Sulfur-containing heterocyclic derivative and use thereof in medicine

Abstract

The present invention relates to a compound of general formula (I), or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, an intermediate thereof, a preparation method therefor, and the use in the preparation of a drug for treating pain.

Description

A sulfur-containing heterocyclic derivative and its application in medicine 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 the cell bodies of neurons located in the dorsal root ganglia (DRG). Ultimately, these impulses are transmitted to 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 an action potential.

[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 sulfur-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, liver microsomal stability, pharmacokinetic properties, 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] In some embodiments, the compound represented by formula (I) is selected from formula (Ia), (Ib), (Ic), and (Id):

[0008] In some embodiments, the compound represented by general formula (I) is selected from general formula (Ic-1) or (Id-1)

[0009] In some embodiments, X is selected from -S(O)- or -S(O)2;

[0010] In some embodiments, Q1 is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 5-10 Carbocyclic ring, 5- to 10-membered heterocyclic ring or The aryl, heteroaryl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 5 R q replace;

[0011] In some embodiments, Q1 is selected from phenyl, benzo 4-6 carbocyclic ring, benzo 4 to 6-membered heterocyclic ring, 5 to 6-membered heteroaryl, 5 to 6-membered heterocyclic ring, 8 to 10-membered heteroaryl ring or The Q1 is optionally replaced by 1 to 4 R q replace;

[0012] In some embodiments, Q1 is selected from The Q1 is optionally replaced by 1 to 4 R q replace;

[0013] In some embodiments, Selected from The Q1 is optionally replaced by 1 to 3 R q replace;

[0014] In some embodiments, R qa Selected from -CH2OH, -CF2CH2OH, NH2, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl);

[0015] In some embodiments, Selected from The Q1 is optionally replaced by 1 to 3 R q Substituted; in some embodiments, R Q1 Selected from H, NR q1 R q2 、-C(=O)NR q1 R q2 、-S(=O)2NR q1 R q2 、OH、=O、-OR q1 、-C(=O)R q1 、-S(=O)2R q1 、-S(=O)(=NR q1 )R q2 or-P(=O)R q1 R q2 ;

[0016] In some embodiments, R Q1 Selected from -C(=O)NR q1 R q2 、-S(=O)2NR q1 R q2 ;

[0017] In some embodiments, R q1 、R q2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 4 to 7 membered heterocyclic ring, said alkyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0018] In some embodiments, R q1 、R q2 Each independently selected from H, C 1-4 Alkyl, C 3-6 Carbocyclic ring, 4 to 7 membered heterocyclic ring, said alkyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0019] In some embodiments, R q1 、R q2 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;

[0020] In some embodiments, alternatively, R q1 、R q2 directly connected to form a 4- to 7-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace;

[0021] In some embodiments, B is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 5-10 Carbocyclic ring, 5 to 10 membered heterocyclic ring, said aryl, heteroaryl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 5 R B replace;

[0022] In some embodiments, B is selected from phenyl, benzo 4-6 Carbocyclic ring, benzo 4 to 6 heterocyclic ring, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl ring, wherein B is optionally substituted by 1 to 4 R B replace;

[0023] In some embodiments, B is selected from or phenyl, said B is optionally replaced by 1 to 4 R B replace;

[0024] In some embodiments, B is selected from

[0025] In some embodiments, B is selected from

[0026] In some embodiments, R 1 、R 2 、R 3 、R 4 Each independently selected from H, 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;

[0027] In some embodiments, R 1 、R 2 、R 3 、R 4 Each independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-6Carbocyclic 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;

[0028] In some embodiments, R 1 、R 2 、R 3 、R 4 Each independently selected from H, F, Cl, Br, cyano, 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;

[0029] In some embodiments, R 1 、R 2 、R 3 、R 4 Each independently selected from H, methyl, ethyl, CH2F, CHF2, CF3;

[0030] 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;

[0031] In some embodiments, R 1 、R 4 Direct connection to form C 3-6 Carbocyclic ring, the carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0032] In some embodiments, R q 、R B Each independently selected from H, 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, 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;

[0033] In some embodiments, Rq 、R B Each independently selected from H, 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, 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;

[0034] In some embodiments, R q 、R B Each independently selected from H, deuterium, =O, F, Cl, Br, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclopropyl-O-, cyclobutyl, vinyl, ethynyl, -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;

[0035] In some embodiments, R q 、R B Each independently selected from H, =O, F, Cl, Br, cyano, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3, ethyl, isopropyl, ethynyl, 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 4 R k replace;

[0036] 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, C2-6 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;

[0037] 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;

[0038] In some embodiments, R k Each independently selected from deuterium, =O, 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;

[0039] In some embodiments, R kEach is independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0040] As a first embodiment of the present invention, the compound represented by the following general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0041] X is selected from -S(O)- or -S(O)2;

[0042] Q1 is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 5-10 Carbocyclic ring, 5- to 10-membered heterocyclic ring or The aryl, heteroaryl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 5 R q replace;

[0043] R Q1 Selected from H, NR q1 R q2 、-C(=O)NR q1 R q2 、-S(=O)2NR q1 R q2 、OH、=O、-OR q1 、-C(=O)R q1 、-S(=O)2R q1 、-S(=O)(=NR q1 )R q2 or-P(=O)R q1 R q2 ;

[0044] R q1 、R q2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 4 to 7 membered heterocyclic ring, said alkyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0045] Alternatively, R q1 、R q2 directly connected to form a 4- to 7-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace;

[0046] B is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 5-10Carbocyclic ring, 5 to 10 membered heterocyclic ring, said aryl, heteroaryl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 5 R B replace;

[0047] R 1 、R 2 、R 3 、R 4 Each independently selected from H, 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;

[0048] 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;

[0049] R q 、R B Each independently selected from H, 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, 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;

[0050] 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 3-6Carbocyclic 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.

[0051] 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,

[0052] R q1 、R q2 Each independently selected from H, C 1-4 Alkyl, C 3-6 Carbocyclic ring, 4 to 7 membered heterocyclic ring, said alkyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0053] Alternatively, R q1 、R q2 directly connected to form a 4- to 7-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace;

[0054] Q1 is selected from phenyl, benzo 4-6 carbocyclic ring, benzo 4 to 6-membered heterocyclic ring, 5 to 6-membered heteroaryl, 5 to 6-membered heterocyclic ring, 8 to 10-membered heteroaryl ring or The Q1 is optionally replaced by 1 to 4 R q replace;

[0055] B is selected from phenyl, benzo 4-6 Carbocyclic ring, benzo 4 to 6 heterocyclic ring, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl ring, wherein B is optionally substituted by 1 to 4 R B replace;

[0056] R 1 、R 2 、R 3 、R 4 Each independently selected from H, 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 Rk replace;

[0057] 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;

[0058] R q 、R B Each independently selected from H, 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, 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;

[0059] 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;

[0060] The remaining groups are defined the same as in the first embodiment of the present invention.

[0061] 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,

[0062] R q1 、R q2Each 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;

[0063] R 1 、R 2 、R 3 、R 4 Each independently selected from H, F, Cl, Br, cyano, 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;

[0064] Alternatively, R 1 、R 4 Direct connection to form C 3-6 Carbocyclic ring, the carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0065] B is selected from or phenyl, said B is optionally replaced by 1 to 4 R B replace;

[0066] R q 、R B Each independently selected from H, deuterium, =O, F, Cl, Br, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclopropyl-O-, cyclobutyl, vinyl, ethynyl, -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;

[0067] R kEach independently selected from deuterium, =O, 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;

[0068] The remaining groups are defined the same as in the first or second embodiment of the present invention.

[0069] 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,

[0070] Q1 is selected from The Q1 is optionally replaced by 1 to 4 R q replace;

[0071] R 1 、R 2 、R 3 、R 4 Each independently selected from H, methyl, ethyl, CH2F, CHF2, CF3;

[0072] R q 、R B Each independently selected from H, =O, F, Cl, Br, cyano, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3, ethyl, isopropyl, ethynyl, 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 4 R k replace;

[0073] R kEach is independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0074] The remaining groups are defined the same as in the first, second or third embodiment of the present invention.

[0075] 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,

[0076] Selected from The Q1 is optionally replaced by 1 to 3 R q replace;

[0077] R qa Selected from -CH2OH, -CF2CH2OH, NH2, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl);

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

[0079] 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,

[0080] Selected from The Q1 is optionally replaced by 1 to 3 R q replace;

[0081] B is selected from Preferred

[0082] The remaining groups are defined the same as in the first, second, third, fourth or fifth embodiment of the present invention.

[0083] 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 below in Table E.

[0084] Table E

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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").

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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 can 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, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 100-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 100-1500 mg / day, 100-10 ... In some embodiments, daily doses include but are not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 200 mg / day, and 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, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, and 1000 mg / day.

[0093] 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.

[0094] 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.

[0095] The present invention relates to the use of the above-mentioned pharmaceutical composition in preparing medicines for treating and / or alleviating pain.

[0096] 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.

[0097] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0098] 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 14 C, 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.

[0099] "Halogen" refers to F, Cl, Br or I.

[0100] "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".

[0101] "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.

[0102] "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.

[0103] "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.

[0104] "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.

[0105] "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.

[0106] "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.

[0107] "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.

[0108] "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.

[0109] "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.

[0110] "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.

[0111] "1 to X substituents selected from..." means substituted by 1, 2, 3, ..., X substituents selected from ..., where X is any integer from 1 to 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "substituted with 1 to 5 substituents selected from..." means substituted with 1, 2, 3, 4, or 5 substituents selected from..." For example, "a heterobridged ring is optionally substituted with 1 to 4 substituents selected from D or F" means that the heterobridged ring is optionally substituted with 1, 2, 3, or 4 substituents selected from D or F.

[0112] 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.

[0113] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid line bond. and the straight dashed line key Indicates the relative configuration of a stereocenter.

[0114] "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.

[0115] "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.

[0116] "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.

[0117] "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.

[0118] "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.

[0119] 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.

[0120] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0121] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0122] "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

[0123] 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.

[0124] 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).

[0125] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0126] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0127] 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.

[0128] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0129] 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.

[0130] T3P: 1-n-propylphosphoric anhydride; DMF: N,N-dimethylformamide; TEA: triethanolamine; DIPEA: N,N-diisopropylethylamine.

[0131] abs1 / abs2 indicates that the chiral center is in a single unknown configuration.

[0132] Example 1: Preparation of Compound 1-3a and Compound 1-3b

[0133] Step 1: Preparation of compound 1b

[0134] 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).

[0135] Step 2: Preparation of compound 1c

[0136] 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).

[0137] LC-MS m / z=317.1[M+H] +

[0138] Step 3: Preparation of compound 1d

[0139] 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.

[0140] Step 4: Preparation of compound 1e

[0141] 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).

[0142] Step 5: Preparation of compound 1f

[0143] 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).

[0144] LC-MS m / z=397.1[M+H] +

[0145] Step 6: Preparation of compounds 1f-2a and 1f-2b

[0146] 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.

[0147] Step 7: Preparation of compounds 1g-2a and 1g-2b

[0148] 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).

[0149] Step 8: Preparation of compounds 1h-2a and 1h-2b

[0150] 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.

[0151] LC-MS m / z=369.0[MH] -

[0152] Step 9: Preparation of compound 1h-2a

[0153] 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 was performed using the following methods: (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).

[0154] SFC preparation conditions: Instrument: Waters 150Prep-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.

[0155] Compound 1h-2a:

[0156] 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).

[0157] Step 10: Preparation of compound 1i-2a

[0158] 1h-2a (1.0 g, 2.7 mmol) was dissolved in tetrahydrofuran (20 mL), and triethylamine (1.64 g, 16.20 mmol) and T3P (3.44 g, 10.79 mmol) were added sequentially. The mixture was stirred at room temperature for 15 minutes, and 1h-2 (0.62 g, 4.07 mmol) was added. The mixture was reacted at room temperature under a nitrogen atmosphere for 18 hours. Saturated aqueous sodium bicarbonate (40 mL) was added, and the mixture was extracted with ethyl acetate (30 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 obtain compound 1i-2a (0.919 g, 67.47% yield).

[0159] Step 11: Preparation of compound 1-2a

[0160] Dissolve 1i-2a (0.919 g, 1.82 mmol) in 7M methanolic ammonia (10 mL) and allow to react at room temperature for 18 h. Concentrate the reaction mixture to obtain a crude product, which is then purified by silica gel column chromatography to afford compound 1-2a (0.87 g, 97.66% yield). The absolute configuration of compound 1-2a was confirmed by Micro-ED.

[0161] Step 12: Preparation of compounds 1-3a and 1-3b

[0162] 1-2a (0.22 g, 0.45 mmol) was dissolved in dichloromethane (5 mL), and m-chloroperbenzoic acid (0.078 g, 0.45 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. Saturated sodium bicarbonate solution (10 mL) was added to the reaction system to quench the reaction. The mixture was extracted with dichloromethane (15 mL × 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 obtain compound 1-3P1 (0.198 g, 87.15% yield) and compound 1-3P2 (0.018 g, 7.92% yield).

[0163] The structure of compound 1-3P1 is one of the above formulas 1-3a and 1-3b; and it is a diastereoisomer of compound 1-3P2, that is, when the structure of compound 1-3P1 is the structure of formula 1-3a, the structure of compound 1-3P2 is the structure of formula 1-3b; when the structure of compound 1-3P1 is the structure of formula 1-3b, the structure of compound 1-3P2 is the structure of formula 1-3a.

[0164] Compound 1-3P1: LCMS m / z=506.0 [M+H] +

[0165] Compound 1-3P2: LCMS m / z=506.1[M+H] +

[0166] Example 2: Preparation of Compounds 6-3 and 6-4

[0167] Step 1: Preparation of compound 6-2a

[0168] 1h-2a (0.037 g, 0.1 mmol) was dissolved in tetrahydrofuran (3 mL), and triethylamine (0.061 g, 0.60 mmol), T3P (0.26 g, 0.40 mmol), and 6-2a-1 (0.023 g, 0.15 mmol) were added sequentially. The mixture was reacted at room temperature under a nitrogen atmosphere for 18 h. Saturated aqueous sodium bicarbonate (10 mL) was added, and the mixture was 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, which was purified by silica gel column chromatography to obtain compound 6-2a (0.036 g, 71.08% yield).

[0169] 1 HNMR (400MHz, CDCl3): δ9.69(s,1H),8.45-8.37(m,1H),8.10-8.04(m,1H),7.15-7.06(m,1H),6.98-6.88(m,2H),6.87-6 .78(m,1H),6.47(s,1H),4.84(d,1H),4.63-4.54(m,1H),4.08(d,3H),2.73-2.63(m,1H),1.93(s,3H),0.93-0.83(m,3H).

[0170] Step 2: Preparation of compounds 6-3 and 6-4

[0171] 6-2a (1.19 g, 2.0 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (0.41 g, 2.0 mmol) was added. The mixture was allowed to react at room temperature for 18 hours. Saturated sodium bicarbonate (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 6-3 (0.570 g, 54.63% yield) and compound 6-4 (0.035 g, 3.25% yield).

[0172] Compound 6-3: LCMS m / z=523.3 [M+H] +

[0173] Compound 6-4: LCMS m / z=539.3 [M+H] +

[0174] Example 3: Preparation of Compound 3

[0175] Step 1: Preparation of compound 3b

[0176] 3a (3.04 g, 20.0 mmol), (Boc)2O (4.8 g, 22 mmol), and 4-dimethylaminopyridine (244 mg, 2.0 mmol) were added to dichloromethane (70 mL) and allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to afford 3b (2.38 g, 33.8% yield).

[0177] LCMS m / z=353.4[M+H] +

[0178] Step 2: Preparation of compound 3c

[0179] 3b (352 mg, 1.0 mmol) was added to dichloromethane (10 mL), placed in an ice bath, and m-chloroperbenzoic acid (516 mg, 3.0 mmol) was added. The reaction was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and purified on a silica gel column to obtain 3c (211 mg, 57.3% yield).

[0180] LCMS m / z=369.2[M+H] +

[0181] Step 3: Preparation of compound 3d

[0182] 3c (134 mg, 0.364 mmol) was added to dichloromethane (2 mL), and a 4N solution of hydrogen chloride in 1,4-dioxane was added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then dichloromethane (2 mL) was added. A 4N solution of hydrogen chloride in 1,4-dioxane was added to the mixture and the reaction continued for 2 hours. The reaction solution was cooled and concentrated under reduced pressure to obtain 3d (71 mg).

[0183] LCMS m / z=169.1[M+H] +

[0184] Step 4: Preparation of compound 3e

[0185] 3d (71 mg) was dissolved in tetrahydrofuran (8 mL), followed by the addition of triethylamine (121.4 mg, 1.2 mmol) and T3P (509 mg of 50% wt in EtOAc, containing 254.5 mg of 1-propylphosphoric anhydride, 0.8 mmol). Finally, substrate 1h-2a (74 mg, 0.2 mmol) was added to the system. After addition, the reaction was allowed to react at room temperature under a nitrogen atmosphere for 20 hours. Aqueous sodium bicarbonate (20 mL) was added to the reaction system to quench the reaction. The reaction was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was then purified on a silica gel column to afford 3e (81 mg, 77.8% yield).

[0186] LCMS m / z=521.1[M+H] +

[0187] Step 5: Preparation of compound 3f

[0188] Substrate 3e (81 mg, 0.155 mmol) was dissolved in 7 M methanolic ammonia solution (10 mL) and allowed to react at room temperature for 2 hours. The reaction system was concentrated to obtain a crude product, which was purified by silica gel column chromatography to afford 3f (42 mg, 53.6% yield).

[0189] LCMS m / z=506.1[M+H] +

[0190] Step 6: Preparation of compound 3

[0191] Substrate 3f (32.0 mg, 0.063 mmol) was dissolved in dichloromethane (3 mL), and m-chloroperbenzoic acid (13.0 mg, 0.063 mmol, Purity 85%) was added to the system. The reaction was continued at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and the residue was dispersed in saturated sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and backwashed with saturated sodium chloride solution (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was prepared by prep-HPLC and lyophilized to obtain compound 3 (10.0 mg, yield 30.29%). Prep-HPLC preparation conditions:

[0192] Instrument: Waters AutoP, preparative column: Sunfire C18 (30 mm × 150 mm). Preparation: Dissolve the crude product in methanol and filter through a 0.45 μm filter to prepare the sample solution. Mobile phase: acetonitrile / water (0.1% TFA); gradient elution, acetonitrile content 10%-60%, flow rate: 30 mL / min, elution time: 25 min.

[0193] The structure of compound 3 is one of the above formulas 3-1 and 3-2.

[0194] LCMS m / z=522.0[M+H] + ;

[0195] 1HNMR (400MHz, DMSO-d6): δ11.67(s,1H),10.52(d,1H),8.46(d,1H),8.32(d,1H),8.25(d,1H),7.77-7.71(m,1H),7 .30-7.15(m,2H),4.73(d,1H),4.38-4.30(m,1H),3.98(d,3H),2.94-2.83(m,1H),1.62(s,3H),1.09-0.98(m,3H).

[0196] Example 4: Preparation of Compound 4

[0197] Step 1: Preparation of compound 4

[0198] Substrate 1-2a (50.0 mg, 0.096 mmol) was dissolved in dichloromethane (1 mL), and m-chloroperbenzoic acid (88.0 mg, 0.43 mmol, Purity 85%) was added to the system. The reaction was continued at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and the residue was dispersed in saturated sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and backwashed with saturated sodium chloride solution (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC and lyophilized to obtain compound 4 (36.0 mg, 69.86% yield).

[0199] Prep-HPLC preparation conditions:

[0200] Instrument: Waters AutoP, preparative column: Sunfire C18 (30 mm × 150 mm). Preparation: Dissolve the crude product in methanol and filter through a 0.45 μm filter to prepare the sample solution. Mobile phase: acetonitrile / water (0.1% TFA); gradient elution, acetonitrile content 10%-60%, flow rate: 30 mL / min, elution time: 25 min.

[0201] LCMS m / z=538.0[M+H] + ;

[0202] 1H NMR(400MHz, CDCl3)δ11.30(s,1H),11.05(s,1H),8.55–8.46(m,2H),8.27(d,1H),7.59(s,1H),6.93–6.82(m,1H), 6.81–6.72(m,1H),4.92(d,1H),4.82–4.74(m,1H),4.09(d,3H),2.86–2.77(m,1H),1.94(s,3H),1.13–1.03(m,3H).

[0203] Example 5: Preparation of Compound 5

[0204] Step 1: Preparation of intermediate 5a

[0205] Substrate 1h-2a (100 mg, 0.27 mmol) was dissolved in 2 M oxalyl chloride in dichloromethane (1 mL), and 0.05 mL of DMF was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, dissolved in dry dichloromethane (1 mL), and substrate 5a-1 (27.0 mg, 0.29 mmol) and TEA (79.0 mg, 0.78 mmol) were added sequentially. The reaction mixture was allowed to react at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to afford 5a (40 mg, 34.83% yield).

[0206] Step 2: Preparation of compound 5

[0207] Substrate 5a (40.0 mg, 0.090 mmol) was dissolved in dichloromethane (1 mL), and m-chloroperbenzoic acid (70.0 mg, 0.40 mmol, Purity 85%) was added to the system. The reaction was continued at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and the residue was dispersed in saturated sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and backwashed with saturated sodium chloride solution (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5 (16.0 mg, 36.12% yield) after prep-HPLC and lyophilization.

[0208] Prep-HPLC preparation conditions:

[0209] Instrument: Waters AutoP, preparative column: Sunfire C18 (30 mm × 150 mm). Preparation: Dissolve the crude product in methanol and filter through a 0.45 μm filter to prepare the sample solution. Mobile phase: acetonitrile / water (0.1% TFA); gradient elution, acetonitrile content 10%-60%, flow rate: 30 mL / min, elution time: 25 min.

[0210] LCMS m / z=495.1[M+H] +

[0211] 1 H NMR (400MHz, CDCl3) δ11.31(s,1H),8.76(s,1H),8.31–8.07(m,2H),7.38(s,1H),7.04–6.82(m,2H ),5.14(d,1H),4.74–4.61(m,1H),4.07(d,3H),2.83–2.70(m,1H),1.90(s,3H),1.08–0.97(m,3H).

[0212] Example 6: Preparation of Compound 6

[0213] Step 1: Compound 6a was synthesized by referring to the synthesis method of Example 5.

[0214] Step 2: Preparation of compound 6

[0215] Substrate 6a (90 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL), and m-chloroperbenzoic acid (330 mg, 1.9 mmol) was added to the system. The reaction was continued at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and the residue was dispersed in saturated sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and backwashed with saturated sodium chloride solution (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC and lyophilized to obtain compound 6 (17.0 mg, 17.67% yield).

[0216] Prep-HPLC preparation conditions:

[0217] Apparatus: Waters 2767 Preparative HPLC; Chromatographic column: XSelect CSH Prep C18 (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: a. Mobile phase A and B composition: Mobile phase A: acetonitrile, Mobile phase B: Water (containing 0.05 M ammonium bicarbonate); b. Gradient elution, mobile phase A content from 30% to 80%; c. Flow rate: 12 ml / min; d. Elution time: 15 min.

[0218] LCMS m / z=495.0[M+H] + ;

[0219] 1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),10.78(s,1H),7.31(d,1H),7.28–7.20(m,1H),6.99–6.92(m,1H),6.57(d,1H) ,6.27–6.22(m,1H),5.11(d,1H),4.53–4.45(m,1H),4.02(d,3H),2.88–2.79(m,1H),1.82(s,3H),0.97–0.89(m,3H).

[0220] Example 7: Preparation of Compound 7

[0221] Step 1: Synthesis of compound 7b

[0222] Substrate 7a (6.0 g, 20.7 mmol) was dissolved in dry 1,4-dioxane (65 mL). Solid sodium thiomethoxide (2.18 g, 31.05 mmol), Pd(dba) (1.9 g, 2.07 mmol), Xant Phos (2395.49 mg, 4.14 mmol), and DIPEA (8025.80 mg, 62.10 mmol) were added sequentially. The mixture was heated to 110°C under a nitrogen atmosphere for 18 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (10 mL x 3). The filtrate was collected and concentrated to obtain the crude product, which was then purified by silica gel column chromatography to afford the desired product 7b (3.4 g, 63.83% yield).

[0223] LCMS m / z=202.0[M-55] +

[0224] 1 H NMR (400MHz, CDCl3): δ7.40–7.34(m,1H),7.08–7.01(m,1H),6.94(t,1H),6.40(s,1H),2.47(s,3H),1.52(s,9H).

[0225] Step 2: Synthesis of compound 7c

[0226] Substrate 7b (3.4 g, 13.21 mmol) was dissolved in methanol (35 mL). Ammonium carbamate (1.96 g, 25.10 mmol) and iodobenzene acetate (6.38 g, 19.82 mmol) were added sequentially under an ice bath. The reaction was continued at room temperature for 18 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography to yield the desired product 7c (2.23 g, 58.5% yield).

[0227] LCMS m / z=289.1[M+1] +

[0228] 1 H NMR (400MHz, CDCl3): δ7.85–7.80(m,1H),7.80–7.72(m,1H),7.16(t,1H),6.74(s,1H),3.27(s,3H),1.52(s,9H).

[0229] SFC preparation conditions:

[0230] Instrumentation: SFC Prep 150AP, Preparative Column: IG (19 mm × 250 mm). Preparation: Dissolve the crude product in methanol and filter through a 0.45 μm filter to prepare the sample solution. Mobile phase: CO2 / methanol (0.05% ammonia), 18% methanol content; Flow rate: 43 mL / min.

[0231] Compound 7c (2.23 g) was prepared by SFC and concentrated to give compound 7c-1 (1.07 g, retention time: 7.43 min) and compound 7c-2 (1.12 g, retention time: 11.9 min).

[0232] Step 3: Preparation of compound 7d-1

[0233] Compound 7c-1 (430 mg, 1.5 mmol) was dissolved in 1,4-dioxane (2.5 mL), and a 4M hydrochloric acid solution in 1,4-dioxane (2.5 mL) was added dropwise. The mixture was heated to 55°C and reacted for 2 hours. The mixture was concentrated under reduced pressure to afford 7d-1 (335 mg). The crude product was used directly in the next reaction without further purification.

[0234] LCMS m / z=189.1[M+H] +

[0235] Step 4: Preparation of compound 7e

[0236] Substrate 1h-2a (1 g, 2.70 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperbenzoic acid (2.33 g, 13.5 mmol) was added. The reaction was continued at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC and lyophilized to afford compound 7e (600 mg, 55.23% yield).

[0237] Step 2: Preparation of compound 7

[0238] Substrate 7e (50 mg, 0.12 mmol) was dissolved in 2 M oxalyl chloride in dichloromethane (1 mL), and 0.05 mL of DMF was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in dry dichloromethane (1 mL), and substrate 7d-1 (33.9 mg, 0.18 mmol) and TEA (60.7 mg, 0.60 mmol) were added sequentially. The reaction mixture was allowed to react at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to afford compound 7 (10.3 mg, 14.48% yield).

[0239] LCMS m / z=573.0[M+H] + ;

[0240] 1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.14–8.09(m,1H),7.86–7.80(m,1H),7.40(t,1H),7.27–7.19(m,1H),7.01–6.94(m,1H) ),5.08(d,1H),4.70(s,1H),4.58–4.50(m,1H),4.03(d,3H),3.16(s,3H),2.90–2.81(m,1H),1.83(s,3H),0.98–0.91(m,3H).

[0241] Example 8: Preparation of Compound 8

[0242] Using 7c-2 as substrate and referring to the synthesis method of Example 7, compound 8 (24 mg, yield 33.73%) was obtained.

[0243] LCMS m / z=573.2[M+H] + ;

[0244] Example 9: Preparation of Compound 9

[0245] Step 1: Compound 9a was synthesized by referring to the synthesis method of Example 5.

[0246] Step 2: Preparation of compound 9

[0247] Substrate 9a (50.0 mg, 0.092 mmol) was dissolved in dichloromethane (1 mL), and m-chloroperbenzoic acid (79.0 mg, 0.46 mmol, Purity 85%) was added to the system. The reaction was allowed to react at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and the residue was dispersed in saturated sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and backwashed with saturated sodium chloride solution (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC and lyophilized to obtain compound 9 (20.0 mg, 37.77% yield).

[0248] Prep-HPLC preparation conditions:

[0249] Instrument: Waters AutoP, preparative column: Sunfire C18 (30 mm × 150 mm). Preparation: Dissolve the crude product in methanol and filter through a 0.45 μm filter to prepare the sample solution. Mobile phase: acetonitrile / water (0.1% TFA); gradient elution, acetonitrile content 10%-60%, flow rate: 30 mL / min, elution time: 25 min.

[0250] LCMS m / z=575.1[M+H] + ;

[0251] 1 H NMR(400MHz, CDCl3)δ9.09(s,1H),8.23–8.16(m,1H),7.84–7.78(m,1H),7.10(t,1H),6.93–6.82(m,2H),5. 56(s,2H),4.87(d,1H),4.73–4.64(m,1H),4.09(d,3H),2.85–2.74(m,1H),1.91(s,3H),1.13–1.04(m,3H).

[0252] Example 10: Preparation of Compound 10

[0253] Step 1: Preparation of compound 10

[0254] Substrate 9a (675.0 mg, 1.24 mmol) was dissolved in dichloromethane (3 mL), and m-chloroperbenzoic acid (251.75 mg, 1.24 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL). Saturated sodium bicarbonate solution (40 mL) was added dropwise under an ice bath, and the mixture was extracted with ethyl acetate (20 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 obtain compound 10 (567.0 mg, 81.59% yield).

[0255] The structure of compound 10 is one of the above formulas 10-1 and 10-2.

[0256] LCMS m / z=559.1[M+H] + ;

[0257] 1 H NMR(400MHz, CDCl3)δ9.73(s,1H),8.25–8.19(m,1H),7.86–7.81(m,1H),7.17(t,1H),7.05–6.99(m,1H),6.97–6.88( m,1H),6.03(s,2H),4.82(d,1H),4.51–4.44(m,1H),4.06(d,3H),2.93–2.84(m,1H),1.71(s,3H),1.18–1.11(m,3H).

[0258] Example 11: Preparation of Compound 11

[0259] Step 1: Preparation of 11a

[0260] On ice, 1h-2a (370.33 mg, 1.0 mmol) was dissolved in DCM (5 mL). Oxalyl chloride (253.86 mg, 2.0 mmol) and DMF (7.31 mg, 0.10 mmol) were added sequentially. The mixture was stirred on ice for 1 hour. After concentration, the residue was dissolved in DCM (2 mL) to obtain a stock solution. Separately, 7d-1 (282.33 mg, 1.5 mmol) was dissolved in DCM (3 mL), and triethylamine (505.95 mg, 5 mmol) was added dropwise. After addition, the mixture was allowed to react at room temperature under a nitrogen atmosphere for 18 hours. Aqueous sodium bicarbonate (20 mL) was added to the reaction system, and the mixture was 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, which was purified by silica gel column chromatography to obtain compound 11a (235.0 mg, 43.48% yield).

[0261] LCMS m / z=541.2[M+H] + ;

[0262] The absolute configuration of compound 11a was determined by MicroED.

[0263] Step 2: Preparation of compound 11

[0264] Compound 11 (70.0 mg, yield 62.89%) was synthesized from substrate 11a (108.11 mg, 0.2 mmol) according to the synthesis method of Example 10.

[0265] The structure of compound 11 is one of the above formulas 11-1 and 11-2.

[0266] LCMS m / z=557.0[M+H] + ;

[0267] 1 H NMR(400MHz,DMSO-d6)δ11.36(s,1H),8.19–8.14(m,1H),7.92–7.85(m,1H),7.42(t,1H),7.32–7.20(m,2H),4.88(d ,1H),4.72(s,1H),4.39–4.32(m,1H),4.00(d,3H),3.18(s,3H),2.94–2.85(m,1H),1.65(s,3H),1.11–1.02(m,3H).

[0268] Example 12: Preparation of Compound 12-1 and Compound 12-2

[0269] Step 1: Preparation of 12b

[0270] Substrate 12a (1 g, 2.70 mmol) was dissolved in dichloromethane (30 mL), and m-chloroperbenzoic acid (2.33 g, 13.5 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL). Saturated sodium bicarbonate solution (40 mL) was added dropwise under ice-cooling, and the mixture was extracted with ethyl acetate (20 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 obtain compound 12b (610.0 mg, 56.15% yield).

[0271] Step 2: Preparation of 12c

[0272] On ice, 12b (50 mg, 0.12 mmol) was dissolved in DCM (5 mL). Oxalyl chloride (304.63 mg, 2.4 mmol) and DMF (0.05 mL) were added sequentially. The mixture was stirred on ice for 1 hour. After concentration, the residue was dissolved in DCM (2 mL) to obtain a stock solution. Separately, 12b-1 (34.96 mg, 0.18 mmol) was dissolved in DCM (3 mL). Triethylamine (60.71 mg, 0.60 mmol) was added and the stock solution was added dropwise to the mixture. After addition, the mixture was allowed to react at room temperature under a nitrogen atmosphere for 18 hours. Aqueous sodium bicarbonate (20 mL) was added to the reaction system, and the mixture was 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, which was purified by silica gel column chromatography to obtain compound 12c (40.0 mg, 55.63% yield).

[0273] Step 3: Preparation of Compound 12-1 and Compound 12-2

[0274] Dissolve 12c (40.0 mg, 0.069 mmol) in dichloromethane (3 mL) and add trifluoroacetic acid (0.6 mL) dropwise. The mixture is allowed to react at room temperature for 2 h. The reaction mixture is concentrated to obtain a crude product, which is then purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to afford a mixture of compound 12-1 and compound 12-2 (15.0 mg, 40.29% yield).

[0275] LCMS m / z=539.2[M+H] + ;

[0276] Example 13: Preparation of Compound 13-1 and Compound 13-2

[0277] Step 1: Preparation of 13b

[0278] Substrate 13a (500 mg, 1.08 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (186.38 mg, 1.08 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL). Saturated sodium bicarbonate solution (40 mL) was added dropwise under an ice bath, and the mixture was extracted with ethyl acetate (20 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 obtain compound 13b (210.0 mg, 40.60% yield).

[0279] Step 2: Preparation of 13c

[0280] On ice, 13b (50 mg, 0.13 mmol) was dissolved in DCM (5 mL). Oxalyl chloride (330.02 mg, 2.6 mmol) and DMF (0.05 mL) were added sequentially. The mixture was stirred on ice for 1 hour. After concentration, the residue was dissolved in DCM (2 mL) to obtain a stock solution. Separately, 12b-1 (37.87 mg, 0.20 mmol) was dissolved in DCM (3 mL). Triethylamine (65.77 mg, 0.65 mmol) was added and the stock solution was added dropwise to the mixture. After addition, the mixture was allowed to react at room temperature under nitrogen for 18 hours. Aqueous sodium bicarbonate (20 mL) was added to the reaction system, and the mixture was 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, which was purified by silica gel column chromatography to obtain compound 13c (11.0 mg, 15.11% yield).

[0281] Step 3: Preparation of Compound 13-1 and Compound 13-2

[0282] 13c (11.0 mg, 0.020 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.2 mL) was added dropwise. The reaction was allowed to react at room temperature for 2 h. The reaction system was concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to afford a mixture of compound 13-1 and compound 13-2 (3.0 mg, 29.36% yield).

[0283] LCMS m / z=523.2[M+H] + ;

[0284] Example 14: Preparation of Compound 14

[0285] Step 1: Preparation of compound 14

[0286] Substrate 14a (100 mg, 0.22 mmol) (synthesized according to WO2024 / 146632A1, CAS: 3049923-80-7) was dissolved in dichloromethane (5 mL), and m-chloroperbenzoic acid (37.97 mg, 0.22 mmol) was added. The reaction was allowed to react at room temperature for 18 hours. The reaction system was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL). Saturated sodium bicarbonate solution (40 mL) was added dropwise under ice-cooling, and the mixture was extracted with ethyl acetate (20 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 then subjected to prep-HPLC and lyophilized to obtain compound 14 (57.26 mg, 55.35% yield).

[0287] Prep-HPLC preparation conditions:

[0288] Instrumentation: Waters 2767 preparative liquid chromatography column: SUNFIRE@Prep C18 (19 mm × 250 mm). Preparation: Dissolve the crude product in DMF and filter through a 0.45 μm filter to prepare the sample solution. Mobile phase: acetonitrile / water (containing 50 mM ammonium bicarbonate); gradient elution, 30%-60% acetonitrile, flow rate: 15 mL / min, elution time: 14 min.

[0289] LCMS m / z=479.1[M+H] + ;

[0290] Example 15: Preparation of Compound 15

[0291] Step 1: Preparation of compound 15

[0292] Substrate 15a (100 mg, 0.19 mmol) (synthesized according to WO2024 / 146632A1, CAS: 3049925-11-0) was dissolved in dichloromethane (5 mL), and m-chloroperbenzoic acid (32.79 mg, 0.19 mmol) was added. The reaction was allowed to react at room temperature for 18 hours. The reaction system was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL). Saturated sodium bicarbonate solution (40 mL) was added dropwise under ice-cooling, and the mixture was extracted with ethyl acetate (20 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 then subjected to prep-HPLC and lyophilized to obtain compound 15 (33.27 mg, 32.31% yield).

[0293] Prep-HPLC preparation conditions:

[0294] Instrumentation: Waters 2767 preparative liquid chromatography column: SUNFIRE@Prep C18 (19 mm × 250 mm). Preparation: Dissolve the crude product in DMF and filter through a 0.45 μm filter to prepare the sample solution. Mobile phase: acetonitrile / water (containing 50 mM ammonium bicarbonate); gradient elution: 30%-65% acetonitrile, flow rate: 15 mL / min, elution time: 15 min.

[0295] LCMS m / z=556.9[M+H] + ;

[0296] Biological Test Example 1

[0297] Nav1.8 manual patch clamp test

[0298] Cell culture

[0299] The CHO cell line stably expressing human Nav1.8 was cultured in Ham's F-12 medium containing 10% fetal bovine serum, 10 μg / mL Blasticidin, 200 μg / mL Hygromycin B, and 100 μg / mL Zeocin. The cell culture temperature was 37°C and the carbon dioxide concentration was 5%. The old culture medium was removed and rinsed once with PBS, then 1 mL of 0.25%-Trypsin-EDTA solution was added and incubated at 37°C for about 1.5 minutes. When the cells detached from the bottom of the dish, complete culture medium preheated to 37°C was added. The cell suspension was gently pipetted with a pipette to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 minutes to collect the cells. The cells were inoculated in 6 cm cell culture dishes, with 2.5×10 cells 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.

[0300] Compound formulation

[0301] Compounds were dissolved in dimethyl sulfoxide (DMSO) and prepared into 30 mM DMSO stock solutions. The stock solutions were diluted to the assay concentrations using extracellular fluid (140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM HEPES, and 1.25 mM NaH2PO4·2H2O, pH adjusted to 7.4 with NaOH). The final DMSO concentration for all assay samples was 0.1%.

[0302] Electrophysiological testing

[0303] First, a recording electrode is drawn from a capillary glass tube using a microelectrode puller. The electrode, filled with intracellular solution (50mM CsCl, 10mM NaCl, 10mM HEPES, 60mM CsF, and 20mM EGTA, with CsOH adjusted to pH 7.2), is then placed in a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in the extracellular solution 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. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is applied. Drug administration begins after the Nav1.8 current recorded in the whole cell stabilizes, and each drug concentration is applied for approximately 5 minutes (or until the current stabilizes). A coverslip containing cells was placed in a recording bath under an inverted microscope. A blank control solution and a working solution of the test compound were gravity-flown through the recording bath, exposing the cells to the current. A peristaltic pump was used for fluid exchange. The current measured in the absence of compound in the recording bath served as the control. All electrophysiological experiments were performed at room temperature. The percentage of peak current produced before and after compound treatment was calculated to determine the inhibitory effect of Nav1.8 on the cells.

[0304] 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 half The 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.

[0305] Table 1 IC inhibitory activity of test compounds on Nav1.8 50

[0306] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good Nav1.8 inhibitory activity, specifically compound 4IC 50 =0.016nM, compound 9IC 50 =0.096nM.

[0307] Biological test example 2: rat pharmacokinetic test

[0308] Test animals: Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats per compound.

[0309] Experimental design: On the day of the experiment, 24 SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0310] Table 2. Dosing Information

[0311] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC

[0312] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose)

[0313] Before and after drug administration, 0.10 mL of blood was collected via the orbital cavity under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0314] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral performance in rats.

[0315] Biological test example 3: mouse pharmacokinetic test

[0316] Test animals: Male C57 mice, 22-25 g, 6 mice per compound.

[0317] Experimental Design: On the day of the experiment, C57 mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0318] Table 3. Dosing Information

[0319] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC

[0320] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose)

[0321] Before and after drug administration, 0.06 mL of blood was collected via the orbital cavity under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 7, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0322] Table 3-1 Pharmacokinetic results of test compounds in mice

[0323] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral efficacy in mice.

[0324] Biological Test Example 4: Beagle Dog Pharmacokinetic Test

[0325] Experimental animals: Male beagle dogs, weighing about 8-11 kg, 6 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.

[0326] Experimental Methods: On the day of the experiment, 12 beagle dogs were randomly divided into groups based on body weight. They were fasted (but not water) for 12-14 hours prior to dosing and fed 4 hours after dosing. Dosing was performed according to Table 4.

[0327] Table 4. Dosing Information

[0328] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC

[0329] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose solution;)

[0330] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. For both the intravenous and oral administration groups, blood was collected at the following time points: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0331] Table 4-1 Pharmacokinetic results of test compounds in dogs

[0332] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral performance in dogs.

[0333] Biological Test Example 5: Monkey Pharmacokinetic Test

[0334] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 6 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0335] Experimental method: On the day of the experiment, 6 monkeys were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0336] Table 5. Dosing Information

[0337] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC (containing 0.5% Tween 80);

[0338] *Dosage is based on the free base.

[0339] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected from both the intravenous and oral administration groups at the following time points: 0, 5 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0340] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral performance in monkeys.

[0341] Biological Test Example 6: CYP450 Enzyme Inhibition Test

[0342] The purpose of this study was to evaluate the effects of test substances on the activities of five isoenzymes of cytochrome P450 (CYP) in human liver microsomes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) using an in vitro test system. Specific probe substrates for the CYP450 isoenzymes were incubated with human liver microsomes and varying concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and the IC values ​​were calculated. 50 The inhibitory potential of the test substance on each CYP enzyme isoform was evaluated.

[0343] Conclusion: The compounds of the present invention, such as the compounds in the examples, have weak CYP inhibition.

[0344] Biological Test Example 7: Caco2 Permeability Test

[0345] The experiment used Caco-2 cell monolayers in 96-well Transwell plates, incubated in triplicate. Transport buffer (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing the compound of the invention (2 μM) or the control compounds digoxin (10 μM), nadolol (2 μM), and metoprolol (2 μM) was added to the apical or basolateral wells of the cell monolayer. Transport buffer containing DMSO was added to the corresponding receiving wells. After incubation at 37 ± 1°C for 2 hours, the cell plate was removed and appropriate samples were taken from the apical and basolateral wells to a new 96-well plate. Proteins were then precipitated by adding acetonitrile containing an internal standard. Samples were analyzed using LC-MS / MS to determine the concentrations of the compound of the invention and the control compound. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to basolateral side of the cell monolayer and from the basolateral to apical side, thereby calculating the efflux rate. The integrity of the cell monolayer after 2 hours of incubation was assessed by leakage of Lucifer Yellow.

[0346] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good permeability.

[0347] Biological Test Example 8: Spinal Nerve Ligation (SNL)-Induced Neuropathic Pain Model in Mice

[0348] 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:

[0349] (1) Sterilization of surgical instruments and ligatures;

[0350] (2) Mice were anesthetized with isoflurane and placed in the prone position on the operating table;

[0351] (3) The mouse was skinned near the hip bone and an incision of approximately 2 cm was made along the spine.

[0352] (4) Separate the fascia along the spine, bluntly separate the muscles, and expose the L5 transverse process;

[0353] (5) Use forceps to carefully bite off the L5 transverse process and expose the L5 spinal nerve;

[0354] (6) Carefully separate the L5 nerve with a glass needle and ligate it with a 5-0 ligature.

[0355] (7) Suture the muscles and skin and disinfect with iodine;

[0356] 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.

[0357] 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.

[0358] Biological Test Example 9: Monkey Liver Microsome Stability Test

[0359] At 37°C, 1 μM of the test compound was incubated with monkey liver microsomes (0.5 mg / mL) supplemented with an NADPH regeneration system for 5, 15, 30, 45, and 60 minutes. The concentration of the test compound in the resulting samples was determined by LC-MS / MS. The half-life (T) of the compound in the monkey liver microsome solution was obtained by calculating the remaining percentage of the compound at each time point. 1 / 2 ) and intrinsic clearance (CL int(mic) ).

[0360] Biological test results:

[0361] Conclusion: The compounds of the present invention have good stability in monkey liver microsomes. The clearance rate of compound 4 in monkey liver microsomes is significantly slowed down and the half-life is significantly prolonged compared with the control compound. 1 / 2 The ratio is about 6.

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(O)- or -S(O)2-; Q1 is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 5-10 Carbocyclic ring, 5- to 10-membered heterocyclic ring or The aryl, heteroaryl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 5 R q replace; R Q1 selected from H, NR q1 R q2 , -C(=O)NR q1 R q2 , -S(=O)2NR q1 R q2 , OH, =O, -OR q1 , -C(=O)R q1 , -S(=O)2R q1 , -S(=O)(=NR q1 )R q2 or-P(=O)R q1 R q2 ; R q1 、R q2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 4 to 7 membered heterocyclic ring, said alkyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, R q1 、R q2 directly connected to form a 4- to 7-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace; B is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 5-10 Carbocyclic ring, 5 to 10 membered heterocyclic ring, said aryl, heteroaryl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 5 R B replace; R 1 、R 2 、R 3 、R 4 Each independently selected from H, 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, =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, 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 q1 、R q2 Each independently selected from H, C 1-4 Alkyl, C 3-6 Carbocyclic ring, 4 to 7 membered heterocyclic ring, said alkyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, R q1 、R q2 directly connected to form a 4- to 7-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace; Q1 is selected from phenyl, benzo 4-6 carbocyclic ring, benzo 4 to 6-membered heterocyclic ring, 5 to 6-membered heteroaryl, 5 to 6-membered heterocyclic ring, 8 to 10-membered heteroaryl ring or The Q1 is optionally replaced by 1 to 4 R q replace; B is selected from phenyl, benzo 4-6 Carbocyclic ring, benzo 4 to 6 heterocyclic ring, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl ring, wherein B is optionally substituted by 1 to 4 R B replace; R 1 、R 2 、R 3 、R 4 Each independently selected from H, 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, =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, 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 q1 、R q2 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, F, Cl, Br, cyano, 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; Alternatively, R 1 、R 4 Direct connection to form C 3-6 Carbocyclic ring, the carbocyclic ring is optionally substituted by 1 to 4 R k replace; B is selected from or phenyl, said B is optionally replaced by 1 to 4 R B replace; R q 、R B Each independently selected from H, deuterium, =O, F, Cl, Br, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclopropyl-O-, cyclobutyl, vinyl, ethynyl, -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, =O, 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: Q1 is selected from The Q1 is optionally replaced by 1 to 4 R q replace; R 1 、R 2 、R 3 、R 4 Each independently selected from H, methyl, ethyl, CH2F, CHF2, CF3; R q 、R B Each independently selected from H, =O, F, Cl, Br, cyano, CH2F, CHF2, CF3, -OCH2F, -OCHF2, -OCF3, -OCD3, methyl, -S-methyl, -S-CF3, ethyl, isopropyl, ethynyl, 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 4 R k replace; R k Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH2OH, methyl, ethyl, 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: Selected from The Q1 is optionally replaced by 1 to 3 R q replace; R qa Selected from -CH2OH, -CF2CH2OH, NH2, -P(=O)(CH3)2, -P(=O)(CH2CH3)2, -P(=O)(CH3)(cyclopropyl).

6. The compound according to claim 5, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: Selected from The Q1 is optionally replaced by 1 to 3 R q replace; B is selected from Preferred 7. The compound according to claim 1, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, 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, or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating and / or alleviating pain.

10. A method for treating or alleviating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount 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, or the pharmaceutical composition according to claim 8, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably pain.

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