WO2020192553A1 - Sulfonyl-substituted benzoheterocyclic formamide derivative, and preparation method therefor and medical use thereof - Google Patents

Abstract

The present invention relates to a sulfonyl-substituted benzoheterocyclic formamide derivative, and a preparation method therefor and a medical use thereof. Specifically, a compound of formula (I) or a pharmaceutically acceptable salt, a stereoisomer, a solvate compound or a prodrug thereof, a preparation method therefor, and a use thereof are disclosed in the present invention, and the definition of each group in the formula is detailed in the description. (I)

Description

Sulfonyl substituted benzoheterocyclic carboxamide derivative, its preparation method and medical use Technical field

The invention belongs to the field of medical technology. Specifically, the present invention particularly relates to a sulfonyl-substituted benzoheterocyclic carboxamide derivative, a preparation method thereof, and application as a sodium ion channel (especially Nav1.7) inhibitor, and a pharmaceutical composition prepared therefrom And medicinal composition.

Background technique

Recently, Cox et al. of the United Kingdom reported on Nature for the first time that the mutation of the SCN9A gene encoding the voltage-gated Nav1.7 channel caused the unexpected results of painlessness in genetic individuals. Individuals with this genetic mutation lose the sense of pain congenitally, but other functions of the body are completely normal. In addition, recent studies have shown that the voltage-gated Nav1.7 channel expressed in DRG neurons is involved in the generation of pain signals and acts as a gate to control the incoming of pain signals. Features. The study suggests that the Nav1.7 channel may become a drug target for selective treatment of pain without side effects.

Several Nav1.7 blockers have been described: Tarantula venom peptide Pro-TX-II is a potent Nav1.7 inhibitor (Schmalhofer et al., Molecular Pharmacology 2008, 74, 1476-1484). A series of benzazepine Nav1.7 blockers have been described to show activity in preclinical pharmacological models of pain (Williams et al., Biochemistry, 2007, 46(50), 14693-14703; McGowan et al., Anesth Analg , 2009, 109, 951-958). Amino-thiazoles and amino-pyridines have been described as Nav1.7 inhibitors (WO2007109324), and isoxazoles are described as Nav1.7 inhibitors (WO2009010784).

The nonsense mutation in SCN9A (the gene encoding Nav1.7) appears to be associated with congenital analgesia (CIP) (Cox et al., Nature, 2006, 444(7121), 894-898). Patients with CIP are basically completely indifferent to the sensations that cause pain in most individuals, such as fractures, burns, dental abscesses, appendicitis, and childbirth. At the same time, they can distinguish other sensations such as thermal (hot)/cold stimuli and tactile (sharp/blunt) stimuli (Goldberg et al., Clinical Genetics, 2007, 71(4), 311-319).

Recent clinical reports indicate that gain-of-function mutations in human Nav1.7 are usually associated with severe pathological conditions. Primary erythematous limb pain is related to the mutations T2573A and T2543C in Nav1.7 (Yang et al., Journal of Medical Genetics, 2004, 41(3), 171-4). Sudden severe pain disorders have been reported to be associated with mutations M1627K, T1464I and I1461T located in the inactive valve area of Nav1.7 (Fertleman et al., Neuron, 2006, 52(5), 767-774).

Nav1.7 (PN1, SCN9A) VGSC is sensitive to the blocking of tetrodotoxin, which is mainly expressed in peripheral sympathetic neurons and sensory neurons. The SCN9A gene has been replicated in a variety of species (including humans, rats, and rabbits), and shows that the amino acids between human and rat genes have about 90% identity.

More and more physical evidence shows that Nav1.7 plays an important role in a variety of pain states (including acute, chronic, inflammatory and/or neuropathic pain). In humans, Nav1.7 protein accumulates in neuromas, Especially neuromas that cause pain. Mutations that increase the function of Nav1.7 (whether inherited or sporadic) have been thought to involve primary erythematous limb pain (a disease characterized by burning and inflammation of the limbs), and sudden extreme pain. The reported results of non-selective sodium channel blockers lidocaine and mexiletine can alleviate the symptoms of hereditary erythematous limb pain, and carbamazepine can effectively reduce the number and severity of PEPD attacks are consistent with the above observations . Additional evidence for the role of Nav1.7 in pain can be found in the phenotype of the loss-of-function mutation of the SCN9A gene. Subsequent studies have shown many different mutations that cause the loss of function of the SCN9A gene and the CIP phenotype.

Since Nav1.7 is specifically expressed in DRG sensory neurons but not in other tissues such as cardiomyocytes and central nervous system, the development of its specific blocker for the treatment of chronic pain may not only improve the efficacy, but also greatly reduce side effects. And the selective inhibitor of Nav1.7 ion channel can be used for almost all kinds of pain treatment.

In addition, Nav1.5 and Nav1.2, which are members of the protein family, are also important ion-type channels. NaV1.5 is mainly expressed in cardiomyocytes (Raymond, CK, etc., op.cit.), including atria, The ventricle, sinoatrial node, atrioventricular node and heart Purkinje fibers. The rapid ascent of the action potential of the heart and the rapid pulse conduction through the heart tissue are due to the opening of NaV1.5. Abnormal function of NaV1.5 can lead to the formation of a variety of arrhythmias. Human NaV1.5 mutations cause a variety of arrhythmia syndromes, including, for example, long QT3 (LQT3), Brugada syndrome (BS), inherited cardiac conduction defects, sudden death syndrome (SUNDS), and sudden infant death Syndrome (SIDS) (Liu, H. et al., Am. J. Pharmacogenomics (2003), 3(3): 173-9). Sodium channel blocker therapy has been widely used to treat arrhythmias. Therefore, inhibition of the Nav1.5 channel will cause cardiotoxicity. In addition, NaV1.2 is highly expressed in the brain (Raymond, C.K., et al., J. Biol. Chem. (2004), 279(44):46234-41) and is important for normal brain function. Therefore, inhibiting the Nav1.2 channel will produce inhibitory toxicity to the brain.

Therefore, in view of the limited efficacy and unacceptable side effects of the currently available agents, there is an urgent need to develop safer and more effective analgesics with higher efficacy and fewer side effects. The Nav1.7 ion channel is an important target for the development of non-addictive analgesics. It is necessary to develop an inhibitor with the Nav1.7 ion channel highly selective and with good pharmacokinetic characteristics.

Summary of the invention

The purpose of the present invention is to provide a selective inhibitor of Nav1.7 ion channel and its application in medicine.

The first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof:

Where

R ₀ is C _1-10 alkyl (preferably C _1-8 alkyl, more preferably C _1-3 alkyl) or NR _a0 R _b0 ;

R ₁ , R ₂ , and R ₃ are each independently hydrogen, halogen (preferably fluorine or chlorine), C _1-10 alkyl, halogenated C _1-10 alkyl, C _1-10 alkoxy or C _{3- 8} cycloalkyl;

R ₄ , R ₅ , and R ₆ are each independently hydrogen, halogen (preferably fluorine or chlorine), C _1-10 alkyl, halogenated C _1-10 alkyl, -O-(CH ₂ ) _n -R _a ；

L is CH ₂ ;

Z ₁ is N; Z ₂ is N; Z ₃ is CR _c ; Z ₄ is N or CR _d ;

Single bond or double bond;

Where R _a is: hydrogen, C _1-10 alkyl, halogenated C _1-10 alkyl, NR _a0 R _b0 , C _3- which is unsubstituted or substituted with 1, 2 or 3 C _1-10 alkyl ₈ -cycloalkyl, or unsubstituted or 4- to 6-membered saturated monocyclic heterocyclic ring substituted with 1, 2 or 3 C _1-10 alkyl groups;

R _c and R _d are each independently hydrogen, C _1-10 alkyl, halogenated C _1-10 alkyl, or C _3-8 cycloalkyl;

n is 0, 1, 2 or 3;

R _a0 and R _b0 are each independently hydrogen or C _1-8 alkyl (preferably C _1-3 alkyl, more preferably methyl).

In another preferred embodiment, the 4- to 6-membered saturated monocyclic heterocycle is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine , Thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.

In another preferred embodiment, R ₀ is methyl.

In another preferred embodiment, R ₆ is hydrogen, halogen (preferably fluorine or chlorine) or _{-O- (CH 2) n -R a} , wherein R _a is methyl, ethyl, isopropyl, methyl-substituted的cyclopropyl or trifluoromethyl.

In another preferred embodiment, R ₆ is halogen (preferably fluorine or chlorine) or _{-O- (CH 2) n -R a} , wherein R _a is trifluoromethyl, n is 0.

In another preferred embodiment, R ₅ is halogen (preferably fluorine or chlorine).

In another preferred embodiment, R ₄ is hydrogen.

In another preferred example, Z ₄ is N or CH.

In another preferred example, Z ₄ is CH.

In another preferred example, Z ₄ is N.

In another preferred embodiment, in formula (I), the structure

As the structure shown in formula (IA):

In another preferred example, R ₁ , R ₂ , and R ₃ are each independently hydrogen or halogen (preferably fluorine or chlorine).

In another preferred embodiment, R ₁ , R ₂ , and R ₃ are each independently hydrogen, fluorine or chlorine.

In another preferred embodiment, R ₁ is hydrogen, chlorine or fluorine; R ₂ and R ₃ are hydrogen.

In another preferred embodiment, R _c is hydrogen, C _1-10 alkyl or C _3-8 cycloalkyl.

In another preferred embodiment, R _c is methyl or cyclopropyl.

In another preferred example, Z ₄ is N or CR _d , and R _d is hydrogen or halogen (preferably fluorine or chlorine).

In another preferred embodiment, in formula (I), the structure

Selected from the following structures:

In another preferred embodiment, the compound is a compound selected from the following group:

The second aspect of the present invention provides a pharmaceutical composition comprising the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof; and pharmacy Acceptable carrier.

The third aspect of the present invention provides the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, or the pharmaceutical composition according to the second aspect of the present invention. Application in preparing medicines for treating diseases or disorders.

In another preferred embodiment, the disease or condition is selected from pain, depression, cardiovascular disease, respiratory system disease, mental disease or a combination thereof.

In another preferred example, the disease or condition is selected from HIV-related pain, HIV treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, bowel disease Acute syndrome, g-Rohn's disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, bone and joint Inflammation, atherosclerosis, sudden dystonia, myasthenia syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudo-aldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety , Schizophrenia, sodium channel toxin-related disorders, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain, cancer, epilepsy, local and general tonic seizures, restless legs syndrome, Arrhythmia, fibromyalgia, neuroprotection in ischemic disease states caused by stroke or nerve damage, tachyarrhythmia, atrial fibrillation and ventricular fibrillation.

In another preferred embodiment, the pain is selected from neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, postoperative pain, birth pain, childbirth pain, toothache, chronic pain, Persistent pain, peripheral-mediated pain, central-mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, trigeminal neuralgia, postherpetic neuralgia, acute Pain, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain or fibromyalgia or a combination thereof.

The fourth aspect of the present invention provides a method for treating a mammalian disease or condition, the method comprising administering to a subject in need (such as a mammal) a therapeutically effective amount of the compound according to the first aspect of the present invention, or a pharmacologically Acceptable salts, solvates, stereoisomers or prodrugs, or the pharmaceutical composition according to the second aspect of the invention.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them here.

detailed description

After extensive and in-depth research, the present inventors unexpectedly discovered that the sulfonyl-substituted benzoheterocyclic carboxamide derivatives of the present invention have high inhibitory activity against Nav1.7, and are expected to be developed for the treatment of extensive pain drug. On this basis, the inventor completed the present invention.

Definition of Terms

As used herein, "C _1-10 alkyl" refers to linear and branched saturated aliphatic hydrocarbon groups containing 1 to 10 carbon atoms, as defined below; more preferably C _1-8 alkyl, non-limiting Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl Propyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2- Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl Group, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2, 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof; more preferably C _{1 -6} alkyl, most preferably C _1-3 alkyl.

As used herein, "C _1-10 alkoxy" refers to -O-(C _1-10 alkyl), where the definition of alkyl is as described above. A C _1-8 alkoxy group is preferred, a C _1-6 alkoxy group is more preferred, and a C _1-3 alkoxy group is most preferred. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy and the like.

As used herein, "C _3-8 cycloalkoxy" refers to -O-(C _3-8 cycloalkyl), wherein cycloalkyl is defined as described above. Preferred is C _3-6 cycloalkoxy. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.

As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.

As used herein, "halo" refers to the replacement of one or more (eg, 1, 2, 3, 4, or 5) hydrogens in a group with halogen.

For example, "halo C _1-10 alkyl" means that an alkyl group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, where the definition of alkyl is as described above. It is preferably a halogenated C _1-8 alkyl group, more preferably a halogenated C _1-6 alkyl group, and most preferably a halogenated C _1-3 alkyl group. Examples of halogenated C _1-10 alkyl groups include (but are not limited to) monochloroethyl, dichloromethyl, 1,2-dichloroethyl, monobromoethyl, monofluoroethyl, monofluoromethyl, Difluoromethyl, trifluoromethyl, etc.

For another example, "halogenated C _1-10 alkoxy" means that the alkoxy group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of alkoxy is as described above. It is preferably a halogenated C _1-8 alkoxy group, more preferably a halogenated C _1-6 alkoxy group, and most preferably a halogenated C _1-3 alkoxy group. Including (but not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy and the like.

For another example, "halo C _3-8 cycloalkyl" refers to a cycloalkyl group substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of cycloalkyl is as described above. Preferably, it is a halogenated C _3-6 cycloalkyl group. Including (but not limited to) trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl and the like.

As used herein, "deuterated C _1-8 alkyl" refers to an alkyl group substituted with one or more (such as 1, 2, 3, 4, or 5) deuterium atoms, where the definition of the alkyl group is as described above. It is preferably a deuterated C _1-6 alkyl group, and more preferably a deuterated C _1-3 alkyl group. Examples of deuterated C _1-20 alkyl groups include (but are not limited to) mono-deuterated methyl, mono-deuterated ethyl, di-deuterated methyl, di-deuterated ethyl, tri-deuterated methyl, tri-deuterated ethyl Base etc.

As used herein, "a bond" means that two groups connected by it are connected by a covalent bond.

As used herein, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group, and "C _3-8 cycloalkyl" refers to a cyclic hydrocarbon group containing 3 to 8 carbon atoms, which may preferably be C _3-6 Cycloalkyl, similar in definition; non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl Group, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl, cyclopentyl, and cyclohexenyl.

As used herein, "spirocyclic ring" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between single rings. These can contain one or more double bonds, but none of the rings have fully conjugated π electrons. system. According to the number of rings, spiro rings are classified into double spiro rings or multi spiro rings, preferably double spiro rings. More preferably, it is preferably a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro ring. E.g:

As used herein, "spiro heterocyclic ring" refers to a polycyclic hydrocarbon sharing one atom (called a spiro atom) between single rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(O)n (where n is an integer 0 to 2) of heteroatoms, the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. According to the number of rings, spiro heterocycles are classified into dispiro heterocycles or polyspiro heterocycles, and dispiro heterocycles are preferred. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro heterocyclic ring. E.g:

As used herein, "bridged ring" refers to a polycyclic group that shares two or more carbon atoms. The shared carbon atoms are called bridgehead carbons. The two bridgehead carbons can be a carbon chain or a bond. , Called the bridge. These can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably it is a double ring or a triple ring bridged ring. E.g:

As used herein, "bridged heterocycle" refers to a polycyclic group that shares two or more atoms, where one or more ring atoms are selected from nitrogen, oxygen, or S(O) _n (where n is an integer from 0 to 2 ), the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably a bicyclic or tricyclic bridged heterocyclic ring. E.g:

As used herein, "8 to 10 membered bicyclic ring" refers to a bridged ring containing two rings containing 8 to 10 ring atoms. The bicyclic ring may be a saturated full carbon bicyclic ring or a partially unsaturated full carbon bicyclic ring, and an 8 to 10 membered bicyclic ring Examples include (but are not limited to):

As used herein, "8 to 10 membered bicyclic heterocyclic ring" refers to a two-ring bridged heterocyclic ring containing 8 to 10 ring atoms, wherein 1, 2, 3, 4 or 5 ring carbon atoms are selected from nitrogen , Oxygen or sulfur heteroatoms. Examples of 8- to 10-membered biheterocycles include, but are not limited to, tetrahydroquinoline rings, tetrahydroisoquinoline rings, decahydroquinoline rings, and the like.

As used herein, "C _6-10 aryl" and "C _6-10 aryl ring" are used interchangeably, and both refer to all-carbon monocyclic or fused polycyclic rings with a conjugated π-electron system (that is, sharing adjacent The ring) group of a carbon atom pair refers to an aryl group containing 6 to 10 carbon atoms; phenyl and naphthyl are preferred, and phenyl is more preferred.

As used herein, "amino" refers to NH _2, "cyano" refers to the CN, "Nitro" refers to NO _2, "benzyl" refers to -CH ₂ - phenyl, "oxo" refers to = O, "carboxy" Refers to -C(O)OH, "acetyl" refers to -C(O)CH ₃ , "hydroxymethyl" refers to -CH ₂ OH, and "hydroxyethyl" refers to -CH ₂ CH ₂ OH or -CHOHCH ₃ , "Hydroxy" refers to -OH, "thiol" refers to SH, and the structure of "cyclopropylene" is:

As used herein, "heteroaryl ring" and "heteroaryl" are used interchangeably and refer to having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl ; The ring array shares 6, 10, or 14 π electrons; and in addition to carbon atoms, there are groups with 1 to 5 heteroatoms. "Heteroatom" refers to nitrogen, oxygen, or sulfur.

As used herein, "3 to 7-membered (4 to 7-membered) saturated or partially unsaturated monocyclic ring" refers to a saturated or partially unsaturated, all-carbon monocyclic ring containing 3 to 7 ring atoms. Examples of 3 to 7-membered saturated or partially unsaturated monocyclic rings include (but are not limited to): cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, ring Hexadienyl ring, cycloheptyl ring, cycloheptatrienyl ring, cyclooctyl ring, etc.

As used herein, "5- to 6-membered monocyclic heteroaryl ring" and "5- to 6-membered monocyclic heteroaryl" are used interchangeably, and both refer to a mono-heteroaryl ring containing 5 to 6 ring atoms, Examples include (but are not limited to): thiophene ring, N-alkane pyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole Ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2, 3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine Ring, pyrimidine ring, pyrazine ring, etc.

As used herein, "8 to 10 membered bicyclic heteroaryl ring" and "8 to 10 membered bicyclic heteroaryl ring" are used interchangeably, and both refer to a bicyclic heteroaryl ring containing 8 to 10 ring atoms, for example including (But not limited to): benzofuran, benzothiophene, indole, isoindole, quinoline, isoquinoline, indazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, cinnoline, Phthalazine, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8 -Naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine.

As used herein, "4- to 6-membered saturated monocyclic heterocyclic ring" means that 1, 2, or 3 carbon atoms in a 4- to 6-membered monocyclic ring are selected from nitrogen, oxygen or S(O) _t (where t is an integer 0 The heteroatom to 2) is substituted, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon; preferably 4 to 6 members, more preferably 5 to 6 members. Examples of 4- to 6-membered saturated monocyclic heterocycles include (but are not limited to) azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine , Dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, etc.

As used herein, "substituted" refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independently substituted with each other Ground is substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.

As used herein, "optionally substituted" means that the group is not substituted by a substituent, or one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with a corresponding number of substituents It is more preferable that 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.

As used herein, any group herein may be substituted or unsubstituted. When the above groups are substituted, the substituents are preferably 1 to 5 or less groups independently selected from CN, halogen, C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 Alkyl), C _1-10 alkoxy (preferably C _1-6 alkoxy, more preferably C _1-3 alkoxy), halogenated C _1-8 alkyl (preferably halogenated C _{1- 6} alkyl, more preferably halogenated C _1-3 alkyl), C _3-8 cycloalkyl (preferably C _3-6 cycloalkyl), halogenated C _1-8 alkoxy (preferably halogenated C _1-6 alkoxy, more preferably halogenated C _1-3 alkoxy), C _1-8 alkyl substituted amino, amino, halogenated C _1-8 alkyl substituted amino, acetyl Group, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, nitro, C _6-10 aryl (preferably phenyl), C _3-8 cycloalkoxy (preferably C _3-6 cycloalkoxy), C _2-10 alkenyl (preferably C _2-6 alkenyl, more preferably C _2-4 alkenyl), C _2-10 alkynyl (preferably C _2-6 alkynyl, more preferably C _2-4 Alkynyl), -CONR _a0 R _b0 , -C(O)OC _1-10 alkyl (preferably -C(O)OC _1-6 alkyl, more preferably -C(O)OC _1-3 alkyl ), -CHO, -OC(O)C _1-10 alkyl (preferably -OC(O)C _1-6 alkyl, more preferably -OC(O)C _1-3 alkyl), -SO ₂ C _1-10 alkyl (preferably -SO ₂ C _1-6 alkyl, more preferably -SO ₂ C _1-3 alkyl), -SO ₂ C _6-10 aryl (preferably -SO ₂ C ₆ Aryl, such as -SO ₂ -phenyl), -COC _6-10 aryl (preferably -COC ₆ aryl, such as -CO-phenyl), 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, 4 to 6-membered saturated or unsaturated monocyclic ring, 5- to 6-membered monocyclic heteroaryl ring, 8- to 10-membered bicyclic heteroaryl ring, spiro ring, spiro heterocyclic ring, bridged ring or bridged heterocyclic ring, wherein R _a0 , R _b0 Each is independently hydrogen or C _1-3 alkyl.

The various substituent groups described herein above can themselves be substituted by the groups described herein.

When the 4- to 6-membered (5- to 6-membered) saturated monocyclic heterocyclic ring described herein is substituted, the positions of the substituents may be in their possible chemical positions. Representative substitution situations of exemplary monocyclic heterocyclic rings are shown below :

Wherein "Sub" represents the various substituents described herein;

Represents the connection with other atoms.

Unless otherwise defined, when the 4- to 6-membered saturated monocyclic heterocyclic ring in the present invention is a substituent, it may itself be substituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, Hydroxy, C _1-3 alkyl, O=, NR _a0 R _b0 , hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC _1-3 alkyl, acetyl, halogenated C _1-3 alkyl , C _1-3 alkoxy, C _3-6 cycloalkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, two Oxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, thiophene ring, N-alkylpyrrole ring, furan ring, thiazole ring , Imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine Ring; wherein R _a0 and R _b0 are each independently hydrogen or C _1-3 alkyl.

The "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.

"Pharmaceutically acceptable base addition salts" include, but are not limited to, salts of inorganic bases such as sodium, potassium, calcium and magnesium salts. Including but not limited to salts of organic bases, such as ammonium salt, triethylamine salt, lysine salt, arginine salt and the like.

The "solvate" mentioned in the present invention refers to a complex formed by the compound of the present invention and a solvent. They either react in a solvent or precipitate or crystallize out of the solvent. For example, a complex formed with water is called a "hydrate". Solvates of compounds of formula (I) fall within the scope of the present invention.

The compound represented by formula (I) of the present invention may contain one or more chiral centers and exist in different optically active forms. When a compound contains a chiral center, the compound contains enantiomers. The present invention includes these two isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When the compound of formula (I) contains more than one chiral center, diastereomers may exist. The present invention includes the resolved optically pure specific isomers and mixtures of diastereomers. Diastereoisomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.

The present invention includes prodrugs of the aforementioned compounds. Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released through enzymatic reactions to obtain the parent compound. For specific preparation methods of prodrugs, please refer to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DMBioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).

Generally, the compound of the present invention or its pharmaceutically acceptable salt, or its solvate, or its stereoisomer, or prodrug can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups. The compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like. The above-mentioned dosage forms can be prepared from the active compound and one or more carriers or excipients through general pharmaceutical methods. The above-mentioned carrier needs to be compatible with the active compound or other excipients. For solid preparations, commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose and the like. Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like. The active compound can form a solution or a suspension with the aforementioned carriers.

The composition of the present invention is formulated, quantified and administered in a manner that conforms to medical practice standards. The "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual to be treated, the cause of the condition, the target of the drug, and the mode of administration.

As used herein, "therapeutically effective amount" refers to the amount of the compound of the present invention that will cause an individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc. the amount.

The therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof contained in the pharmaceutical composition of the present invention is preferably 0.1 mg-5 g/kg (body weight).

As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or any type of excipient, which is compatible with the patient and most It is preferably a mammal, more preferably a human, which is suitable for delivering the active agent to the target target without terminating the activity of the agent.

As used herein, "patient" refers to an animal, preferably a mammal, and more preferably a human. The term "mammal" refers to warm-blooded spinal mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.

As used herein, "treating" refers to reducing, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment also includes curing one or more symptoms of the disease or condition, preventing its development, or alleviating to a certain degree.

Preparation

The experimental methods without specific conditions in the following examples are usually in accordance with the conventional conditions such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or in accordance with the conditions described in the manufacturer The suggested conditions.

Unless otherwise defined, the terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the content described can be applied to the present invention.

The compound of formula (I) of the present invention can be easily prepared by various synthetic operations according to the specific compound structure with reference to the exemplary preparation methods in the following examples, and these operations are well mastered by those skilled in the art. The reagents and raw material compounds used in the preparation process are all commercially available, or those skilled in the art can prepare them by referring to known methods according to the structure of different compounds designed.

Compared with the prior art, the main advantages of the present invention are:

The series of compounds of the invention have novel structures and high Nav1.7 inhibitory activity and Nav1.7 selective inhibitory activity. The series of compounds of the present invention not only have obvious pharmacokinetic absorption effect and good bioavailability, but also have obvious metabolic stability, so they are expected to be developed into drugs for extensive pain treatment.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods that do not indicate specific conditions in the following examples usually follow the conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight. Unless otherwise defined, the terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the content described can be applied to the present invention.

As used herein, DMB is 2,4-dimethoxybenzyl, THF is tetrahydrofuran, EA is ethyl acetate, PE is petroleum ether, Ac ₂ O is acetic anhydride, NBS is N-bromosuccinimide, DCM is dichloromethane, AIBN is azobisisobutyronitrile, Pd(dppf)Cl ₂ is 1,1'-bis(diphenylphosphoferrocene]palladium dichloride, TFA is trifluoroacetic acid, TBSCl Is tert-butyldimethylchlorosilane, NCS is N-chlorosuccinimide, DHP is dihydropyran, LiAlH ₄ is lithium aluminum hydride, PMB is p-methoxybenzyl, LiHMDS is di(tri Methylsilyl) lithium amide, Pd ₂ (dba) ₃ is tris(dibenzylideneacetone) dipalladium, RuPhos is 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1 '-Biphenyl, DMAP is 4-dimethylaminopyridine, THP is tetrahydropyran, n-BuLi is n-butyl lithium, TMsOTf is trimethylsilyl trifluoromethanesulfonate, TEBAC is triethylbenzyl Ammonium chloride, HATU is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, DMF is dimethylformamide, DMSO is two Methyl sulfoxide, DIEA is N,N-diisopropylethylamine, BINAP is (2R,3S)-2,2'-bisdiphenylphosphino-1,1'-binaphthyl.

As used herein, room temperature refers to about 20-25°C.

Preparation method of compound 2-a:

Step a: Add N-bromosuccinimide (3.15 g, 17.60 mmol) to a 50 ml acetonitrile solution of compound 2-a-1 (2 g, 16 mmol), and stir at room temperature for 4 hours. After the reaction is over, add sodium thiosulfate to wash, separate the organic phase, extract the aqueous phase with ethyl acetate, separate and combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, add petroleum ether to wash, filter, and dry the filter cake The compound 2-a-2 (2g) was obtained, which was directly used in the next reaction with a purity of 100% and a yield of 80%. MS m/z (ESI): 204[M+H] ⁺ .

Step b: Add sodium nitrite (405 mg, 5.91 mmol) to 30 ml of acetic acid solution of compound 2-a-2 (1 g, 4.92 mmol), and stir at room temperature for 4 hours. After the reaction is over, add sodium hydroxide (50%) to adjust the pH to 7-8, separate the organic phase, extract with ethyl acetate, separate and combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 2-a -3 (1g), directly used in the next reaction, purity 100%, yield 80%, MS m/z (ESI): 215[M+H] ⁺ .

Step c: To compound 2-a-3 (3g, 14mmol), 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene (4.05g, 14mmol) in 60ml dimethylformaldehyde Cesium carbonate (10g, 30mmol) was added to the amide solution and stirred at room temperature for 4 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by Combi-flash column chromatography to obtain compound 2-a-4 (0.80g), which was directly used in the next reaction with a purity of 66% and a yield of 80%. MS m/ z(ESI): 423[M+H] ⁺ .

Step d: Dissolve compound 2-a-4 (1.27g, 2.99mmol) in methanol (25mL), add Pd(dppf) ₂ Cl ₂ (127mg), Et ₃ N (0.67g, 6mmol), at 0.6MPa carbon monoxide Stir at 100°C for 18h under pressure. It was filtered and spin-dried, and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid compound 2-a (1.02 g, yield 85%). MS m/z(ESI): 403.0[M+H] ⁺

Preparation method of compound 4-a:

Step: Dissolve compound 4-a-1 (5g, 23.20mmol) in methanol (50mL), add Pd(dppf) ₂ Cl ₂ (0.85g, 1.20mmol), Et ₃ N (4.70g, 46.40mmol), in Stir at 100°C for 18 hours under 0.6MPa carbon monoxide pressure. It was filtered and spin-dried, and purified by column chromatography (dichloromethane: methanol = 10:1) to obtain 4.70 g of crude product. 30 mL of petroleum ether: ethyl acetate=1:1 was added to the crude product, stirred for 5 minutes, filtered the insoluble solid, and dried to obtain a yellow solid compound 4-a (2.40 g, yield 53%). MS m/z (ESI): 195.0 [M+H] ⁺ .

Preparation method of compound 6-a:

Step a: Compound 2-a-2 (29.01g, 0.14mol) was dissolved in DMF (0.3L) and NCS (24.88g, 0.19mol) was added at 0°C, and the reaction was stirred at 70°C for 2 hours. After cooling, add 1 liter of saturated sodium chloride solution, extract with ethyl acetate (3*1L), dry and spin dry. Purification by column chromatography (petroleum ether: ethyl acetate = 10:1) gave compound 6-a-3 (22.38 g, yield 66%) as a pale yellow oil. MS m/z (ESI): 239.9 [M+H] ⁺ .

Step b: Dissolve compound 6-a-3 (22.31g, 0.093mol) in acetic acid/toluene (500mL, 5% v/v) and add isoamyl nitrite (10.67g, 0.10mol) at 0°C, The reaction was stirred at 0°C for 1 hour. Potassium acetate (27.30g, 0.28mol) was added, the reaction was stirred at room temperature for 18 hours, 1 liter of saturated sodium chloride solution was added, extracted with ethyl acetate (3*1L), dried and spin-dried. Purification by column chromatography (petroleum ether: ethyl acetate = 10:1) gave compound 6-a-4 (11.31 g, yield 48%) as a white solid. MS m/z (ESI): 250.9 [M+H] ⁺ .

Step c: Dissolve compound 6-a-4 (11.31g, 0.045mol) in methanol (250mL), add Pd(dppf) ₂ Cl ₂ (1.10g), Et ₃ N (9.17g, 0.091mol), in 0.6 Stir at 100°C for 18 hours under MPa carbon monoxide pressure. It was filtered and spin-dried, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain white solid compound 6-a (1.41 g, yield 10%). MS m/z (ESI): 229.0 [M+H] ⁺ .

Preparation method of compound 7-a:

Step a: Mix compound 7-a-1 (8g, 0.042mol) and aluminum trichloride (13.7g, 0.10mol) together, and stir at 60°C for 10 minutes. Then, acetyl chloride (4.90 g, 0.063 mol) was slowly added dropwise to the reaction system at 60°C, and after the addition, the reaction was stirred at 95°C for 6 hours. After the reaction, the system was cooled to -10°C, ice water (15g) was slowly added, extracted with ethyl acetate (3*100mL), dried and spin-dried to obtain a crude product (8g) of compound 7-a-2 as a yellow oil.

Step b: Compound 7-a-2 (8g, 0.034mol) was dissolved in 2,4-dioxane (20mL), hydrazine hydrate (5mL) was slowly added, and the reaction was stirred at 130°C for 16 hours. TLC monitors the disappearance of the reaction raw materials, the reaction solution is cooled to room temperature and added with 50 mL of water, extracted with ethyl acetate (3*100 mL), and the organic phase is dried and spin-dried. Purification by column chromatography (petroleum ether: ethyl acetate = 10:1) gave compound 7-a-3 as a yellow oil (3.80 g, yield 40% in the second step).

Step c: Dissolve compound 7-a-3 (3g, 0.013mol) in methanol (50mL), add Pd(dppf)2Cl2 (1g, 1.30mmol) and bubbling with carbon monoxide gas. The system was stirred at 100°C for 16 hours. LC-MS monitored the disappearance of the reaction materials, the mixture was filtered, and the filter residue was washed with methanol (100 mL). The filtrate was spin-dried. Purification by column chromatography (petroleum ether: ethyl acetate = 10:1 to 8:1) gave compound 7-a (1.20 g, yield 44%) as a yellow solid.

Example 2 1-(3-Chloro-4-(trifluoromethoxy)benzyl)-4-fluoro-N-(methylsulfonyl)-1H-indazole-5-carboxamide (Z-2) Preparation

Step 1: Add sodium hydroxide (4N, 20ml) to 20ml of dioxane solution of compound 2-a (0.50g, 0.0012mol), and stir at room temperature for 1 to 2 hours. After the reaction was completed, hydrochloric acid (2N) adjusted the pH to 2~3, added ethyl acetate, separated the organic phase, washed with 25% brine, separated the organic phase, and concentrated under reduced pressure to obtain the crude compound 2-b (0.46g). MS m/z(ESI): 389.02[M+H]+

Step 2: Add DIPEA (N,N-diisopropylethylamine) (0.20g, 0.0016mol), HATU(2-(7) to 20ml dichloromethane solution of compound 2-b (0.25g, 0.00064mol) -Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate) (0.29g, 0.00077mol), methylsulfonamide (0.090g, 0.00095mol), room temperature Stir for 2 to 3 hours. After the reaction was completed, water was added, the organic phase was separated, and the solid was concentrated under reduced pressure to obtain 0.18 g of solid. After liquid phase separation and purification, solid compound Z-2 (38.65 mg) was obtained, with a yield of 12.9%. MS m/z(ESI): 466.7[M+H]+

Example 4 1-(3-Chloro-4-(trifluoromethoxy)benzyl)-6-fluoro-N-(methylsulfonyl)-1H-indazole-5-carboxamide (Z-4) Preparation

Step 1: Compound 4-a (500mg, 2.58mmol), 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene (745mg, 2.58mmol), cesium carbonate (1.68g, 5.16 mmol) in 10 ml of dimethylformamide solution, stirred at room temperature for 5 hours. After the reaction is over, pour into water, add dichloromethane for extraction, separate the organic phase, wash with water (4×20ml), separate the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Purify by chromatography to obtain a white solid compound 4-b (754mg), directly used in the next reaction, purity 97%, MS m/z (ESI): 403[M+H] ⁺ .

Step 2: A mixture of compound 4-b (200 mg, 0.50 mmol) and lithium hydroxide (84 mg, 2 mmol) in 4 ml methanol and 1 ml aqueous solution was stirred at room temperature for 4 hours. At the end of the reaction, the reaction solution was concentrated under reduced pressure, water was added, and the pH was adjusted to 2 with hydrochloric acid, extracted with ethyl acetate, the combined organic phase was separated, washed with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain white The solid compound 4-c (194 mg) was directly used in the next reaction with a purity of 100%. MS m/z (ESI): 389 [M+H] ⁺ .

Step 3: Compound 4-c (102mg, 0.26mmol), methylsulfonamide (24mg, 0.26mmol), HATU (2-(7-azobenzotriazole)-N, N, N', N' -Tetramethylurea hexafluorophosphate) (110 mg, 0.29 mmol), a mixture of triethylamine (54 mg, 0.53 mmol) in 3 ml of dichloromethane, stirred at room temperature for 4 hours. After the reaction is over, the reaction solution is washed with water to separate the organic phase, washed with saturated brine, the organic phase is separated, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product. After preparative liquid phase separation and purification, a yellow solid compound Z-4 (9.80 mg) was obtained with a purity of 83%. Popper data: MS m/z(ESI): 466[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.23 (s, 1H), 8.16 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 11.2 Hz, 1H), 7.60 (d, J =2.0Hz, 1H), 7.54(dd, J=1.2Hz, 8.4Hz, 1H), 7.27(dd, J=2.0Hz, 8.4Hz, 1H), 5.68(s, 2H), 3.01(s, 3H) .

Example 5 Preparation of 1-(3,4-dichlorobenzyl)-6-fluoro-N-(methylsulfonyl)-1H-indazole-5-carboxamide (Z-5)

Step 1: Compound 4-a (500mg, 2.58mmol), 4-(bromomethyl)-1,2-dichlorobenzene (619mg, 2.58mmol), cesium carbonate (1.68g, 5.15mmol) in 10ml dimethyl The mixture of the formamide solution was stirred at room temperature for 4 hours. After the reaction is over, pour into water, extract with dichloromethane (2×30ml), separate and combine the organic phases, wash with water (4×20ml), separate the organic phase, wash with saturated brine (20ml), dry with anhydrous sodium sulfate, filter, and reduce the filtrate. The crude product was obtained by pressure concentration and purified by Combi-flash column chromatography [PE:EA=100:0～80:20] to obtain the white solid compound 5-b (344mg), which was directly used in the next reaction. Yield: 37.8%; Purity: 95%; MS m/z (ESI): 353.0 [M+H] ⁺ .

Step 2: Add lithium hydroxide (72 mg, 1.70 mmol) to compound 5-b (150 mg, 0.43 mmol) in 8 ml of methanol and 2 ml of water, and stir overnight at room temperature. After the reaction was completed, most of the methanol was concentrated under reduced pressure, 10ml of water was added, the mixture was adjusted to pH 3, filtered, the filter cake was washed with water, and dried to obtain a white solid compound 5-c (127mg), which was directly used in the next reaction with a purity of 94.1%. The yield was 88.2%. MS m/z (ESI): 339.0 [M+H] ⁺ .

Step 3: To compound 5-c (127mg, 0.38mmol), methylsulfonamide (36mg, 0.38mmol), triethylamine (76mg, 0.75mmol) in 5ml dichloromethane solution was added HATU (2-(7- Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate) (157mg, 0.41mmol), stirred at room temperature for 2 hours. After the reaction is over, pour into 20ml water, extract with dichloromethane (2×20ml), separate and combine the organic phases, wash with water (2×10ml), separate the organic phase, wash with saturated brine (10ml), dry with anhydrous sodium sulfate, filter, and filtrate The crude product was obtained by concentration under reduced pressure, and the white solid compound Z-5 (10.60 mg) was obtained by preparative liquid phase separation and purification, with a purity of 100% and a yield of 6.8%. Popper data: MS m/z (ESI): 415.9 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ , 400MHz): = 8.24 (s, 1H), 8.16 (d, J = 6.8 Hz, 1H), 7.70 (d, J = 10.8 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.19 (d, J=8.0 Hz, 2H), 5.65 (s, 2H), 3.08 ppm (br.s., 3H).

Example 6 Preparation of 7-chloro-1-(3,4-dichlorobenzyl)-4-fluoro-N-(methylsulfonyl)-1H-indazole-5-carboxamide (Z-6)

Step 1: Add 4-(bromomethyl)-1,2-dichlorobenzene (0.46g, 0.0019mmol), cesium carbonate to 10ml dimethylformamide solution of compound 6-a (0.4g, 0.0017mol) (1.42g, 0.0043mol), stir at room temperature for 2-4 hours. After the reaction is over, pour into water, extract with ethyl acetate, separate and combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is purified by Combi-flash column chromatography to obtain a white solid compound 6 b (0.17g), used directly in the next reaction. MS m/z (ESI): 386.98 [M+H] ⁺ .

Step 2: Add sodium hydroxide (4N, 16ml) to the 16ml dioxane solution of compound 6-b (0.15g, 0.00038mol), and stir at room temperature for 2 hours. After the reaction is over, adjust the pH to 2～3 with hydrochloric acid (2N), add ethyl acetate, separate the organic phase, wash with saturated brine, separate the organic phase, and concentrate under reduced pressure to obtain crude compound 6-c (0.13g), which is used directly in the next step reaction. MS m/z(ESI): 372.96[M+H] ⁺

Step 3: Add HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetrazolium to compound 6-c (0.13g, 0.00034mol) in 5ml dichloromethane solution Methylurea hexafluorophosphate) (0.16g, 0.00042mol), methylsulfonamide (0.049g, 0.00052mol), DIPEA (N,N-diisopropylethylamine) (0.11g, 0.00087mol), 30 Stir at Celsius for 1 to 2 hours. After the reaction was completed, water was added, the organic phase was separated, and the solid was concentrated under reduced pressure to obtain 0.11 g of solid. After liquid phase separation and purification, solid compound Z-6 (12.15 mg) was obtained with a yield of 7.9%. MS m/z(ESI): 449.96[M+H] ⁺

Example 9 1-(3-Chloro-4-(trifluoromethoxy)benzyl)-3-methyl-N-(methylsulfonyl)-1H-indazole-5-carboxamide (Z-9 ) Preparation

Step 1: Add iodine (3.05g, 12mmol) and potassium hydroxide (1g, 18mmol) to the 10ml dimethylformamide solution of compound 9-a (1.06g, 6mmol), and stir at room temperature for 2 hours. After the reaction is over, add ethyl acetate, wash with saturated sodium thiosulfate, separate and combine the organic phase, wash with saturated sodium bicarbonate, separate and combine the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is purified by chromatography The yellow solid compound 9-b (1.30 g) was directly used in the next reaction. The yield was 72%, and the purity was 74%. MS m/z (ESI): 302.9 [M+H] ⁺ .

Step 2: Add 3,4-dihydro-2H-pyran (336mg, 4mmol) and p-toluenesulfonic acid (30mg) to 10ml dichloromethane solution of compound 9-b (600mg, 2mmol) and stir at room temperature overnight. After the reaction is over, add dichloromethane, wash with saturated sodium bicarbonate, separate and combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a yellow oily compound, which is purified by chromatography (PE:EA=4:1) to obtain white The solid compound 9-c (800 mg) was directly used in the next reaction with a yield of 100% and a purity of 85%. MS m/z (ESI): 302.9 [M+H-THP] ⁺ .

Step 3: To a mixed solution of compound 9-c (600mg, 1.56mmol) in 6ml toluene and 1ml water was added trimethylboroxine (300mg, 2.34mmol), cesium carbonate (1g, 3.12mmol), four three Palladium phenylphosphorus (60mg), under the protection of argon, stirred overnight at 120°C. After the reaction is complete, cool to room temperature, add ethyl acetate, wash with saturated sodium bicarbonate, separate and combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a yellow oil, which is purified by chromatography to obtain a yellow oily compound 9-d (300mg), directly used in the next reaction, yield 71%, purity 61%, MS m/z (ESI): 191.1 [M+H] ⁺ .

Step 4: Add 2ml of hydrochloric acid/dioxane to compound 9-d (200mg, 0.73mmol) and stir at 40°C for 3 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was concentrated under reduced pressure to obtain a yellow solid compound 9-e (150 mg), which was directly used in the next reaction with a yield of 100%. MS m/z (ESI): 191 [M+H] ⁺ .

Step 5: Add 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene (274mg) to the solution of compound 9-e (150mg, 0.79mmol) in 4ml of anhydrous dimethylformamide , 0.95mmol), cesium carbonate (520mg, 1.58mmol), stirred at room temperature for 3 hours. After the reaction is over, add ethyl acetate, wash with saturated sodium bicarbonate, separate and combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a yellow oil 9-f (200mg), which is directly used in the next reaction with purity 32%, MS m/z (ESI): 399.1 [M+H] ⁺ .

Step 6: Add sodium hydroxide (50 mg, 1.26 mmol) to compound 9-f (250 mg, 0.63 mmol) in 2 ml methanol and 2 ml aqueous solution, and stir at room temperature for 2 hours. After the reaction is over, adjust the pH to 1 with hydrochloric acid (1N), extract with ethyl acetate, separate and combine the organic phases, wash with saturated brine, separate the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a yellow solid compound 9-g (170mg), directly used in the next reaction, purity 44%, yield 70%. MS m/z (ESI): 385.1 [M+H] ⁺ .

Step 7: To compound 9-g (100mg, 0.26mmol) in 2ml 1,2-dichloroethane, methylsulfonamide (30mg, 0.31mmol), HATU (2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate) (150mg, 0.39mmol), diisopropylethylamine (93mg, 0.72mmol), 4-dimethylaminopyridine (4mg, 0.030 mmol), stirring at 60 degrees Celsius for 1 hour. After the reaction is completed, the reaction solution is cooled to room temperature, the reaction solution is washed with saturated sodium bicarbonate, the organic phase is separated, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a yellow solid. After preparative liquid phase separation and purification, a white solid compound Z-9 (18 mg) was obtained with a purity of 100% and a yield of 15%. Popper data: MS m/z (ESI): 462.0 [M+H] ⁺ . 1H NMR (400MHz, DMSO-d6): δ 8.32 (s, 1H), 8.02 (d, J = 8 Hz, 1H), 7.59-7.57 (m, 2H), 7.52 (d, J = 8 Hz, 1H), 7.24 (d, J=8 Hz, 1H), 5.62 (s, 2H), 3.42 (s, 3H), 2.85 (s, 3H).

Example 11 1-(3-Chloro-4-(trifluoromethoxy)benzyl)-6-fluoro-3-methyl-N-(methylsulfonyl)-1H-indazole-5-carboxamide (Z-11) Preparation

Step 1: Compound 7-a (150mg, 0.72mmol), 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene (209mg, 0.72mmol), cesium carbonate (469mg, 1.44mmol) ) In 5 ml of anhydrous dimethylformamide solution, stirred at room temperature for 4 hours. After the reaction is over, pour into water, add ethyl acetate, separate the organic phase, wash with water, separate the organic phase, wash with saturated brine, separate the organic phase, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain a crude product, pass it through a Combi-flash column Chromatographic purification gave compound 11-b (291 mg) as a white solid, which was directly used in the next reaction with a purity of 92%, MS m/z (ESI): 417.0 [M+H] ⁺ .

Step 2: A mixture of compound 11-b (100 mg, 0.24 mmol) and lithium hydroxide (41 mg, 0.96 mmol) in 4 ml methanol and 1 ml aqueous solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, added with water, adjusted to pH 2 with hydrochloric acid, filtered, and the filter cake was collected and dried to obtain a white solid compound 11-c (91 mg), which was directly used in the next reaction with a purity of 81.5% and a yield of 94% . MS m/z (ESI): 403.1 [M+H] ⁺ .

Step 3: Compound 11-c (106mg, 0.26mmol), methylsulfonamide (50mg, 0.53mmol), HATU (2-(7-azobenzotriazole)-N, N, N', N' -Tetramethylurea hexafluorophosphate) (100mg, 0.26mmol), diisopropylethylamine (68mg, 0.53mmol), 4-dimethylaminopyridine (4mg, 0.026mmol) in 3ml dimethylformamide The mixture was stirred at 60 degrees Celsius for 24 hours. After the reaction is over, cool to room temperature, pour the reaction solution into water, extract with ethyl acetate, separate the organic phase, wash with water, separate the organic phase, wash with saturated brine, separate the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain Crude. After preparative liquid phase separation and purification, a yellow solid compound Z-11 (9.2 mg) was obtained with a purity of 100%. Popper data: MS m/z (ESI): 480.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.16 (d, J = 6.8 Hz, 1H), 7.70 (d, J = 11.2 Hz, 1H), 7.60 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 5.60 (s, 2H), 3.20 (s, 3H), 1.24 (s, 3H).

Electrophysiological measurement

Test Example 1 Manual patch clamp experiment of hNav1.7 channel

Patch voltage clamp electrophysiology can directly measure and quantify the current blocking of voltage-gated sodium channels (various Navs) and determine the time and voltage dependence of the blocking. It has been interpreted as the resting, opening and The binding difference of the inactivation state reflects the inhibitory or activating effect of the compound (Hille, B., Journal of General Physiology (1977), 69:497-515).

The representative compounds of the present invention are carried out using manual patch clamp experiments. The purpose of this study is to use the manual patch clamp method to test the effect of compounds on the ion channel currents on stable cell lines transfected with specific ion channels. The stable cell line CHO-hNav1.7 used was from Genionics.

The manual patch clamp experiment protocol is as follows:

(1) Preparation of solution and compound: whole-cell patch clamp technique was used to record hNav1.7 current. In the experiment, the composition (mM) of the extracellular fluid: HEPES: 5, NaCl: 40, KCl: 3, CaCl ₂ :1, MgCl ₂ :1, CdCl ₂ : 0.1, TEA-Cl: 20. Adjust the pH value to 7.3 with NaOH, and adjust the osmotic pressure to 310-320mOsm with sucrose, and store at 4°C after filtration. The composition of the intracellular fluid (mM): HEPES: 10, NaCl: 10, CsOH: 5, CsF: 140, EGTA: 1. Adjust the pH value to 7.3 with CsOH, and adjust the osmotic pressure to 280-290mOsm with sucrose, and store at -20°C after filtration.

The positive control drug and the test compound are first dissolved in 100% DMSO (Sigma-Aldrich, D2650, and configured as a stock solution of a certain concentration (100nM, 1000nM). Before the experiment, the above-mentioned stock solution is serially diluted with DMSO, and then extracellular The solution is further diluted to obtain a test solution of the required concentration. The final concentration of DMSO in the extracellular solution does not exceed 0.30%.

(2) Manual patch clamp experiment: Take the cell suspension and add it to a 35mm petri dish, and place it on the inverted microscope stage. After the cells adhere to the wall, they are perfused with extracellular fluid at a flow rate of 1-2 mL/min. The glass microelectrode is drawn by a microelectrode drawing instrument in two steps, and its water resistance value is 2-5MΩ. Through Digidata 1440 (Molecular Devices) and pCLAMP software (version 10.2, Molecular Devices) A/DD/A digital-to-analog conversion, stimulus delivery and signal acquisition; patch clamp amplifier (Multiclamp 700B, Molecular Devices) amplifies the signal and filters to 4KHz .

Two different voltage stimulation procedures were used in the hNav1.7 manual patch clamp experiment.

One is the inactivation stimulation program, the clamping potential is set at V _{1/2 of the} corresponding channel, that is, about 50% of the channels are in an inactive state. Then apply voltage to -120mV for 50ms. Then it depolarizes to -10mV, draws sodium current for 20ms, and finally returns to the clamping potential. This kind of stimulation program can also be called a channel state-dependent voltage stimulation program.

The other is a non-inactivation stimulation program, which keeps the clamping potential at -120mV, gives a voltage stimulation to -10mV, and elicits a sodium current for 20ms, and finally returns to the clamping potential. That is to say, under the condition of this kind of stimulation program, all the channels have not experienced inactivation state, but directly activated from the resting state.

The time interval of the above two voltage stimulation procedures is 10s. The inhibitory effect of the compound is calculated by the current change before and after the addition of the drug, and the IC ₅₀ value is obtained by fitting the Hill equation. If the compound shows a certain multiple difference in the channel effect under the above two different voltage stimuli, then the compound is state-dependent on the channel.

data analysis

Standardize the current after each drug concentration with the blank control current (compound peak tailing current/control peak tailing current), and then calculate the inhibition rate corresponding to each drug concentration (1-(compound peak tailing current/control Peak tailing current)). Calculate the average and standard error for each concentration, and use the following equation to calculate the half inhibitory concentration of each compound:

Inhibition rate = 1/(1+(IC ₅₀ /c) ^h )

The above equation is used to perform a nonlinear fitting of the dose-dependent effect, where c represents the drug concentration, IC ₅₀ is the half-inhibitory concentration, and h represents the Hill coefficient. The curve fitting and IC ₅₀ calculation are done using IGOR software.

Test the representative compound of the present invention has a higher inhibitory activity on Nav1.7 at both 100nM (%) and 1000nM (%) concentrations. The test results show that the representative compound of the present invention has a higher inhibitory activity on Nav1.7 .

All documents mentioned in the present invention are cited as references in this application, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

1. A compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof:

   

   In the formula, R ₀ is C _1-10 alkyl or NR _a0 R _b0 ;

   R ₁ , R ₂ , and R ₃ are each independently hydrogen, halogen, C _1-10 alkyl, halogenated C _1-10 alkyl, C _1-10 alkoxy or C _3-8 cycloalkyl;

   R ₄ , R ₅ , and R ₆ are each independently hydrogen, halogen, C _1-10 alkyl, halogenated C _1-10 alkyl, -O-(CH ₂ ) _n -R _a ;

   L is CH ₂ ;

   Z ₁ is N; Z ₂ is N; Z ₃ is CR _c ; Z ₄ is N or CR _d ;

   

   Single bond or double bond;

   Where R _a is: hydrogen, C _1-10 alkyl, halogenated C _1-10 alkyl, NR _a0 R _b0 , C _3- which is unsubstituted or substituted with 1, 2 or 3 C _1-10 alkyl ₈ -cycloalkyl, or unsubstituted or 4- to 6-membered saturated monocyclic heterocyclic ring substituted with 1, 2 or 3 C _1-10 alkyl groups;

   R _c and R _d are each independently hydrogen, C _1-10 alkyl, halogenated C _1-10 alkyl, or C _3-8 cycloalkyl;

   n is 0, 1, 2 or 3;

   R _a0 and R _b0 are each independently hydrogen or C _1-8 alkyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein R ₆ is hydrogen, halogen or -O-(CH ₂ ) _n -R _a, wherein R _a is methyl, ethyl, isopropyl, cyclopropyl substituted methyl or trifluoromethyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein R ₅ is halogen.
4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein R ₄ is hydrogen.
5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein R ₀ is a C _1-3 alkyl group.
6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein Z ₄ is N or CH.
7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein the structure

   

   Selected from the following structures:

   
8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein the compound is a compound selected from the following group:

   
9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof; and a pharmaceutically acceptable Carrier.
10. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, or the pharmaceutical composition according to claim 9 in the preparation of the treatment of diseases or The application in medicine for a disease, the disease or disease is selected from pain, depression, cardiovascular disease, respiratory system disease, mental disease or a combination thereof.