CN111825595A

CN111825595A - Sodium channel blockers

Info

Publication number: CN111825595A
Application number: CN201910298249.8A
Authority: CN
Inventors: 方文奎
Original assignee: Shandong Xuanzhu Pharma Co Ltd; Raqualia Pharma Inc
Current assignee: Shandong Xuanzhu Pharma Co Ltd; Raqualia Pharma Inc
Priority date: 2019-04-15
Filing date: 2019-04-15
Publication date: 2020-10-27

Abstract

The invention belongs to the field of medicines, and particularly relates to a compound shown as a formula (I), a pharmaceutically acceptable salt, a solvate or an isomer thereof, a pharmaceutical composition containing the compound, the pharmaceutically acceptable salt, the solvate or the isomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt, the solvate or the isomer thereof, and application of the compound, the pharmaceutically acceptable salt, the solvate or the isomer thereof in preparation of medicines for treating and/or preventing Na and Na of a subject_v1.7 channel-associated diseases.

Description

Sodium channel blockers

Technical Field

Background

Voltage-gated sodium channels (VGSCs) are transmembrane macromolecular proteins that can stimulate the formation and conduction of action potentials in cells, and selectively allow sodium to pass through the membrane. Consists of an alpha subunit and one or several beta subunits. The alpha subunit is a functional subunit comprising four homologous domains (DomainI, II, III and IV), each domain comprising six transmembrane regions (Segments). Beta subunit isSingle transmembrane glycoproteins have important regulatory roles in channel gating, voltage-dependent activation and inactivation, subcellular localization, and tissue-specific distribution. VGSCs have at least 9 subtypes (Na) according to the difference of alpha subunit gene sequence_v1.1－Na_v1.9), the tenth subtype NaX/NaG may also function as sodium channels. The designation of VGSCs is specified as Na_VThe chemical symbol (Na) and the major physiological regulator, voltage (v), representing the permeant ion, followed by a number separated by a decimal point, represent, in turn, the subfamily of the channel and the homoisomer. VGSCs of different subtypes have large differences in tissue distribution, biophysical properties, drug sensitivity, and the like, and are specifically shown in the following table:

classification of Voltage-gated sodium channels

CNS: the central nervous system; PNS: peripheral nervous system

Sodium channel inhibitors are commonly used clinically as antiepileptic, anti-neurological, anti-arrhythmic agents, but there is increasing evidence that sodium channels may play an important role in a variety of pain states, especially Na_v1.7 channels. Na (Na)_v1.7 is a tetrodotoxin-sensitive sodium channel encoded by the SCN9A gene sequence, which is selectively highly expressed in peripheral nerve endings and sympathetic nerves and distributed in the sensory impulse-inducing peripheral region. With Na_v1.4 and Na_v1.6 similarly, Na_v1.7 the current can be quickly activated and quickly deactivated; in contrast, Na_v1.7 recovery from the inactivated state is slower. Further, Na_v1.7 has the characteristic of slow inactivation under negative membrane potential. From the early stages of dorsal root nerve electrical activity generation, peripheral excitation can induce membrane potential depolarization. The subthreshold sodium current can improve depolarization level of neurons to external stimulation, so that impulse is amplified to activate nociceptorsNa on_v1.8 channels. Na (Na)_v1.7 the "amplifier effect" that amplifies the initial pain electrical signal and promotes sustained excitation of the nerve is a special function distinct from other sodium channel subtypes.

Cox et al in UK reported for the first time in Nature to encode voltage-gated Na_V1.7 SCN9A gene mutation in channel led to the unexpected finding that inherited individuals were free of pain. The genetically mutated individual has congenital analgesia, but the other functions of the body are completely normal, which suggests that Na_V1.7 channels may be drug targets for selective treatment of pain without side effects. There is evidence to date that Na is present_V1.7 channels are associated with diseases such as acute pain, chronic pain, inflammatory pain and/or neuropathic pain.

At present, sodium channel blocker medicaments which can be used for treating painful diseases have poor selectivity and Na blocking effect_V1.7 channels while blocking Na_V1.5 channels, thereby causing strong side effects such as arrhythmia and the like, and therefore, the research and development of the sodium channel blocker with high efficiency, high selectivity and low toxicity has important clinical significance for treating various painful diseases.

Disclosure of Invention

It is an object of the present invention to provide a compound useful as Na_v1.7 channel blocker compounds, preferably the compounds of the present invention bind Na with high selectivity_v1.7 channels, for other sodium channels, especially Na_v1.5 channels showed little affinity.

In one aspect, the present invention provides a compound of formula (I), a pharmaceutically acceptable salt, solvate, or isomer thereof,

wherein R is¹Selected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylamino radical C_1-6An alkyl group, a carboxyl group,two (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylaminocarbonyl radical C_1-6Alkyl, di (C)_1-6Alkyl) aminocarbonyl group C_1-6Alkyl radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl, 3-8 membered cycloalkyl C_1-6Alkyl, 3-8 membered cycloalkylcarbonyl C_1-6Alkyl, 3-8 membered heterocyclyl C_1-6Alkyl and 3-8 membered heterocyclylcarbonyl C_1-6An alkyl group;

R²selected from hydrogen, amino, C_1-6Alkyl, halo C_1-6Alkyl, optionally substituted with one or more (e.g., 2,3,4,5, or 6) Q¹Substituted of the following groups: 3-15 membered cycloalkyl, 3-15 membered cycloalkyl C_1-6Alkyl, 3-15 membered cycloalkyl C_1-6Alkoxy, 3-15 membered heterocyclyl C_1-6Alkyl, 3-15 membered heterocyclyl C_1-6Alkoxy, 6-12 membered aryl C_1-6Alkyl, 5-12 membered heteroaryl and 5-12 membered heteroaryl C_1-6An alkyl group; each Q¹Independently selected from halogen, hydroxy, amino, carboxy, cyano, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino and di (C)_1-6Alkyl) amino;

R³、R⁴、R⁵each independently selected from hydrogen, halogen, hydroxy, amino, cyano, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy and 3-8 membered cycloalkyl;

R⁶selected from hydrogen, C_1-6Alkyl and halo C_1-6An alkyl group;

x is selected from C-R⁷Or N, said R⁷Selected from hydrogen, halogen, hydroxy, amino, carboxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-12 membered aryl and 5-12 membered heteroaryl;

ring a is absent, or selected from optionally substituted with one or more (e.g., 2,3,4,5, or 6) Q²Substituted 3-15 membered cycloalkyl, 3-15 membered heterocyclyl, 5-15 membered spirocyclyl, 5-15 membered spiroheterocyclyl, 5-15 membered bridged cyclyl, 5-15 membered bridged heterocyclyl, 6-12 membered aryl and 5-12 membered heteroaryl; each Q²Independently selected from halogen, hydroxy, amino, carboxy, cyano, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, C_1-6Alkyl carbonyloxy, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl and C_1-6An alkylsulfonylamino group;

l is absent, or is selected from optionally substituted with one or more (e.g., 2,3,4,5, or 6) Q³Substituted C_1-6Alkylene radical, C_2-6Alkenylene and C_2-6An alkynylene group; said C is_1-6Alkylene radical, C_2-6Alkenylene radical, C_2-6Any one or more carbon atoms of the alkynylene group being optionally substituted with O, NR⁸C (O), S, S (O) or S (O)₂Is replaced by one or more hetero atoms or groups, said R⁸Selected from hydrogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl and C_1-6An alkylsulfonyl group; each Q³Independently selected from halogen, hydroxy, amino, carboxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-12 membered aryl and 5-12 membered heteroaryl;

and, rings a and L cannot be simultaneously absent;

ar is selected from optionally substituted with one or more (e.g., 2,3,4,5, or 6) Q⁴Substituted 6-12 membered aryl and 5-12 membered heteroaryl; each Q⁴Independently selected from halogen, hydroxy, amino, carboxyl, nitro, cyano, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylamino radical C_1-6Alkyl, di (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl radical, C_1-6Alkylaminocarbonyl, di (C)_1-6Alkyl) aminocarbonyl, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl radical, C_1-6Alkylsulfonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkyl C_1-6Alkyl, 3-8 membered cycloalkyl C_1-6Alkylamino, 3-8 membered cycloalkyl C_1-6Alkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclyl C_1-6Alkyl, 3-8 membered heterocyclyl C_1-6Alkylamino and 3-8 membered heterocyclyl C_1-6An alkoxy group.

In certain embodiments, R¹Selected from hydrogen, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylsulfonyl, 3-8 membered cycloalkyl and 3-8 membered heterocyclyl;

R²selected from hydrogen, amino, C_1-6Alkyl, halo C_1-6Alkyl and optionally substituted by 1-3Q¹Substituted of the following groups: 3-8 membered cycloalkyl, 3-8 membered cycloalkyl C_1-6Alkyl, 3-8 membered cycloalkyl C_1-6Alkoxy, 3-to 8-membered heterocyclyl C_1-6Alkyl and 3-8 membered heterocyclyl C_1-6An alkoxy group; each Q¹Independently selected from halogen, hydroxy, amino, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino and di (C)_1-6Alkyl) amino;

R³、R⁴、R⁵each independently selected from hydrogen, halogen, hydroxy, amino, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl and halo C_1-6Alkoxy radical；

R⁶Selected from hydrogen and C_1-6An alkyl group;

x is selected from C-R⁷And N, said R⁷Selected from hydrogen, halogen, hydroxy, amino, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl, 3-8 membered cycloalkyl and 3-8 membered heterocyclyl;

ring A is absent, or is optionally substituted with 1-3Q²Substituted 3-10 membered cycloalkyl and 3-10 membered heterocyclyl; each Q²Independently selected from halogen, hydroxy, amino, carboxy, cyano, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, C_1-6Alkylcarbonyloxy and C_1-6An alkylamido group;

l is absent, or is optionally substituted by 1-3Q³Substituted C_1-6Alkylene radical of the formula C_1-6Any one or more carbon atoms of the alkylene group being optionally O, NR⁸C (O), S, S (O) or S (O)₂Is replaced by one or more hetero atoms or groups, said R⁸Selected from hydrogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl and C_1-6An alkylsulfonyl group; each Q³Independently selected from halogen, hydroxy, amino, C_1-6Alkyl radical, C_1-6Alkoxy and halo C_1-6An alkyl group;

and, rings a and L cannot be simultaneously absent;

ar is selected from the group consisting of optionally substituted 1-3Q⁴Substituted 6-10 membered aryl and 5-10 membered heteroaryl; each Q⁴Independently selected from halogen, hydroxy, amino, nitro, cyano, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylsulfonyl, 3-6 membered cycloalkyl C_1-6Alkyl, 3-6 membered cycloalkyl C_1-6Alkylamino, 3-6-membered cycloalkyl C_1-6Alkoxy, 3-6 membered heterocyclyl C_1-6Alkyl, 3-6 membered heterocyclyl C_1-6Alkylamino and 3-6 membered heterocyclyl C_1-6An alkoxy group.

In certain embodiments, ring a is absent, or selected from optionally substituted with 1-3Q²Substituted 3-8 membered cycloalkyl and 3-8 membered heterocyclyl; each Q²Independently selected from halogen, hydroxy, amino, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino and di (C)_1-6Alkyl) amino;

and, rings a and L cannot be simultaneously absent;

ar is selected from the group consisting of optionally substituted 1-3Q⁴Substituted 6-8 membered monocyclic aryl, 8-10 membered fused aryl, 5-8 membered monocyclic heteroaryl and 8-10 membered fused heteroaryl; each Q⁴Independently selected from halogen, hydroxy, amino, nitro, cyano, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylsulfonyl, 3-6 membered cycloalkyl C_1-6Alkyl, 3-6 membered cycloalkyl C_1-6Alkylamino, 3-6-membered cycloalkyl C_1-6Alkoxy, 3-6 membered heterocyclyl C_1-6Alkyl, 3-6 membered heterocyclyl C_1-6Alkylamino and 3-6 membered heterocyclyl C_1-6An alkoxy group.

In certain embodiments, R¹Selected from hydrogen, C_1-4Alkyl, halo C_1-4Alkyl, hydroxy C_1-4Alkyl, amino C_1-4Alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocyclyl；

R²Selected from hydrogen, amino, C_1-4Alkyl, halo C_1-4Alkyl, optionally substituted by 1-2Q¹Substituted of the following groups: 3-6 membered cycloalkyl, 3-6 membered cycloalkyl C_1-4Alkyl, 3-6 membered heterocyclyl and 3-6 membered heterocyclyl C_1-4An alkyl group; each Q¹Independently selected from halogen, hydroxy, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy radical, C_1-4Alkylamino and di (C)_1-4Alkyl) amino;

R³、R⁴、R⁵each independently selected from hydrogen, halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkyl and halo C_1-4An alkoxy group;

R⁶selected from hydrogen and C_1-4An alkyl group;

x is selected from C-R⁷And N, said R⁷Selected from hydrogen, halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino and halogeno C_1-4An alkyl group;

ring A is absent, or is optionally substituted with 1-2Q²Substituted 4-6 membered cycloalkyl and 4-6 membered heterocyclyl; each Q²Independently selected from halogen, hydroxy, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy and C_1-4An alkylamino group;

l is absent, or is optionally substituted by 1-2Q³Substituted C_1-4Alkylene radical of the formula C_1-4Any one or more carbon atoms of the alkylene group being optionally O, NR⁸C (O), S, S (O) or S (O)₂Is replaced by one or more hetero atoms or groups, said R⁸Selected from hydrogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl and C_1-4An alkylsulfonyl group; each Q³Independently selected from halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy and halo C_1-4An alkyl group;

and, rings a and L cannot be simultaneously absent;

ar is selected from the group consisting of optionally substituted 1-3Q⁴Substituted phenyl and 5-6 membered monocyclic heteroaryl, each Q⁴Independently selected from halogen, hydroxy, amino, nitro, cyano, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy radical, C_1-4Alkylamino, di (C)_1-4Alkyl) amino, C_1-4Alkoxy radical C_1-4Alkyl radical, C_1-4Alkylamino radical C_1-4Alkyl radical, C_1-4Alkylcarbonyl, 3-6 membered cycloalkyl C_1-4Alkyl, 3-6 membered cycloalkyl C_1-4Alkoxy, 3-6 membered heterocyclyl C_1-4Alkyl and 3-6 membered heterocyclyl C_1-4An alkoxy group.

In certain embodiments, the compound has a structure as shown in formula (II),

wherein R is¹、R²、R³、R⁴、R⁵、R⁶A, Ar, X are as defined above.

In certain embodiments, the compound has a structure as shown in formula (III),

wherein R is¹、R²、R³、R⁴、R⁵、R⁶L, Ar, X are as defined above.

In certain embodiments, R¹Selected from hydrogen, C_1-4Alkyl, halo C_1-4Alkyl, 3-6 membered saturated cycloalkyl and 3-6 membered saturated heterocyclyl;

R²selected from hydrogen, amino, C_1-4Alkyl, halo C_1-4Alkyl and optionally substituted by 1-2Q¹Substituted byThe following groups: 3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl C_1-4Alkyl, 3-6 membered saturated heterocyclic group or 3-6 membered saturated heterocyclic group C_1-4An alkyl group; each Q¹Independently selected from halogen, hydroxy, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy radical, C_1-4Alkylamino and di (C)_1-4Alkyl) amino;

when R is²Is optionally substituted by 1-2Q¹Substituted 3-6 membered saturated heterocyclyl, preferably linked to the sulfonyl group through a heteroatom in the ring;

R³、R⁴、R⁵each independently selected from hydrogen, halogen and C_1-4An alkyl group;

R⁶selected from hydrogen and C_1-4An alkyl group;

x is selected from CH and N;

ring A is optionally substituted with 1-2Q²Substituted 4-6 membered saturated cycloalkyl and 4-6 membered saturated heterocyclyl, said heterocyclyl comprising one or more (e.g. 1,2,3 or 4) heteroatoms selected from O, S and N; preferably, the heteroatoms in the heterocyclic group comprise at least one nitrogen atom, and optionally also one O, S or N; each Q²Independently selected from halogen, hydroxy, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy and C_1-4An alkylamino group;

preferably, when ring A is selected from optionally substituted 1-2Q²Substituted 4-6 membered saturated heterocyclyl, which is attached to L or Ar through a ring heteroatom thereof;

l is absent, or is optionally substituted by 1-2Q³Substituted C_1-4Alkylene radical of the formula C_1-4Any one or more carbon atoms of the alkylene group being optionally O, NR⁸Or one or more heteroatoms or groups of C (O), R⁸Selected from hydrogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl and C_1-4An alkylsulfonyl group; each Q³Independently selected from halogenHydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy and halo C_1-4An alkyl group;

ar is selected from the group consisting of optionally substituted 1-2Q⁴Substituted phenyl and 5-6 membered monocyclic heteroaryl, the heteroatoms in said heteroaryl being selected from 1 nitrogen atom and 0-1 of the following atoms: o, S or N; each Q⁴Independently selected from halogen, hydroxy, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino, 3-6 membered saturated cycloalkyl C_1-4Alkyl or 3-6 membered saturated cycloalkyl C_1-4An alkoxy group.

In certain embodiments, R¹Selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxyethyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, and morpholinyl;

R²selected from the group consisting of hydrogen, amino, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, epoxyethyl, epoxyethylmethyl, aziridinyl, aziridinylmethyl, oxetanyl, azetidinylmethyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, and piperazinyl;

when R is²In the case of a saturated heterocyclic group, it is preferably attached to the sulfonyl group via a heteroatom;

R³、R⁴、R⁵each independently selected from hydrogen, fluoro, chloro, bromo, methyl and ethyl;

R⁶selected from hydrogen, methyl, ethyl and propyl;

ring A is optionally substituted with 1-2Q²Substituted cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, and morpholinyl; each Q²Independently selected from the group consisting of fluoro, chloro, bromo, hydroxy, amino, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methylamino and ethylamino;

preferably, when ring a is heterocyclyl, it is attached through its ring heteroatom to L or Ar; preferably a nitrogen atom;

l is absent, or is optionally substituted by 1-2Q³Substituted C_1-2Alkylene radical of the formula C_1-2Any carbon atom in the alkylene radical being optionally O, NR⁸Or C (O), said R⁸Selected from the group consisting of hydrogen, methyl, ethyl, propyl, methylcarbonyl and methylsulfonyl; each Q³Independently selected from the group consisting of fluoro, chloro, bromo, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, chloromethyl, fluoromethyl, and trifluoromethyl;

ar is selected from the group consisting of optionally substituted 1-2Q⁴Substituted phenyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl; each Q⁴Independently selected from the group consisting of fluoro, chloro, bromo, hydroxy, amino, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, propoxy, isopropyloxy, n-butyloxy, 1-methylpropoxy, 2, 2-dimethylpropoxy, n-butyloxy, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy.

R²selected from hydrogen, amino, C_1-4Alkyl, halo C_1-4Alkyl and optionally substituted by 1-2Q¹Substituted of the following groups: 3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl C_1-4Alkyl, 3-6 membered saturated heterocyclic group or 3-6 membered saturated heterocyclic group C_1-4An alkyl group; each Q¹Independently selected from halogen, hydroxy, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy radical, C_1-4Alkylamino and di (C)_1-4Alkyl) amino;

R⁶selected from hydrogen and C_1-4An alkyl group;

x is selected from CH and N;

ring a is absent;

l is optionally substituted by 1-2Q³Substituted C_1-4Alkylene radical of the formula C_1-4Any one or more carbon atoms of the alkylene group being optionally O, NR⁸Or one or more heteroatoms or groups of C (O), R⁸Selected from hydrogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl and C_1-4An alkylsulfonyl group; each Q³Independently selected from halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy and halo C_1-4An alkyl group;

ar is selected from the group consisting of optionally substituted 1-2Q⁴Substituted phenyl and 5-6 membered monocyclic heteroaryl, said heteroaryl comprising one or more (e.g., 1,2,3, or 4) heteroatoms selected from O, S and N; preferably, the heteroatom in said heteroaryl groupComprises at least one nitrogen atom and optionally further comprises an O, S or N; each Q⁴Independently selected from halogen, hydroxy, amino, nitro, cyano, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino, 3-6 membered saturated cycloalkyl C_1-4Alkyl or 3-6 membered saturated cycloalkyl C_1-4An alkoxy group.

R⁶selected from hydrogen, methyl, ethyl and propyl;

l is optionally substituted by 1-2Q³Substituted C_1-3Alkylene radical of the formula C_1-3Any one or more carbon atoms of the alkylene group being optionally O, NR⁸Or one or more hetero atoms or groups in C (O)Said R is⁸Selected from the group consisting of hydrogen, methyl, ethyl, propyl, methylcarbonyl and methylsulfonyl; each Q²Independently selected from the group consisting of fluoro, chloro, bromo, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, chloromethyl, fluoromethyl, and trifluoromethyl;

preferably, at least one carbon atom in L is replaced by NH and is bound to Ar via NH;

ar is selected from the group consisting of optionally substituted 1-2Q⁴Substituted phenyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl; each Q⁴Independently selected from the group consisting of fluoro, chloro, bromo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, propoxy, isopropoxy, n-butyloxy, 1-methylpropoxy, 2, 2-dimethylpropoxy, n-butyloxy, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy.

The selection of any substituent in any embodiment described in the present invention can be combined with each other, and the combined technical scheme is still included in the protection scope of the present invention.

The compounds of formula (I) according to the invention may be selected from compounds having the following structure:

in one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt, solvate, or isomer thereof, optionally together with one or more pharmaceutically acceptable carriers.

The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. In certain embodiments, the dosage form is selected from the group consisting of powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections, sprays, aerosols, dusts, lotions, liniments, ointments, plasters, pastes, patches, gargles, and suppositories. In certain embodiments, the formulation may be administered to a patient or subject in need of prevention and/or treatment by any suitable administration, e.g., oral, parenteral, rectal, pulmonary, or topical administration. When used for oral administration, the formulation may be an oral formulation, for example, an oral solid formulation such as a tablet, capsule, pill, granule, etc.; or oral liquid preparations such as oral solution, oral suspension, syrup, etc. The oral formulation may further comprise suitable fillers, binders, disintegrants, lubricants and the like. When used for parenteral administration, the preparation may be in the form of injection, including injection solution, sterile powder for injection and concentrated solution for injection. For injections, the production can be carried out by conventional methods in the pharmaceutical field. When an injection is prepared, no additive can be added into the preparation, and an appropriate additive can be added according to the property of the medicine. When used for rectal administration, the formulations may be suppositories and the like. For pulmonary administration, the formulation may be an inhalant or a spray, etc.

In certain embodiments, the pharmaceutical compositions of the present invention further comprise one or more second therapeutically active agents selected from the group consisting of the following compounds or drugs and pharmaceutically acceptable salts or solvate thereof:

(1) other Na_v1.7 channel modulators, arylsulfonamides Na as disclosed in WO2010/079443A1, WO2012095781A1 and the like_v1.7 channel modulators; triazines Na as disclosed in WO2010/022055_v1.7 channel modulators;

(2)Na_v1.3 channel modulators, such as the compounds disclosed in WO 2008/118758;

(3)Na_v1.8 channel modulators, such as the compounds disclosed in WO 2008/2008135826;

(4)Na_v1.9 channel modulators;

(5) compounds capable of increasing endogenous cannabinoid concentrations, for example compounds capable of inhibiting Fatty Acid Amide Hydrolase (FAAH) activity, such as the compounds disclosed in WO 2008/135826;

(6) inhibitors of mPEGs-1;

(7) opioid analgesics such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, methamidone, mepartron, meperidine, phenatanib, cocaine, codeine, dihydrocodeine, hydroxydihydrocodeinone, dihydrocodeinone, propoxyphene, nalmefene, nalprofen, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;

(8) non-steroidal anti-inflammatory drugs, such as aspirin, paracetamol, benconazole, sodium difluorooctanoate, etodolac, phenylpyruvic acid, fenoprofen, florfenicol, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, meloxicam, nalbumetone, naproxen (naproxen), nimesulide, nitroflurbiprofen, oxalazine, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac;

(9) sedatives such as barbiturate sedatives, benzodiazepines, H1 antagonists and other sedatives; preferably, the barbiturate sedative agent is selected from the group consisting of: amobarbital, aprbiturate, barbital, butabarbital, methylphenbarbital, methylbarbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbarbital, cembrel, and thiopental; preferably, the benzodiazepine drug is selected from the group consisting of chlordiazepoxide, potassium clodronate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, and triazolam; preferably, the H1 antagonist is selected from diphenhydramine, pyrilamine, promethazine hydrochloride, chlorpheniramine and clorazine; preferably, the other sedative drug is selected from the group consisting of glutethimide, meprobamate, methaqualone, and dichlofenoxate;

(10) skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, or methocarbamol;

(11) NMDA receptor antagonists, such as dextromethorphan hydrobromide, ketamine, memantine, budipine, topiramate, neramexane, ifenprodil, or traxoprodil;

(12) alpha-adrenoceptor antagonists such as phentermine, tamsulosin, alfuzosin, prazosin, terazosin, doxazosin or naftopidil;

(13) alpha-adrenoceptor agonists such as guanfacine, dexmedetomidine, norepinephrine, alamine or methoxamine;

(14) tricyclic antidepressants, such as desipramine, imipramine, amitriptyline or nortriptyline;

(15) antiepileptics, such as carbamazepine, lamotrigine, topiramate, or valproate;

(16) tachykinin antagonists such as ananapropamide, lanapiptan or dapiprant;

(17) muscarinic antagonists such as oxybutynin, tolterodine, propiverine, trospium chloride hydrochloride, darifenacin, solifenacin, tilmicorine, or ipratropium;

(18) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etacoxib, or lumiracoxib;

(19) (ii) a psychotropic inhibitor, such as droperidol, chlorpromazine, haloperidol, hydroxypiperidazine, thioridazine, mesoridazine, fluperazine, hydroxypiperoxazine, clozapine, olanzapine, lispirone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepprazole, blonanserin, iloperidone, perospiroxamine, raclopride, zotepine, diphenox, amoxapine, lurasidone, amisulpride, palindole, eletrin, osane, osanetant, rimonabant, or thalizolpidem;

(20) capsaicin receptor agonists or antagonists, such as resiniferatoxin, capsaicin, and the like;

(21) beta-adrenergic agents, such as polonahaler;

(22) local anesthetics, such as mexiletine;

(23) corticosteroids, such as dexamethasone;

(24)5-HT receptor agonists or antagonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan, and the like;

(25)5-HT2A receptor antagonists such as sarpogrelate;

(26) PDE-V inhibitors such as sildenafil, vardenafil, tadalafil, avanafil, udenafil and the like;

(27) α -2-ligands such as gabapentin, pregabalin, and the like;

(28) cannabis;

(29) metabotropic glutamate subgroup 1 receptor (mGluR1) antagonists;

(30) serotonin reuptake inhibitors such as sertraline, desmethylsertraline, fluoxetine, norfluoxetine, fluvoxamine, paroxetine, citalopram, desmethylcitalopram, escitalopram, fenfluramine, femoxetine, ifoxetine, Cyanodothiepin, ritoxetine, dapoxetine, nefazodone, westernchloramine, and kenolton (trazodone), and the like;

(31) norepinephrine reuptake inhibitors such as maprotiline, lofepramine, mirtazapine, oxaprotiline, phentolamine, tomoxetine, mianserin, bupropion, hydroxyamphetazone, nomifensine, viloxazine, reboxetine, and the like;

(32) dual serotonin-norepinephrine reuptake inhibitors such as, for example, venlafaxine, norvenlafaxine, clomipramine, desmethylclomipramine, duloxetine, milnacipran, imipramine, and the like;

(33) nitric oxide synthase inhibitors;

(34) acetylcholinesterase inhibitors such as donepezil;

(35) prostaglandin E2 subgroup 4 antagonists;

(36) 5-lipoxygenase inhibitors, such as zileuton;

(37) a gamma-aminobutyric acid derivative.

In certain embodiments, the pharmaceutical composition is for use in the prevention and/or treatment of Na in a subject_v1.7 channel-associated diseases. In certain embodiments, the reaction with Na_v1.7 channel-related disorders are painful disorders.

In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt, solvate, or isomer thereof, and the second therapeutically active agent in the pharmaceutical composition can be present in the same formulation or in different formulations. In certain embodiments, the compound of formula (I), a pharmaceutically acceptable salt, solvate, or isomer thereof and the second therapeutically active agent in the pharmaceutical composition can be administered simultaneously or sequentially.

In another aspect, the invention also relates to the use of a compound of formula (I), a pharmaceutically acceptable salt, solvate or isomer thereof, for the manufacture of a medicament for the prevention and/or treatment of Na in a subject_v1.7 channel-associated diseases. In certain embodiments, the reaction with Na_v1.7 channel-related disorders are painful disorders.

In another aspect, the invention also relates to a method for preventing and/or treating Na in a subject_v1.7 a method of channel-related diseases comprising administering to a subject in need thereof an effective amount of a compound represented by formula (I), a pharmaceutically acceptable salt, solvate or isomer thereof. In certain embodiments, the reaction with Na_v1.7 channel-related disorders are painful disorders.

The painful conditions described herein include, but are not limited to, one or more of inflammatory pain, visceral pain, cancer-induced pain, chemotherapy pain, trauma pain, surgical and post-surgical pain, labor pain, acute pain, chronic pain, intractable pain, somatic pain, nociceptive pain, neuropathic pain, blood-borne pain, immunoborne pain, endocrine-derived pain, metabolic-induced pain, cardiogenic pain, headache, phantom limb pain, and dental pain.

In certain embodiments, the painful condition is selected from the group consisting of acute pain, chronic pain, neuropathic pain, inflammatory pain, and nociceptive pain. In certain embodiments, the painful disorder is neuropathic pain.

"pain" in the context of the present invention refers to an unpleasant sensory and emotional experience associated with tissue damage and potential tissue damage or similar damage. The basic process of nerve conduction in pain development can be divided into 4 stages: firstly, pain sensation sensing of nociceptors, namely skin, body, vascular tissues, viscera and other nociceptors can convert stimulation on an organism into nerve impulses which are transmitted to spinal cords; secondly, pain sensation transmission of ascending tracts such as primary afferent fibers, spinal cord dorsal horn, spinal cord-thalamic tract and the like, signals of nociceptive stimulation are transmitted into the spinal cord dorsal horn from the primary afferent fibers, and after primary integration, the signals act on ventral horn motor cells to cause local defensive reflex on one hand, and continue to be transmitted upwards on the other hand, and ascending routes from the spinal cord to the brain can be divided into: the pain pathways of the trunk and limbs, the head and face, and the visceral pain pathways, where many receptors participate in the transmission of pain signals. Integrating the pain sense of the cortex and the marginal system, forming a secondary neuron after the spinothalamic tract enters the thalamus, and integrating and transmitting various sensory information to the cerebral cortex to form the pain sense; downward control and pain sense regulation and control of nerve medium means that a pain sense signal regulation and control system exists in the body; the pain sense signal regulating system is an endogenous pain sense modulation system, and the system not only can sense and distinguish pain signals, but also can generate stronger self-analgesia; downstream regulation may include four levels of regulation: regulation and control of spinal cord level, regulation and control of brain level, descending pain sensation facilitation system, and regulating factors of descending pain sensation regulation and control system.

Pain can be generally classified as acute or chronic. Acute is generally associated with tissue injury, inflammation or disease processes, with pain suddenly beginning and lasting for a short period (usually less than 3 months) of a type of pain, such as stinging, labor and birth pain, etc. Acute pain does not generally result in any persistent psychological response. The chronic pain is a pain type which still exists after the tissue injury is healed or lasts for more than 3-6 months, such as cancer pain, fibromyalgia, postherpetic neuralgia and the like. Chronic pain often causes psychological and emotional problems for the patient.

Nociceptive pain is induced by intense stimulation that damages or may cause damage to tissues. Nociceptors can activate two types of afferent nerve fibers during signaling, myelinated A-fibers conduct rapidly and are responsible for the sensation of acute and sharp pain, while unmyelinated C-fibers conduct more slowly and conduct stuffy or sore pain. Moderate to severe acute nociceptive pain is an important feature of pain from the central nervous system including trauma, sprains, strains, burns, myocardial infarction and acute pancreatitis, post-operative pain, post-traumatic pain, renal colic, cancer pain and back pain. Cancer pain may be chronic pain, such as pain associated with tumors (e.g., bone pain, headache, facial pain, or visceral pain) or pain caused by cancer therapy (e.g., pain resulting from chemotherapy, immunotherapy, or radiation therapy). Back pain may be caused by a herniated or ruptured disc or by abnormalities in the lumbar facet joints, the iliac joints, the lateral spine muscles or the posterior longitudinal ligaments. Back pain may be eliminated naturally, but for some patients, back pain persists for more than 12 weeks and becomes a chronic disease.

Neuropathic pain is pain that is caused or caused by primary damage or dysfunction of the nervous system. Nerve damage can be caused by trauma and disease, and thus "neuropathic pain" encompasses many diseases of different etiologies, including but not limited to: peripheral neuropathy, diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central neuralgia after stroke, chronic pelvic pain, complex regional pain syndrome, and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, or vitamin deficiency. Neuropathic pain includes unconscious pain (sustainable), and paroxysmal or abnormally induced pain (e.g., hyperalgesia and allodynia).

Inflammatory pain is a complex result of biochemical and cellular processes that are activated in response to tissue damage or the presence of foreign substances, resulting in swelling and pain. Common inflammatory pain includes: arthritis (such as rheumatic arthritis, rheumatoid arthritis, osteoarthritis, gouty arthritis, ankylosing spondylitis, reactive arthritis, infectious arthritis, traumatic arthritis, psoriatic arthritis, enteropathic arthritis, etc.), and organ pain (which can be classified into digestive organ pain and non-digestive organ pain).

Cardiac pain refers to the painful manifestations associated with heart disease or functional changes, such as angina pectoris, myocardial infarction, pericarditis, cardiac chest pain, cardiac toothache, etc.

The immune pain refers to pain caused by autoimmune diseases and allergic diseases, such as erythromelalgia, systemic lupus erythematosus, scleroderma, polyneuritis, etc.

Endocrine-derived pain refers to pain caused by endocrine-related diseases.

Headache includes migraine, chronic headache, cluster headache, tension headache, mixed headache and pain related to vascular diseases such as sinus headache, etc.

The pain caused by metabolic diseases refers to pain caused by diseases caused by abnormal metabolism of the body, such as pain caused by gout.

In the present invention, certain types of pain have multiple etiologies and therefore may be divided into more than one area, for example, back pain and cancer pain each having nociceptive and neuropathic pain components.

The compounds of the present invention are also useful in the treatment of other diseases mediated by sodium channels, including but not limited to, central nervous diseases, such as epilepsy, anxiety, depression, and bipolar disease; cardiovascular diseases such as arrhythmia, atrial fibrillation, and ventricular fibrillation; neuromuscular diseases such as restless legs syndrome and muscle paralysis or tetanus. The compounds of the present invention have neuroprotective effects against stroke, nerve damage and multiple sclerosis.

The invention also provides a kit comprising a compound of the invention, a pharmaceutically acceptable salt, solvate, or isomer thereof, and optionally further comprising instructions for use. In certain embodiments, the kit is administered by acting on Na_v1.7 channels inhibit pain transmission.

The invention also provides a method for inhibiting the Na ion passage in cells_v1.7A method of channel comprising administering to said cell an effective amount of a compound of the present invention, a pharmaceutically acceptable salt, solvate or isomer thereof. In certain embodiments, the methods are used in vivo, e.g., the cell is a cell in a subject; alternatively, the method is used in vitro, e.g., the cell is an in vitro cell (e.g., a cell line or a cell from a subject). In certain embodiments, the subject is a subject with a painful condition.

In the present invention, the subject is preferably a mammal, e.g., bovine, equine, porcine, canine, feline, rodent, primate, e.g., human.

The invention also provides a preparation method of the compound shown in the formula (I), which comprises the following steps:

method 1, when both L and Ring A are present

The raw material 1 and the raw material 4 react under the action of a palladium catalyst to obtain an intermediate III, the intermediate III optionally reacts with the raw material 5 after hydrogenation and deesterification to obtain an intermediate IV, the intermediate IV undergoes deesterification to obtain an intermediate V, and the intermediate V reacts with the raw material 3 under the action of a condensing agent to obtain the compound shown in the formula (I).

Method 2, when Ring A is absent

The raw material 5 and the raw material 2 react to obtain an intermediate VI, the intermediate VI is subjected to a de-esterification reaction to obtain an intermediate VII, and the intermediate VII and the raw material 3 react under the action of a condensing agent to obtain the compound shown in the formula (I).

Method 3 when L is not present

The raw material 1 and the raw material 4 react under the action of a palladium catalyst to obtain an intermediate III, the intermediate III and the raw material 6 react under the action of an alkaline reagent to obtain an intermediate VIII, the intermediate VIII undergoes a deesterification reaction to obtain an intermediate IX, and the intermediate IX and the raw material 3 react under the action of a condensing agent to obtain the compound shown in the formula (I).

Substituents R mentioned in the above preparation¹、R²Ring A, L, Ar is as defined in the previous claims. H is halogen; g is hydrogen or a leaving group, such as halogen, 4,5, 5-tetramethyl-1, 3, 2-dioxaboropentyl; m is C_1-6An alkyl group.

In the above preparation method, the palladium catalyst may be selected from 1,1 '-bis-diphenylphosphino ferrocene palladium dichloride dichloromethane complex, tetratriphenylphosphine palladium, 1' -bis-diphenylphosphino ferrocene palladium dichloride, bis (triphenylphosphine) palladium dichloride, and the like; the condensing agent may be selected from 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, N-Dicyclohexylcarbodiimide (DCC) and the like. The specific preparation method of the compound of the present invention is not limited to the above preparation method, and all the preparation methods of the compound of the present invention are included in the scope of the present invention. In the above preparation method, the raw materials may be commercially available or self-made, and the preparation method is also included in the scope of the present invention. In the above preparation method, each intermediate may optionally be subjected to a simple reaction for structural modification and then subjected to the next reaction.

In the specification and claims of this application, compounds are named according to chemical structural formula, and if the name of a compound does not match the chemical structural formula when the same compound is represented, the chemical structural formula is taken as the standard.

In the present application, unless otherwise specified, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, however, in order to better understand the present invention, definitions of some terms are provided below. Where the definitions and explanations of terms provided herein do not conform to the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.

The term "halo" as used herein means substituted with "halogen atom" which means fluorine atom, chlorine atom, bromine atom or iodine atom.

The expression "ring A is absent" in the present invention means that L is directly bonded to a ring atom in the condensed ring mother nucleus by a chemical bond. "L is absent" in the present invention, meaning that Ar is directly bonded to ring A through a chemical bond.

"C" according to the invention_1-6Alkyl "denotes straight or branched alkyl having 1 to 6 carbon atoms, including for example" C_1-5Alkyl group "," C_1-4Alkyl group "," C_1-3Alkyl group "," C_1-2Alkyl group "," C_2-6Alkyl group "," C_2-5Alkyl group "," C_2-4Alkyl group "," C_2-3Alkyl group "," C_3-6Alkyl group "," C_3-5Alkyl group "," C_3-4Alkyl group "," C_4-6Alkyl group "," C_4-5Alkyl group "," C_5-6Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" according to the invention_1-4Alkyl "means C_1-6Specific examples of the alkyl group having 1 to 4 carbon atoms.

"C" according to the invention_1-6Alkoxy "means" C_1-6alkyl-O- ", said" C_1-6Alkyl "is as defined above. "C" according to the invention_1-4Alkoxy "means" C_1-4alkyl-O- ", said" C_1-4Alkyl "is as defined above.

"C" according to the invention_2-6Alkenyl "means a straight, branched or cyclic alkenyl group having 2 to 6 carbon atoms containing at least one double bond, and includes, for example," C_2-5Alkenyl group "," C_2-4Alkenyl group "," C_2-3Alkenyl group "," C_3-6Alkenyl group "," C_3-5Alkenyl group "," C_3-4Alkenyl group "," C_4-6Alkenyl group "," C_4-5Alkenyl group "," C_5-6Alkenyl groups "and the like. Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1, 3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1, 4-hexadienyl, cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadienyl and the like.

"C" according to the invention_1-6Alkylene "refers to a straight chain alkane containing 1 to 6 carbon atoms derived from the removal of two hydrogens not on the same carbon atom, and includes" C_1-5Alkylene group "," C_1-4Alkylene group "," C_1-3Alkylene group "," C_1-2Alkylene ", specific examples include, but are not limited to: -CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-CH₂CH₂CH₂CH₂-、-CH₂CH₂CH₂CH₂CH₂-、-CH₂CH₂CH₂CH₂CH₂CH₂-and the like. "C" according to the invention_1-4Alkylene group "," C_1-3Alkylene group "," C_1-2Alkylene "independently denotes C_1-6Specific examples of the alkylene group having 1 to 4, 1 to 3, and 1 to 2 carbon atoms.

"C" according to the invention_2-6Alkenylene "means a straight chain containing 2-6Olefins of carbon atoms having groups derived by removal of two hydrogens not on the same carbon atom, including "C_2-5Alkenylene group and C_2-4Alkenylene group and C_2-3Alkenylene ", specific examples include, but are not limited to, -CH ═ CH-, -CH ═ CHCH —₂-、-CH₂CH＝CHCH₂-、-CH＝CHCH＝CH-、-CH₂CH₂CH＝CHCH₂-and the like.

"C" according to the invention_2-6Alkynylene "refers to a straight chain alkyne of 2 to 6 carbon atoms derived from the removal of two hydrogens not on the same carbon atom, and includes" C_2-5Alkynylene group and C_2-4Alkynylene group and C_2-3Alkynylene ", specific examples include, but are not limited to: -C.ident.C-, -C.ident.CCH₂-、-H₂CC≡CCH₂-、-C≡CCH₂CH-、-H₂CC≡CCH₂CH-、-H₂CC≡CCH₂C ≡ C-, etc.

"C" in the invention_1-6Alkylene radical, C_2-6Alkenylene radical, C_2-6Any one or more carbon atoms of the alkynylene group being optionally substituted with O, NR⁸C (O), S, S (O) or S (O)₂By one or more heteroatoms or groups "is meant C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6One or more carbon atoms in the carbon chain of the alkynylene group may be replaced by one or more of the heteroatoms or groups described above, forming groups such as those of the following structure: -C (O) -CH₂-、-CH₂-NH-、-O-CH₂-、-CH₂-C(O)-NH-、-S(O)₂-CH₂-NH₂-CH₂-、-CH＝CHNH₂-、-CH＝CHC(O)-、-N＝CHCH₂-、-H₂CC≡C-O-、-HN-C≡CCH₂-and the like.

The "halo C" of the present invention_1-6Alkyl "refers to one or more (e.g., 2,3,4,5, or 6) halogen atoms substituted for C_1-6Radicals derived from one or more hydrogen atoms of alkyl radicals, said "halogen atoms" and "C_1-6Alkyl "is as defined above. The "halo C" of the present invention_1-4Alkyl "denotes halogeno C_1-6Specific examples of the alkyl group having 1 to 4 carbon atoms.

The "hydroxy group C" of the present invention_1-6Alkyl "refers to one or more (e.g., 2,3,4,5, or 6) hydroxy-substituted C_1-6A group derived from one or more hydrogen atoms of an alkyl group, said "C_1-6Alkyl "is as defined above. The "hydroxy group C" of the present invention_1-4Alkyl "means hydroxy C_1-6Specific examples of the alkyl group having 1 to 4 carbon atoms.

"amino group C" according to the invention_1-6Alkyl "refers to one or more (e.g., 2,3,4,5, or 6) amino substituted C_1-6A group derived from one or more hydrogen atoms of an alkyl group, said "C_1-6Alkyl "is as defined above. "amino group C" according to the invention_1-4Alkyl means amino C_1-6Specific examples of the alkyl group having 1 to 4 carbon atoms.

"C" according to the invention_1-6Alkylamino "," di (C)_1-6Alkyl) amino "," C_1-6Alkoxy radical C_1-6Alkyl group and C_1-6Alkylamino radical C_1-6Alkyl group and di (C)_1-6Alkyl) amino C_1-6Alkyl group and C_1-6Alkylcarbonyl group and C_1-6Alkoxycarbonyl and (C)_1-6Alkylaminocarbonyl "," di (C)_1-6Alkyl) aminocarbonyl "," C_1-6Alkylaminocarbonyl radical C_1-6Alkyl group and di (C)_1-6Alkyl) aminocarbonyl group C_1-6Alkyl group and C_1-6Alkylsulfonyl group "," C_1-6Alkylsulfinyl "," C_1-6Alkylcarbonyloxy "," C_1-6Alkylamido "," C_1-6Alkylsulfonylamino "refers to a group formed by: c_1-6alkyl-NH-, (C)_1-6Alkyl radical)₂N-，C_1-6alkyl-O-C_1-6Alkyl radical, C_1-6alkyl-NH-C_1-6Alkyl radical (C)_1-6Alkyl radical)₂N-C_1-6Alkyl radical, C_1-6alkyl-C (O) -, C_1-6alkyl-O-C (O) -, C_1-6alkyl-NH-C (O) -,(C_1-6alkyl radical)₂NH-C(O)-，C_1-6alkyl-NH-C (O) -C_1-6Alkyl-, (C)_1-6Alkyl radical)₂N-C(O)-C_1-6Alkyl-, C_1-6alkyl-S (O)₂-，C_1-6alkyl-S (O) -, C_1-6alkyl-C (O) -O-, C_1-6alkyl-C (O) -NH-, C_1-6alkyl-S (O)₂-NH₂- ", said" C_1-6Alkyl "is as defined above.

"C" according to the invention_1-4Alkylamino "," di (C)_1-4Alkyl) amino "," C_1-4Alkoxy radical C_1-4Alkyl group and C_1-4Alkylamino radical C_1-4Alkyl group and di (C)_1-4Alkyl) amino C_1-4Alkyl group and C_1-4Alkylcarbonyl group and C_1-4Alkoxycarbonyl and (C)_1-4Alkylaminocarbonyl "," di (C)_1-4Alkyl) aminocarbonyl "," C_1-4Alkylaminocarbonyl radical C_1-4Alkyl group and di (C)_1-4Alkyl) aminocarbonyl group C_1-4Alkyl group and C_1-4Alkylsulfonyl group "," C_1-4Alkylsulfinyl "," C_1-4Alkylcarbonyloxy "," C_1-4Alkylamido "," C_1-4Alkylsulfonylamino "refers to a group formed by: c_1-4alkyl-NH-, (C)_1-4Alkyl radical)₂N-，C_1-4alkyl-O-C_1-4Alkyl radical, C_1-4alkyl-NH-C_1-4Alkyl radical (C)_1-6Alkyl radical)₂N-C_1-4Alkyl radical, C_1-4alkyl-C (O) -, C_1-4alkyl-O-C (O) -, C_1-4alkyl-NH-C (O) -, (C)_1-4Alkyl radical)₂NH-C(O)-，C_1-4alkyl-NH-C (O) -C_1-4Alkyl-, (C)_1-4Alkyl radical)₂N-C(O)-C_1-4Alkyl-, C_1-4alkyl-S (O)₂-，C_1-4alkyl-S (O) -, C_1-4alkyl-C (O) -O-, C_1-4alkyl-C (O) -NH-, C_1-4alkyl-S (O)₂-NH₂- ", said" C_1-4Alkyl "is as defined above.

The 3-15 membered cycloalkyl group described in the present invention includes a 3-8 membered cycloalkyl group and a 6-15 membered fused cycloalkyl group; the "3-to 10-membered cycloalkyl" described in the present invention includes "3-to 8-membered cycloalkyl" and "8-to 10-membered fused cycloalkyl".

The "3-to 8-membered cycloalkyl" according to the present invention means a monocyclic saturated or partially saturated alkyl group having 3 to 8 carbon atoms and having no aromaticity, and includes "3-to 8-membered saturated cycloalkyl" and "3-to 8-membered partially saturated cycloalkyl"; preferred are "3-to 4-membered cycloalkyl", "3-to 5-membered cycloalkyl", "3-to 6-membered cycloalkyl", "3-to 7-membered cycloalkyl", "4-to 5-membered cycloalkyl", "4-to 6-membered cycloalkyl", "4-to 7-membered cycloalkyl", "4-to 8-membered cycloalkyl", "5-to 6-membered cycloalkyl", "5-to 7-membered cycloalkyl", "5-to 8-membered cycloalkyl", "6-to 7-membered cycloalkyl", "7-to 8-membered cycloalkyl", "3-to 6-membered saturated cycloalkyl", "5-to 8-membered saturated cycloalkyl", "5-to 7-membered saturated cycloalkyl", "5-to 6-membered saturated cycloalkyl", and the like. Specific examples of said "3-to 8-membered saturated cycloalkyl" include, but are not limited to: a cyclopropane group (cyclopropyl), a cyclobutane group (cyclobutyl), a cyclopentyl group (cyclopentyl), a cyclohexane group (cyclohexyl), a cycloheptyl group (cycloheptyl), a cyclooctyl group (cyclooctyl), etc.; specific examples of the "3-to 8-membered partially saturated cycloalkyl group" include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexa-1, 3-diene, cyclohexa-1, 4-diene, cycloheptenyl, cyclohepta-1, 3-dienyl, cyclohepta-1, 4-dienyl, cyclohepta-1, 3, 5-trienyl, cyclooctenyl, cycloocta-1, 3-dienyl, cycloocta-1, 4-dienyl, cycloocta-1, 5-dienyl, cycloocta-1, 3, 5-trienyl, cyclooctatetraenyl and the like.

The "6-to 15-membered fused cycloalkyl group" refers to a saturated or partially saturated, nonaromatic cyclic group containing 6 to 15 ring atoms, one of which may be aromatic, but the fused ring as a whole does not have aromaticity, formed by two or more cyclic structures sharing two adjacent carbon atoms with each other, and includes, but is not limited to, "8-to 14-membered fused cycloalkyl group", "8-to 10-membered fused cycloalkyl group", "8-to 9-membered fused cycloalkyl group", and the like, and examples thereof include, but are not limited to: bicyclo [3.1.0] hexanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, octahydropentanyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthryl, bicyclo [3.1.0] hex-2-enyl, bicyclo [4.1.0] hept-3-enyl, bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] oct-3-enyl, 1,2,3,3 a-tetrahydropentanyl, 2,3,3a,4,7,7 a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8 a-octahydronaphthyl, 1,2,4a,5,6,8 a-hexahydronaphthyl, 1,2,3,4,5, 8 a-hexahydronaphthyl, 10-decahydrophenanthryl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl, and the like.

The "3-15 membered heterocyclic group" described in the present invention includes "3-8 membered heterocyclic group" and "6-15 membered fused heterocyclic group"; the "3-to 10-membered heterocyclic group" described in the present invention includes "3-to 8-membered heterocyclic group" and "8-to 10-membered fused heterocyclic group".

The "3-to 8-membered heterocyclic group" as used herein means a saturated or partially saturated and non-aromatic monocyclic cyclic group containing at least one hetero atom (e.g., 1,2,3,4 or 5) which is a nitrogen atom, an oxygen atom and/or a sulfur atom, and having 3 to 8 ring atoms, and optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo. The "3-to 8-membered heterocyclic group" described in the present invention includes "3-to 8-membered saturated heterocyclic group" and "3-to 8-membered partially saturated heterocyclic group". Preferably, the "3-8 membered heterocyclyl" of the present invention contains 1-3 heteroatoms; preferably, the "3-to 8-membered heterocyclic group" of the present invention contains 1 to 2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and/or oxygen atoms; preferably, the "3-to 8-membered heterocyclic group" according to the present invention contains 1 nitrogen atom. The "3-to 8-membered heterocyclic group" is preferably "3-to 7-membered heterocyclic group", "3-to 6-membered heterocyclic group", "4-to 7-membered heterocyclic group", "4-to 6-membered heterocyclic group", "6-to 8-membered heterocyclic group", "5-to 7-membered heterocyclic group", "5-to 6-membered heterocyclic group", "3-to 6-membered saturated heterocyclic group", "5-to 6-membered saturated heterocyclic group", "3-to 8-membered oxygen-containing heterocyclic group", "5-to 6-membered saturated oxygen-containing heterocyclic group", "3-to 8-membered nitrogen-containing heterocyclic group", "5-to 6-membered saturated nitrogen-containing heterocyclic group. The heteroatom in the "nitrogen-containing heterocyclic group" includes at least one nitrogen atom, for example, only 1 or 2 nitrogen atoms, or includes one nitrogen atom and 1 or 2 other heteroatoms (for example, oxygen atom and/or sulfur atom), or includes 2 nitrogen atoms and 1 or 2 other heteroatoms (for example, oxygen atom and/or sulfur atom); the heteroatom in the "oxygen-containing heterocyclic group" includes at least one oxygen atom, for example, only 1 or 2 oxygen atoms, or includes one oxygen atom and 1 or 2 other heteroatoms (for example, nitrogen atom and/or sulfur atom), or includes 2 oxygen atoms and 1 or 2 other heteroatoms (for example, nitrogen atom and/or sulfur atom). Specific examples of "3-8 membered heterocyclyl" include, but are not limited to: aziridinyl, 2H-aziridinyl, diazacyclopropenyl, 3H-diazacyclopropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuryl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, 3H-diazacyclopropenyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidyl, piperidonyl, tetrahydropyridinyl, piperidyl, piperazinyl, morpholinyl, 4, oxazolidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl and the like.

The "6-15 membered fused heterocyclic group" refers to a saturated or partially saturated, nonaromatic cyclic group containing 6 to 15 ring atoms, wherein at least one ring atom is a heteroatom, which may be an aromatic ring, but the fused ring as a whole does not have aromaticity, formed by two or more cyclic structures sharing two adjacent atoms with each other, and the fused ring may have aromaticity, and the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, and optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo, and includes, but is not limited to, "8-14 membered fused heterocyclic group", "8-10 membered fused heterocyclic group", "8-9 membered fused heterocyclic group", and the like, and specific examples include, but are not limited to: pyrrolidinyl cyclopropyl, cyclopenta-cyclopropyl, pyrrolidinyl cyclobutyl, pyrrolidinyl, pyrrolidinyl piperidinyl, pyrrolidinyl piperazinyl, pyrrolidinyl morpholinyl, piperidinyl morpholinyl, pyrrolidinyl, tetrahydroimidazo [4,5-c ] pyridinyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 1, 3-dihydroisobenzofuranyl, 2H-chromenyl, 2H-chromen-2-one, 4H-chromenyl, 4H-chromen-4-one, chromanyl, 4H-1, 3-benzoxazinyl, 4, 6-dihydro-1H-furo [3,4-d ] imidazolyl, pyrrolidinyl cyclopropyl, piperidinyl, morpholinyl, pyrrolidinyl, piperidinyl, pyrrolidinyl, 1, 3-dihydroquinazolinyl, 2H-chromenyl, 4-one, 4H-1,3-, 3a,4,6,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ] imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazolyl, benzimidazolyl, octahydro-benzo [ d ] imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuroimidazolyl, 4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazolyl, octahydrocyclopenta [ c ] pyrrolyl, indolinyl, dihydroisoindolyl, benzoxazolinyl, benzothiazolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2,3, 4-tetrahydroquinolinyl, 4H-1, 3-benzoxazinyl, and the like.

The "5-15 membered spirocyclic group" as used herein means a cyclic structure containing 5 to 15 ring carbon atoms, which is formed by two or more cyclic structures sharing one carbon atom with each other. Optionally, the carbon atom in the cyclic structure may be oxo. The "5-15-membered spiro ring group" includes, for example, "4-11-membered spiro ring group", "6-11-membered spiro ring group", "5-10-membered spiro ring group", "7-10-membered spiro ring group", "6-9-membered spiro ring group", "7-8-membered spiro ring group", "9-10-membered spiro ring group" and the like. Specific examples include, but are not limited to:

and the like. The "5-10 membered spirocyclic group" means a specific example containing 5 to 10 ring atoms in the 5-15 membered spirocyclic group。

The "5-15 membered bridged cyclic group" as used herein means a cyclic structure containing 5 to 15 ring carbon atoms, which is formed by two or more cyclic structures sharing two non-adjacent carbon atoms with each other. Optionally, the carbon atom in the cyclic structure may be oxo. "5-15-membered bridge ring group" includes, for example, "5-11-membered bridge ring group", "6-11-membered bridge ring group", "5-10-membered bridge ring group", "7-10-membered bridge ring group", "6-9-membered bridge ring group", "7-8-membered bridge ring group", "9-10-membered bridge ring group" and the like. Specific examples include, but are not limited to:

and the like. The "5-to 10-membered bridged ring group" means a specific example of 5-to 15-membered bridged ring group containing 5-to 10-ring atoms.

The "5-to 15-membered spiroheterocyclic group" as used herein means a cyclic structure containing 5 to 15 ring atoms (at least one of which is a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom) formed by two or more cyclic structures sharing one ring atom with each other, and includes "5-to 15-membered saturated spiroheterocyclic group" and "5-to 15-membered partially saturated spiroheterocyclic group". Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. The "5-15-membered spiroheterocyclic group" includes, for example, "5-11-membered spiroheterocyclic group", "6-11-membered spiroheterocyclic group", "5-10-membered spiroheterocyclic group", "6-9-membered spiroheterocyclic group", "7-9-membered spiroheterocyclic group", "9-10-membered spiroheterocyclic group", "5-15-membered nitrogen-containing spiro ring group", "5-10-membered nitrogen-containing spiroheterocyclic group", "7-11-membered nitrogen-containing spiroheterocyclic group", "7-9-membered nitrogen-containing spiroheterocyclic group", "8-9-membered nitrogen-containing spiroheterocyclic group", "7-9-membered nitrogen-containing saturated spiroheterocyclic group", "8-9-membered nitrogen-containing saturated spiroheterocyclic group" and the like. Specific examples include, but are not limited to:

and the like. The "5-to 10-membered spiroheterocyclic group" means a specific example containing 5 to 10 ring atoms in the 5-to 15-membered spiroheterocyclic group.

The "5-to 15-membered bridged heterocyclic group" as used herein means a cyclic structure containing 5 to 15 ring atoms (at least one of which is a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom) formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other, and includes "5-to 15-membered saturated bridged heterocyclic group" and "5-to 15-membered partially saturated bridged heterocyclic group". Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. The "5-to 15-membered bridged heterocyclic group" includes, for example, "5-to 10-membered bridged heterocyclic group", "6-to 11-membered bridged heterocyclic group", "6-to 9-membered bridged heterocyclic group", "6-to 10-membered bridged heterocyclic group", "7-to 9-membered nitrogen-containing bridged heterocyclic group", "7-to 8-membered nitrogen-containing bridged heterocyclic group", "5-to 9-membered nitrogen-containing bridged heterocyclic group", "5-to 15-membered nitrogen-containing bridged heterocyclic group", "5-to 10-membered bridged heterocyclic group", "7-to 9-membered nitrogen-containing saturated bridged heterocyclic group" and the like. Specific examples include, but are not limited to:

and the like. The "5-to 10-membered bridged heterocyclic group" means a specific example containing 5 to 10 ring atoms in the 5-to 15-membered bridged heterocyclic group.

The "6-to 12-membered aryl" as referred to herein includes "6-to 8-membered monocyclic aryl" and "8-to 12-membered fused ring aryl".

The "6-to 8-membered monocyclic aryl" as referred to herein means a monocyclic aryl group containing 6 to 8 ring carbon atoms, examples of which include, but are not limited to: phenyl, cyclooctatetraenyl, and the like; phenyl is preferred.

The "8-to 12-membered condensed ring aryl" as referred to herein means an unsaturated aromatic cyclic group having 8 to 12 ring carbon atoms, formed by two or more cyclic structures sharing two adjacent atoms with each other, and is preferably a "9-to 10-membered condensed ring aryl", and specific examples thereof are naphthyl and the like. The "8-to 10-membered fused aromatic group" is a specific example containing 8 to 10 ring carbon atoms in the above-mentioned "8-to 12-membered fused aromatic group".

The "6-to 10-membered aryl" according to the present invention means the above-mentioned "6-to 12-membered aryl" having 6 to 10 ring atoms, and includes "6-to 8-membered monocyclic aryl" and "8-to 10-membered fused aryl".

The "5-12 membered heteroaryl" described in the present invention includes "5-8 membered monocyclic heteroaryl" and "8-12 membered fused heteroaryl".

The "5-to 8-membered monocyclic heteroaryl group" according to the present invention means a monocyclic cyclic group having aromaticity, which contains 5 to 8 ring atoms, at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. "5-to 8-membered monocyclic heteroaryl" includes, for example, "5-to 7-membered monocyclic heteroaryl", "5-to 6-membered monocyclic nitrogen-containing heteroaryl", "6-membered monocyclic nitrogen-containing heteroaryl", and the like, in which the heteroatom contains at least one nitrogen atom, for example, contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and 1 or 2 other heteroatoms (for example, oxygen atom and/or sulfur atom), or contains 2 nitrogen atoms and 1 or 2 other heteroatoms (for example, oxygen atom and/or sulfur atom). Specific examples of "5-to 8-membered monocyclic heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepinyl, 1, 3-diazacycloheptenyl, azepinyl, and the like. The "5-6 membered monocyclic heteroaryl" refers to a specific example containing 5 to 6 ring atoms in a 5-8 membered heteroaryl.

The "8-12 membered fused heteroaryl group" according to the present invention means an unsaturated aromatic cyclic structure containing 8 to 12 ring atoms (at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. The "8-12 membered thick heteroaryl group" includes "8-10 membered thick heteroaryl group", "8-9 membered thick heteroaryl group" and the like; specific examples include, but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furothiophene, pyrazoloxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like. The "8-to 10-membered fused heteroaryl group" refers to a specific example containing 8 to 10 ring atoms in the 8-to 12-membered fused heteroaryl group.

The "5-to 10-membered heteroaryl" according to the present invention means a cyclic group having 5 to 10 ring atoms in the above-mentioned "5-to 12-membered heteroaryl", and includes "5-to 8-membered monocyclic heteroaryl" and "8-to 10-membered fused heteroaryl".

The expression "carbon atom, nitrogen atom or sulfur atom is oxo" as used herein means that C-O, N-O, S-O or SO is formed₂The structure of (1).

The term "optionally substituted with a substituent" as used herein means substituted or unsubstituted with a substituent.

The term "pharmaceutically acceptable salt" as used herein refers to an acidic functional group (e.g., -COOH, -OH-SO₃H, etc.) with a suitable inorganic or organic cation (base), including salts with alkali or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and basic functional groups present in the compound (e.g. -NH)₂Etc.) with a suitable inorganic or organic anion (acid), including salts with inorganic or organic acids (e.g., carboxylic acids, etc.). Suitable acid salts are formed from acids that form non-toxic salts, examples of which include, but are not limited to, acetate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, thiocyanate, sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyalafenate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthenate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, glucarate, stearate, succinate, tartrate, Tosylate, or trifluoroacetate, and the like. Suitable base salts are formed from bases which form non-toxic salts, examples of which include, but are not limited to, potassium, sodium, aluminum, magnesium, calcium, zinc, arginine, N' -dibenzylethylenediamine, choline, ethylenediamine, glycolamine, glycine, caseinate, meglumine, ethanolamine, trimethylolmethylamine, and the like.

The "isomers" described herein include structural isomers and stereoisomers. The structural isomerism is further classified into (carbon) chain isomerism, positional isomerism and functional group isomerism. "stereoisomerism" is divided into conformational and configurational isomerism, and configurational isomerism is also divided into cis-trans isomerism and optical isomerism (enantiomers). Conformational isomerism is a stereoisomerism phenomenon in which organic molecules having a certain configuration are rotated or twisted due to carbon and carbon single bonds, so that atoms or atom groups of the molecules generate different arrangement modes in space, and the common structures include structures of alkanes and cycloalkanes, such as chair conformation and ship conformation which appear in cyclohexane structure. "optical isomers (enantiomers)", when the compounds of the invention contain one or more asymmetric centers, are intended to be racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers that each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. The compounds of the present invention, if they contain an olefinic double bond, include cis-isomers and trans-isomers, unless otherwise specified. The compounds of the invention may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through one or more double bond shifts, e.g., a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included within the scope of the present invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of the compounds are included within the scope of the present invention.

The term "solvate" as used herein refers to a compound that forms a complex with one or more pharmaceutically acceptable organic solvent molecules or water molecules through non-covalent interactions. The organic solvent includes all kinds understood by those skilled in the art, such as alcohols, ethers, esters, aromatic hydrocarbons or aliphatic hydrocarbons, and the like.

The "dosage form" of the present invention refers to a form prepared from the drug suitable for clinical use, including, but not limited to, powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections, sterile powders for injections and concentrated solutions for injections), sprays, aerosols, powders, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably powders, tablets, granules, capsules, solutions, injections, ointments, gargles or suppositories.

The "carrier" of the present invention includes, but is not limited to, fillers, diluents, binders, wetting agents, disintegrants, lubricants, surfactants, preservatives, colorants, flavors, fragrances, effervescent agents, emulsifiers, flocculants, deflocculants, bacteriostats, and solubilizers. Specific examples include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, polyethylene-polyoxypropylene-block polymers, lanolin or any combination thereof.

In the present invention, "optionally substituted" includes both cases of "substituted" and "unsubstituted"; "optionally also comprising" includes both "comprising" and "not comprising".

The technical solutions cited in the references cited in this application are included in the disclosure of the present invention, and can be used to explain the contents of the present invention.

Advantageous effects of the invention

(1) The compounds of the present invention can effectively bind Na_v1.7 channels, shown as Na_v1.7 functional Activity of channel blockers, and preferably for other sodium channels, especially Na_v1.5, the affinity is very weak or shows little affinity.

(2) The compounds of the invention have one or more of the following improved properties: can be well absorbed by the digestive tract; has metabolic stability; having an improved metabolic profile, in particular toxicity or allergenicity for the metabolites formed; has good pharmacokinetic properties.

Experimental example 1 in vitro cytology of Compounds of the application

Test substances the compounds of the formula (I) according to the invention, prepared in house, are given in the preparation examples for their chemical names and structures.

The abbreviations used in the following experiments have the following meanings:

NaCl: sodium chloride

KCl: potassium chloride

CaCl₂: calcium chloride

MgCl₂: magnesium chloride

D-glucose: dextroglucose

HEPES (high efficiency particulate air): hydroxyethylpiperazine ethanethiosulfonic acid

MW: molecular weight

Experimental methods

Cell line: CHO cell line stably expressing 1.7 subtype of human Na-ion channel (hNa)_v1.7_ WT/CHO), the cells were thawed and expanded before the experiment, plated to a black bottom-penetrating 96-well plate with a density of 1.0X 10⁶cells/mL, 100. mu.L per well.

Preparation before experiment:

a buffer solution as in Table 1 below was prepared, and the pH was adjusted to 7.4 with 2mol/L NaOH.

TABLE 1 concentration of the components in the buffer solution

Preparing a detection reagent: membrane potential fluorescent probe 1 solution, detailed in table 2; membrane potential fluorescent probe 2 solution, detailed in table 3; are all prepared as before.

TABLE 2 Membrane potential fluorescent Probe 1 solution

PTS 18: membrane potential fluorescent probe 1 (Donor donor)

TABLE 3 Membrane potential fluorescent Probe 2 solution

Diseac 2 (3): membrane potential fluorescent probe 2 (receptor); xylene fast yellow: acid yellow 17

The experimental steps are as follows:

removing the culture medium from the 96-well plate; adding 50 mu L of membrane potential fluorescent probe 1 solution into each hole; 37 ℃ and 5% CO₂Incubating for 60 min; starting up the FDSS 30min before use, and setting detection parameters; removing the membrane potential fluorescent probe 1 solution in a 96-well plate, and adding 160 mu L of buffer solution into each well; removing the buffer solution, and then adding 160 mu L of membrane potential fluorescent probe 2 solution; incubating at room temperature in dark for 25 min; preparing a test compound solution at a final concentration of 5 times; adding 40 mu L of compound solution to be detected with the final concentration 5 times into each hole; and (4) putting the 96-hole plate to be detected into the corresponding position of the FDSS machine, reading the plate for 1min, and storing data.

Results of the experiment

In this experiment, all compounds tested were paired with Na_v1.7 IC₅₀Are all less than 3 μ M, preferably compound p Na_v1.7 IC₅₀Less than 1 μ M; for Na_v1.7 IC₅₀Less than 0.5. mu.M are: compounds 2,3,4,5,6,7,8,9,10, 11, 12, 13.

All test compound pairs Na_v1.5 all showed weaker inhibitory activity, compound vs. Na_v1.5 to Na_v1.7 is at least over 30 times selective.

And (4) experimental conclusion:

the compounds of the present application have good Na_v1.7 channel blocking action, and relative to Na_v1.5 channels have better selectivity, which indicates that the compound has potential value as a medicine for treating painful diseases.

Experimental example 2 in vivo efficacy test of the Compound of the present application

Test materials Compound 9 of the present invention, chemical name and structure thereof, are shown in the preparation examples.

Experimental methods

Test article

Preparation of 20mg/mL suspension: weighing 70.37mg of test sample (compound 9), adding a small amount of 0.5% methylcellulose suspension, uniformly grinding at the speed of 1000rpm, transferring into a centrifuge tube, washing the tissue grinder with 0.5% methylcellulose suspension for a plurality of times, transferring the grinding fluid into the centrifuge tube, adding 3.314mL of 0.5% methylcellulose suspension to obtain uniform suspension.

The experimental steps are as follows: mice were randomized according to body weight and drug solution or vehicle (0.5% methylcellulose suspension) was administered in advance, and the detailed administration method, administration dose and administration route are shown in table 5. The mice are placed into an observation box to adapt for at least 30min, 0.1% ethanol is injected subcutaneously on the dorsum of feet of a normal group and 15 mu L of 3 mu g/mL aconitine ethanol solution is injected subcutaneously on the dorsum of feet of a model group and a compound group after a certain time after administration, the mice are immediately placed into the observation box of a detection system, monitoring is carried out for 1h, observation is carried out for 0-40 min after the experiment is finished, and paw licking time within every 10min is recorded.

TABLE 5 administration route, dosage and regimen for aconitine pain model pharmacodynamic experiments

Evaluation index of experiment

After injecting aconitine solution, the mice lick paw within every 10 min.

Statistical treatment

Statistical analysis, including mean and Standard Error (SEM) of paw licking time for each time point for each group. The one-way ANOVA is used for analyzing the comparison among the groups, and if the F value has significant difference, the Games-Howell method is used for testing. If there is no significant difference in F value, analysis is performed by the Dunnet (2-sized) method. All data analyses were performed with SPSS 19.0. Significant differences were considered with p < 0.05.

Formula for calculation

Inhibition ratio%_{Compound (I)}/t_{Model (model)})*100％

Wherein: t is t_{Compound (I)}Represents the mean paw licking time, t, of the animals in the compound group_{Model (model)}Representative model group animals average paw licking time

TABLE 6 in vivo pharmacodynamic Activity data of Compounds in mouse Aconitine pain model

Test article	Inhibition rate	p value^a
			Compound 9	78.6％	<0.01

Note: a, comparison with model groups

And (4) experimental conclusion:

compared with a model group, the compound can obviously reduce the paw licking time of mice in a mouse aconitine pain model, and has statistical difference (p <0.01), which indicates that the compound has obvious pharmacodynamic action on treating painful diseases.

Detailed Description

The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

PE: petroleum ether

EA: ethyl acetate

DCM: methylene dichloride

MeOH: methanol

DMAP: 4-dimethylaminopyridine

EDCI: 1-Ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride

TFA: trifluoroacetic acid

DIPEA: n, N-diisopropylethylamine

DMF: n, N-dimethylformamide

Preparation example 1

1) Preparation of methyl 3-bromo-1H-indazole-6-carboxylate

Methyl 1H-indazole-6-carboxylate (17.4g,98.9mmol) and N-bromosuccinimide (19.4g,109.0mmol) were added to N, N-dimethylformamide (200mL), and the reaction was stirred at 25 ℃ for 4 hours. Water (200mL) was added to the reaction mixture, which was filtered under reduced pressure and the filter cake was dried to give the product (22.0g, 87.2% yield).

2) Preparation of methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate

Methyl 3-bromo-1H-indazole-6-carboxylate (22.0g,86.3mmol) and potassium carbonate (29.8g,215.9mmol) were dissolved in acetonitrile (200mL), iodomethane (24.5g,172.5mmol) was added dropwise at 0 ℃, the reaction was stirred at 25 ℃ for 12 hours, suction filtered under reduced pressure, the filtrate was spun dry, and purified by silica gel column chromatography (PE: EA ═ 20:1) to give the product (13.5g, 58.2% yield).

¹H-NMR(400MHz,CDCl₃):8.14(s,1H),7.86-7.84(m,1H),7.64(d,J＝8.4Hz,1H),4.11(s,3H),3.99(s,3H).

Preparation example 2

1) Preparation of methyl 3-bromo-1-methyl-1H-indole-6-carboxylate

Methyl 3-bromo-1H-indole-6-carboxylate (10g,39.4mmol) was dissolved in N, N-dimethylformamide (50mL), potassium carbonate (11g,79.6mmol) was added, cooled to 0 deg.C, methyl iodide (6g,42.3mmol) was added, and the reaction was stirred at 25 deg.C for 16 hours. The reaction was filtered and the filtrate was concentrated to give the product (10g, 94.8% yield).

Preparation example 3

1) Preparation of methyl 3-iodo-1H-indazole-6-carboxylate

Methyl 1H-indazole-6-carboxylate (1.0g,5.7mmol) was added to N, N-dimethylformamide (10mL), potassium hydroxide (0.95g,16.9mmol) and iodine particles (1.7g,6.7mmol) were added, the reaction was stirred at 25 ℃ for 5 hours, the reaction mixture was poured into water (100mL), extracted with ethyl acetate (100mL), and separated to obtain an organic phase, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (1.2g, crude product) as a solid.

2) Preparation of methyl 3-iodo-1-methyl-1H-indazole-6-carboxylate

Methyl 3-iodo-1H-indazole-6-carboxylate (1.0g,3.3mmol) was added to N, N-dimethylformamide (20mL), potassium carbonate (0.91g,6.6mmol) and iodomethane (0.61g,4.3mmol) were added, the reaction was stirred at 25 ℃ for 24 hours, the reaction solution was poured into water (100mL), extracted with ethyl acetate (100mL), the organic phase was separated, spin-dried, and the resulting product was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:10) to give a product (540mg, yield 51.9%).

Example 13 preparation of (4- (4-chloro-3- (trifluoromethyl) benzyl) piperazin-1-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indole-6-carboxamide (Compound 1)

1) Preparation of methyl 3- (4- (tert-butoxycarbonyl) piperazin-1-yl) -1-methyl-1H-indole-6-carboxylate

Methyl 3-bromo-1-methyl-1H-indole-6-carboxylate (1.5g,5.6mmol, see preparation 2) and tert-butylpiperazine-1-carboxylic acid (2.1g,11.3mmol) were dissolved in toluene (100mL), palladium acetate (125mg,0.56mmol), (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (383mg,0.62mmol) and cesium carbonate (5.5g,16.9mmol) were added, heated to 100 ℃ and reacted for 16 hours. Filtration, spin-drying of the filtrate and column chromatography of the residue (petroleum ether: ethyl acetate: 3:1) gave the product (60mg, 2.8% yield).

2) Preparation of methyl 1-methyl-3- (piperazin-1-yl) -1H-indole-6-carboxylate

Methyl 3- (4- (tert-butoxycarbonyl) piperazin-1-yl) -1-methyl-1H-indole-6-carboxylate (60mg,0.16mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (2mL) was added, and stirring was carried out at 25 ℃ for 2 hours. The solvent was spun dry and the residue was used directly in the next reaction (44mg, 100% yield).

Molecular formula C₁₅H₁₉N₃O₂Molecular weight 273.3LC-MS (M/e) 274.2(M + H)⁺)

3) Preparation of methyl 3- (4- (4-chloro-3- (trifluoromethyl) benzyl) piperazin-1-yl) -1-methyl-1H-indole-6-carboxylate

Methyl 1-methyl-3- (piperazin-1-yl) -1H-indole-6-carboxylate (44mg,0.16mmol) and 4-chloro-3- (trifluoromethyl) benzaldehyde (100mg,0.48mmol) were dissolved in dichloromethane (10mL), stirred at 25 ℃ for 10 minutes, sodium triacetoxyborohydride (102mg,0.48mmol) was added and stirred at 25 ℃ for 16 hours. Saturated sodium bicarbonate solution and dichloromethane (20mL) were added, the layers were separated, the organic phase was spin-dried, and the residue was separated by column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the product (40mg, yield 53.3%).

Molecular formula C₂₃H₂₃ClF₃N₃O₂Molecular weight 465.9LC-MS (M/e) 466.3(M + H)⁺)

4) Preparation of 3- (4- (4-chloro-3- (trifluoromethyl) benzyl) piperazin-1-yl) -1-methyl-1H-indole-6-carboxylic acid

Methyl 3- (4- (4-chloro-3- (trifluoromethyl) benzyl) piperazin-1-yl) -1-methyl-1H-indole-6-carboxylate (40mg,0.086mol) was dissolved in a mixed solution of methanol (4mL), tetrahydrofuran (2mL) and water (2mL), and sodium hydroxide (14mg,0.35mmol) was added, heated to 50 ℃, and reacted for 2 hours. Ethyl acetate (20mL), water (10mL) and hydrochloric acid (2mL) were added in this order, the layers were separated, the aqueous layer was extracted with ethyl acetate (20mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was spun dry, and the residue was used directly in the next reaction (38.8mg, 100% yield).

Molecular formula C₂₂H₂₁ClF₃N₃O₂Molecular weight 451.9LC-MS (M/e):452.2(M + H)⁺)

5) Preparation of 3- (4- (4-chloro-3- (trifluoromethyl) benzyl) piperazin-1-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indole-6-carboxamide

3- (4- (4-chloro-3- (trifluoromethyl) benzyl) piperazin-1-yl) -1-methyl-1H-indole-6-carboxylic acid (38.8mg,0.086mmol) and cyclopropanesulfonamide (21mg,0.17mmol) were dissolved in dichloromethane (10mL), 1- (3-dimethylaminopropyl) -3-ethyl-carbonyldiimine hydrochloride (36mg,0.19mmol) and 4-dimethylaminopyridine (26mg,0.21mmol) were added and stirred at 25 ℃ for 16H. Dichloromethane (20mL) and citric acid (10%, 10mL) were added, the layers were separated, the organic phase was spin-dried, and the residue was subjected to column chromatography (dichloromethane: methanol 20:1) to give the product (24mg, 50.5% yield).

Molecular formula C₂₅H₂₆ClF₃N₄O₃Molecular weight of S555.0 LC-MS (M/e):555.2(M + H)⁺)

¹H-NMR(400MHz,CDCl₃):7.91(s,1H),7.73(s,1H),7.68(d,J＝8.4Hz,1H),7.48-7.53(m,2H),7.42-7.49(m,1H),6.82(s,1H),3.81(s,3H),3.63(s,2H),3.16-3.21(m,1H),3.06-3.12(m,4H),2.69-2.72(m,4H),1.46-1.53(m,2H),1.25-1.30(m,2H).

Example 23 preparation of- (1- (4-chloro-3- (trifluoromethyl) benzyl) piperidin-4-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indole-6-carboxamide (Compound 2)

1) Preparation of methyl 3- (1- (tert-butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) -1-methyl-1H-indole-6-carboxylate

Methyl 3-bromo-1-methyl-1H-indole-6-carboxylate (2.0g,7.46mmol) was dissolved in a mixed solvent of 1, 4-dioxane (50mL) and water (10mL), and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1- (2H) -carboxylic acid tert-butyl ester (3.46g,11.2mmol), (1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (546mg,0.75mmol) and sodium carbonate (1.6g,15.1mmol) were added, reacted at 90 ℃ for 16 hours, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the product (1.5g, yield 54.3%).

The molecular formula is as follows: c₂₁H₂₆N₂O₄Molecular weight: 370.4LC-MS (M/e):371.2(M + H)⁺)315.2(M-56+H⁺)

2) Preparation of methyl 3- (1- (tert-butoxycarbonyl) piperidin-4-yl) -1-methyl-1H-indole-6-carboxylate

Methyl 3- (1- (tert-butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) -1-methyl-1H-indole-6-carboxylate (1.5g, 4.05mmol) was dissolved in methanol (50mL) and palladium on carbon (300mg, 10%) was added under a hydrogen atmosphere to react at 25 ℃ for 16 hours. After completion of the reaction, filtration was performed, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 3:1) to give the product (1.4g, yield 92.8%).

The molecular formula is as follows: c₂₁H₂₈N₂O₄Molecular weight: 372.5LC-MS (M)/e):317.2(M-56+H⁺)273.2(M-100+H⁺)

3) Preparation of methyl 1-methyl-3- (piperidin-4-yl) -1H-indole-6-carboxylate

Methyl 3- (1- (tert-butoxycarbonyl) piperidin-4-yl) -1-methyl-1H-indole-6-carboxylate (744mg,2.0mmol) was dissolved in dichloromethane (30mL), trifluoroacetic acid (15mL) was added, the reaction was carried out at 25 ℃ for 1 hour, and the product was concentrated to give the crude product.

The molecular formula is as follows: c₁₆H₂₀N₂O₂Molecular weight: 272.3LC-MS (M/e):273.2(M + H)⁺)

4) Preparation of methyl 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) piperidin-4-yl) -1-methyl-1H-indole-6-carboxylate

The crude methyl 1-methyl-3- (piperidin-4-yl) -1H-indole-6-carboxylate was dissolved in dichloromethane (50mL), 4-chloro-3- (trifluoromethyl) benzaldehyde (834mg,4.0mmol) and sodium triacetoxyborohydride (1.3g,6.1mmol) were added, reacted at 25 ℃ for 4 hours, sodium bicarbonate solution (100mL) was added, extracted with dichloromethane (50mL × 2), the organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give a product (770mg, two-step yield 82.8%).

The molecular formula is as follows: c₂₄H₂₄ClF₃N₂O₂Molecular weight: 464.9LC-MS (M/e):465.2(M + H)⁺)

5) Preparation of 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) piperidin-4-yl) -1-methyl-1H-indole-6-carboxylic acid

Methyl 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) piperidin-4-yl) -1-methyl-1H-indole-6-carboxylate (770mg,1.66mmol) was dissolved in a mixed solvent of methanol (20mL) and water (10mL), sodium hydroxide (331mg,8.3mmol) was added, reaction was performed at 50 ℃ for 4 hours, concentration was performed, pH was adjusted to acidity with 2N hydrochloric acid, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, concentration was performed, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 1:1) to obtain a product (650mg, yield 86.9%).

The molecular formula is as follows: c₂₃H₂₂ClF₃N₂O₂Molecular weight: 450.9LC-MS (M/e):451.4(M + H)⁺)

6) Preparation of 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) piperidin-4-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indole-6-carboxamide

3- (1- (4-chloro-3- (trifluoromethyl) benzyl) piperidin-4-yl) -1-methyl-1H-indole-6-carboxylic acid (100mg,0.22mmol) was dissolved in methylene chloride (30mL), and cyclopropylsulfonamide (41mg,0.34mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (77mg,0.4mmol) and 4-dimethylaminopyridine (55mg,0.45mmol) were added to react at 25 ℃ for 16 hours. Citric acid (10%, 100mL) was added, extraction was performed with dichloromethane (50mL × 2), the organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to give the product (83mg, yield 68.0%).

The molecular formula is as follows: c₂₆H₂₇ClF₃N₃O₃S molecular weight: 554.0LC-MS (M/e):554.2 (M)⁺)

¹H-NMR(400MHz,MeOD):8.02(s,1H),7.92(s,1H),7.63-7.74(m,4H),7.16(d,J＝4.0Hz,1H),4.01(s,2H),3.79(d,J＝3.6Hz,3H),3.24-3.28(m,2H),3.14-3.18(m,1H),2.95-3.06(m,1H),2.69(t,J＝12.0Hz,2H),2.13(d,J＝13.6Hz,2H),1.91-1.97(m,2H),1.27-1.29(m,2H),1.05-1.09(m,2H).

Example 33 preparation of- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide (Compound 3)

1) Preparation of methyl 3- (1- (tert-butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) -1-methyl-1H-indazole-6-carboxylate

Tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (1.29g,4.2mmol), methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate (1.02g,3.8mmol), sodium carbonate (806mg,7.6mmol), and 1,1' -bis diphenylphosphino ferrocene palladium dichloride (311mg,0.38mmol) were added to a mixed solution of dioxane (50mL) and water (10mL), stirred under nitrogen at 100 ℃ for 12 hours, then cooled to 25 ℃, the reaction solution was spin-dried, and the product was purified by silica gel column chromatography (PE: EA ═ 4:1) (1.2g, yield 85.0%).

The molecular formula is as follows: c₂₀H₂₅N₃O₄Molecular weight: 371.4LC-MS (M/e):316.2(M-55)

2) Preparation of methyl 3- (1- (tert-butoxycarbonyl) piperidin-4-yl) -1-methyl-1H-indazole-6-carboxylate

Methyl 3- (1- (tert-butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) -1-methyl-1H-indazole-6-carboxylate (1.2g,3.2mmol) was added to ethanol (100mL) and THF (10mL), followed by addition of PtO₂(120mg) was reacted at 25 ℃ for 6 hours under a hydrogen atmosphere, celite was added to the reaction solution, suction filtration was performed under reduced pressure, the filter cake was washed with ethanol (20mL) several times, and concentration and spin-drying were performed to obtain a product (1.1g, yield 92%).

3) Preparation of methyl 1-methyl-3- (piperidin-4-yl) -1H-indazole-6-carboxylate

Reacting methyl 3- (1- (tert-butoxycarbonyl)) Piperidin-4-yl) -1-methyl-1H-indazole-6-carboxylate (1.1g,2.9mmol) was added to DCM (20mL), TFA (10mL) was added, reaction was carried out at 25 ℃ for 6 hours, the reaction solution was spin-dried, and saturated NaHCO was added₃The solution was adjusted to pH 8, the combined layers were extracted with water (20mL) and DCM (50mL), and the organic phase was dried over anhydrous sodium sulfate and dried to give the product (700mg, 88.4% yield).

The molecular formula is as follows: c₁₅H₁₉N₃O₂Molecular weight: 273.3LC-MS (M/e):274.2(M + H)⁺)

4) Preparation of methyl 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) -1-methyl-1H-indazole-6-carboxylate

Methyl 1-methyl-3- (piperidin-4-yl) -1H-indazole-6-carboxylate (700mg,2.6mmol), 2, 3-dichloro-5- (trifluoromethyl) pyridine (831mg,3.85mmol) and DIPEA (1.0g,7.8mmol) were added to DMF (40mL), reacted at 40 ℃ for 12 hours, EA (100mL) and water (50mL) were added to the reaction solution for extraction and separation, and the organic phase was dried over anhydrous sodium sulfate and dried to give the product (900mg, yield 76.4%).

The molecular formula is as follows: c₂₁H₂₀ClF₃N₄O₂Molecular weight: 452.9LC-MS (M/e):453.2(M + H)⁺)

5) Preparation of 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) -1-methyl-1H-indazole-6-carboxylic acid

Methyl 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) -1-methyl-1H-indazole-6-carboxylate (900mg,2.0mmol) was dissolved in a mixed solution of methanol (10mL) and tetrahydrofuran (10mL), an aqueous solution (5mL) of lithium hydroxide monohydrate (336mg,8.0mmol) was added, the temperature was raised to 40 ℃, the reaction was stirred for 4 hours, the temperature was lowered to 25 ℃, HCl (1N) was slowly added to adjust the pH to 4. The organic solvent was spun off, water (30mL) was added and the filtrate was suction filtered under reduced pressure, the filter cake was washed several times with water (20mL) and dried to give the product (800mg, 91.1% yield).

The molecular formula is as follows: c₂₀H₁₈ClF₃N₄O₂Molecular weight: 438.8LC-MS (M/e):439.1(M + H)⁺)

6) Preparation of 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide

3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) -1-methyl-1H-indazole-6-carboxylic acid (439mg,1.0mmol), cyclopropanesulfonamide (182mg,1.5mmol) and 4-dimethylaminopyridine (244mg,2.0mmol) were added to DCM (20mL), 1-ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride (382mg,2.0mmol) was added, the reaction was stirred at 25 ℃ for 12 hours, HCl (1N) was added to adjust pH to 4, DCM (40mL) and water (30mL) were added for extraction and separation, the organic phase was dried over anhydrous sodium sulfate, dried by spinning, and purified by silica gel column chromatography (DCM: MeOH ═ 40:1) to obtain a product (389mg, yield 71.8%).

The molecular formula is as follows: c₂₃H₂₃ClF₃N₅O₃S molecular weight: 542.0LC-MS (M/e):542.2(M + H)⁺)

¹H-NMR(400MHz,CDCl₃):8.82(s,1H),8.42(s,1H),8.01(s,1H),7.87(d,J＝8.4Hz,1H),7.79(d,J＝2.4Hz,1H),7.55-7.51(m,1H),4.25-4.21(m,2H),4.11(s,3H),3.38-3.32(m,1H),3.25-3.08(m,3H),2.28-2.11(m,4H),1.52-1.48(m,2H),1.23-1.20(m,2H).

Example 43 preparation of (1- (4-chloro-3- (trifluoromethyl) benzyl) piperidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide (Compound 4)

1) Preparation of tert-butyl 3- (((trifluoromethyl) sulfonyl) oxy) -5, 6-dihydropyridine-1 (2H) -carboxylate

Tert-butyl 3-oxopiperidine-1-carboxylate (2.0g,10.0mmol) was dissolved in tetrahydrofuran (30mL), cooled to-78 deg.C, slowly added dropwise lithium bis (trimethylsilyl) amide (11.0mL,11.0mmol), -after stirring at 78 deg.C for 30 minutes, N-phenylbis (trifluoromethanesulfonimide) (3.6g,10.1mmol) in tetrahydrofuran (10mL) was slowly added dropwise, after completion of the addition, the reaction was allowed to reach 25 deg.C for 3 hours, saturated sodium bicarbonate solution (10mL) was added, the reaction was concentrated, and the product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 15:1) to give 1.7g, 51.4% yield.

2) Preparation of tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate

Tert-butyl 3- (((trifluoromethyl) sulfonyl) oxy) -5, 6-dihydropyridine-1 (2H) -carboxylate (1.5g,4.5mmol), bis-pinacolato borate (1.7g,6.7mmol), potassium acetate (0.9g,9.2mmol) and 1,1' -bis-diphenylphosphinoferrocene palladium dichloride (330mg,0.45mmol) were dissolved in dioxane (50mL) and, after displacement of nitrogen, the reaction was stirred at 90 ℃ for 12 hours. Filtration, concentration of the filtrate and column chromatography (petroleum ether: ethyl acetate: 10:1) gave the product (0.54g, 38.8% yield).

3) Preparation of methyl 3- (1- (tert-butoxycarbonyl) -1,2,5, 6-tetrahydropyridin-3-yl) -1-methyl-1H-indazole-6-carboxylate

Tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (0.5g,1.6mmol), methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate (430mg,1.6mmol, see preparation 1) and sodium carbonate (340mg,3.2mmol) were dissolved in a mixed solution of dioxane (20mL) and water (1mL), 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (120mg,0.16mmol) is added, and after stirring reaction at 100 ℃ for 2 hours, the temperature was reduced to 25 ℃, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give the product (469mg, 78.9% yield).

4) Preparation of methyl 3- (1- (tert-butoxycarbonyl) piperidin-3-yl) -1-methyl-1H-indazole-6-carboxylate

Methyl 3- (1- (tert-butoxycarbonyl) -1,2,5, 6-tetrahydropyridin-3-yl) -1-methyl-1H-indazole-6-carboxylate (450mg,1.2mmol) was dissolved in methanol (10mL), palladium on carbon (10%, 50mg) was added to replace hydrogen, and after stirring and reacting at 25 ℃ for 12 hours, the reaction was filtered, and the filtrate was concentrated to obtain a product (400mg, yield 88.5%).

5) Preparation of methyl 1-methyl-3- (piperidin-3-yl) -1H-indazole-6-carboxylate

Methyl 3- (1- (tert-butoxycarbonyl) piperidin-3-yl) -1-methyl-1H-indazole-6-carboxylate (400mg,1.1mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (5mL) was added dropwise, the reaction was stirred at 25 ℃ for 1 hour, then concentrated, a saturated sodium carbonate solution was added dropwise, pH was adjusted to 7, the concentration was performed, and the product was purified by gel column chromatography (dichloromethane: methanol ═ 10:1) to obtain a product (268mg, yield 89.0%).

6) Preparation of methyl 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) piperidin-3-yl) -1-methyl-1H-indazole-6-carboxylate

Methyl 1-methyl-3- (piperidin-3-yl) -1H-indazole-6-carboxylate (100mg,0.37mmol) and 4-chloro-3- (trifluoromethyl) benzaldehyde (80mg,0.38mmol) were dissolved in dichloromethane (5mL), trifluoroacetic acid (0.1mL) was added dropwise and stirred for 1 hour, sodium triacetoxyborohydride (160mg,0.75mmol) was added, stirring was continued for 1 hour, a saturated sodium bicarbonate solution (5mL) was added after completion of the reaction, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 10:1) to give a product (117mg, yield 67.9%)

7) Preparation of 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) piperidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid

Methyl 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) piperidin-3-yl) -1-methyl-1H-indazole-6-carboxylate (115mg,0.25mmol) was dissolved in a mixed solution of methanol (2mL) and tetrahydrofuran (2mL), 2N sodium hydroxide (0.2mL) was added dropwise, and the reaction was stirred at 60 ℃ for 2 hours. The reaction was concentrated, 10% citric acid was added dropwise to adjust the pH to 5, ethyl acetate (5mL) was added, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to give the product (80mg, yield 71.7%).

8) Preparation of 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) piperidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide

3- (1- (4-chloro-3- (trifluoromethyl) benzyl) piperidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid (80mg,0.18mol), cyclopropanesulfonamide (44mg,0.36mmol), 4-dimethylaminopyridine (44mg,0.36mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (70mg,0.37mmol) were dissolved in dichloromethane (15mL) and the reaction was stirred at 25 ℃ for 12 hours. 10% citric acid was added dropwise to adjust pH to 5, and the organic phase was separated, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane: methanol 10:1) to give the product (40mg, yield 40.0%).

The molecular formula is as follows: c₂₅H₂₆CF₃N₄O₃S molecular weight: 555.0LC-MS (M/e):555.2 (M)⁺)

¹H-NMR(400MHz,CDCl₃):7.94(s,1H),7.73(s,1H),7.56(d,J＝7.6Hz,2H),7.48-7.50(m,1H),7.45(d,J＝8.4Hz,1H),3.96(s,3H),3.75(s,2H),3.31-3.41(m,1H),3.15-3.19(m,1H),3.07-3.10(m,2H),2.50(s,1H),2.25(s,1H),2.11(d,J＝13.6Hz,1H),1.86(s,2H),1.67-1.70(m,2H),1.37-1.40(m,3H).

Example 53 preparation of (1- (4-chloro-3- (trifluoromethyl) benzyl) pyrrolidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide (Compound 5)

1) Preparation of methyl 3- (1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrol-3-yl) -1-methyl-1H-indazole-6-carboxylate

Tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate (1.1g,3.7mmol) and methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate (1.2g,4.5mmol) were dissolved in a mixed solvent of toluene (20mL), ethanol (20mL) and water (10mL), tetrakis (triphenylphosphine) palladium (214mg,0.19mmol) and sodium carbonate (784mg,7.4mmol) were added, reacted at 90 ℃ for 16 hours, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give a product (800mg, yield 60.6%).

The molecular formula is as follows: c₁₉H₂₃N₃O₄Molecular weight: 357.4LC-MS (M/e):358.2(M + H)⁺)302.1(M-56+H⁺)

2) Preparation of methyl 3- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylate

Methyl 3- (1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrol-3-yl) -1-methyl-1H-indazole-6-carboxylate (400mg,1.1mmol) was dissolved in methanol (50mL), and palladium on carbon (100mg, 10%) was added under a hydrogen atmosphere to react at 25 ℃ for 16 hours. After completion of the reaction, filtration was performed, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 5:1) to give the product (387mg, yield 96.2%).

3) Preparation of methyl 1-methyl-3- (pyrrolidin-3-yl) -1H-indazole-6-carboxylate

Methyl 3- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylate (387mg, 1.1mmol) was dissolved in dichloromethane (30mL), trifluoroacetic acid (15mL) was added, the reaction was carried out at 25 ℃ for 1 hour, and the mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1) to give a product (260mg, yield 93.1%).

4) Preparation of methyl 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylate

Methyl 1-methyl-3- (pyrrolidin-3-yl) -1H-indazole-6-carboxylate (130mg,0.5mmol) was dissolved in dichloromethane (30mL), 4-chloro-3- (trifluoromethyl) benzaldehyde (210mg,1.0mmol) and sodium triacetoxyborohydride (318mg,1.5mmol) were added, reacted at 25 ℃ for 4 hours, sodium bicarbonate solution (100mL) was added, extracted with dichloromethane (50mL × 2), the organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give a product (170mg, 75.2%).

5) Preparation of 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid

Methyl 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylate (170mg,0.38mmol) was dissolved in a mixed solvent of methanol (20mL) and water (10mL), and sodium hydroxide (75mg,1.9mmol) was added. React at 50 ℃ for 4 hours, concentrate, adjust the pH to acidity with 2N hydrochloric acid, extract with ethyl acetate (50 mL. times.3), combine the organic phases and concentrate to obtain the crude product.

The molecular formula is as follows: c₂₁H₁₉ClF₃N₃O₂Molecular weight: 437.8LC-MS (M/e):438.1(M + H)⁺)

6) Preparation of 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) pyrrolidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide

The crude product of the previous step of 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid was dissolved in dichloromethane (30mL), cyclopropylsulfonamide (69mg,0.57mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (131mg,0.68mmol) and 4-dimethylaminopyridine (93mg,0.76mmol) were added and reacted at 25 ℃ for 16 hours. Citric acid (10%, 100mL) was added, extraction was performed with dichloromethane (50mL × 2), the organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to give the product (35mg, two-step yield 17.0%).

The molecular formula is as follows: c₂₄H₂₄ClF₃N₄O₃S molecular weight: 541.0LC-MS (M/e):541.2 (M)⁺)

¹H-NMR(400MHz,DMSO-d₆):8.21(s,1H),7.92-7.95(m,1H),7.83(d,J＝8.4Hz,1H),7.74(s,2H),7.66(d,J＝8.8Hz,1H),4.07(s,5H),3.85-3.89(m,1H),3.05-3.11(m,2H),2.97(s,2H),2.39-2.44(m,1H),2.14-2.19(m,1H),1.03(d,J＝3.6Hz,2H),0.93-0.96(m,2H).

Example 63 preparation of- (1- (4-chloro-3- (trifluoromethyl) benzyl) azetidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide (Compound 6)

1) Preparation of methyl 3- (1- (tert-butyloxycarbonyl) azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylate

Zinc powder (2.1g,32.1mmol) is added into dry N, N-dimethylformamide (10mL), nitrogen is used for protection, the mixture is placed under an oil bath at 40 ℃ and stirred, 1, 2-dibromoethane (0.45mL) and trimethylchlorosilane (0.75mL) are sequentially added, the mixture is stirred and reacted for 0.5 hour at 40 ℃, and a solution of 1-Boc-3-iodoazetidine (4.54g,16.05mmol) in N, N-dimethylformamide (5mL) is slowly added into the reaction liquid and reacted for 0.5 hour at 40 ℃, and the reaction liquid is reserved. Methyl 3-iodo-1-methyl-1H-indazole-6-carboxylate (2.53g,8mmol, see preparation 3), 1' -bis diphenylphosphinoferrocene palladium dichloride (506mg) and CuI (506mg) were added to N, N-dimethylformamide (15mL), under nitrogen, stirred at 50 ℃, the above-mentioned reaction solution was slowly added thereto, and the reaction was stirred at 50 ℃ for 1 hour. The reaction solution was added to water (100mL), extracted three times with ethyl acetate (100mL × 3), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:4) to give the product (2.24g, yield 81.1%).

The molecular formula is as follows: c₁₈H₂₃N₃O₄Molecular weight: 345.4LC-MS (M/e): 290.1(M-56+ H)⁺)

¹H NMR(CDCl₃):8.16(s,1H),7.81(d,J＝8.4Hz,1H),7.76(d,J＝8.4Hz,1H),4.42-4.46(m,2H),4.31-4.35(m,2H),4.11-4.18(m,1H),4.02(s,3H),4.00(s,3H),1.50(s,9H).

2) Preparation of methyl 3- (azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylate

The compound methyl 3- (1- (tert-butoxycarbonyl) azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylate (2.24g,6.5mmol) was dissolved in dichloromethane (20mL), trifluoroacetic acid (10mL) was added and the reaction was carried out at 25 ℃ for 3 hours, after the reaction was complete, the solvent was concentrated to give the crude product which was used in the next reaction without purification.

The molecular formula is as follows: c₁₃H₁₅N₃O₂Molecular weight：245.3LC-MS(M/e)：246.1(M+H⁺)

3) Preparation of methyl 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylate

The compounds methyl 3- (azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylate (343mg,1.4mmol), 4-chloro-3-trifluoromethylbenzaldehyde (349mg,1.68mmol) and sodium triacetoxyborohydride (890mg,4.2mmol) were dissolved in dichloromethane (5mL) and reacted at 25 ℃ for 6 hours. After the reaction was completed, water (30mL) was added, dichloromethane was extracted (30mL × 3), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:1) to give the product (501mg, yield 81.9%).

The molecular formula is as follows: c₂₁H₁₉ClF₃N₃O₂Molecular weight: 437.8LC-MS (M/e):438.1,440.2 (M + H)⁺)

4) Preparation of 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid

The compound methyl 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) azetidin-3-yl) -1 methyl-1H-indazole-6-carboxylate (300mg,0.69mmol) and lithium hydroxide monohydrate (87mg,2.07mmol) were added to a mixed solvent of tetrahydrofuran (3mL) and water (3mL), stirred at 25 ℃ for 12 hours, the reaction solution was adjusted to pH 6 with 2N hydrochloric acid, extracted with ethyl acetate (50mL), separated to obtain an organic phase, dried over anhydrous sodium sulfate, and concentrated to obtain a product (260mg, yield 89.1%).

The molecular formula is as follows: c₂₀H₁₇ClF₃N₃O₂Molecular weight: 423.8LC-MS (M/e): 424.1,426.1(M + H)⁺)

5) Preparation of 3- (1- (4-chloro-3- (trifluoromethyl) benzyl) azetidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide

3- (1- (4-chloro-3- (trifluoromethyl) benzyl) azetidin-3-yl) -1-methyl-1H-indazol-6-carboxylic acid (260mg,0.61mmol) was added to dichloromethane (5mL), 4-dimethylaminopyridine (223mg,1.83mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (177mg,0.92mmol) and cyclopropylsulfonamide (111mg,0.92mmol) were added, the reaction was stirred at 25 ℃ for 12 hours, the reaction was concentrated, and the product was purified by column chromatography (dichloromethane: methanol ═ 20:1) (182mg, yield 56.7%).

The molecular formula is as follows: c₂₃H₂₂ClF₃N₄O₃S molecular weight: 526.96LC-MS (M/e): 527.2,529.1(M + H)⁺)

¹H NMR(CDCl₃):8.15(s,1H),7.83-7.88(m,2H),7.68-7.70(d,J＝6.3Hz,1H),7.56-7.60(m,2H),4.45(s,3H),4.28(s,2H),4.05-4.13(m,5H),3.09-3.13(m,1H),1.45-1.48(m,2H),1.15-1.25(m,2H)

Example 73 preparation of- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) piperidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide (Compound 7)

1) Preparation of methyl 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) piperidin-3-yl) -1-methyl-1H-indazole-6-carboxylate

Methyl 1-methyl-3- (piperidin-3-yl) -1H-indazole-6-carboxylate (100mg,0.37mmol, see example 4, steps 1-5) and 2, 3-dichloro-5- (trifluoromethyl) pyridine (80mg,0.37mmol) were dissolved in N, N-dimethylformamide (5mL), potassium carbonate (105mg,0.76mmol) was added, the temperature was raised to 70 ℃, the reaction was stirred for 12 hours, ethyl acetate (20mL) and water (25mL) were added to the filtrate, liquid separation was performed, the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a product (115mg, yield 68.6%).

2) Preparation of 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) piperidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid

Methyl 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) piperidin-3-yl) -1-methyl-1H-indazole-6-carboxylate (115mg,0.25mmol) was dissolved in a mixed solution of methanol (2mL) and tetrahydrofuran (2mL), 2N sodium hydroxide (0.2mL) was added dropwise, and the reaction was stirred at 60 ℃ for 2 hours. The reaction was concentrated, 10% citric acid was added dropwise to adjust the pH to 5, ethyl acetate (5mL) was added, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to give the product (90mg, yield 82.0%).

3) Preparation of 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) piperidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide

3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) piperidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid (90mg,0.21mmol), cyclopropanesulfonamide (51mg,0.42mmol), 4-dimethylaminopyridine (51mg,0.42mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (81mg,0.42mmol) were dissolved in dichloromethane (15mL) and reacted with stirring at 25 ℃ for 12 hours. 10% citric acid was added dropwise to adjust pH to 5, and the organic phase was separated, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane: methanol 10:1) to give the product (47mg, yield 41.3%).

The molecular formula is as follows: c₂₃H₂₃CF₃N₅O₃S molecular weight: 542.0LC-MS (M/e):542.2 (M)⁺)

¹H-NMR(400MHz,DMSO-d₆):12.15(s,1H),8.56(d,J＝1.2Hz,1H),8.30(s,1H),8.16(d,J＝1.6Hz,1H),7.98(d,J＝8.8Hz,1H),7.64(dd,J₁＝8.4Hz,J₂＝7.2Hz 1H),4.29(d,J＝12.8Hz,2H),4.10-4.16(m,3H),3.45-3.52(m,1H),3.23-3.26(m,1H),3.13-3.20(m,1H),3.04-3.10(m,1H),2.19-2.22(m,1H),1.75-1.95(m,3H),1.05-1.25(m,4H).

Example preparation of 83- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) pyrrolidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide (Compound 8)

1) Preparation of ethyl 3- (1- (tert-butyloxycarbonyl) -2, 5-dihydro-1H-pyrrol-3-yl) -1-methyl-1H-indazole-6-carboxylate

Methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate (0.92g,3.4mmol, see preparation example 1) and tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate (1g,3.4mmol) were dissolved in a mixed solvent of toluene (10mL) and ethanol (10mL), tetrakis (triphenylphosphine) palladium (0.1g,0.086mmol) and an aqueous solution of sodium carbonate (3.5mL,7.0mmol,2M) were added, the reaction was stirred at 90 ℃ for 16 hours, the reaction mixture was filtered, the filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to obtain a product (0.45g, yield 35.7%).

The molecular formula is as follows: c₂₀H₂₅N₃O₄Molecular weight: 371.4LC-MS (M/e) 372.2(M + H)⁺)

2) Preparation of ethyl 3- (1- (tert-butyloxycarbonyl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylate

Ethyl 3- (1- (tert-butoxycarbonyl) -2, 5-dihydro-1H-pyrrol-3-yl) -1-methyl-1H-indazole-6-carboxylate (0.45g,1.2mmol) was dissolved in methanol (10mL), palladium on carbon (0.5g) was added, and the reaction was stirred under hydrogen pressure at 25 ℃ for 16 hours. The reaction was filtered and the filtrate was concentrated to dryness to give the product (0.4g, 88.9% yield).

The molecular formula is as follows: c₂₀H₂₇N₃O₄Molecular weight: 373.5LC-MS (M/e):374.2(M + H)⁺)

3) Preparation of ethyl 1-methyl-3- (pyrrolidin-3-yl) -1H-indazole-6-carboxylate

Ethyl 3- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylate (0.4g,1.1mmol) was dissolved in dichloromethane (4mL), trifluoroacetic acid (2mL) was added, the reaction was stirred at 25 ℃ for 2 hours, and the reaction was concentrated to give the product (0.29g, 100% yield).

4) Preparation of ethyl 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylate

Ethyl 1-methyl-3- (pyrrolidin-3-yl) -1H-indazole-6-carboxylate (0.15g,0.55mmol) and 2, 3-dichloro-5- (trifluoromethyl) pyridine (0.15g,0.69mmol) were dissolved in N, N-dimethylformamide (3mL), potassium carbonate (0.15g,1.1mmol) was added, the mixture was heated to 70 ℃ and stirred for reaction for 2 hours, the reaction mixture was filtered, the filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to obtain the product (0.16g, yield 64.0%).

5) Preparation of 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid

Ethyl 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylate (0.16g,0.35mmol) was dissolved in a mixed solvent of tetrahydrofuran (2mL) and ethanol (2mL), an aqueous solution of sodium hydroxide (1mL,2mmol,2M) was added, and the reaction was stirred at 25 ℃ for 3 hours. Citric acid aqueous solution was added to adjust pH to 6, the reaction solution was concentrated, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 1) to obtain the product (0.11g, yield 73.3%).

The molecular formula is as follows: c₁₉H₁₆ClF₃N₄O₂Molecular weight: 424.8LC-MS (M/e):425.1(M + H)⁺)

6) Preparation of 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) pyrrolidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide

3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid (0.1g,0.24mmol), cyclopropylsulfonamide (30mg,0.25mmol), DMAP (60mg,0.49mmol) and EDCI (65mg,0.34mmol) were dissolved in dichloromethane (10mL) and the reaction was stirred under nitrogen at 25 ℃ for 16H. The reaction solution was concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 1) to obtain the product (96mg, yield 75.8%).

The molecular formula is as follows: c₂₂H₂₁ClF₃N₅O₃S molecular weight: 527.9LC-MS (M/e):528.2(M + H)⁺)

¹H-NMR(400MHz,CDCl₃):8.58(brs,1H),8.27(s,1H),7.98(s,1H),7.81(d,J＝8.4Hz,1H),7.65(s,1H),7.50(dd,J₁＝8.4Hz,J₂＝1.2Hz,1H),4.26-4.31(m,1H),4.13-4.18(m,1H),4.09(s,3H),3.99-4.05(m,2H),3.86-3.91(m,1H),3.13-3.18(m,1H),2.39-2.52(m,2H),1.46-1.51(m,2H),1.16-1.20(m,2H).

Example 93 preparation of (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) azetidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide (Compound 9)

1) Preparation of methyl 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylate

Methyl 3- (azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylate (355mg,1.45mmol, see example 6, step 1-2), 2, 3-dichloro-5-trifluoromethylpyridine (313mg,1.45mmol) and potassium carbonate (400mg,2.9mmol) were added to N, N-dimethylformamide (10mL) and the reaction was stirred at 70 ℃ for 2 hours. After completion of the reaction, water (50mL) was added, dichloromethane was extracted (50mL × 3), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:4) to give the product (502mg, yield 81.6%).

The molecular formula is as follows: c₁₉H₁₆ClF₃N₄O₂Molecular weight: 424.8LC-MS (M/e):425.1,427.1 (M + H)⁺)

2) Preparation of 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid

Methyl 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylate (502mg,1.18mmol) and lithium hydroxide monohydrate (149mg,3.54mmol) were added to a mixed solution of tetrahydrofuran (2mL), methanol (2mL) and water (2mL), the reaction was stirred at 25 ℃ for 12 hours, the reaction solution was adjusted to pH 6 or so with 2N hydrochloric acid, ethyl acetate (50mL) was added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to give the product (450mg, 93.0% yield).

The molecular formula is as follows: c₁₈H₁₄ClF₃N₄O₂Molecular weight: 410.8LC-MS (M/e): 411.1,413.1(M + H)⁺)

3) Preparation of 3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) azetidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide

3- (1- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid (250mg,0.61mmol) was added to dichloromethane (5mL), 4-dimethylaminopyridine (223mg,1.83mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (175mg,0.91mmol) and cyclopropylsulfonamide (110mg,0.91mmol) were added, the reaction was stirred at 25 ℃ for 12 hours, the reaction was concentrated, and the product was purified by column chromatography (dichloromethane: methanol ═ 20:1) (98mg, 31.3% yield).

The molecular formula is as follows: c₂₁H₁₉ClF₃N₅O₃S molecular weight: 513.92LC-MS (M/e): 514.1,516.1(M + H)⁺)

¹H-NMR(CDCl₃)::8.30(s,1H),8.01(s,1H),7.85(d,J＝6.3Hz,1H),7.63(d,J＝0.9Hz,1H),7.52(d,J＝6.3Hz,1H),8.45(t,J＝6.6Hz,2H),4.67-4.70(m,2H),4.27-4.43(m,1H),4.11(s,3H),3.12-3.19(m,1H),1.10-1.25(m,4H).

Example 103 preparation of (1- (2-chloro-4- (trifluoromethyl) phenyl) azetidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide (Compound 10)

1) Preparation of 3- (1- (2-chloro-4- (trifluoromethyl) phenyl) azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid

Methyl 3- (azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylate (161mg, crude, preparation method for which see example 6, steps 1-2), 1, 2-dichloro-4-trifluoromethylbenzene (197mg,0.92mmol) and cesium carbonate (449mg,1.38mmol) were added to N, N-dimethylacetamide (3mL), and the reaction was stirred at microwave 150 ℃ for 3 hours. After the reaction was completed, ethyl acetate (20mL) was added, washed with water (20mL × 3), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to give a product (82mg, yield 43.6% in two steps (including the step of preparing methyl 3- (azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylate).

The molecular formula is as follows: c₁₉H₁₅ClF₃N₃O₂Molecular weight: 409.8LC-MS (M/e): 410.1,412.1(M + H)⁺)

2) Preparation of 3- (1- (2-chloro-4- (trifluoromethyl) phenyl) azetidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide

3- (1- (2-chloro-4- (trifluoromethyl) phenyl) azetidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid (82mg,0.2mmol) was added to dichloromethane (5mL), 4-dimethylaminopyridine (73mg,0.6mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (58mg,0.3mmol) and cyclopropylsulfonamide (36mg,0.3mmol) were added and the reaction stirred at 35 ℃ for 3 hours. Dichloromethane (15mL) was added, the organic phase was washed with 1M aqueous citric acid solution (20mL × 3), dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to give the product (18mg, yield 17.6%).

The molecular formula is as follows: c₂₂H₂₀ClF₃N₄O₃S molecular weight: 512.93LC-MS (M/e): 513.1,515.1(M + H)⁺)

¹H-NMR(MeOD):8.22(s,1H),7.82-7.93(m,2H),7.45-7.60(m,2H),6.77(d,J＝6.0Hz,1H),4.73-4.65(m,3H),4.48-4.45(m,2H),4.08(s,3H),3.36(s,1H),3.09(s,1H),0.96-1.23(m,4H).

Example 113 preparation of (1- (2-chloro-4- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide (Compound 11)

1) Preparation of methyl 3- (1- (2-chloro-4- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylate

Methyl 1-methyl-3- (tetrahydropyrrol-3-yl) -1H-indazole-6-carboxylate (259mg,1mmol, see example 5, steps 1-3), 1, 2-dichloro-4-trifluoromethylbenzene (322mg,1.5mmol) and cesium carbonate (978mg,3mmol) were added to N, N-dimethylacetamide (20mL) and reacted in a microwave reactor at 150 ℃ for 3 hours. Water (30mL) was added, extraction was performed with dichloromethane, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE: EA: 5:1) to obtain the title compound (137mg, yield 31.4%)

2) Preparation of 3- (1- (2-chloro-4- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid

Methyl 3- (1- (2-chloro-4- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylate (128mg,0.29mmol) and lithium hydroxide monohydrate (61mg,1.46mmol) were added to a mixed solvent of methanol, tetrahydrofuran and water (15mL, v/v/v ═ 2:2:1), and the reaction was stirred at 25 ℃ for 5 hours, the reaction mixture was concentrated, diluted hydrochloric acid was added to adjust pH to 5, and a solid was precipitated, which was filtered with suction and dried to obtain the title compound (123mg, 100%).

3) Preparation of 3- (1- (2-chloro-4- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide

3- (1- (2-chloro-4- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1-methyl-1H-indazole-6-carboxylic acid (123mg,0.29mmol), 4-dimethylaminopyridine (107mg,0.87mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (84mg,0.43mmol) and cyclopropylsulfonamide (71mg,0.58mmol) were dissolved in dichloromethane (20mL), stirred at 30 ℃ for 10 hours, the reaction was concentrated, and preparative chromatography gave the title compound (13mg, 8.5% yield)

The molecular formula is as follows: c₂₃H₂₂ClF₃N₄O₃S molecular weight: 526.1LC-MS (M/e): 527.2(M + H)⁺)

¹H-NMR(CDCl₃):8.06-8.04(m,1H),7.84(d,J＝8.0Hz,1H),7.59-7.57(m,2H),7.40-7.38(m,1H),6.91(d,J＝8.0Hz,1H),4.16(s,3H),3.99-3.82(m,4H),3.69-3.66(m,1H),3.17(s,1H),2.53-2.37(m,2H),1.48-1.45(m,2H),1.27-1.21(m,2H)。

Example 123- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) ethyl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide preparation (Compound 12)

1) Preparation of methyl 3- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) ethyl) -1-methyl-1H-indazole-6-carboxylate

Methyl 3- (2-aminoethyl) -1-methyl-1H-indazole-6-carboxylate (100mg,0.43mmol), 1, 2-dichloro-4- (trifluoromethyl) benzene (140mg,0.65mmol), palladium acetate (10mg,0.045mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (54mg,0.087mmol), and cesium carbonate (350mg,1.1mmol) were dissolved in toluene (10mL), warmed to 105 ℃, stirred for reaction for 12 hours, filtered, the filtrate was concentrated, and purified by column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the product (75mg, 42.4% yield).

2) Preparation of 3- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) ethyl) -1-methyl-1H-indazole-6-carboxylic acid

Methyl 3- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) ethyl) -1-methyl-1H-indazole-6-carboxylate (75mg,0.18mmol) was dissolved in a mixed solution of methanol (1mL) and tetrahydrofuran (1mL), 2N sodium hydroxide (0.5mL) was added dropwise, and the reaction was stirred at 60 ℃ for 1 hour. The reaction mixture was concentrated, 10% citric acid was added dropwise to adjust the pH to 6, and the mixture was extracted with ethyl acetate (10 mL. times.3), separated to obtain an organic phase, dried over anhydrous sodium sulfate, and concentrated to obtain a product (60mg, yield 83.8%).

3) Preparation of 3- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) ethyl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide

3- (2- ((2-chloro-4- (trifluoromethyl) phenyl) amino) ethyl) -1-methyl-1H-indazole-6-carboxylic acid (60mg,0.15mol), cyclopropanesulfonamide (36mg,0.30mmol), 4-dimethylaminopyridine (37mg,0.30mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (58mg,0.30mmol) were dissolved in dichloromethane (5mL) and the reaction was stirred at 25 ℃ for 6 hours. 10% citric acid was added dropwise to adjust the pH to 6, and the mixture was extracted with ethyl acetate (30mL × 3), separated to obtain an organic phase, dried over anhydrous sodium sulfate, and purified by column chromatography (dichloromethane: methanol ═ 10:1) to obtain a product (40mg, yield 53.3%).

The molecular formula is as follows: c₂₁H₂₀ClF₃N₄O₃S molecular weight: 500.9LC-MS (M/e):501.1 (M)⁺)

¹H-NMR(400MHz,CDCl₃):9.00(s,1H),8.03(s,1H),7.73(d,J＝8.4Hz,1H),7.56(d,J＝8.4Hz,1H),7.50(s,1H),7.39(d,J＝8.4Hz,1H),6.74(d,J＝8.4Hz,1H),5.13-5.17(m,1H),4.13(s,3H),3.67-3.70(m,2H),3.33-3.37(m,2H),3.16-3.19(m,1H),1.44-1.51(m,2H),1.19-1.34(m,2H).

Example preparation of 133- (1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide (compound 13)

1) Preparation of methyl 3- (1-butoxyvinyl) -1-methyl-1H-indazole-6-carboxylate

Methyl 3-bromo-1-methyl-1H-indazole-6-carboxylate (1.5g,5.6mmol), palladium acetate (126mg,0.56mmol), 1- (vinyloxy) butane (2.8g,27.9mmol) and cesium carbonate (5.5g,16.9mmol) were dissolved in acetonitrile (10mL), placed in a microwave reactor at 120 ℃ for reaction for 7 hours, cooled to 25 ℃ after completion of the reaction, filtered, added with water (20mL), extracted with ethyl acetate (30mL × 3), and purified by column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the product (0.6g, 37.5% yield).

2) Preparation of methyl 3-acetyl-1-methyl-1H-indazole-6-carboxylate

Methyl 3- (1-butoxyvinyl) -1-methyl-1H-indazole-6-carboxylate (0.5g,1.7mmol) was dissolved in hydrochloric acid (2N,5mL), the reaction was stirred at 25 ℃ for 12 hours, ethyl acetate (20mL × 3) was extracted, the organic phase was dried over anhydrous sodium sulfate, and the product was obtained after concentration (200mg, yield 50.6%).

3) Preparation of methyl (Z) -3- (1- (hydroxyimino) ethyl) -1-methyl-1H-indazole-6-carboxylate

Methyl 3-acetyl-1-methyl-1H-indazole-6-carboxylate (200mg,0.86mmol), hydroxylamine hydrochloride (90mg,1.3mmol) and sodium hydroxide (60mg,1.5mmol) were dissolved in methanol (5mL), and after stirring and reacting at 70 ℃ for 3 hours, the reaction solution was concentrated, water (3mL) was added, and the precipitated solid was filtered and dried to obtain a product (200mg, yield 93.9%).

4) Preparation of methyl 3- (1-aminoethyl) -1-methyl-1H-indazole-6-carboxylate

Methyl (Z) -3- (1- (hydroxyimino) ethyl) -1-methyl-1H-indazole-6-carboxylate (200mg,0.81mmol) was dissolved in methanol (5mL), palladium on carbon (10%, 20mg) was added, hydrogen was replaced, the reaction was stirred at 25 ℃ for 12 hours, filtered, and the filtrate was concentrated to obtain the product (150mg, yield 79.4%).

5) Preparation of methyl 3- (1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -1-methyl-1H-indazole-6-carboxylate

Methyl 3- (1-aminoethyl) -1-methyl-1H-indazole-6-carboxylate (150mg,0.64mmol), 2, 3-dichloro-5- (trifluoromethyl) pyridine (210mg,0.97mmol) was dissolved in N, N-dimethylformamide (5mL), potassium carbonate (180mg,1.3mmol) was added, the temperature was raised to 70 ℃, the reaction was stirred for 12 hours, water (20mL) was added, ethyl acetate (15mL × 3) was extracted, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the product (80mg, yield 30.3%).

6) Preparation of 3- (1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -1-methyl-1H-indazole-6-carboxylic acid

Methyl 3- (1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -1-methyl-1H-indazole-6-carboxylate (80mg,0.19mmol) was dissolved in a mixed solution of methanol (1mL) and tetrahydrofuran (1mL), 2N sodium hydroxide (0.3mL) was added dropwise, and the reaction was stirred at 60 ℃ for 2 hours. The reaction mixture was concentrated, 10% citric acid was added dropwise to adjust the pH to 6, and the mixture was extracted with ethyl acetate (15 mL. times.3), separated to give an organic phase, dried over anhydrous sodium sulfate, and concentrated to give a product (50mg, yield 65.8%).

7) Preparation of 3- (1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide

3- (1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) ethyl) -1-methyl-1H-indazole-6-carboxylic acid (50mg,0.13mol), cyclopropanesulfonamide (32mg,0.26mmol), 4-dimethylaminopyridine (32mg,0.26mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (50mg,0.26mmol) were dissolved in dichloromethane (5mL), the reaction was stirred at 25 ℃ for 12 hours, 10% citric acid was added dropwise to adjust pH to 7, ethyl acetate (10mL × 3) was extracted, the organic phase was separated, dried over anhydrous sodium sulfate, and the product was purified by column chromatography (dichloromethane: methanol ═ 10:1) to give 22mg, yield 33.8%).

The molecular formula is as follows: c₂₀H₁₉ClF₃N₅O₃S molecular weight: 501.9LC-MS (M/e):502.1 (M)⁺)

¹H-NMR(400MHz,CDCl₃):9.11-9.35(brs,1H),8.32(s,1H),8.05(s,1H),7.85(d,J＝8.0Hz,1H),7.76(s,1H),7.59(d,J＝8.0Hz,1H),6.16(d,J＝7.6Hz,1H),5.87-5.91(m,1H),4.20(s,3H),3.16(s,1H),1.76(d,J＝6.4Hz,3H),1.59-1.62(m,2H),1.17-1.18(m,2H).

EXAMPLE 143- (((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) methyl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide preparation (Compound 14)

1) Preparation of methyl 3-formyl-1H-indazole-6-carboxylate

Methyl 1H-indole-6-carboxylate (5.0g,28.5mmol) was dissolved in tetrahydrofuran (100mL), cooled to 0 ℃, water (500mL) was added, sodium nitrite (20.0g,0.29mol) was slowly added, concentrated hydrochloric acid (22.5mL) was added dropwise while maintaining 0 ℃, after addition, the temperature was raised to 25 ℃, stirred for 4 hours, ethyl acetate (100mL × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain the product (2.4g, yield 41.4%).

2) Preparation of methyl 3-formyl-1-methyl-1H-indazole-6-carboxylate

Methyl 3-formyl-1H-indazole-6-carboxylate (1.0g,4.9mmol) was dissolved in dimethyl sulfoxide (50mL), potassium carbonate (1.4g,10.1mmol) was added, methyl iodide (0.7g,4.9mmol) was slowly added, the reaction was stirred at 25 ℃ for 1 hour, water (300mL) was added, ethyl acetate (100mL × 3) was extracted, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether ═ 5:1) to obtain a product (0.4g, yield 36.4%).

3) Preparation of methyl (E) -3- ((hydroxyimino) methyl) -1-methyl-1H-indazole-6-carboxylate

Methyl 3-formyl-1-methyl-1H-indazole-6-carboxylate (0.40g,1.8mmol), hydroxylamine hydrochloride (0.19g,2.7mmol) and sodium hydroxide (0.15g,3.8mmol) were dissolved in methanol (10mL), and after stirring and reacting at 75 ℃ for 3 hours, the reaction solution was cooled, concentrated, water (10mL) was added, and the precipitated solid was filtered and dried to obtain a product (0.20g, yield 47.6%).

4) Preparation of methyl 3- (aminomethyl) -1-methyl-1H-indazole-6-carboxylate

Methyl (E) -3- ((hydroxyimino) methyl) -1-methyl-1H-indazole-6-carboxylate (0.2g,0.86mmol) was dissolved in methanol (5mL), radium niobium nickel (50mg) was added, the reaction was stirred at 25 ℃ for 5 hours after replacement of hydrogen, filtered, and the filtrate was concentrated to give the product (150mg, yield 79.6%).

5) Preparation of methyl 3- (((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) methyl) -1-methyl-1H-indazole-6-carboxylate

Methyl 3- (aminomethyl) -1-methyl-1H-indazole-6-carboxylate (150mg,0.68mmol) and 2, 3-dichloro-5- (trifluoromethyl) pyridine (220mg,1.0mmol) were dissolved in N, N-dimethylformamide (5mL), potassium carbonate (190mg,1.4mmol) was added, the temperature was raised to 70 ℃, the reaction was stirred for 12 hours, water (20mL) was added, ethyl acetate (15mL × 3) was extracted, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate ═ 5:1) to obtain a product (170mg, yield 62.7%).

6) Preparation of 3- (((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) methyl) -1-methyl-1H-indazole-6-carboxylic acid

Methyl 3- (((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) methyl) -1-methyl-1H-indazole-6-carboxylate (150mg,0.38mmol) was dissolved in a mixed solution of methanol (1mL) and tetrahydrofuran (1mL), 2N sodium hydroxide (0.5mL) was added dropwise, and the reaction was stirred at 60 ℃ for 2 hours. The reaction mixture was concentrated, 10% citric acid was added dropwise to adjust the pH to 6, and the mixture was extracted with ethyl acetate (15 mL. times.3), separated to give an organic phase, dried over anhydrous sodium sulfate, and concentrated to give the product (120mg, yield 82.2%).

7) Preparation of 3- (((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) methyl) -N- (cyclopropylsulfonyl) -1-methyl-1H-indazole-6-carboxamide

3- (((3-chloro-5- (trifluoromethyl) pyridin-2-yl) amino) methyl) -1-methyl-1H-indazole-6-carboxylic acid (120mg,0.31mol), cyclopropanesulfonamide (75mg,0.62mmol), 4-dimethylaminopyridine (76mg,0.62mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (120mg,0.63mmol) were dissolved in dichloromethane (5mL) and the reaction was stirred at 25 ℃ for 12 hours. 10% citric acid was added dropwise to adjust the pH to 7, and the mixture was extracted with ethyl acetate (10 mL. times.3), separated to give an organic phase, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane: methanol. RTM. 10:1) to give a product (80mg, yield 53.0%).

The molecular formula is as follows: c₁₉H₁₇ClF₃N₅O₃S molecular weight: 487.9LC-MS (M/e):488.1 (M)⁺)

¹H-NMR(400MHz,DMSO-d₆):12.15(s,1H),8.29-8.31(m,2H),7.98(d,J＝2.0Hz,2H),7.92(d,J＝8.4Hz,1H),7.58(d,J＝1.2Hz,1H),4.96(d,J＝6.0Hz,2H),4.03(s,3H),3.13(s,1H),1.05-1.13(m,4H).

In the preparation examples of the compounds of the present invention, the preparation methods of all intermediate compounds having the same structure can be referred to each other.

Claims

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt, a solvate or an isomer thereof,

wherein R is¹Selected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylamino radical C_1-6Alkyl, di (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylaminocarbonyl radical C_1-6Alkyl, di (C)_1-6Alkyl) aminocarbonyl group C_1-6Alkyl radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl, 3-8 membered cycloalkyl C_1-6Alkyl, 3-8 membered cycloalkylcarbonyl C_1-6Alkyl, 3-8 membered heterocyclyl C_1-6Alkyl and 3-8 membered heterocyclylcarbonyl C_1-6An alkyl group;

R⁶selected from hydrogen, C_1-6Alkyl and halo C_1-6An alkyl group;

x is selected from C-R⁷And N, said R⁷Selected from hydrogen, halogen, hydroxy, amino, carboxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-12 membered aryl and 5-12 membered heteroaryl;

ring a is absent, or selected from optionally substituted with one or more (e.g., 2,3,4,5, or 6) Q²Substituted 3-15 membered cycloalkyl, 3-15 membered heterocyclyl, 5-15 membered spirocyclyl, 5-15 membered spiroheterocyclyl, 5-15 membered bridged cyclyl, 5-15 membered bridged heterocyclyl, 6-12 membered aryl and 5-12 membered heteroaryl; each Q²Independently selected from halogen, hydroxy, amino, carboxy, cyano, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino, di (C)_1-6Alkyl) ammoniaBase, C_1-6Alkyl carbonyloxy, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl and C_1-6An alkylsulfonylamino group;

and, rings a and L cannot be simultaneously absent;

ar is selected from optionally substituted with one or more (e.g., 2,3,4,5, or 6) Q⁴Substituted 6-12 membered aryl and 5-12 membered heteroaryl; each Q⁴Independently selected from halogen, hydroxy, amino, carboxyl, nitro, cyano, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylamino radical C_1-6Alkyl, di (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl radical, C_1-6Alkylaminocarbonyl, di (C)_1-6Alkyl) aminocarbonyl, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfinyl radical, C_1-6Alkyl sulfonamidesA group of 3-8 membered cycloalkyl, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkyl C_1-6Alkyl, 3-8 membered cycloalkyl C_1-6Alkylamino, 3-8 membered cycloalkyl C_1-6Alkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclyl C_1-6Alkyl, 3-8 membered heterocyclyl C_1-6Alkylamino and 3-8 membered heterocyclyl C_1-6An alkoxy group.

2. The compound, pharmaceutically acceptable salt, solvate, or isomer thereof according to claim 1,

R¹selected from hydrogen, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylsulfonyl, 3-8 membered cycloalkyl and 3-8 membered heterocyclyl;

R²selected from hydrogen, amino, C_1-6Alkyl, halo C_1-6Alkyl and optionally substituted by 1-3Q¹Substituted of the following groups: 3-8 membered cycloalkyl, 3-8 membered cycloalkyl C_1-6Alkyl, 3-8 membered cycloalkyl C_1-6Alkoxy, 3-to 8-membered heterocyclyl C_1-6Alkyl or 3-8 membered heterocyclyl C_1-6An alkoxy group; each Q¹Independently selected from halogen, hydroxy, amino, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino and di (C)_1-6Alkyl) amino;

R³、R⁴、R⁵each independently selected from hydrogen, halogen, hydroxy, amino, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl and halo C_1-6An alkoxy group;

R⁶selected from hydrogen and C_1-6An alkyl group;

x is selected from C-R⁷And N, said R⁷Selected from hydrogen, halogen, hydroxy, amino, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, halo C_1-6Alkyl, 3-8 membered cycloalkyl and 3-8 memberedA heterocyclic group;

and, rings a and L cannot be simultaneously absent;

ar is selected from the group consisting of optionally substituted 1-3Q⁴Substituted 6-10 membered aryl and 5-10 membered heteroaryl; each Q⁴Independently selected from halogen, hydroxy, amino, nitro, cyano, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylsulfonyl, 3-6 membered cycloalkyl C_1-6Alkyl, 3-6 membered cycloalkyl C_1-6Alkylamino, 3-6-membered cycloalkyl C_1-6Alkoxy, 3-6 membered heterocyclyl C_1-6Alkyl, 3-6 membered heterocyclyl C_1-6Alkylamino and 3-6 membered heterocyclyl C_1-6Alkoxy radical。

3. The compound, pharmaceutically acceptable salt, solvate, or isomer of claim 1 or 2,

ring A is absent, or is optionally substituted with 1-3Q²Substituted 3-8 membered cycloalkyl and 3-8 membered heterocyclyl; each Q²Independently selected from halogen, hydroxy, amino, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino and di (C)_1-6Alkyl) amino;

and, rings a and L cannot be simultaneously absent;

4. The compound, pharmaceutically acceptable salt, solvate, or isomer of any of claims 1-3, wherein,

R¹selected from hydrogen, C_1-4Alkyl, halo C_1-4Alkyl, hydroxy C_1-4Alkyl, amino C_1-4Alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocyclyl;

R²is selected from the group consisting of hydrogen,amino group, C_1-4Alkyl, halo C_1-4Alkyl and optionally substituted by 1-2Q¹Substituted of the following groups: 3-6 membered cycloalkyl, 3-6 membered cycloalkyl C_1-4Alkyl, 3-6 membered heterocyclyl or 3-6 membered heterocyclyl C_1-4An alkyl group; each Q¹Independently selected from halogen, hydroxy, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy radical, C_1-4Alkylamino and di (C)_1-4Alkyl) amino;

R⁶selected from hydrogen and C_1-4An alkyl group;

ring A is absent, or is optionally substituted with 1-2Q²Substituted 4-6 membered cycloalkyl and 4-6 membered heterocyclyl, each Q²Independently selected from halogen, hydroxy, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy and C_1-4An alkylamino group;

l is absent, or is optionally substituted by 1-2Q³Substituted C_1-4Alkylene radical of the formula C_1-4Any one or more carbon atoms of the alkylene group being optionally O, NR⁸C (O), S, S (O) or S (O)₂Is replaced by one or more hetero atoms or groups, said R⁸Selected from hydrogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl or C_1-4An alkylsulfonyl group; each Q³Independently selected from halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy and halo C_1-4An alkyl group;

and, rings a and L cannot be simultaneously absent;

5. The compound, pharmaceutically acceptable salt, solvate, or isomer thereof according to any one of claims 1-4, wherein,

R¹selected from hydrogen, C_1-4Alkyl, halo C_1-4Alkyl, 3-6 membered saturated cycloalkyl and 3-6 membered saturated heterocyclyl;

R⁶selected from hydrogen and C_1-4An alkyl group;

x is selected from CH and N;

ring A is optionally substituted with 1-2Q²Substituted 4-6 membered saturated cycloalkyl and 4-6 membered saturated heterocyclyl, said heterocyclyl containing one or more (e.g., 1,2,3, or 4) heteroatoms selected from O, S and N; preferably, the heteroatoms in the heterocyclic group comprise at least one nitrogen atom, and optionally also one O, S or N; each Q²Independently selected from halogen, hydroxy, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy and C_1-4An alkylamino group;

preferably, when ring A is optionally substituted with 1-2Q²Substituted 4-6 membered saturated heterocyclyl, which is attached to L or Ar through a ring heteroatom thereof;

l is absent, or is optionally substituted by 1-2Q³Substituted C_1-4Alkylene radical of the formula C_1-4Any one or more carbon atoms of the alkylene group being optionally O, NR⁸Or one or more heteroatoms or groups of C (O), R⁸Selected from hydrogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl and C_1-4An alkylsulfonyl group; each Q³Independently selected from halogen, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy and halo C_1-4An alkyl group;

ar is selected from the group consisting of optionally substituted 1-2Q⁴Substituted phenyl and 5-6 membered monocyclic heteroaryl, said heteroaryl comprising one or more (e.g., 1,2,3, or 4) heteroatoms selected from O, S and N; preferably, the heteroatoms in the heteroaryl group comprise at least one nitrogen atom, and optionally also one O, S or N; each Q⁴Independently selected from halogen, hydroxy, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino, 3-6 membered saturated cycloalkyl C_1-4Alkyl or 3-6 membered saturated cycloalkyl C_1-4An alkoxy group.

6. The compound, pharmaceutically acceptable salt, solvate, or isomer thereof according to claim 5, wherein,

R¹selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxyethyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, and morpholinyl;

R⁶selected from hydrogen, methyl, ethyl and propyl;

preferably, when ring a is heterocyclyl, it is attached through its ring heteroatom to L or Ar;

l is absent, or is optionally substituted by 1-2Q³Substituted C_1-2Alkylene radical of the formula C_1-2Any carbon atom in the alkylene radical being optionally O, NR⁸Or C (O), said R⁸Selected from the group consisting of hydrogen, methyl, ethyl, propyl, methylcarbonyl and methylsulfonyl; each Q³Independently selected from the group consisting of fluorine, chlorine,

bromine, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, chloromethyl, fluoromethyl and trifluoromethyl;

7. The compound of claim 6, a pharmaceutically acceptable salt, solvate, or isomer thereof, selected from the group consisting of:

8. the compound, pharmaceutically acceptable salt, solvate, or isomer thereof according to any one of claims 1-4, wherein,

R⁶selected from hydrogen and C_1-4An alkyl group;

x is selected from CH and N;

ring a is absent;

ar is selected from the group consisting of optionally substituted 1-2Q⁴Substituted phenyl and 5-6 membered monocyclic heteroaryl, said heteroaryl comprising one or more (e.g., 1,2,3, or 4) heteroatoms selected from O, S and N; preferably, the heteroatom in the heteroaryl group comprisesAt least one nitrogen atom and optionally further comprising an O, S or N; each Q⁴Independently selected from halogen, hydroxy, amino, nitro, cyano, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino, 3-6 membered saturated cycloalkyl C_1-4Alkyl and 3-6 membered saturated cycloalkyl C_1-4An alkoxy group.

9. The compound, pharmaceutically acceptable salt, solvate, or isomer thereof according to claim 8,

R⁶selected from hydrogen, methyl, ethyl and propyl;

l is optionally substituted by 1-2Q³Substituted C_1-3Alkylene radical ofC is_1-3Any one or more carbon atoms of the alkylene group being optionally O, NR⁸Or one or more heteroatoms or groups of C (O), R⁸Selected from the group consisting of hydrogen, methyl, ethyl, propyl, methylcarbonyl and methylsulfonyl; each Q³Independently selected from the group consisting of fluoro, chloro, bromo, hydroxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, chloromethyl, fluoromethyl, and trifluoromethyl;

ar is selected from the group consisting of optionally substituted 1-2Q⁴Substituted phenyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl; each Q⁴Independently selected from the group consisting of fluoro, chloro, bromo, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, methoxy, ethoxy, propoxy, isopropoxy, n-butyloxy, 1-methylpropoxy, 2, 2-dimethylpropoxy, n-butyloxy, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy.

10. The compound of claim 9, a pharmaceutically acceptable salt, solvate, or isomer thereof, selected from the group consisting of:

11. a pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, solvate or isomer thereof according to any of claims 1-10, optionally further comprising one or more pharmaceutically acceptable carriers.

12. The pharmaceutical composition of claim 11, further comprising one or more second therapeutically active agents selected from the group consisting of: na (Na)_v1.3 channel modulators, Na_v1.8 channel modulators, Na_v1.9 channel modulators, other Na_v1.7 channel modulators, inhibitors of lipoamide hydrolase, mPGES-1 inhibitors, opioid analgesics, non-steroidal anti-inflammatory drugs, sedatives, skeletal muscle relaxants, NMDA receptor antagonists, alpha-adrenoceptor agonists, tricyclic antidepressants, antiepileptics, tachykinin antagonists, muscarinic antagonists, COX-2 selective inhibitors, psychotropic inhibitors, capsaicin receptor agonists or antagonists, beta-adrenergic agents, local anesthetics, corticosteroids, 5-HT receptor agonists or antagonists, 5-HT2A receptor antagonists, PDE-V inhibitors, gamma-aminobutyric acid derivatives, metabotropic glutamate subgroup 1 receptor antagonists, serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dual serotonin-norepinephrine reuptake inhibitors, Nitric oxide synthase inhibitors, acetylcholinesterase inhibitors, prostaglandin E2 subgroup 4 antagonists, 5-lipoxygenase inhibitors, and pharmaceutically acceptable salts or solvate compounds thereof.

13. Use of a compound of any one of claims 1-10, a pharmaceutically acceptable salt, solvate or isomer thereof for the manufacture of a medicament for the prevention and/or treatment of Na in a subject_v1.7 channel-associated diseases; preferably, the reaction with Na_v1.7 channel-related disorders are painful disorders;

preferably, the painful condition is selected from the group consisting of inflammatory pain, visceral pain, cancer-induced pain, chemotherapy pain, trauma pain, surgical and post-surgical pain, labor pain, acute pain, chronic pain, intractable pain, somatic pain, nociceptive pain, neuropathic pain, blood-borne pain, immunoborne pain, endocrinologically-derived pain, metabolic pathology-induced pain, cardiogenic pain, headache, phantom limb pain and toothache.

14. A kit comprising a compound of any one of claims 1-10, a pharmaceutically acceptable salt, solvate, or isomer thereof, optionally, the kit further comprising instructions for use; preferably, the kit acts on Na_v1.7 channels inhibit pain transmission.