WO2024188367A1 - Tetrahydrofuran derivative and use thereof in medicine - Google Patents

Abstract

A compound as represented by general formula (I) or a stereoisomer, crystal form, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and an intermediate thereof and a preparation method therefor, and the use thereof in the preparation of a drug for treating pain.

Description

A tetrahydrofuran derivative and its application in medicine Technical Field

The present invention relates to a compound described by general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and intermediates and preparation methods thereof, as well as use of the compound in preparing drugs for treating or relieving pain.

Background Art

Pain originates from nociceptors in the peripheral nervous system. It can convert the thermal, mechanical or chemical stimulation it senses into nerve impulses (action potentials) and transmit them to the cell body located in the dorsal root ganglia (DRG) via afferent nerve fibers, and finally to higher nerve centers, causing pain. The generation and conduction of action potentials in neurons depends on voltage-gated sodium channels (VGSCS) on the cell membrane. When the cell membrane depolarizes, the sodium channels are activated and open, causing sodium ions to flow in, further depolarizing the cell membrane and leading to the generation of action potentials.

VGSCSs consist of a pore-forming α-subunit (approximately 260 kDa) and an associated β-subunit of smaller size (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 the central nervous system (including the brain and spinal cord).

The key role of Nav1.8 in pain signaling has been supported by multiple lines of evidence. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new type of analgesic therapy. Currently, drugs targeting this target have entered clinical research.

Summary of the invention

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

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.

In some embodiments,

When X1 _is O, ^RQ1 is selected from -C(= ^S ) ^NRq1Rq2 , -C(= ^{NRq3 ) NRq1Rq2} ;

^{When X} ₁ ^{is S or NR} _​ ^{​ ​} S(＝O)NR ^q1 R ^q2 , -C(＝NR ^q3 )NR ^q1 R ^q2 ,OH,＝O,-OR ^q1 ,-C(＝O)R ^q1 ,-S(＝O) ₂ R ^q1 , -S(=O)(=NR ^q1 )R ^q2 ;

In some embodiments, R ^x and R ^q3 are each independently selected from H, CN, C _1-6 alkyl, C _3-10 carbocycle, 4 to 10 membered heterocycle, -OR ^q1 , -SR ^q1 , -C(═O)NR ^q1 R ^q2 , -C(═S)NR ^q1 R ^q2 , -S(═O) ₂ NR ^q1 R ^q2 , -S(═O) ₂ R ^q1 , -S(═O)NR ^q1 R ^q2 , wherein the alkyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^k ; in some embodiments, R ^x and R ^q3 are each independently selected from H, CN, C _1-5 alkyl, C _3-6 carbocycle, 4 to 7 membered heterocycle, -OR ^q1 , -SR ^q1 , -C(═O)NR ^q1 R ^q2 , -C(═S)NR ^q1 R ^q2 , -S(=O) ₂ NR ^q1 R ^q2 , -S(=O) ₂ R ^q1 , -S(=O)NR ^q1 R ^q2 , wherein the alkyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R ^k ;

In some embodiments, R ^x , R ^q3 are each independently selected from H, CN, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, -OR ^q1 , -SR ^q1 , -C(═O)NR ^q1 R ^q2 , -C(═S)NR ^q1 R ^q2 , -S(═O) ₂ NR ^q1 R ^q2 , -S(═O) ₂ R ^q1 , -S(═O)NR ^q1 R ^q2 , wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted with 1 to 4 R ^k ;

In some embodiments, when _Xi is ^NR , ^NR is selected from NH, N-CN, N-methyl, N-ethyl, N-propyl, N-cyclopropyl, NO-methyl, NO-ethyl, NO-propyl, NO-cyclopropyl, NS-methyl, NS-ethyl, NS-propyl, NS-cyclopropyl, NC(=O)N(methyl) ₂ , NC(=O)N(ethyl) ₂ , NC(=S)N(methyl) ₂ , NC(=S)N(ethyl) ₂ , NC(=O)NH-methyl, NC(=O)NH-ethyl, NC(=O)NH-methyl, -S(=O) _2N (methyl) ₂ , -S(=O) _2N (ethyl) ₂ , S(=O)N(methyl) ₂ , S(=O)N(ethyl) ₂ , -S(=O) _2methyl , -S(=O) _2ethyl ;

In some embodiments, Q ₁ 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 Q ₁ is optionally substituted with 1 to 5 R ^q ;

In some embodiments, Q ₁ is selected from phenyl, benzo C _4-6 carbocycle, benzo 4 to 6 heterocycle, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl or The Q ₁ is optionally substituted with 1 to 4 R ^q ;

In some embodiments, _Q is selected from The Q ₁ is optionally substituted with 1 to 5 R ^q ;

In some embodiments, R ^Q1 is selected from H, -C(＝O)NR ^q1 R ^q2 , -S(＝O) ₂ NR ^q1 R ^q2 , -S(＝O) NR ^q1 R ^q2 , OH, ＝O, -OR ^q1 , -C(＝O)R ^q1 , -S(＝O) ₂ R ^q1 , -S(＝O)(＝NR ^q1 )R ^q2 , -C(＝NR ^q3 )NR ^q1 R ^q2 ;

In some embodiments, when X ₁ is O, Selected from The Q ₁ is optionally substituted with 1 to 3 R ^q ;

When _X1 is S or ^NRx , Selected from The Q ₁ is optionally substituted by 1 to 3 R ^q ; in some embodiments, R ^q1 and R ^q2 are each independently selected from H, C _1-6 alkyl, C _3-6 carbocycle, 4 to 7 membered heterocycle, and the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R ^k ;

Alternatively, R ^q1 and R ^q2 are directly linked to form a 4- to 7-membered heterocyclic ring, which is optionally substituted with 1 to 4 R ^k ;

In some embodiments, R ^q1 and R ^q2 are each independently selected from H, C _1-4 alkyl, C _3-6 carbocycle, 4 to 7 membered heterocycle, and the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R ^k ;

Alternatively, R ^q1 and R ^q2 are directly linked to form a 4- to 7-membered heterocyclic ring, which is optionally substituted with 1 to 4 R ^k ;

In some embodiments, R ^q1 and R ^q2 are 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 with 1 to 4 R ^k ;

In some embodiments, B is selected from C _6-10 aryl, 5 to 10 membered heteroaryl, C _5-10 carbocycle, 5 to 10 membered heterocycle, said aryl, heteroaryl, carbocycle or heterocycle optionally substituted with 1 to 4 R ^B ;

In some embodiments, B is selected from phenyl, benzoC _4-6 carbocycle, benzo4 to 6 heterocycle, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, said B is optionally substituted with 1 to 4 R ^B ;

In some embodiments, B is selected from or phenyl, said B is optionally substituted with 1 to 5 R ^B ;

In some embodiments, B is selected from

In some embodiments, R ¹ and R ² are 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 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^k , provided that R ¹ and R ² are not H at the same time;

In some embodiments, R ¹ and R ² are 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 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^k , provided that R ¹ and R ² are not H at the same time;

In some embodiments, R ¹ and R ² are 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 are optionally substituted with 1 to 4 R ^k , provided that R ¹ and R ² are not H at the same time;

In some embodiments, R ¹ and R ² are each independently selected from H, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ , Provided that R ¹ and R ² are not H at the same time;

In some embodiments, R ³ , R ⁴ , R ^q , ^RB are each independently selected from H, deuterium, halogen, CN, OH, NH ₂ , 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 carbocycle, -OC _3-7 carbocycle, 3 to 7 membered heterocycle, and the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^k ;

In some embodiments, R ³ , R ⁴ , R ^q , ^RB are each independently selected from H, deuterium, halogen, CN, OH, NH ₂ , 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 carbocycle, -OC _3-7 carbocycle, 3 to 7 membered heterocycle, and the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^k ;

In some embodiments, R ³ , R ⁴ , R ^q , and ^RB are each independently selected from H, deuterium, F, Cl, Br, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclopropyloxy, cyclobutyl, vinyl, and ethynyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl are optionally substituted with 1 to 4 R ^k ;

In some embodiments, R ³ and R ⁴ are each independently selected from H, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ ;

In some embodiments, R ^q , ^RB are each independently selected from H, F, Cl, Br, cyano, CH ₂ F, CHF ₂ , CF ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OCD ₃ , methyl, -S-methyl, -S-CF ₃ , ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, -O-cyclopropyl, wherein the methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, cyclopropyl is optionally substituted with 1 to 4 R ^k ;

In some embodiments, R ^k is selected from deuterium, =0, halogen, CN, OH, NH ₂ , 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 carbocycle, -NH-3 to 7 membered heterocycle, -C _1-4 alkylene-C _3-6 carbocycle, -C _1-4 alkylene-3 to 7 membered heterocycle, C _3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =0, CN, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy;

In some embodiments, R ^k is selected from deuterium, =0, halogen, CN, OH, NH ₂ , 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 carbocycle, -O-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy;

In some embodiments, R ^k is selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH ₂ , NH(CH ₃ ), NH(CH ₂ CH ₃ ), N(CH ₃ ) ₂ , N(CH ₂ CH ₃ ) ₂ , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH ₂ -cyclopentyl, -CH 2 -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, cyclohexyl, cyclopropyl, cyclobutyl, ...propyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl, cyclo cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy;

In some embodiments, R ^k is selected from deuterium, F, Cl, Br, I, CN, OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

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,

_Q1 is selected from _C6-10 aryl, 5-10 membered heteroaryl, _C5-10 carbocyclic ring, 5-10 membered heterocyclic ring or The Q ₁ is optionally substituted with 1 to 5 R ^q ;

When X1 _is O, ^RQ1 is selected from -C(= ^S ) ^NRq1Rq2 , -C(= ^{NRq3 ) NRq1Rq2} ;

^{When X} ₁ ^{is S or NR} _​ ^{​ ​} S(＝O)NR ^q1 R ^q2 , -C(＝NR ^q3 )NR ^q1 R ^q2 ,OH,＝O,-OR ^q1 ,-C(＝O)R ^q1 ,-S(＝O) ₂ R ^q1 , -S(=O)(=NR ^q1 )R ^q2 ;

R ^x and R ^q3 are each independently selected from H, CN, C _1-6 alkyl, C _3-10 carbocycle, 4- to 10-membered heterocycle, -OR ^q1 , -SR ^q1 , -C(═O)NR ^q1 R ^q2 , -C(═S)NR ^q1 R ^q2 , -S(═O) ₂ NR ^q1 R ^q2 , -S(═O) ₂ R ^q1 , -S(═O) NR ^q1 R ^q2 , wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R ^k ;

R ^q1 and R ^q2 are each independently selected from H, C _1-6 alkyl, C _3-6 carbocycle, 4 to 7 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R ^k ;

Alternatively, R ^q1 and R ^q2 are directly linked to form a 4- to 7-membered heterocyclic ring, which is optionally substituted with 1 to 4 R ^k ;

B is selected from C _6-10 aryl, 5-10 membered heteroaryl, C _5-10 carbocycle, 5-10 membered heterocycle, wherein the aryl, heteroaryl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^B ;

R ¹ and R ² are 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 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^k , provided that R ¹ and R ² are not H at the same time;

R ³ , R ⁴ , R ^q , and ^RB are each independently selected from H, deuterium, halogen, CN, OH, NH ₂ , 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 carbocycle, -OC _3-6 alkyl, _7- membered carbocyclic ring, 3- to 7-membered heterocyclic ring, wherein the alkyl, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R ^k ;

R ^k is selected from deuterium, =O, halogen, CN, OH, NH ₂ , 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 carbocycle, -NH-3 to 7 membered heterocycle, -C _1-4 alkylene-C _3-6 carbocycle, -C _1-4 alkylene-3 to 7 membered heterocycle, C _3-6 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy.

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,

R ^x and R ^q3 are each independently selected from H, CN, C _1-5 alkyl, C _3-6 carbocycle, 4- to 7-membered heterocycle, -OR ^q1 , -SR ^q1 , -C(═O)NR ^q1 R ^q2 , -C(═S)NR ^q1 R ^q2 , -S(═O) ₂ NR ^q1 R ^q2 , -S(═O) ₂ R ^q1 , -S(═O) NR ^q1 R ^q2 , wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R ^k ;

R ^q1 and R ^q2 are each independently selected from H, C _1-4 alkyl, C _3-6 carbocycle, 4 to 7 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R ^k ;

Alternatively, R ^q1 and R ^q2 are directly linked to form a 4- to 7-membered heterocyclic ring, which is optionally substituted with 1 to 4 R ^k ;

_Q1 is selected from phenyl, _benzoC4-6 carbocyclic ring, benzo4 to 6 heterocyclic ring, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl ring or The Q ₁ is optionally substituted with 1 to 4 R ^q ;

B is selected from phenyl, benzoC _4-6 carbocycle, benzoC 4 to 6 heterocycle, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, and said B is optionally substituted by 1 to 4 R ^B ;

R ¹ and R ² are 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 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^k , provided that R ¹ and R ² are not H at the same time;

R ³ , R ⁴ , R ^q , and ^RB are each independently selected from H, deuterium, halogen, CN, OH, NH ₂ , 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 carbocycle, -OC _3-7 carbocycle, and 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^k ;

R ^k is selected from deuterium, =0, halogen, CN, OH, NH ₂ , 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 carbocycle, -O-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy;

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

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,

R ^x and R ^q3 are each independently selected from H, CN, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, -OR ^q1 , -SR ^q1 , -C(═O)NR ^q1 R ^q2 , -C(═S)NR ^q1 R ^q2 , -S(═O) ₂ NR ^q1 R ^q2 , -S(═O) ₂ R ^q1 , -S(═O)NR ^q1 R ^q2 , wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted by 1 to 4 R ^k ;

R ^q1 and R ^q2 are 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 ;

R ¹ and R ² are 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 with 1 to 4 R ^k , provided that R ¹ and R ² are not H at the same time;

B is selected from or phenyl, said B is optionally substituted with 1 to 5 R ^B ;

R ³ , R ⁴ , R ^q , and ^RB are each independently selected from H, deuterium, F, Cl, Br, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclopropyloxy, cyclobutyl, vinyl, and ethynyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl are optionally substituted with 1 to 4 R ^k ;

R ^k is selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH ₂ , NH(CH ₃ ), NH(CH ₂ CH ₃ ), N(CH ₃ ) ₂ , N(CH ₂ CH ₃ ) ₂ , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH ₂ , C _1-4 alkyl ... The remaining groups are defined the same as in the first, second or third embodiment of _the present invention.

As a fourth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, deuterated substances, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

Q ₁ is selected from The Q ₁ is optionally substituted by 1 to 5 R ^q ; R ³ and R ⁴ are each independently selected from H, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ ;

R ¹ and R ² are each independently selected from H, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ , provided that R ¹ and R ² are not H at the same time;

R ^q and ^RB are each independently selected from H, F, Cl, Br, cyano, CH ₂ F, CHF ₂ , CF ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OCD ₃ , methyl, -S-methyl, -S-CF ₃ , ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, -O-cyclopropyl, wherein the methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, cyclopropyl is optionally substituted with 1 to 4 R ^k ;

R ^k is selected from deuterium, F, Cl, Br, I, CN, OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the remaining groups are defined the same as in the first, second, third or fourth embodiment of the present invention.

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,

When _X1 is 0, Selected from The Q ₁ is optionally substituted with 1 to 3 R ^q ;

When _X1 is S or ^NRx , Selected from The Q ₁ is optionally substituted with 1 to 3 R ^q ;

B is selected from

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

The present invention relates to the compound shown below or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures shown below in Table E.

Table E

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 pharmaceutically acceptable carriers.

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.

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 "preparation strength").

"Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition being treated (e.g., treating and/or alleviating pain) to some extent. 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 composition comprising 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, 90-500 mg, 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, 40-200 mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

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 the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal.

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

A method for treating or alleviating a disease in a mammal, the method comprising administering a drug compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof to a subject at a daily dose of 1-1000 mg/day, the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 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.

The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and 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 its amount in the above-mentioned pharmaceutical composition.

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 co-crystals in the preparation of drugs for treating and/or alleviating pain.

The present invention relates to the use of the above-mentioned pharmaceutical composition in preparing a drug for treating or/and alleviating pain.

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.

The present invention provides a crystalline form of a compound (Compound 2-a) represented by the following formula (Ia):

In some embodiments, the crystal of the compound shown in (Ia) is Form A, and using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 8.3°±0.2°, 11.8°±0.2°, 15.0°±0.2°, 16.2°±0.2°, 18.6°±0.2° and 22.2°±0.2°, and further, it also has characteristic diffraction peaks at the following 2θ positions: 20.6°±0.2°, 21.8°±0.2°, 23.5°±0.2°, 25.0°±0.2°, 25.2°±0.2° and 28.3°±0.2°, and further, it also has characteristic diffraction peaks at the following 2θ positions: 29.1°±0.2°, 32.5°±0.2°, 33.4°±0.2°.

In some embodiments, the crystal of the compound shown in (Ia) is Form A, and using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in FIG1 ; further, the differential scanning calorimetry analysis spectrum of Form A is shown in FIG2 ; further, the thermogravimetric analysis curve of Form A is shown in FIG3 .

In some embodiments, the crystal of the compound shown in (Ia) is Form E, and using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in Figure 4. In some embodiments, the differential scanning calorimetry analysis pattern of further Form E is shown in Figure 5. In some trial schemes, the thermogravimetric analysis curve of further Form E is shown in Figure 6.

In some embodiments, the crystal of the compound shown in (Ia) is Form F, and using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in Figure 7. In some embodiments, the differential scanning calorimetry analysis pattern of further Form F is shown in Figure 8. In some trial schemes, the thermogravimetric analysis curve of further Form F is shown in Figure 9.

The present invention provides a method for synthesizing a compound represented by formula (Ia):

The general formula (Z1) reacts with 4-acetylaminobenzenesulfonyl azide to obtain the corresponding general formula (Z2), the general formula (Z2) is protected with silanol to obtain the corresponding general formula (Z3), the general formula (Z3) is condensed with the general formula (Z4) to obtain the corresponding general formula (Z5), the general formula (Z5) is self-cyclized to obtain the corresponding general formula (Z6), the general formula (Z6) is reacted with trifluoromethanesulfonic anhydride to obtain the corresponding general formula (Z7), the general formula (Z7) and the aromatic fragment (BX) are coupled to obtain the corresponding general formula (Z8), the general formula (Z8) is hydrolyzed under alkaline conditions to obtain the corresponding general formula (Z9), the general formula (Z9) is condensed with the amino fragment (R ^Q1 -Q ₁ -NH ₂ ) to obtain the corresponding general formula (Ia).

X is halogen, boronic acid or boronic ester.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen, F, Cl, Br, and I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds described in the present invention are optionally replaced by one or more of their corresponding isotopes, wherein carbon isotopes include ¹² C, ¹³ C, and ¹⁴ C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), and 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 Cl, and bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Halogen" refers to F, Cl, Br or I.

"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, substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substituted" is abbreviated as "halo".

"Alkyl" refers to a substituted or unsubstituted straight or branched chain 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; the alkyl groups appearing herein are defined in accordance with this definition. Alkyl groups may be monovalent, divalent, trivalent, or tetravalent.

"Alkylene" refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including -(CH ₂ ) _v - (v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.

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

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

"Alkenyl" refers to a substituted or unsubstituted straight chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a main chain including but not limited to 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, etc.; the alkenyl groups appearing in this article have the same definition as this definition. The alkenyl group can be monovalent, divalent, trivalent or tetravalent.

"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 main 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- 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, 4-decynyl and the like; the alkynyl group may be monovalent, divalent, trivalent or tetravalent.

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

"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, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

"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 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The N and S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclyl can be attached to a heteroatom or a carbon atom, the heterocyclyl can be attached to an aromatic ring or a non-aromatic ring, and the heterocyclyl can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxadiazine, azetidinyl, 1,3-dioxolane, 1,4-dioxolanyl, pentyl, 1,3-dioxane, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydro furanyl, 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]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"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 includes but is 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, furanyl, 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 The heteroaryl groups appearing in this article have the same definition as this definition. The heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the heteroaryl ring.

"Substituted" or "substituted" means substituted 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, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring group, spirocyclyl, cyclocyclyl, 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 ) _mS (=O) _nR ^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 , wherein R ^b and R ^c are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, Alternatively, R ^b and R ^c may form a five- or six-membered cycloalkyl or heterocyclic group, and R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, spirocyclic group or cyclized group.

"1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from...", X is selected from any integer between 1 and 10. For example, "1 to 4 R ^k substituted" means substituted by 1, 2, 3 or 4 R ^k . For example, "1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from...". For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from D or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from D or F.

X-Y membered rings (X is an integer, and 3≤X＜Y, Y is selected from any integer between 4 and 12) include X, X+1, X+2, X+3, X+4...Y membered rings. 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 rings" refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings, and "5-10 membered heterocyclic rings" refer to 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic rings.

"Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes situations where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.

"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, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

"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.

"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.

"Preparation specification" refers to the weight of the main drug contained in each vial, tablet or other unit preparation. "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, which includes both binary eutectics formed between two neutral solids and A polymorphic eutectic formed by a neutral solid and a salt or solvate.

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

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

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

" _IC50 " is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of such a process, such as an enzyme, receptor, cell, etc.) by half.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an X-ray powder diffraction pattern of Form A of Compound 2-a.

Figure 2 is a differential scanning calorimetry analysis spectrum of Form A of Compound 2-a.

Figure 3 is a thermogravimetric analysis curve of Form A of Compound 2-a.

Figure 4 is an X-ray powder diffraction pattern of Form E of Compound 2-a.

Figure 5 is a differential scanning calorimetry analysis spectrum of Form E of Compound 2-a.

Figure 6 is a thermogravimetric analysis curve of Form E of Compound 2-a.

Figure 7 is an X-ray powder diffraction pattern of Form F of Compound 2-a.

Figure 8 is a differential scanning calorimetry analysis spectrum of Form F of Compound 2-a.

Figure 9 is a thermogravimetric analysis curve of Form F of Compound 2-a.

DETAILED DESCRIPTION

The following embodiments 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.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the solvent, and tetramethylsilane (TMS) as the internal standard;

For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));

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

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4 mm-0.5mm;

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;

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 technicians in the field, 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., Tokyo Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

THF: Tetrahydrofuran; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; HATU: CAS 148893-10-1

Example 1: Preparation of Compound 1-a and Compound 1-b

Step 1: Preparation of a mixture of 1B-a and 1B-b

In a 50mL reaction bottle, add a mixture of 1A-a and 1A-b (140mg, 0.40mmol) (preparation method refers to WO2021113627A1), 4-amino-2-cyanopyridine (71.5mg, 0.60mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (224.5mg, 0.80mmol), N-methylimidazole (98.5mg, 1.20mmol) and N,N-dimethylformamide (3mL) in sequence, and stir at room temperature for 5 hours after addition. Add water (50mL), extract with ethyl acetate (50mL×3), combine the organic phases and dry with anhydrous sodium sulfate, filter, concentrate the filtrate and separate and purify it on a silica gel column to obtain a mixture of 1B-a and 1B-b (90mg, yield 49%). LCMS m/z＝456.1[M+H] ⁺

Step 2: Preparation of a mixture of compound 1-a and compound 1-b

The mixture of 1B-a and 1B-b (80 mg, 0.18 mmol) was added to methanol (3 mL), and ammonium sulfide (24.5 mg, 0.36 mmol) was added, and the mixture was reacted at 80°C for 1 h, and then concentrated under reduced pressure. The mixture was separated and purified by silica gel column (PE/EA=5/1) to obtain a mixture of compound 1-a and compound 1-b (27 mg, yield 30.7%). LC-MS m/z=490.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.86(s,1H),10.16(s,1H),9.89(s,1H),8.70(d,1H),8.47(d,1H),7.92 -7.88(m,1H),7.23-7.09(m,2H),5.11(d,1H),4.30-4.22(m,1H),3.95(d,3H),2.85-2.73(m,1H),1.61 (s,3H),0.73(d,3H).

Example 2: Preparation of Compound 2-a and Compound 2-b

Step 1: Preparation of compounds 2B-a and 2B-b

In a microwave tube, 2A-a and 2A-b (400 mg, 0.82 mmol) (preparation method refer to WO2021113627A1), Lawesson reagent (CAS: 19172-47-5, 500 mg, 1.24 mmol) and xylene (10 mL) were added in sequence, and microwave reaction was performed at 150 ° C for 1 hour. The solvent was concentrated and separated and purified by silica gel column to obtain a mixture of 2B-a and 2B-b (180 mg, yield 44%). LCMS m/z＝505.1[M+H] ⁺

Step 2: Preparation of Compound 2-a and Compound 2-b

Ammonia methanol solution (7M, 2 mL) was added to 2B-a and 2B-b (130 mg, 0.18 mmol), reacted at room temperature for 18 h, concentrated under reduced pressure, and a mixture of compound 2-a and compound 2-b (11 mg, yield 8.64%) was obtained by preparative separation and purification.

Preparation conditions:

Instrument and preparative column: Waters AUTOP was used to prepare the liquid phase; the preparative column model was SunFire@Prep C18 (19mm×250mm). Preparation method: The crude product was dissolved in methanol and filtered with a 0.45μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution: acetonitrile content 30-80%, elution flow rate: 15mL/min, elution time 20min. LCMS m/z＝490.1[M+H]+

1H NMR (400MHz, DMSO-d6): δ12.09(s,1H),8.64(d,1H),8.52(d,1H),8.28-8.24(m,1H),8.11(s,1H),7.69 (s,1H),7.21-7.12(m,2H),5.44(d,1H),4.57-4.50(m,1H),3.93(d,3H),2.82-2.73(m,1H),1.64(s ,3H),0.76(d,3H).

Example 3: Preparation of Compound 2-a Crystalline Form

Example 3-1: Preparation of Form A

According to the conditions of Example 2, 12 g of a mixture of compounds 2-a and 2-b was synthesized, prepared by SFC, and freeze-dried to obtain compound 2-a (5.6 g, retention time: 10.47 min) and compound 2-b (5.3 g, retention time: 12.40 min).

Chiral preparation method: 1. Instrument: SFC Prep 150AP; Chromatographic column: Daicel IG-H (19mm×250mm). 2. Dissolve the sample in methanol and filter with a 0.45μm filter to prepare a sample solution. 3. Preparation chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: CO ₂ , Mobile phase B: methanol. b. Isocratic elution: Mobile phase B content 10%. c. Flow rate 44ml/min. ).

Under nitrogen protection, 5.6 g of compound 2-a was dissolved in 10 ml of methanol, and 100 ml of n-hexane was slowly added dropwise at room temperature. After solids were precipitated, stirring was continued for 15 h, and filtration was performed to obtain the crystalline form A of compound 2-a. Its XRD, DSC, and TGA analysis spectra are shown in Figures 1-3, respectively.

Example 3-2: Preparation of Form E

50 mg of compound 2-a was placed in a 2 mL sample bottle, and 1 mL of dichloromethane/MIBK = 1/1 was added to prepare a clear solution, and the filtrate was evaporated at room temperature after filtration. Centrifugation was performed, and the solid was vacuum dried at 50°C to obtain the crystalline form E of the compound. Its XRD, DSC, and TGA analysis spectra are shown in Figures 4-6 respectively.

Example 3-3: Preparation of Form F

50 mg of the compound of formula 2-a was placed in a 2 mL sample bottle, 0.2 mL of ethyl acetate was added to dissolve, and after filtering, the filtrate was added to a sample bottle containing 2 mL of n-heptane, and solids were precipitated. Centrifugation was performed, and the solids were vacuum dried at 50°C to obtain the crystalline form F of the compound, whose XRD, DSC, and TGA are shown in Figures 7-9 respectively.

Crystal characterization and performance testing

X-ray powder diffractometer (XRD)/DSC/TGA test

(I) XRD test:

Experimental instruments:

The X-ray powder diffractometer (XRD) was Malvern Panalytica X’pert Powder.

Scanning conditions: starting angle 4°; ending angle 40°; step length 0.01°; scanning time per step 30 s.

Incident light path parameters: Soller slit 0.04 rad; shading plate 10 mm; divergence slit 1/8°; anti-scattering slit 1/4°.

Diffraction optical path parameters: filter is nickel plate; Soller gap is 0.04rad; anti-scattering gap is 7.5mm;

DetectorPIXcel1D detector.

XRD test results:

Table 1: XRD peak list of 2-a compound crystal form A

Table 2: XRD peak list of Form E of Compound 2-a

Table 3: XRD peak list of Form F of Compound 2-a

(II)DSC/TGA/DVS/1C test

Table 4 DSC/TGA test instruments and parameters

Summary: The DSC/TGA test results of crystal forms A, E, and F are shown in the attached figure.

Biological test cases

Nav1.8 manual patch clamp test

(1) Cell culture

CHO cell lines stably expressing human Nav1.8 were cultured in Ham's F-12 medium containing 10% fetal bovine serum and 10μg/mL Blasticidin, 200μg/mL Hygromycin B, and 100μg/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 1mL of 0.25%-Trypsin-EDTA solution was added and incubated at 37°C for about 1.5min. When the cells detached from the bottom of the dish, complete culture medium preheated at 37°C was added. The cell suspension was gently blown with a pipette to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000rpm for 5min to collect the cells. The cells were inoculated in 6cm cell culture dishes, and the cell amount inoculated in each cell culture dish was 2.5x10 ⁵ cells (final volume was 5mL) for expansion or maintenance culture. To maintain the electrophysiological activity of the cells, the cell density should not exceed 80%. Before the patch clamp test, cells were detached with 0.25%-Trypsin-EDTA, 6.5x10 ³ cells were plated on coverslips and cultured in 24-well plates (final volume 500 μL). Line detection.

(2) Compound preparation

The compound was dissolved in dimethyl sulfoxide (DMSO) and prepared into a 30 mM DMSO stock solution. The stock solution was diluted to the test concentration with extracellular fluid (140 mM NaCl, 3.5 mM KCl, 1 mM MgCl ₂ ·6H ₂ O, 2 mM CaCl ₂ ·2H ₂ O, 10 mM D-Glucose, 10 mM HEPES and 1.25 mM NaH ₂ PO ₄ ·2H ₂ O, pH adjusted to 7.4 with NaOH), and the final DMSO concentration of all test samples was 0.1%.

(3) Electrophysiological test

First, use a microelectrode puller to pull a capillary glass tube into a recording electrode, then load the electrode filled with intracellular fluid (50mM CsCl, 10mM NaCl, 10mM HEPES, 60mM CsF and 20mM EGTA, CsOH to adjust the pH to 7.2) into the microelectrode holder, and manipulate the microelectrode manipulator under an inverted microscope to immerse the electrode in the extracellular fluid and record the electrode resistance (Rpip). Then slowly contact the electrode to the cell surface, apply negative pressure to form a GΩ seal. At this time, perform fast capacitance compensation, continue to apply negative pressure to break the cell membrane, and form a whole-cell recording mode. Finally, perform slow capacitance compensation and record experimental parameters such as series resistance (Rs). No leakage compensation is given. When the Nav1.8 current recorded by the whole cell is stable, start drug administration, and each drug concentration acts for about 5 minutes (or the current is stable). The coverslip with cells was placed in a recording bath under an inverted microscope. The blank control external solution and the working solution of the compound to be tested flowed through the recording bath by gravity perfusion to act on the cells, and the liquid was exchanged by a peristaltic pump. The current detected by the cells in the external solution without the compound was used as the control group. All electrophysiological tests were performed at room temperature. The inhibition rate of the compound on Nav1.8 was determined by calculating the relative percentage of the peak current generated before and after the compound treated cells.

The voltage stimulation scheme for whole-cell patch clamp recording of Nav1.8 sodium current is as follows: After the whole-cell seal is formed, 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 given to obtain a half-inactivation voltage (Vhalf). Then Vhalf is used as the stimulation voltage and maintained for 5s, and then the voltage is restored to -120mV and maintained for 20ms, and then a depolarizing pulse (TP2) is given to 0mV for 50ms to detect the sodium current in the half-inactivation state. Finally, it is restored to the clamping voltage of -120mV, and data is repeatedly collected every 20ms to observe the effect of the drug on the peak of the sodium current. The experimental data are collected by the EPC 10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.

Table 5 IC ₅₀ of the inhibitory activity of the test compounds on Nav1.8

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

Biological test example 2: Rat pharmacokinetic test

Test animals: male SD rats, about 220 g, 6 to 8 weeks old, 6 rats/compound.

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

Table 6. Dosing Information

Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC

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

Before and after drug administration, 0.10 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Conclusion: The compounds of the present invention, such as the compounds in the examples, especially compound 2-a, have good oral performance in rats.

Biological test example 3: mouse pharmacokinetic test

Test animals: male C57 mice, 22-25 g, 6 mice/compound.

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 one day before administration and fed 4 hours after administration.

Table 7 Dosage information

Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC

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

Before and after drug administration, 0.06 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 7, 24, 48 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Table 7-1 Pharmacokinetic results of the test compounds in mice

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral performance in mice.

Biological test example 4: beagle dog pharmacokinetic test

Experimental animals: Male beagle dogs, about 8-11 kg, 6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

Test method: On the day of the test, 12 beagle dogs were randomly divided into groups according to their body weight. They were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration. The administration was performed according to Table 4.

Table 8. Dosing Information

Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC

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

Before and after administration, 1 ml of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral properties in dogs.

Biological test example 5: monkey pharmacokinetic test

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

Test method: On the day of the test, six monkeys were randomly divided into groups according to their body weight. They were fasted but not watered for 14-18 hours one day before administration and fed 4 hours after administration.

Table 9. Dosing Information

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

*Dosage is based on free base.

Before and after administration, 1.0 mL of blood was collected from the limb veins and placed in EDTAK2 centrifuge tubes. The cells were centrifuged at ℃ for 10 min and plasma was collected. The blood sampling time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h. Before analysis and testing, all samples were stored at -80℃ and quantitatively analyzed by LC-MS/MS.

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

Biological test example 6: CYP450 enzyme inhibition test

The purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system. Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH). After the reaction, the metabolites produced by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the changes in CYP enzyme activity, calculate IC ₅₀ values, and evaluate the inhibitory potential of the test substances on each CYP enzyme subtype.

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

Biological Test Example 7: Caco2 Permeability Test

The experiment used a monolayer of Caco-2 cells and was incubated in triplicate in a 96-well Transwell plate. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), nadolol (2 μM) and metoprolol (2 μM) was added to the dosing port well on the apical side or the basolateral side. A transport buffer solution containing DMSO was added to the corresponding receiving port well. After incubation at 37 ± 1 ° C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate. Subsequently, acetonitrile containing an internal standard was added to precipitate the protein. The samples were analyzed using LC MS/MS and the concentrations of the compound of the present invention and the control compound were determined. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical side to the basolateral side of the monolayer cells and from the basolateral side to the apical side, thereby calculating the efflux rate. The integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.

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

Biological Test Example 8: Spinal Nerve Ligation (SNL)-Induced Mouse Neuropathic Pain Model

The model was established after one week of adaptive breeding of male C57BL/6J mice purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd. The specific establishment method is as follows:

(1) Sterilization of surgical instruments and ligatures;

(2) The mouse was anesthetized with isoflurane and placed in the prone position on the operating table;

(3) The hair and skin of the mouse were cut near the hip bone and a wound of about 2 cm was made along the spine;

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

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

(6) Carefully separate the L5 nerve with a glass dividing needle and ligate the L5 nerve with a 5-0 ligature.

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

The next day after modeling, mice that failed to establish a model were removed (sign of successful modeling: mouse hind paws curled up). After modeling, mice were stroked for 3 to 5 minutes every day to ensure that the animals were familiar with the experimenters. Then, the mice were placed on a metal pain tester for 40 to 60 minutes to adapt to the environment. After the third day, Von Frey fiber ( The baseline values of the test animals before administration (Ascending test method) were measured twice for each animal, and the average value was taken, with an interval of at least 5 minutes between each test. The animals were grouped according to the baseline values (10 animals per group). After grouping, the test compound (3 and 30 mg/kg) or the vehicle (0.5% methylcellulose) was administered orally, and the mechanical pain threshold (MPT) of the mice was tested at different time points after administration. The time-MPT curve was drawn using GraphPad 8.3.0, and statistical analysis was performed.

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.

Crystal stability test

Stability study of crystal form A/E/F competition experiment

Take an appropriate amount of the mixed crystals of Form A/E/F and add the pre-saturated solvent to suspend and slurry at room temperature and 50°C, and test the results. The specific data is as follows. The test results show that Form A/E/F turns into anhydrous Form A after being suspended and slurried in different aqueous solvents and water solvents at room temperature and 50°C, that is, Form A is a stable form.

Table 10. Competitive beating results of crystal forms A/E/F at room temperature/50°C

Claims (14)

A compound or a stereoisomer, a crystal form, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds represented by general formula (I),
in: _Q1 is selected from _C6-10 aryl, 5-10 membered heteroaryl, _C5-10 carbocyclic ring, 5-10 membered heterocyclic ring or The Q ₁ is optionally substituted with 1 to 5 R ^q ; When X1 _is O, ^RQ1 is selected from -C(= ^S ) ^NRq1Rq2 , -C(= ^{NRq3 ) NRq1Rq2} ; ^{When X} ₁ ^{is S or NR} _​ ^{​ ​} S(＝O)NR ^q1 R ^q2 , -C(＝NR ^q3 )NR ^q1 R ^q2 ,OH,＝O,-OR ^q1 ,-C(＝O)R ^q1 ,-S(＝O) ₂ R ^q1 , -S(=O)(=NR ^q1 )R ^q2 ; R ^x and R ^q3 are each independently selected from H, CN, C _1-6 alkyl, C _3-10 carbocycle, 4- to 10-membered heterocycle, -OR ^q1 , -SR ^q1 , -C(═O)NR ^q1 R ^q2 , -C(═S)NR ^q1 R ^q2 , -S(═O) ₂ NR ^q1 R ^q2 , -S(═O) ₂ R ^q1 , -S(═O) NR ^q1 R ^q2 , wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R ^k ; R ^q1 and R ^q2 are each independently selected from H, C _1-6 alkyl, C _3-6 carbocycle, 4 to 7 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R ^k ; Alternatively, R ^q1 and R ^q2 are directly connected to form a 4- to 7-membered heterocyclic ring, which is optionally substituted by 1 to 4 R ^k ; B is selected from C _6-10 aryl, 5-10 membered heteroaryl, C _5-10 carbocycle, 5-10 membered heterocycle, wherein the aryl, heteroaryl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^B ; R ¹ and R ² are 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 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^k , provided that R ¹ and R ² are not H at the same time; R ³ , R ⁴ , R ^q , and ^RB are each independently selected from H, deuterium, halogen, CN, OH, NH ₂ , 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 carbocycle, -OC ₃ - ₇ carbocycle, and 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^k ; R ^k is selected from deuterium, =0, halogen, CN, OH, NH ₂ , 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 carbocycle, ring, -NH-3 to 7 membered heterocycle, -C _1-4 alkylene-C _3-6 carbocycle, -C _1-4 alkylene-3 to 7 membered heterocycle, C _3-6 carbocycle, 3 to 7 membered heterocycle, the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy. The compound according to claim 1 or its stereoisomer, crystal form, pharmaceutically acceptable salt or cocrystal, R ^x and R ^q3 are each independently selected from H, CN, C _1-5 alkyl, C _3-6 carbocycle, 4- to 7-membered heterocycle, -OR ^q1 , -SR ^q1 , -C(═O)NR ^q1 R ^q2 , -C(═S)NR ^q1 R ^q2 , -S(═O) ₂ NR ^q1 R ^q2 , -S(═O) ₂ R ^q1 , -S(═O) NR ^q1 R ^q2 , wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R ^k ; R ^q1 and R ^q2 are each independently selected from H, C _1-4 alkyl, C _3-6 carbocycle, 4 to 7 membered heterocycle, wherein the alkyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R ^k ; Alternatively, R ^q1 and R ^q2 are directly connected to form a 4- to 7-membered heterocyclic ring, which is optionally substituted by 1 to 4 R ^k ; _Q1 is selected from phenyl, _benzoC4-6 carbocyclic ring, benzo4 to 6 heterocyclic ring, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl ring or The Q ₁ is optionally substituted with 1 to 4 R ^q ; B is selected from phenyl, benzoC _4-6 carbocycle, benzoC 4 to 6 heterocycle, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, and said B is optionally substituted by 1 to 4 R ^B ; R ¹ and R ² are 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 carbocycle, 3 to 7 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^k , provided that R ¹ and R ² are not H at the same time; R ³ , R ⁴ , R ^q , and ^RB are each independently selected from H, deuterium, halogen, CN, OH, NH ₂ , 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 carbocycle, -OC _3-7 carbocycle, and 3- to 7-membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R ^k ; R ^k is selected from deuterium, =0, halogen, CN, OH, NH ₂ , 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 carbocycle, -O-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy; The remaining groups are defined the same as in claim 1. The compound according to claim 2 or its stereoisomer, crystal form, pharmaceutically acceptable salt or cocrystal, R ^x and R ^q3 are each independently selected from H, CN, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclo Pentyl, -OR ^q1 , -SR ^q1 , -C(═O)NR ^q1 R ^q2 , -C(═S)NR ^q1 R ^q2 , -S(═O) ₂ NR ^q1 R ^q2 , -S(═O) ₂ R ^q1 , -S(═O) NR ^q1 R ^q2 , wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted by 1 to 4 R ^k ; R ^q1 and R ^q2 are 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 ; R ¹ and R ² are 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 with 1 to 4 R ^k , provided that R ¹ and R ² are not H at the same time; B is selected from or phenyl, said B is optionally substituted with 1 to 5 R ^B ; R ³ , R ⁴ , R ^q , and ^RB are each independently selected from H, deuterium, F, Cl, Br, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclopropyloxy, cyclobutyl, vinyl, and ethynyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, vinyl, and ethynyl are optionally substituted with 1 to 4 R ^k ; R ^k is selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH ₂ , NH(CH ₃ ), NH(CH ₂ CH ₃ ), N(CH ₃ ) ₂ , N(CH ₂ CH ₃ ) ₂ , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy. The compound according to claim 3 or its stereoisomer, crystal form, pharmaceutically acceptable salt or cocrystal, wherein: Q ₁ is selected from The Q ₁ is optionally substituted by 1 to 5 R ^q ; R ³ and R ⁴ are each independently selected from H, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ ; R ¹ and R ² are each independently selected from H, methyl, ethyl, CH ₂ F, CHF ₂ , CF ₃ , provided that R ¹ and R ² are not H at the same time; R ^q and ^RB are each independently selected from H, F, Cl, Br, cyano, CH ₂ F, CHF ₂ , CF ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OCD ₃ , methyl, -S-methyl, -S-CF ₃ , ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, -O-cyclopropyl, wherein the methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy, isopropyloxy, cyclopropyl is optionally substituted with 1 to 4 R ^k ; R ^k is selected from deuterium, F, Cl, Br, I, CN, OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The compound according to claim 4 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: When _X1 is 0, Selected from The Q ₁ is optionally substituted with 1 to 3 R ^q ; When _X1 is S or NR ^X , Selected from The Q ₁ is optionally substituted with 1 to 3 R ^q ; B is selected from The compound according to claim 1 or its stereoisomer, crystal form, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition comprises 1 to 1500 mg of a compound according to any one of claims 1 to 6 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof. Use of the compound according to any one of claims 1 to 6 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal for preparing a drug for treating and/or alleviating pain. A method for treating or alleviating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably pain. Crystals of the compound represented by formula (Ia):
The crystal according to claim 10, characterized in that the crystal form A uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 8.3°±0.2°, 11.8°±0.2°, 15.0°±0.2°, 16.2°±0.2°, 18.6°±0.2° and 22.2°±0.2°. The crystal according to claim 11, characterized in that the crystal form A uses Cu-Kα radiation, and its X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 20.6°±0.2°, 21.8°±0.2°, 23.5°±0.2°, 25.0°±0.2°, 25.2°±0.2° and 28.3°±0.2°. The crystal according to claim 12, characterized in that the crystal form A uses Cu-Kα radiation, and its X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 29.1°±0.2°, 32.5°±0.2°, and 33.4°±0.2°. The crystal according to claim 10, characterized in that the X-ray powder diffraction pattern of crystal form A is based on This is shown in Figure 1.