a series of animal studies and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a novel analgesic therapy. Drugs targeting this target are currently in clinical trials. Summary of the Invention

[0005] The purpose of the present invention is to provide a class of amidine-containing heterocyclic derivatives with inhibitory activity on Nav1.8. This class of compounds selectively inhibits Nav1.8, can effectively reduce side effects, and has good analgesic activity and oral bioavailability.

[0006] The present invention provides a compound represented by general formula (I) or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0007]

[0008] In some embodiments, the compound represented by formula (I) is selected from formula (Ia):

[0009]

[0010] In some embodiments, X is selected from -S-, -S(=O)-, or -S(=O)2;

[0011] In some embodiments, Q is selected from phenyl or 5-6 membered heteroaryl or The phenyl, heteroaryl or Optional 1 to 4 R q replace;

[0012] In some embodiments, Q is selected from the group consisting of q Substituted groups include phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridonyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, or

[0013] In some embodiments, Q is selected from the group consisting of q Substituted groups: Connected with -CO-NH-;

[0014] In some embodiments, Q is selected from the group consisting of q Substituted groups: Its left end is connected to -CO-NH-;

[0015] In some embodiments, B1, B2, B3, B4, and B5 are each independently selected from N or CR B ; B1, B2, B3, B4, B5 are not simultaneously selected from N; In some embodiments, three of B1, B2, B3, B4, B5 are selected from CR B , the other two items are selected from N or CR B In some embodiments, B1, B2, B3, B4, and B5 are all selected from CR B In some embodiments, four of B1, B2, B3, B4, and B5 are selected from CR B , another one is selected from N;

[0016] In some embodiments, Selected from B4 and B5 are each independently selected from N or CR B ; In some embodiments, B4 and B5 are each independently selected from CH or CD; In some embodiments, Selected from

[0017] In some embodiments, Selected from

[0018] Preferred

[0019] In some embodiments, R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0020] In some embodiments, R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, halogen, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0021] In some embodiments, R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl, wherein the methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl is optionally substituted by 1 to 4 R k replace;

[0022] In some embodiments, R 1 、R 2 、R 3 、R 4Each independently selected from H, deuterium, methyl, ethyl, CD3, CH2F, CHF2, CF3;

[0023] In some embodiments, R 1 、R 4 Direct connection to form C 3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 6 R k replace;

[0024] In some embodiments, R 1 、R 4 directly connected to form ring C, ring C is selected from C 3-10 carbocyclic or 4 to 10 membered heterocyclic ring, wherein the ring C is optionally substituted by 1 to 6 R k In some embodiments, ring C is selected from C 3-6 Carbocyclic or 4 to 7 membered heterocyclic ring, wherein the ring C is optionally substituted by 1 to 6 R k replace;

[0025] In some embodiments, Selected from The ring C is selected from the group consisting of 1 to 4 R k Substituted groups such as: cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, oxolanyl, oxalanyl, dioxolanyl;

[0026] In some embodiments, Selected from The ring C is optionally substituted with 1 to 4 R k replace;

[0027] In some embodiments, Selected from

[0028] In some embodiments, R 5 、R 6 、R 7 Each independently selected from H, CN, OH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)R 5a 、-C(=O)OR 5a 、-S(=O)2R 5a 、C 3-6 Carbocycle, 4- to 7-membered heterocycle, -OC 3-7 Carbocycle, the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k replace;

[0029] In some embodiments, R 5 、R 6、R 7 Each independently selected from H, CN, OH, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C(=O)R 5a 、-C(=O)OR 5a 、-S(=O)2R 5a 、C 3-6 Carbocycle, 4- to 7-membered heterocycle, -OC 3-7 Carbocycle, the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k replace;

[0030] In some embodiments, R 5 、R 6 、R 7 Each independently selected from H, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, -O-cyclopropyl, cyclobutyl, -O-cyclobutyl, -C(=O)methyl, -C(=O)O-methyl, -C(=O)ethyl, -C(=O)O-ethyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, -cyclobutyl are optionally substituted by 1 to 3 R k replace;

[0031] In some embodiments, R 6 、R 7 Each independently selected from H;

[0032] In some embodiments, R 5a Each independently selected from H, C 1-6 Alkyl, C 3-6 Carbocyclic ring, the alkyl group, the carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0033] In some embodiments, R 5a Each independently selected from H, C 1-4 Alkyl, C 3-6 Carbocyclic ring, the alkyl group, the carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0034] In some embodiments, R 5a Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted by 1 to 4 R k replace;

[0035] In some embodiments, R q 、R BEach independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-7 Carbon ring, -OC 3-7 Carbocycle, 3- to 7-membered heterocycle, or -P(=O)R q1 R q2 The alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0036] In some embodiments, R q 、R B Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-7 Carbon ring, -OC 3-7 Carbocycle, 3- to 7-membered heterocycle, or -P(=O)R q1 R q2 The alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0037] In some embodiments, R q 、R B Each independently selected from H, deuterium, F, Cl, Br, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, -O-cyclopropyl, cyclobutyl, vinyl, ethynyl, propynyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl is optionally substituted by 1 to 4 R k replace;

[0038] In some embodiments, R q 、R BEach independently selected from H, deuterium, F, Cl, Br, cyano, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3, ethyl, isopropyl, ethynyl, propynyl, methoxy, ethoxy, isopropyloxy, propyloxy, cyclopropyl, -O-cyclopropyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, propyloxy, cyclopropyl is optionally substituted by 1 to 3 R k replace;

[0039] In some embodiments, R q Each is independently selected from H, F, Cl, Br, cyano, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3;

[0040] In some embodiments, R B Each is independently selected from F, Cl, Br, cyano, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3, ethyl, isopropyl, ethynyl, propynyl, methoxy, ethoxy, isopropyloxy, propyloxy, cyclopropyl, -O-cyclopropyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl);

[0041] In some embodiments, R k Each independently selected from deuterium, =O, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbocyclic ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6substituted by an alkoxy substituent;

[0042] In some embodiments, R k Each independently selected from deuterium, =O, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, wherein the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 members selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0043] In some embodiments, R k Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted by 1 to 4 selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0044] In some embodiments, R k Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH2OH, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0045] In some embodiments, R k Each is independently selected from deuterium, F, Cl, Br, CN, OH, -CH2OH, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3.

[0046] As a first embodiment of the present invention, the compound represented by the above general formula (I) or (Ia) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0047] X is selected from -S-, -S(=O)- or -S(=O)2;

[0048] Q is selected from phenyl or 5-6 membered heteroaryl or The phenyl, heteroaryl or Optional 1 to 4 R q replace;

[0049] R 5 、R 6 、R 7 Each independently selected from H, CN, OH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)R 5a 、-C(=O)OR 5a 、-S(=O)2R 5a 、C 3-6 Carbocycle, 4- to 7-membered heterocycle, -OC 3-7 Carbocycle, the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k replace;

[0050] R 5a Each independently selected from H, C 1-6 Alkyl, C 3-6 Carbocyclic ring, the alkyl group, the carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0051] B1, B2, B3, B4, and B5 are each independently selected from N or CR B ; B1, B2, B3, B4, B5 are not simultaneously selected from N;

[0052] R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0053] Alternatively, R1 、R 4 Direct connection to form C 3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 6 R k replace;

[0054] R q 、R B Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-7 Carbon ring, -OC 3-7 Carbocycle, 3- to 7-membered heterocycle, or -P(=O)R q1 R q2 The alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0055] R k Each independently selected from deuterium, =O, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbocyclic ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

[0056] As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0057] R 5 、R 6 、R7 Each independently selected from H, CN, OH, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C(=O)R 5a 、-C(=O)OR 5a 、-S(=O)2R 5a 、C 3-6 Carbocycle, 4- to 7-membered heterocycle, -OC 3-7 Carbocycle, the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k replace;

[0058] R 5a Each independently selected from H, C 1-4 Alkyl, C 3-6 Carbocyclic ring, the alkyl group, the carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0059] R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, halogen, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0060] Alternatively, R 1 、R 4 Direct connection to form C 3-6 Carbocyclic or 4- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0061] R q 、R B Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-7 Carbon ring, -OC 3-7 Carbocycle, 3- to 7-membered heterocycle, or -P(=O)R q1 R q2The alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0062] R k Each independently selected from deuterium, =O, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, wherein the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 members selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0063] The remaining groups are defined the same as in the first embodiment of the present invention.

[0064] As a third embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0065] R 5a Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted by 1 to 4 R k replace;

[0066] R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl, wherein the methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl is optionally substituted by 1 to 4 R k replace;

[0067] or, Selected from The ring C is selected from the group consisting of 1 to 4 R k Substituted groups such as: cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, oxolanyl, oxalanyl, dioxolanyl;

[0068] Q is selected from 1 to 4 R qSubstituted groups include phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridonyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, or

[0069] R q 、R B Each independently selected from H, deuterium, F, Cl, Br, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, -O-cyclopropyl, cyclobutyl, vinyl, ethynyl, propynyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl is optionally substituted by 1 to 4 R k replace;

[0070] R k Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted by 1 to 4 selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0071] The remaining groups are defined the same as in the first or second embodiment of the present invention.

[0072] As a fourth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0073] Q is selected from 1 to 4 R q Substituted groups: Its left end is connected to -CO-NH-;

[0074] R 5 、R 6 、R 7Each independently selected from H, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, -O-cyclopropyl, cyclobutyl, -O-cyclobutyl, -C(=O)methyl, -C(=O)O-methyl, -C(=O)ethyl, -C(=O)O-ethyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, -cyclobutyl are optionally substituted by 1 to 3 R k replace;

[0075] Selected from B4 and B5 are each independently selected from N or CR B ;

[0076] R q 、R B Each independently selected from H, deuterium, F, Cl, Br, cyano, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3, ethyl, isopropyl, ethynyl, propynyl, methoxy, ethoxy, isopropyloxy, propyloxy, cyclopropyl, -O-cyclopropyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, propyloxy, cyclopropyl is optionally substituted by 1 to 3 R k replace;

[0077] R k Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH2OH, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0078] The remaining groups are defined the same as in the first, second or third embodiment of the present invention.

[0079] As a fifth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0080] R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, methyl, ethyl, CD3, CH2F, CHF2, CF3;

[0081] or, Selected from The ring C is optionally substituted with 1 to 4 R k replace;

[0082] Q is selected from 1 to 3 R q Substituted groups: Its left end is connected to -CO-NH-;

[0083] R q Each is independently selected from H, F, Cl, Br, cyano, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3;

[0084] Selected from

[0085] The remaining groups are defined the same as in the first, second, third or fourth embodiment of the present invention.

[0086] As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0087] R 6 、R 7 Each independently selected from H;

[0088] Selected from

[0089] R k Each independently selected from deuterium, F, Cl, Br, CN, OH, -CH2OH, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3;

[0090] Selected from Preferred

[0091] The remaining groups are defined the same as in the first, second, third, fourth or fifth embodiment of the present invention.

[0092] The present invention relates to the compound shown below or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E.

[0093] The present invention relates to a pharmaceutical composition comprising any of the above compounds or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0094] The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0095] The present invention relates to a method for treating or alleviating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of the above-mentioned compound or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably pain.

[0096] In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as the "preparation strength").

[0097] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., treating and / or alleviating pain). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg , 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-40 0mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250- 400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg , 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

[0098] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg , 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0099] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, preferably 1-1500 mg, wherein the disease is preferably the treatment or relief of pain.

[0100] A method for treating or alleviating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1000 mg / day, wherein the daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day,

[0101] In some embodiments, daily doses include but are not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 500 mg / day, 1000 mg / day, 20 ...

[0102] day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day.

[0103] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0104] The present invention relates to the use of any of the above compounds or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating and / or alleviating pain.

[0105] The present invention relates to the use of the above-mentioned pharmaceutical composition in preparing medicines for treating and / or alleviating pain.

[0106] The amount of the compound of the invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof is in each case calculated as the free base.

[0107] Synthesis method 1:

[0108]

[0109] The general formula (Z1) and the general formula (Z2) are reacted through a Wittig reaction to obtain the corresponding general formula (Z3), the general formula (Z3) is subjected to an addition reaction with ethyl mercaptoacetate to obtain the corresponding general formula (Z4), the general formula (Z4) is subjected to intramolecular ester condensation to obtain the corresponding general formula (Z5), the protecting group on the general formula (Z5) obtains the corresponding general formula (Z6), the general formula (Z6) and the general formula (Z6-1) are coupled to obtain the corresponding general formula (Z7), the general formula (Z7) is reduced to obtain the corresponding general formula (Z8), the general formula (Z8) is hydrolyzed under alkaline conditions to obtain the corresponding general formula (Z9), the general formula (Z9) and the general formula (Z10) are condensed to obtain the corresponding general formula (Z11), and the general formula (Z11) and an amine compound are reacted under alkaline conditions to obtain the corresponding general formula (Ia).

[0110] X is halogen, boronic acid or boronic ester.

[0111] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0112] The carbon, hydrogen, oxygen, sulfur, nitrogen, F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds of the present invention are optionally replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0113] "Halogen" refers to F, Cl, Br or I.

[0114] "Halogen-substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halo".

[0115] "Alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups appearing herein have the same definition as this one. Alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0116] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0117] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Cycloalkyl groups as used herein are as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0118] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S. The N and S optionally substituted in the ring of the heterocycloalkyl can be oxidized to various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. The heterocycloalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0119] "Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2- Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene; alkenyl groups appearing herein have the same definition as this one. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0120] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, including but not limited to 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone chain. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- Alkynyl groups include methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, and 4-decynyl. Alkynyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0121] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0122] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, or a 10-15 membered tricyclic ring system, and the carbocyclyl can be attached to the aromatic or non-aromatic ring, which can be optionally a monocyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0123] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The N and S optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, py ... furanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0124] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring is but not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the heteroaryl ring.

[0125] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c Can form a five- or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0126] "1 to X substituents selected from ... substituted" means substituted by 1, 2, 3 ... X substituents selected from ..., where X is selected from any integer between 1 and 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4, or 5 substituents selected from..." For example, "a heterobridged ring is optionally substituted by 1 to 4 substituents selected from D or F" means that the heterobridged ring is optionally substituted by 1, 2, 3, or 4 substituents selected from D or F.

[0127] XY-membered rings (X is an integer, 3≤X<Y, and Y is any integer between 4 and 12) include rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7-membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0128] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0129] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0130] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0131] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0132] "Prescription strength" refers to the weight of the active ingredient per vial, tablet, or other unit of preparation. "Prodrug" refers to a compound of the present invention that can be metabolized in vivo to possess biological activity. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups within a compound of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrug of the present invention is administered to a mammalian subject, it is cleaved to form free amino or carboxyl groups.

[0133] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0134] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0135] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0136] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers. DETAILED DESCRIPTION

[0137] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0138] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0139] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0140] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0141] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0142] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0143] In order to accomplish the purpose of the present invention, the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

[0144] Reagent abbreviations: m-CPBA: meta-chloroperbenzoic acid, CAS No: 937-14-4;

[0145] Example 1: Preparation of Compound 1

[0146]

[0147] Step 1: Preparation of compound 1b

[0148] 1a-1 (30.96 g, 129.95 mmol) was dissolved in tetrahydrofuran (130 mL) under an ice bath. Sodium hydride (5.20 g, 130 mmol) was added portionwise. The mixture was reacted under a nitrogen atmosphere and ice bath for 30 minutes. 1a (11.20 g, 100 mmol) was dissolved in tetrahydrofuran (20 mL) and added dropwise to the reaction system. The temperature was naturally raised to room temperature under a nitrogen atmosphere and the reaction was allowed to proceed for 18 hours. Under an ice bath, 1M hydrochloric acid was slowly added dropwise to the reaction system until the pH reached 7-8. The reaction system was extracted with diethyl ether (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated (at room temperature) to obtain the crude product. The crude product was purified by silica gel column chromatography to afford 1b (14.1 g, 71.88% yield, E / Z configuration mixture).

[0149] Step 2: Preparation of compound 1c

[0150] Under ice-cooling, 1b-1 (8.63 g, 71.88 mmol) was added to a round-bottom flask. Piperidine (1.22 g, 14.38 mmol) was added dropwise, followed by 1b (6.0 g, 71.88 mmol). The mixture was reacted at 50°C under nitrogen for 24 h. The reaction was quenched with 0.1 M hydrochloric acid (100 mL) under ice-cooling, and extracted with diethyl ether (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated (at 25°C) to afford crude 1c, which was then purified by silica gel column chromatography to afford 1c (6.3 g, 27.96% yield).

[0151] LC-MS m / z=317.1[M+H] +

[0152] Step 3: Preparation of compound 1d

[0153] On ice, 1c (6.3 g, 19.92 mmol) was dissolved in diethyl ether (120 mL). Under nitrogen, potassium tert-butoxide (2.91 g, 25.90 mmol) was slowly added dropwise to the system. The mixture was allowed to react on ice for 2 h. Glacial acetic acid (1.56 mL) and water (100 mL) were added to the reaction system to quench the reaction. The mixture was extracted with diethyl ether (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1d.

[0154] Step 4: Preparation of compound 1e

[0155] 1d (4.05 g, 15 mmol) was dissolved in dichloromethane (40 mL) and precooled at -78°C for 15 minutes. N,N-diisopropylethylamine (2.32 g, 17.99 mmol) was added dropwise under a nitrogen atmosphere. Trifluoromethanesulfonic anhydride (4.23 g, 15 mmol) dissolved in dichloromethane (10 mL) was slowly added dropwise to the system. After addition, the reaction was continued at -78°C for 2 hours. Under an ice bath, saturated aqueous sodium bicarbonate (50 mL) was slowly added to the reaction system to quench the reaction. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to afford 1e (5.2 g, 86.16% yield).

[0156] Step 5: Preparation of compound 1f

[0157] 1e (5.2 g, 12.92 mmol) was dissolved in toluene (50 mL), followed by the addition of 1e-1 (2.67 g, 14.21 mmol) and Pd(PPh3)4 (0.75 g, 0.65 mmol). A 2M aqueous solution of potassium phosphate (8.23 g, 38.71 mmol) was added to the system, and the reaction was incubated at 100°C for 6 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (10 mL × 2). The filtrate was separated and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to afford 1f (5.1 g, 99.59% yield).

[0158] LC-MS m / z=397.1[M+H] +

[0159] Step 6: Preparation of compounds 1f-2a and 1f-2b

[0160] 1f (3.7 g, 9.33 mmol) was dissolved in methanol (50 mL), and palladium on carbon (1.99 g, 18.56 mmol) was added. After addition, the mixture was reacted at room temperature under a hydrogen atmosphere, pressurized to 2 MPa, for 24 h. The reaction mixture was filtered and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to afford a mixture of 1g-1a and 1g-1b (1.02 g, 27.44% yield). A mixture of unreacted starting materials 1f-2a and 1f-2b (0.148 g, 4.00% yield) was also recovered.

[0161] Step 7: Preparation of compounds 1g-2a and 1g-2b

[0162] A mixture of 1f-2a and 1f-2b (0.148 g, 0.38 mmol) was dissolved in methanol (10 mL), and palladium on carbon (0.15 g, 1.41 mmol) was added. After addition, the mixture was pressurized to 2.5 MPa under a hydrogen atmosphere and reacted at 90°C for 24 h. The reaction mixture was filtered and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to afford a mixture of 1g-2a and 1g-2b (0.052 g, 34.35% yield).

[0163] Step 8: Preparation of compounds 1h-2a and 1h-2b

[0164] Under a nitrogen atmosphere and an ice bath, a mixture of 1g-2a and 1g-2b (0.052 g, 0.13 mmol) was dissolved in tetrahydrofuran (5 mL) and pre-cooled for 15 minutes. Potassium tert-butoxide (0.048 g, 0.43 mmol) was slowly added dropwise to the system (internal temperature <13°C). After addition, the mixture was allowed to react on ice for 2 hours. Under an ice bath, 1N hydrochloric acid was slowly added dropwise to the system (internal temperature <13°C) until pH = 1. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of 1h-2a and 1h-2b.

[0165] LC-MS m / z=369.0[MH] -

[0166] Step 9: Preparation of compound 1h-2a

[0167] A 3.0 g mixture of compounds 1h-2a and 1h-2b was prepared by SFC and lyophilized to yield compounds 1h-2a (1.28 g, chiral HPLC retention time: 0.760 min) and 1h-2b (1.11 g, chiral HPLC retention time: 0.966 min). Chiral HPLC analysis method: (Instrument: SHIMADZU LC-30AD, Chiralcel IG column. Preparation: The crude product was dissolved in acetonitrile to prepare a sample solution. Mobile phase: CO2 / 0.05% DEA in ethanol. Elution gradient: 5%-40%, elution time: 3 min).

[0168] SFC preparation conditions: Instrument: Waters 150 Prep-SFC A, Preparative column: Chiralcel IG column. Preparation method: Dissolve the crude product in acetonitrile to a sample concentration of 2 mg / mL. Mobile phase: CO2 / ethanol, 10% ethanol; flow rate: 100 mL / min, elution time: 2 min.

[0169] Compound 1h-2a:

[0170] 1 HNMR (400MHz, CDCl3): δ6.91–6.78(m,2H),4.53(d,1H),4.46–4.34(m,1H),4.02(d,3H),2.68–2.54(m,1H),1.93(s,3H),0.88–0.75(m,3H).

[0171] Step 10: Preparation of compound 1i

[0172] Substrate 1h-2a (100 mg, 0.27 mmol) was dissolved in tetrahydrofuran (5 mL), and 2-HATU (153.99 mg, 0.41 mmol) and N,N-diisopropylethylamine (69.79 mg, 0.54 mmol) were added sequentially. Finally, substrate 1i-1 (40.43 mg, 0.30 mmol) was added to the system. After addition, the reaction was allowed to react at room temperature under a nitrogen atmosphere for 18 hours. Water (10 mL) was added to the reaction system to quench the reaction. The reaction was then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to afford 1i (120 mg, 90.98% yield).

[0173] LC-MS m / z=489.0[M+H] +

[0174] Step 11: Preparation of compound 1j

[0175] Substrate 1i (49 mg, 0.1 mmol) was dissolved in dichloromethane (3 mL), and m-chloroperbenzoic acid (20 mg, 0.10 mmol, Purity 85%) was added. After addition, the reaction was allowed to react at room temperature for 2 hours. The reaction system was concentrated to remove the solvent, and saturated sodium bicarbonate (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and backwashed with saturated sodium chloride (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 1j (50 mg, 98.80% yield).

[0176] LC-MS m / z=505.3[M+H] +

[0177] Step 12: Preparation of Compound 1

[0178] Substrate 1j (50 mg, 0.099 mmol) was dissolved in DMSO (3 mL), and an aqueous solution of hydroxylamine (65.40 mg, 0.99 mmol, 50% wt) was added dropwise. The mixture was reacted at 30°C for 18 hours. Water (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and backwashed with saturated sodium chloride (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain compound 1 (40 mg, 75.08% yield).

[0179] LC-MS m / z=538.3[M+H] +

[0180] Example 2: Preparation of Compound 2

[0181]

[0182] Substrate 1i (151.42 mg, 0.31 mmol) was dissolved in DMSO (5 mL), and aqueous hydroxylamine solution (0.20 g, 3.1 mmol, 50% wt) was added. The reaction was allowed to react at room temperature for 18 hours. Water (30 mL) was added to the system, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and backwashed with saturated sodium chloride (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 2 (146 mg, 90.31% yield).

[0183] LC-MS m / z=522.2[M+H] +

[0184] Example 3: Preparation of Compound 3

[0185]

[0186] Step 1: Preparation of intermediate 3a

[0187] Intermediate 1i (100 mg, 0.20 mmol) was dissolved in dichloromethane (3 mL), and m-CPBA (101.51 mg, 0.50 mmol) was slowly added. After addition, the mixture was allowed to react at room temperature for 2 hours. Aqueous sodium bicarbonate (10 mL) was added to the reaction system to quench the reaction. The mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude intermediate 3a (106 mg, 99.48% yield), which was used directly in the next step.

[0188] LC-MS m / z=521.4[M+H] +

[0189] Step 2: Preparation of compound 3

[0190] Intermediate 3a (50 mg, 0.096 mmol) was dissolved in DMSO (1 mL), and an aqueous solution of hydroxylamine (63.42 mg, 0.96 mmol) was slowly added dropwise. The reaction was allowed to react at room temperature for 16 hours. Water (10 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to prep-HPLC and lyophilized to afford compound 3 (7 mg, 13.16% yield).

[0191] LC-MS m / z=554.0[M+H] +

[0192] Example 4: Preparation of Compound 4

[0193]

[0194] Step 1: Preparation of intermediate 4a

[0195] Intermediate 1h-2a (100 mg, 0.27 mmol) was dissolved in dichloromethane (1 mL), and m-CPBA (137.04 mg, 0.68 mmol) was slowly added. After addition, the mixture was allowed to react at room temperature for 2 hours. Water (10 mL) was added to the reaction system to quench the reaction. The mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude intermediate 4a (150 mg), which was used directly in the next reaction.

[0196] Step 2: Preparation of intermediate 4b

[0197] A mixture of substrate 4a (150 mg, 0.37 mmol) was dissolved in tetrahydrofuran (2 mL). DIPEA (112.32 mg, 1.11 mmol) and T3P (941.81 mg, 1.48 mmol) were added sequentially, followed by substrate 4a-1 (66.11 mg, 0.55 mmol). The reaction was allowed to react at room temperature under a nitrogen atmosphere for 18 hours. Aqueous sodium bicarbonate (10 mL) was added to quench the reaction, followed by extraction with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product, which was then purified by column chromatography to afford intermediate 4b (106 mg, 56.47% yield).

[0198] LC-MS m / z=504.4[M+H] +

[0199] Step 3: Preparation of compound 4

[0200] Intermediate 4b (50 mg, 0.099 mmol) was dissolved in DMSO (1 mL), and an aqueous solution of hydroxylamine (65.40 mg, 0.99 mmol) was slowly added dropwise. The reaction was allowed to react at room temperature for 16 hours. Water (5 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to prep-HPLC and lyophilized to afford compound 4 (6 mg, 11.26% yield).

[0201] LC-MS m / z=537.2[M+H] +

[0202] Example 5: Preparation of Compound 5

[0203]

[0204] Step 1: Preparation of intermediate 5a

[0205] Substrate 1h-2a (200 mg, 0.54 mmol) was dissolved in 2 M oxalyl chloride in dichloromethane (2 mL). One drop of DMF was added to initiate the reaction. After addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo and dissolved in dry dichloromethane (2 mL). Substrate 4a-1 (72.90 mg, 0.61 mmol) and TEA (154.82 mg, 1.53 mmol) were then added sequentially. After addition, the mixture was allowed to react at room temperature overnight. The crude product was concentrated in vacuo to afford the product, which was then purified by column chromatography to afford intermediate 5a (85 mg, 35.05% yield).

[0206] LC-MS m / z=472.2[M+H] +

[0207] Step 2: Preparation of intermediate 5b

[0208] Intermediate 5a (85 mg, 0.18 mmol) was dissolved in dichloromethane (1 mL), and m-CPBA (124.25 mg, 0.72 mmol) was slowly added. The reaction was allowed to react at room temperature for 2 hours. Aqueous sodium bicarbonate (10 mL) was added to the reaction system to quench the reaction. The mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude intermediate 5b (93 mg, 99.30% yield), which was used directly in the next reaction.

[0209] LC-MS m / z=520.2[M+H] +

[0210] Step 3: Preparation of compound 5

[0211] Intermediate 5b (93 mg, 0.18 mmol) was dissolved in DMSO (1 mL), and an aqueous solution of hydroxylamine (118.91 mg, 1.80 mmol) was slowly added dropwise. After addition, the mixture was allowed to react at room temperature for 16 hours. Water (10 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to prep-HPLC and lyophilized to afford compound 5 (30 mg, 30.55% yield).

[0212] LC-MS m / z=553.2[M+H] +

[0213] Example 6: Preparation of Compound 6

[0214]

[0215] Step 1: Preparation of intermediate 6a

[0216] Substrate 1h-2a (200 mg, 0.54 mmol) was dissolved in 2 M oxalyl chloride in dichloromethane (2 mL). One drop of DMF was added to initiate the reaction. After addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo and dissolved in dry dichloromethane (2 mL). Substrate 6a-1 (82.69 mg, 0.61 mmol) and TEA (154.82 mg, 1.53 mmol) were then added sequentially. After addition, the mixture was allowed to react at room temperature overnight. The crude product was concentrated in vacuo to afford the product, which was then purified by column chromatography to afford intermediate 6a (132 mg, 52.64% yield).

[0217] LC-MS m / z=488.1[M+H] +

[0218] Step 2: Preparation of compound 6

[0219] Intermediate 6a (50 mg, 0.10 mmol) was dissolved in DMSO (1 mL), and an aqueous solution of hydroxylamine (66.06 mg, 1.00 mmol) was slowly added dropwise. The reaction was allowed to react at room temperature for 16 hours. Water (10 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to prep-HPLC and lyophilized to afford compound 6 (16 mg, 29.97% yield).

[0220] LC-MS m / z=521.7[M+H] +

[0221]

[0222] Biological test example 1:

[0223] Nav1.8 manual patch clamp test

[0224] (1) Cell culture

[0225] The CHO cell line stably expressing human Nav1.8 was cultured in a medium containing 10% fetal bovine serum, 10 μg / mL Blasticidin, 200 μg / mL

[0226] Culture in Ham's F-12 medium containing Hygromycin B and 100μg / mL Zeocin. The cell culture temperature is 37°C and the carbon dioxide concentration is 5%. Remove the old culture medium and rinse once with PBS, then add 1mL of 0.25%-Trypsin-EDTA solution and incubate at 37°C for about 1.5 minutes. When the cells detach from the bottom of the dish, add complete culture medium preheated at 37°C. Gently blow the cell suspension with a pipette to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000rpm for 5 minutes to collect the cells. Inoculate the cells in a 6cm cell culture dish, with 2.5×10 cells inoculated in each cell culture dish. 5 cells (final volume 5 mL) for expansion or maintenance culture. To maintain the electrophysiological activity of the cells, the cell density should not exceed 80%. Before patch clamp testing, the cells were separated with 0.25%-Trypsin-EDTA and 6.5×10 3 Cells were plated onto coverslips and cultured in 24-well plates (final volume 500 μL) and assayed after 18 hours.

[0227] (2) Compound preparation

[0228] The compound was dissolved in dimethyl sulfoxide (DMSO) and prepared into a 30 mM DMSO stock solution.

[0229] NaCl, 3.5mM KCl, 1mM MgCl2·6H2O, 2mM CaCl2·2H2O, 10mM D-Glucose, 10mMHEPES and

[0230] The stock solution was diluted to the test concentration using 1.25 mM NaH2PO4·2H2O, with NaOH adjusting the pH to 7.4. The final DMSO concentration of all test samples was 0.1%.

[0231] (3) Electrophysiological test

[0232] First, a capillary glass tube was drawn into a recording electrode using a microelectrode drawing instrument, and then filled with intracellular solution (50mMCsCl, 10mM

[0233] An electrode containing NaCl, 10mM HEPES, 60mM CsF and 20mM EGTA (pH adjusted to 7.2 with CsOH) is placed in a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is manipulated to immerse the electrode in the extracellular fluid and record the electrode resistance (Rpip). The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to form a GΩ seal. At this time, fast capacitance compensation is performed, and negative pressure is continued to be applied to break the cell membrane, forming a whole-cell recording mode. Finally, slow capacitance compensation is performed and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is given. When the Nav1.8 current recorded in the whole cell is stable, drug administration is started, and each drug concentration acts for about 5 minutes (or until the current stabilizes). The coverslip with cells is placed in a recording bath under an inverted microscope. The blank control external solution and the working solution of the test compound are flowed through the recording bath by gravity perfusion to act on the cells, and liquid exchange is performed using a peristaltic pump. The current detected by the cell in the external solution without the compound is used as the control group. All electrophysiological experiments were performed at room temperature. The inhibition rate of Nav1.8 by the compound was determined by calculating the relative percentage of the peak current generated before and after compound treatment of cells.

[0234] The voltage stimulation protocol for whole-cell patch clamp recording of Nav1.8 sodium current is as follows: after forming a whole-cell seal, the cell voltage is clamped at -120mV. First, the voltage is stepped from -110mV to -30mV in 10mV steps, maintained for 5s, and then a 0mV depolarizing pulse is applied to obtain the half-inactivation voltage (V half ). Then use V halfThe stimulation voltage was maintained for 5 seconds, followed by a return to -120 mV and a 20-ms hold. A depolarizing pulse (TP2) was then applied to 0 mV for 50 ms to measure the sodium current in the semi-inactivated state. Finally, the holding voltage was returned to -120 mV, and data were collected repeatedly every 20 ms to observe the effect of the drug on the peak sodium current. The experimental data were acquired using an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0235] Table 1 IC inhibitory activity of test compounds on Nav1.8 50

[0236] Test compound <![CDATA[IC 50 (nM)]]> Compound 1 <1 Compound 2 <0.1 Compound 3 <1 Compound 5 <1 Compound 6 <0.1

[0237] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good Nav1.8 inhibitory activity.

[0238] Biological test example 2:

[0239] CYP3A4 induction activity test

[0240] 1. Cell seeding

[0241] 1) DPX2 cells were cultured in growth medium containing 10% fetal bovine serum.

[0242] 2) DPX2 cells were cultured in a T-75 culture flask in an incubator at 37° C., 5% CO 2 , and 95% relative humidity, and the cells were digested when the cells covered 80-90% of the bottom of the culture flask.

[0243] 3) Wash the surface of the T-75 cultured cells with 10 mL of PBS, aspirate the PBS, add 3-5 mL of trypsin, and digest at 37°C for 5 minutes or until the cells are digested and suspended. Add an excess of culture medium containing fetal bovine serum to terminate the trypsin digestion.

[0244] 4) Transfer the cell suspension to a conical-bottom centrifuge tube and centrifuge at 150g for 5 minutes at room temperature. Carefully aspirate the supernatant and resuspend the cells in treatment medium to a concentration of 3.2×10 5 cells / mL (incubation time was 24 hours, seeding density was 4.0×10 5 Add 25 μL of cell suspension to each well of a 384-well cell culture plate. Incubate the plate in an incubator at 37°C, 5% CO2, and 95% relative humidity for 24 hours.

[0245] 2. Compound preparation

[0246] 1) Prepare 1000× stock solutions of the test compound, positive control (rifampicin), and negative control (propranolol) in DMSO. The final concentrations of the positive control (rifampicin) are 1 μM and 10 μM, and the final concentration of the negative control (propranolol) is 10 μM. The final concentrations of the test compound are 10, 1, 0.1 μM, or 30, 10, 3, 1, 0.3, and 0.1 μM. The final DMSO concentration is 0.1%.

[0247] 2) Remove the cell culture plate from the incubator and directly add 25 nL of the positive or negative control drug or test compound stock solution using an Echo. Set up three replicates for each concentration. Return the cell plate to the incubator and continue incubation for 48 hours.

[0248] 3) Before beginning experiments with the substrate, inspect cell morphology and monolayer integrity to ensure the monolayer is of acceptable quality for your studies.

[0249] 3. Quantitative detection of PXR activation

[0250] 1) 48 hours after drug treatment, cultures can be used for quantitative detection of PXR activation.

[0251] 2) CellTiter-Fluor TM Equilibrate the Cell Viability Assay Kit and One-Glo Luciferase Reagent to room temperature. Add GF-AFC Substrate (10 μL) to Assay Buffer (10 mL) to create a 2X reagent, which is then diluted with 10 mL of PBS to a 1X reagent. Add ONE-Glo Luciferase Substrate to ONE-Glo Luciferase Assay Buffer.

[0252] 3) Take out the culture plate from the incubator, discard the culture medium, and add 1X CellTiter-Fluor TM The reagent was poured into the sample tank, and 25 μL of the reagent was added to each well of the culture plate using a pipetting workstation, and then placed in the incubator for incubation for 30 minutes.

[0253] 4) Remove the cell culture plate from the incubator, cool it slightly to room temperature, and measure the fluorescence value using an automatic quantitative microplate reader with an excitation wavelength of 400 nm and an emission wavelength of 505 nm.

[0254] 5) Pour ONE-Glo reagent into the sample reservoir, add 25 μL to each well, gently mix the plate, incubate at room temperature for 5 minutes, and measure the luminescence value.

[0255] 4. Data Analysis

[0256] All data were calculated using Microsoft Excel.

[0257] 1) Luciferase activity is expressed as RFU / RLU, where RLU is the average luminescence intensity of three replicates of each compound at each concentration, and RFU is the average fluorescence intensity of three replicates of each compound at each concentration.

[0258] The activation fold of mRNA was calculated using the following formula:

[0259] Fold activation=(RLU test / RFU test) / (RLUvehicle / RFUvehicle)

[0260] 2) The cell viability percentage of the compound was calculated according to the following formula:

[0261] Cell Viability%=(RFUtest / RFUvehicle)×100

[0262] 3) The percentage relative to the positive control drug is calculated according to the following formula:

[0263] Percent of positive control (%) = (Fold activation test / FoldactivationPositive control) × 100

[0264] The experimental results are shown in Table 2:

[0265] Table 2

[0266] Compound Concentration (μM) CYP3A4 enzyme activity multiple CYP3A4 mRNA fold Compound 3 0.1 <2 <2 VX-548 (control 1) 0.1 3.78 5.67

[0267] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no CYP3A4 induction effect or have a weak CYP3A4 induction effect, and have a lower risk of drug-drug interactions.

[0268] Biological test example 3:

[0269] Spinal nerve ligation (SNL)-induced neuropathic pain model in mice

[0270] Male C57BL / 6J mice purchased from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd. were adaptively raised for one week before establishing the model. The specific establishment method is as follows:

[0271] (1) Sterilization of surgical instruments and ligatures;

[0272] (2) Mice were anesthetized with isoflurane and placed in the prone position on the operating table;

[0273] (3) The mouse was skinned near the hip bone and an incision of approximately 2 cm was made along the spine.

[0274] (4) Separate the fascia along the spine, bluntly separate the muscles, and expose the L5 transverse process;

[0275] (5) Use forceps to carefully bite off the L5 transverse process and expose the L5 spinal nerve;

[0276] (6) Carefully separate the L5 nerve with a glass needle and ligate it with a 5-0 ligature.

[0277] (7) Suture the muscles and skin and disinfect with iodine;

[0278] The day after modeling, mice with unsuccessful modeling were eliminated (sign of successful modeling: the hind paw of the mouse curled up). After modeling, the mice were stroked for 3 to 5 minutes every day to ensure that the animals were familiar with the experimenter. Then, the mice were placed on a metal pain test frame to adapt for 40 to 60 minutes. After the third day, after environmental adaptation, the mice were placed on a metal pain test frame to adapt for 40 to 60 minutes. Pre-dose baseline values ​​(Ascending test) were obtained for test animals (0.16, 0.4, 0.6, 1.0, 1.4, and 2.0 g). Each animal was measured twice, with at least 5 minutes between measurements, and the average was calculated. The animals were then grouped according to baseline values ​​(10 animals per group). After grouping, the test compound (3 and 30 mg / kg) or vehicle (0.5% methylcellulose) was administered orally, and the mechanical pain threshold (MPT) of the mice was measured at various time points after administration. Time-MPT curves were plotted and statistically analyzed using GraphPad 8.3.0.

[0279] Conclusion: According to the area under the time-MPT curve analysis, the compounds of the present invention, such as the example compounds, have significant analgesic effects. Specifically, compound 3 has significant analgesic effects at a dose of 30 mg / kg.

Claims

1. A compound or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the group consisting of compounds represented by general formula (I), X is selected from -S-, -S(=O)- or -S(=O)2; Q is selected from phenyl or 5-6 membered heteroaryl or The phenyl, heteroaryl or Optional 1 to 4 R q replace; R 5 、R 6 、R 7 Each independently selected from H, CN, OH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C(=O)R 5a 、-C(=O)OR 5a 、-S(=O)2R 5a 、C 3-6 Carbocycle, 4- to 7-membered heterocycle, -OC 3-7 Carbocycle, the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k replace; R 5a Each independently selected from H, C 1-6 Alkyl, C 3-6 Carbocyclic ring, the alkyl group, the carbocyclic ring is optionally substituted by 1 to 4 R k replace; B1, B2, B3, B4, and B5 are each independently selected from N or CR B ; B1, B2, B3, B4, B5 are not simultaneously selected from N; R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, R 1 、R 4 Direct connection to form C 3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, said carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 6 R k replace; R q 、R B Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-7 Carbon ring, -OC 3-7 Carbocycle, 3- to 7-membered heterocycle, or -P(=O)R q1 R q2 The alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, =O, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbocyclic ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

2. The compound according to claim 1 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, R 5 、R 6 、R 7 Each independently selected from H, CN, OH, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C(=O)R 5a 、-C(=O)OR 5a 、-S(=O)2R 5a 、C 3-6 Carbocycle, 4- to 7-membered heterocycle, -OC 3-7 Carbocycle, the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R k replace; R 5a Each independently selected from H, C 1-4 Alkyl, C 3-6 Carbocyclic ring, the alkyl group, the carbocyclic ring is optionally substituted by 1 to 4 R k replace; R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, halogen, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-6 Carbocyclic ring, 3 to 7 membered heterocyclic ring, said alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, R 1 、R 4 Direct connection to form C 3-6 Carbocyclic or 4- to 7-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R q 、R B Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-7 Carbon ring, -OC 3-7 Carbocycle, 3- to 7-membered heterocycle, or -P(=O)R q1 R q2 The alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, =O, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, wherein the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 members selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent.

3. The compound according to claim 2, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, R 5a Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted by 1 to 4 R k replace; R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl, wherein the methyl, ethyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl is optionally substituted by 1 to 4 R k replace; or, Selected from The ring C is selected from the group consisting of 1 to 4 R k Substituted groups such as: cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, oxolanyl, oxalanyl, dioxolanyl; Q is selected from 1 to 4 R q Substituted groups include phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridonyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, or R q 、R B Each independently selected from H, deuterium, F, Cl, Br, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, -O-cyclopropyl, cyclobutyl, vinyl, ethynyl, propynyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, ethynyl is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted by 1 to 4 selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent.

4. The compound according to claim 3, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: Q is selected from 1 to 4 R q Substituted groups: Its left end is connected to -CO-NH-; R 5 、R 6 、R 7 Each independently selected from H, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, -O-cyclopropyl, cyclobutyl, -O-cyclobutyl, -C(=O)methyl, -C(=O)O-methyl, -C(=O)ethyl, -C(=O)O-ethyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, -cyclobutyl are optionally substituted by 1 to 3 R k replace; Selected from B4 and B5 are each independently selected from N or CR B ; R q 、R B Each independently selected from H, deuterium, F, Cl, Br, cyano, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3, ethyl, isopropyl, ethynyl, propynyl, methoxy, ethoxy, isopropyloxy, propyloxy, cyclopropyl, -O-cyclopropyl, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl), wherein the methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, propyloxy, cyclopropyl is optionally substituted by 1 to 3 R k replace; R k Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH2OH, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

5. The compound according to claim 4, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, methyl, ethyl, CD3, CH2F, CHF2, CF3; or, Selected from The ring C is optionally substituted with 1 to 4 R k replace; Q is selected from 1 to 3 R q Substituted groups: Its left end is connected to -CO-NH-; R q Each is independently selected from H, F, Cl, Br, cyano, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3; Selected from 6. The compound according to claim 5, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: R 6 、R 7 Each independently selected from H; Selected from R k Each independently selected from deuterium, F, Cl, Br, CN, OH, -CH2OH, methyl, ethyl, CD3, OCD3, CH2F, CHF2, CF3; Selected from Preferred 7. The compound according to claim 1 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E:

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition comprises 1 to 1500 mg of the compound according to any one of claims 1 to 7 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

9. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal for the preparation of a drug for treating and / or alleviating pain.

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