CN107406380B

CN107406380B - Heterocyclic substituted N-sulfonyl benzamide derivative, preparation method and medical application thereof

Info

Publication number: CN107406380B
Application number: CN201680008177.3A
Authority: CN
Inventors: 兰炯; 周福生; 赵金柱; 黄栋; 谢婧; 胡毅; 吕强
Original assignee: Yangtze River Pharmaceutical Group Co Ltd; Shanghai Haiyan Pharmaceutical Technology Co Ltd
Current assignee: Yangtze River Pharmaceutical Group Co Ltd; Shanghai Haiyan Pharmaceutical Technology Co Ltd
Priority date: 2015-02-04
Filing date: 2016-02-03
Publication date: 2020-04-28
Anticipated expiration: 2036-02-03
Also published as: WO2016124141A1; CN107428683B; CN107406380A; CN107207430B; WO2016124139A1; CN107207430A; WO2016124140A1; CN107428683A

Abstract

The invention discloses a heterocyclic substituted N-sulfonyl benzamide derivative, a preparation method and a medical application thereof. Specifically, the invention discloses a compound of formula (I) or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, and a preparation method and application thereof, wherein the definitions of all groups in the formula are shown in the specification.

Description

Heterocyclic substituted N-sulfonyl benzamide derivative, preparation method and medical application thereof

Technical Field

The invention belongs to the technical field of medicines. In particular, the invention relates to a heterocyclic substituted N-sulfonyl benzamide derivative, a preparation method thereof, an application of the heterocyclic substituted N-sulfonyl benzamide derivative as a sodium ion channel (especially Nav1.7) inhibitor, and a pharmaceutical composition and a medicinal composition prepared from the heterocyclic substituted N-sulfonyl benzamide derivative.

Background

Recently, Cox et al in UK reported for the first time in Nature the unexpected results of a mutation in the SCN9A gene encoding a voltage-gated Nav1.7 channel that led to an indolent condition in the inherited individual. The individuals with this genetic mutation are inherently deprived of pain, but other functions of the body are completely normal, and recent studies have shown that the voltage-gated Nav1.7 channel expressed in DRG neurons is involved in the generation of pain signals and exerts a gate function that controls the transmission of pain signals. This study suggests that the Nav1.7 channel may be a drug target for selective treatment of pain without side effects.

Nav1.7(PN1, SCN9A) VGSC are sensitive to blockade by tetrodotoxin, which is expressed predominantly in peripheral sympathetic and sensory neurons. The SCN9A gene has been replicated by a variety of species, including human, rat, and rabbit, and shows about 90% identity in amino acids between human and rat genes.

There is increasing body evidence that Nav1.7 plays an important role in a variety of pain states, including acute, chronic, inflammatory and/or neuropathic pain, and in humans, Nav1.7 protein accumulates in neuromas, particularly those that cause pain. Mutations (whether genetic or episodic) that increase Nav1.7 function have been implicated in primary erythromelalgia, a disease characterized by burning and inflammation of the extremities, and sudden extreme pain symptoms. The reported results regarding the nonselective sodium channel blockers lidocaine and mexiletine to alleviate the symptoms of hereditary erythromelalgia, and carbamazepine to effectively reduce the number and severity of attacks of PEPD, are consistent with the above observations. Additional evidence for the role of Nav1.7 in pain can be found in the phenotype of a loss-of-function mutation of the SCN9A gene. Subsequent studies have shown many different mutations that result in loss of function of the SCN9A gene and CIP phenotype.

Since Nav1.7 is specifically expressed in DRG sensory neurons but not in other tissues such as cardiomyocytes and the central nervous system, development of a specific blocker for treating chronic pain is likely to improve the therapeutic effect and to greatly reduce the side effects, and a selective inhibitor of Nav1.7 ion channels is almost useful for the treatment of various pains.

Since many patients with acute or chronic pain disorders respond poorly to current pain therapies and are often resistant and insensitive to opiates. In addition, the efficacy of currently used sodium channel blockers for the above-mentioned disease conditions is largely limited by a number of side effects. These side effects include various CNS disorders such as blurred vision, dizziness, nausea, and sedation, as well as more potentially life-threatening arrhythmias and heart failure.

Thus, in view of the limited efficacy and unacceptable side effects of currently available agents, there is an urgent need to develop safer and more effective analgesics with higher efficacy and fewer side effects. While the Nav1.7 ion channel is an important target for developing non-addiction analgesic drugs, the Nav1.7 ion channel highly selective inhibitor can be used for wide-range pain treatment, so the development of a novel Nav1.7 ion channel highly selective inhibitor is necessary.

Disclosure of Invention

The invention aims to provide a highly selective inhibitor of Nav1.7 ion channels and application thereof in medicines.

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

in the formula, R₁、R₂、R₃、R₄Each independently hydrogen, hydroxy, CN, NO₂Halogen, -NR_aR_b、C_1-20Alkyl radical, C_3-20Cycloalkyl radical, C_3-20Cycloalkoxy, C_2-20Alkenyl radical, C_2-20Alkynyl, C_1-20Alkoxy, -CHO, -CO- (C)_1-20Alkyl), -CO- (C)_6-20Aryl group), C_6-20Aryl, -CONR_aR_b、-C(O)O-(C_1-20Alkyl), -OC (O) - (C)_1-20Alkyl), -SO₂-(C_1-20Alkyl) or-SO₂-(C_6-20Aryl groups);

R₅is hydrogen, C_1-20Alkyl radical, C_3-20Cycloalkyl, halo C_1-20An alkyl group;

R₆is C_6-20Aryl radical, C_1-20Alkyl, -NR_aR_b(ii) a Wherein R is_a、R_bEach independently is hydrogen, C_1-20Alkyl radical, C_3-20Cycloalkyl or C_6-20An aryl group;

L₁、L₂at any different position on the ring, independently of one anotherA bond, or-C (O) N (R)^y)-、-N(R^y)C(O)-、-N(R^y)SO₂-、-SO₂N(R^y)-、-OC(O)-、-C(O)O-、-(CR^yR^x)_r1(O)_r2(CR^yR^x)_r3-、-S(O)-、-SO₂-、-N(R^y) -, -O-, -S-, -C (O) -or cyclopropylene; wherein R is^y、R^xEach independently hydrogen, halogen, hydroxy, CN, NO₂、C_1-20Alkyl, halo C_1-20Alkyl radical, C_3-20Cycloalkyl radical, C_2-20Alkenyl radical, C_2-20Alkynyl or C_6-20An aryl group; r1, r3 are each independently 0, 1, 2 or 3; r2 is 0 or 1;

W₁、W₂each independently C, N, O or S;

n and m are each independently 0, 1, 2 or 3, and n and m are not 0 at the same time; wherein, when n is 0 or m is 0, W₁And W₂Are connected through a single bond;

(R₀)_pis hydrogen at any position on the ring by p R₀Substituted, p is 0, 1, 2, 3, 4 or 5, each R₀The same or different, each independently is hydrogen, deuterium, C_1-20Alkyl, deuterated C_1-20Alkyl or halo C_1-20An alkyl group; or any two R₀By a single bond or- (CH)₂)_p1-linked, p1 is 1, 2 or 3;

a is C_6-20Aryl, 3-to 7-membered monocyclic, 8-to 10-membered bicyclic, 3-to 7-membered monocyclic heterocycle, 8-to 10-membered bicyclic heterocycle, 5-or 6-membered monocyclic heteroaryl ring, 8-to 10-membered bicyclic heteroaryl ring, benzo 3-to 7-membered monocyclic heterocycle, 5-to 6-membered monocyclic heteroaryl ring and 3-to 7-membered monocyclic heterocycle;

wherein the alkyl, cycloalkyl, cycloalkoxy, alkenyl, alkynyl, alkoxy, aryl, 3-to 7-membered monocyclic, 8-to 10-membered bicyclic, 5-or 6-membered monocyclic heteroaryl ring, 8-to 10-membered bicyclic heteroaryl ring, benzo 3-to 7-membered monocyclic, 5-to 6-membered monocyclic heteroaryl ring, and 3-to 7-membered monocyclicOr 5-to 6-membered monocyclic heteroaryl ring and 3-to 7-membered monocyclic heterocycle is substituted or unsubstituted; and said substitution means that 1 to 5 hydrogens in the group are substituted with a substituent selected from the group consisting of: halogen, nitro, hydroxy, cyano, C_6-20Aryl radical, C_1-20Alkyl, halo C_1-20Alkyl radical, C_1-20Alkoxy, halo C_1-20Alkoxy radical, C_3-20Cycloalkyl, halo C_3-20Cycloalkyl radical, C_3-20Cycloalkoxy, halo C_3-20Cycloalkoxy, C_2-20Alkenyl, halo C_2-20Alkenyl radical, C_2-20Alkynyl, halo C_2-20Alkynyl, C_1-20Alkylthio, halo C_1-20Alkylthio radical, C_1-20Alkylamino, halogeno C_1-20Alkylamino, thiol, 3-to 20-membered heterocycloalkyl, 3-to 20-membered heterocycloalkyloxy, C_3-20Cycloalkylthio, halogeno C_3-20Cycloalkylthio, 3-to 20-membered heterocycloalkylthio, oxo, C_1-20Hydroxyalkyl, carboxyl, -NR_aR_b、-C(O)NR_aR_b、-N(R_a)C(O)-(C_1-20Alkyl), -N (R)_a)SO₂-(C_1-20Alkyl), -SO₂N(R_aR_b)、-C(O)O-(C_1-20Alkyl), -CHO, -OC (O) - (C)_1-20Alkyl), -SO₂-(C_1-20Alkyl), -SO₂-(C_6-20Aryl), -CO- (C)_6-20Aryl groups); r_a、R_bEach independently is hydrogen, C_1-20Alkyl radical, C_3-20Cycloalkyl or C_6-20And (4) an aryl group.

In another preferred embodiment, W₂Is N, O, S or C, when W is₂When O or S is present, L₂And on the ring except W₁And W₂To any other carbon atom than W₂When is N or C, L₂And on the ring except W₁And any other ring atom attached. Preferably, L₂And W₂And (4) connecting.

In another preferred embodiment, L₂Is a bond, A and W on the ring₁And any other ring atom attached.

In another preferred embodiment, L₂Is a bond, W₂Is N, O, S or C, when W is₂When O or S is present, A and the ring are removed by W₁And W₂To any other carbon atom than W₂When N or C is present, A and the ring are removed by W₁And any other ring atom attached.

In another preferred embodiment, W₁Is N, O, S or C, when W is₁When O or S is present, L₁And on the ring except W₁And W₂To any other carbon atom than W₁When is N or C, L₁And on the ring except W₂Other than by any ring atom, preferably L₁And W₁And (4) connecting.

In another preferred embodiment, the compound is a compound represented by formula (II):

in the formula, R₀、R₁、R₂、R₃、R₄、R₅、R₆、A、L₁、W₁、W₂N, p, m are as defined in claim 1.

In another preferred embodiment, each R₀The same or different, each independently hydrogen.

In another preferred embodiment, A is C_6-20Aryl or a 5 or 6 membered monocyclic heteroaryl ring.

In another preferred embodiment, a is phenyl or pyridyl; said phenyl or pyridyl is substituted or unsubstituted; and said substitution means that 1 to 5 hydrogens in the group are substituted with a substituent selected from the group consisting of: halogen, C_1-20Alkyl, halo C_1-20Alkyl radical, C_1-20Alkoxy, halo C_1-20Alkoxy radical, C_3-20Cycloalkyl, and C_3-20A cycloalkoxy group.

In another advantageIn the alternative, L₁Is a bond, or- (CR)^yR^x)_r1(O)_r2(CR^yR^x)_r3-; wherein R is^y、R^xEach independently is hydrogen; r1, r3 are each independently 0, 1, 2 or 3; r2 is 0 or 1.

In another preferred embodiment, the compound is of formula (III):

in the formula, R₀、R₁、R₂、R₃、R₄、R₅、R₆、R^x、R^y、r1、r2、r3、A、W₁、W₂N, p, m are as defined in claim 1.

In another preferred embodiment, in the compound of formula (III), W₁Is N, O, S or C, when W is₁When it is O or S, (CR)^yR^x)_r1And on the ring except W₁And W₂To any other carbon atom than W₁When is N or C, (CR)^yR^x)_r1And on the ring except W₂And any other ring atom attached, r1 is as defined above.

In a further preferred embodiment of the method,

selected from:

in another preferred embodiment, W₂Is N.

In another preferred embodiment, W₁N, O, S or C.

In a further preferred embodiment of the method,

selected from:

in a further preferred embodiment of the method,

selected from:

wherein, A, L₁、R₀The definition is the same as before.

In a further preferred embodiment of the method,

selected from:

wherein, A, L₁、R₀The definition is the same as before.

In a further preferred embodiment of the method,

selected from:

wherein, A, L₁、R₀The definition is the same as before.

In a further preferred embodiment of the method,

selected from:

and L is₁Is a bond, or- (CR)^yR^x)_r1(O)_r2(CR^yR^x)_r3-; wherein R is^y、R^xEach independently is hydrogen; r1, r3 are each independently 0, 1, 2 or 3; r2 is 0 or 1; each R₀The same or different, each independently hydrogen.

In another preferred embodiment, A is

Wherein R is₁’、R₂’、R₃’、R₄’、R₅' as defined in the specification.

In another preferred embodiment, A is

Wherein R is₂₁、R₃₁、R₄₁、R₅₁、R₁₂、R₃₂、R₄₂、R₅₂、R₁₃、R₂₃、R₄₃、R₅₃Each independently is hydrogen, halogen, nitro, hydroxy, cyano, C_6-20Aryl radical, C_1-20Alkyl, halo C_1-20Alkyl, halo C_1-20Alkoxy radical, C_1-20Alkoxy radical, C_3-20Cycloalkyl, halo C_3-20Cycloalkyl radical, C_3-20Cycloalkoxy, halo C_3-20Cycloalkoxy, C_2-20Alkenyl, halo C_2-20Alkenyl radical, C_2-20Alkynyl, halo C_2-20Alkynyl, -NR_aR_b、-C(O)NR_aR_b、-N(R_a)C(O)-(C_1-20Alkyl), -N (R)_a)SO₂-(C_1-20Alkyl), -SO₂N(R_aR_b)、-C(O)O-(C_1-20Alkyl), -CHO, -OC (O) - (C)_1-20Alkyl), -SO₂-(C_1-20Alkyl), -SO₂-(C_6-20Aryl), -CO-(C_1-20Alkyl), -CO- (C)_6-20Aryl groups); r_a、R_bAs defined above.

In a further preferred embodiment of the method,

selected from:

wherein, A, L₁、R₀The definition is the same as before.

In a further preferred embodiment of the method,

selected from:

wherein, A, L₁、R₀The definition is the same as before.

In another preferred embodiment, the compound is of formula (IV):

in the formula, R₀、R₁、R₂、R₃、R₄、R₅、R₆、R^x、R^y、r1、r2、r3、A、W₂N, p and m are as defined above; w₁Is N or C.

In another preferred embodiment, r2 is 0.

In another preferred embodiment, r1 and r3 are 0; r2 is 1.

In another preferred embodiment, r1 is 1, 2 or 3; r2 is 1; r3 is 0.

In another preferred embodiment, r1 is 0; r2 is 1; r3 is 1, 2 or 3.

In another preferred example, r1, r2, r3 are 0.

In another preferred embodiment, the compound is of formula (V):

in the formula, R₀、R₁、R₂、R₃、R₄、R₅、R₆、L₁、W₁、W₂N, p and m are as defined above; r₁’、R₂’、R₃’、R₄’、R₅' independently of one another are hydrogen, halogen, nitro, hydroxy, cyano, C_6-20Aryl radical, C_1-20Alkyl, halo C_1-20Alkyl, halo C_1-20Alkoxy radical, C_1-20Alkoxy radical, C_3-20Cycloalkyl, halo C_3-20Cycloalkyl radical, C_3-20Cycloalkoxy, halo C_3-20Cycloalkoxy, C_2-20Alkenyl, halo C_2-20Alkenyl radical, C_2-20Alkynyl, halo C_2-20Alkynyl, -NR_aR_b、-C(O)NR_aR_b、-N(R_a)C(O)-(C_1-20Alkyl), -N (R)_a)SO₂-(C_1-20Alkyl), -SO₂N(R_aR_b)、-C(O)O-(C_1-20Alkyl), -CHO, -OC (O) - (C)_1-20Alkyl), -SO₂-(C_1-20Alkyl), -SO₂-(C_6-20Aryl), -CO- (C)_1-20Alkyl), -CO- (C)_6-20Aryl groups); r_a、R_bAs defined above.

In another preferred embodiment, R₁’、R₂’、R₃’、R₄’、R₅' independently of one another are hydrogen, halogen, C_1-20Alkyl, halo C_1-20Alkyl, halo C_1-20Alkoxy radical, C_1-20Alkoxy radical, C_3-20Cycloalkyl radical, C_3-20A cycloalkoxy group.

In another preferred embodiment, R₂₁、R₃₁、R₄₁、R₅₁、R₁₂、R₃₂、R₄₂、R₅₂、R₁₃、R₂₃、R₄₃、R₅₃Each independently of the others is hydrogen, halogen, C_1-20Alkyl, halo C_1-20Alkyl, haloC_1-20Alkoxy radical, C_1-20Alkoxy radical, C_3-20Cycloalkyl radical, C_3-20A cycloalkoxy group.

In another preferred embodiment, in the compounds of the formula (V), L₁Is- (CR)^yR^x)_r1(O)_r2(CR^yR^x)_r3-, r1, r2, r3 are as defined above.

In another preferred embodiment, in the compounds of the formula (V), W₁Is N, O, S or C, when W is₁When O or S is present, L₁And on the ring except W₁And W₂To any other carbon atom than W₁When is N or C, L₁And on the ring except W₂Other than by any ring atom, preferably L₁And W₁And (4) connecting.

In another preferred embodiment, in the compounds of the formula (V), W₂Is N.

In another preferred embodiment, R₁、R₂、R₃、R₄Each independently of the others is hydrogen, halogen, C_1-20Alkyl radical, C_3-20A cycloalkyl group;

R₅is hydrogen;

R₆is C_1-20Alkyl, -NR_aR_b；

Wherein R is_a、R_bEach independently is hydrogen, or C_1-20An alkyl group;

W₁、W₂each independently C, O, S or N;

L₂is a bond;

L₁is a bond, or- (CR)^yR^x)_r1(O)_r2(CR^yR^x)_r3-, -O-or-C (O) -; wherein R is^y、R^xEach independently is hydrogen; r1, r3 are each independently 0 or 1; r2 is 0 or 1;

n and m are each independently 1 or 2;

(R₀)_pis hydrogen at any position on the ring by p R₀Substituted, p is 0;

a is phenyl;

and when W₁And/or W₂When O or S is present, L₁And A is independently removed from the ring by W₁And W₂Any other carbon atom linkage;

when W is₁And/or W₂When N or C is present, A and the ring are removed by W₁To any other ring atom other than, L₁And on the ring except W₂Any other ring atom other than;

wherein the alkyl, cycloalkyl or phenyl is substituted or unsubstituted; and said substitution means that 1 to 5 hydrogens in the group are substituted with a substituent selected from the group consisting of: halogen, C_1-20Alkyl, halo C_1-20Alkyl radical, C_1-20Alkoxy, halo C_1-20An alkoxy group.

In another preferred embodiment, R₂And R₄Is hydrogen, and R₁、R₃Each independently is halogen, C_3-6Cycloalkyl radical, C_1-3Alkyl radical, C_3-6Cycloalkoxy or C_1-3An alkoxy group.

In another preferred embodiment, L₂Is a bond (representing A and the ring except W₁Any other ring atom other than that attached), or is- (CH)₂)_r1(O)_r2(CH₂)_r3-、-S-、-C(O)-、-S(O)-、-SO₂-or-N (R)^y) -, where R1, R2, R3, R^yIs as defined above.

In another preferred embodiment, the compound is a compound represented by any one of formulas (I) to (V), wherein R is₁、R₂、R₃、R₄Each independently of the others is hydrogen, halogen, C_1-20Alkyl radical, C_3-20A cycloalkyl group;

R₅is hydrogen;

R₆is C_1-20Alkyl, -NR_aR_b(ii) a Wherein R is_a、R_bEach independently is hydrogen, C_1-20An alkyl group.

In another preferred embodiment, L₂Is a bond; or L₁Is a bond, or- (CR)^yR^x)_r1(O)_r2(CR^yR^x)_r3-; wherein R is^y、R^xEach independently is hydrogen; r1, r3 are each independently 0, 1, 2 or 3; r2 is 0 or 1.

In a further preferred embodiment of the method,

selected from:

a is C_6-20Aryl or a 5 or 6 membered monocyclic heteroaryl ring;

L₁is a bond, or- (CR)^yR^x)_r1(O)_r2(CR^yR^x)_r3-; wherein R is^y、R^xEach independently is hydrogen; r1, r3 are each independently 0, 1, 2 or 3; r2 is 0 or 1;

each R₀The same or different, each independently hydrogen;

the alkyl, cycloalkyl, aryl, 5 or 6 membered monocyclic heteroaryl ring is substituted or unsubstituted; and said substitution means that 1 to 5 hydrogens in the group are substituted with a substituent selected from the group consisting of: halogen, nitro, hydroxy, cyano, C_6-20Aryl radical, C_1-20Alkyl, halo C_1-20Alkyl radical, C_1-20Alkoxy, halo C_1-20Alkoxy radical, C_3-20Cycloalkyl, halo C_3-20Cycloalkyl radical, C_3-20Cycloalkoxy, halo C_3-20Cycloalkoxy, C_2-20Alkenyl, halo C_2-20Alkenyl radical, C_2-20Alkynyl, halo C_2-20Alkynyl, C_1-20Alkylthio, halo C_1-20Alkylthio radical, C_1-20Alkylamino, halogeno C_1-20Alkylamino, thiol, 3-to 20-membered heterocycloalkyl, 3-to 20-membered heterocycloalkyloxy, C_3-20Cycloalkylthio, halogeno C_3-20Cycloalkylthio, 3-to 20-membered heterocycloalkylthio, oxo, C_1-20Hydroxyalkyl, carboxyl, -NR_aR_b、-C(O)NR_aR_b、-N(R_a)C(O)-(C_1-20Alkyl), -N (R)_a)SO₂-(C_1-20Alkyl), -SO₂N(R_aR_b)、-C(O)O-(C_1-20Alkyl), -CHO, -OC (O) - (C)_1-20Alkyl), -SO₂-(C_1-20Alkyl), -SO₂-(C_6-20Aryl), -CO- (C)_6-20Aryl groups); r_a、R_bEach independently is hydrogen, C_1-20Alkyl radical, C_3-20Cycloalkyl or C_6-20And (4) an aryl group.

In another preferred embodiment, a is phenyl or pyridyl; said phenyl or pyridyl is substituted or unsubstituted; and said substitution means that 1 to 5 hydrogens in the group are substituted with a substituent selected from the group consisting of: halogen, C_1-20Alkyl, halo C_1-20Alkyl radical, C_1-20Alkoxy, halo C_1-20Alkoxy radical, C_3-20Cycloalkyl radical, C_3-20A cycloalkoxy group.

In another preferred embodiment, the phenyl is

Wherein R is₁’、R₂’、R₃’、R₄’、R₅' independently of one another are hydrogen, halogen, C_1-20Alkyl, halo C_1-20Alkyl, halo C_1-20Alkoxy radical, C_1-20Alkoxy radical, C_3-20Cycloalkyl radical, C_3-20A cycloalkoxy group.

In another preferred embodiment, the pyridyl is

Wherein R is₂₁、R₃₁、R₄₁、R₅₁、R₁₂、R₃₂、R₄₂、R₅₂、R₁₃、R₂₃、R₄₃、R₅₃Each independently of the others is hydrogen, halogen, C_1-20Alkyl, halo C_1-20Alkyl, halo C_1-20Alkoxy radical, C_1-20Alkoxy radical, C_3-20Cycloalkyl radical, C_3-20A cycloalkoxy group.

In a further preferred embodiment of the method,

selected from:

each R₀The same or different, each independently hydrogen.

In another preferred embodiment, r1 is 0; r3 is 1; r2 is 0.

In a further preferred embodiment of the method,

selected from:

each R₀The same or different, each independently hydrogen.

In another preferred embodiment, r1 and r3 are 0; r2 is 1.

In a further preferred embodiment of the method,

selected from:

each R₀The same or different, each independently hydrogen.

In another preferred embodiment, r1 is 1, 2 or 3; r2 is 1; r3 is 0.

In another preferred embodiment, r1 is 1; r2 is 1; r3 is 0.

In another preferred embodiment, R₁、R₃Each independently of the others is hydrogen, halogen, C_1-20Alkyl or C_3-20A cycloalkyl group; r₂And R₄Is hydrogen.

In another preferred embodiment, C_1-20The alkyl is methyl, ethyl, n-propyl, isopropyl or n-butyl.

In another preferred embodiment, C_3-20Cycloalkyl is cyclopropyl.

In another preferred embodiment, halo C_1-20The alkyl group is trifluoromethyl.

In another preferred embodiment, halo C_1-20The alkoxy is trifluoromethoxy, trifluoroethoxy or difluoromethoxy.

In another preferred embodiment, C_1-20The alkoxy is methoxy, ethoxy, isopropoxy, tert-butoxy or isobutoxy.

In another preferred embodiment, C_3-20Cycloalkoxy is cyclopropoxy.

In another preferred embodiment, halogen is fluorine or chlorine.

In another preferred embodiment, the compound is selected from the group consisting of:

in another preferred embodiment, R is₁、R₂、R₃、R₄、R₅、R₆、R_a、R_b、L₁、R^y、R^x、W₁、W₂、n、m、R₀A, etc. are each independently the corresponding groups in each of the specific compounds of formula I in the examples.

In another preferred embodiment, the compounds of formula I according to the invention are each of the specific compounds mentioned in the examples section, in particular any of the compounds Z-4 to Z-171.

In another preferred embodiment, the compound is a compound prepared in the examples herein.

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

In a third aspect, the present invention provides the use of a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, or a pharmaceutical composition according to the second aspect of the present invention, in the manufacture of a medicament for the treatment of a disease or condition.

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

In another preferred embodiment, the disease or disorder is selected from the group consisting of HIV-associated pain, HIV therapy-induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, acute pain, heat-sensitivity, sarcoidosis, irritable bowel syndrome, crohn's disease, pain associated with Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, sudden dystonia, myasthenia syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-associated disorders, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, and allodynia, Local and systemic tonic seizures, restless legs syndrome, cardiac arrhythmias, fibromyalgia, neuroprotection in ischemic disease states caused by stroke or nerve injury, tachyarrhythmia, atrial fibrillation and ventricular fibrillation.

In another preferred embodiment, the pain is selected from neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, labor pain, childbirth pain, dental pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, trigeminal neuralgia, post-herpetic neuralgia, acute pain, familial erythromelalgia, primary erythromelalgia, familial rectal pain or fibromyalgia, or a combination thereof.

In a fourth aspect, the present invention provides a method of treating a disease or disorder in a mammal, the method comprising administering to a subject (e.g. a mammal) in need thereof a therapeutically effective amount of a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, or a pharmaceutical composition according to the second aspect of the present invention.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1 shows graphs of hind limb licking times over time for groups of rats tested in Two way ANOVA; in fig. 1, P < 0.05, 0.01, and 0.001 in each of the test compound groups and the blank group.

FIG. 2 shows the area under the curve of the number of hind limbs licking by the corresponding groups of rats in the unpaired t-test; in fig. 2, P < 0.05, 0.01, and 0.001 represent the test compounds compared to the blank group, respectively.

FIG. 3 shows a graph of the time taken for each group of rats to lick the hind limb in the Two way ANOVA test; in fig. 3, P < 0.05, 0.01, and 0.001 of the test compound compared to the blank group are indicated.

FIG. 4 shows the area under the curve of time taken for each group of corresponding rats to lick the hind limb in unpaired t-test; in fig. 4, P < 0.05, 0.01, and 0.001 represent the test compounds compared to the blank group, respectively.

FIG. 5 shows the baseline of the rat cold pain test for Compound Z-97 in the spinal nerve ligation rat model.

FIG. 6 shows the effect of Compound Z-97 in inhibiting cold-stimulated allodynia in a spinal nerve ligation rat model.

FIG. 7 shows the baseline cold pain test in rats of Compound Z-40 in the spinal nerve ligation rat model.

FIG. 8 shows the effect of Compound Z-40 in inhibiting cold-stimulated allodynia in a spinal nerve ligation rat model.

FIG. 9 shows the baseline cold pain test in rats of Compound Z-73, 85 in the spinal nerve ligation rat model.

FIG. 10 shows the effect of compound Z-73, 85 in inhibiting cold-stimulated allodynia in a rat model of spinal nerve ligation.

FIG. 11 shows the baseline cold pain test in rats of Compound Z-22 in the spinal nerve ligation rat model.

FIG. 12 shows the effect of Compound Z-22 on the inhibition of Cold-stimulated allodynia in a rat model of spinal nerve ligation

Detailed Description

The inventors of the present invention have extensively and deeply studied and unexpectedly found that the heterocyclic substituted N-sulfonyl benzamide derivative of the present invention has a high inhibitory activity against Nav1.7, a significantly weak inhibitory activity against Nav1.5, and a significantly selective inhibitory activity against Nav1.7. Meanwhile, the series of compounds also show obvious analgesic effect in a pain model test, so that the series of compounds can be developed into medicines for treating extensive pain. On this basis, the inventors have completed the present invention.

Definition of terms

As used herein, "C" is_1-20Alkyl "refers to straight and branched chain saturated aliphatic hydrocarbon groups containing 1 to 20 carbon atoms, similarly defined below; more preferably C_1-10Alkyl groups, non-limiting examples include: methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1-dimethylpropyl group, 1, 2-dimethylpropyl group, 2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1, 2-trimethylpropyl group, 1-dimethylbutyl group, 1, 2-dimethylbutyl group, 2-dimethylbutyl group, 1, 3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2, 3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 2-methylpentyl group, 3-methylh, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl3, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like; more preferably C_1-6Alkyl, most preferably C_1-3An alkyl group.

As used herein, "alkenyl" refers to an aliphatic hydrocarbon group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, "C_2-20Alkenyl "refers to straight and branched chain alkenyl groups containing 2 to 20 carbon atoms, similarly defined below; more preferably C_2-10An alkenyl group; more preferably C_2-6An alkenyl group; most preferably C_2-4Alkenyl groups such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.

As used herein, "alkynyl" refers to an aliphatic hydrocarbon group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, "C_2-20Alkynyl "refers to straight and branched chain alkynyl groups containing 2 to 20 carbon atoms, similarly defined below; more preferably C_2-10An alkynyl group; more preferably C_2-6An alkynyl group; more preferably C_2-4An alkynyl group; for example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl and the like.

As used herein, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, "C_3-20Cycloalkyl "means a cyclic hydrocarbon group containing from 3 to 20 carbon atoms, as defined below; more preferably C_3-10A cycloalkyl group; more preferably C_3-8A cycloalkyl group; most preferably C_3-6A cycloalkyl group. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like, with cyclopropyl, cyclopentyl, cyclohexenyl being preferred. Non-limiting examples of polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.

As used herein, "heterocycloalkyl" and "heterocycleThe group "used interchangeably refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, preferably a 3-to 20-membered heterocycloalkyl group (meaning that the heterocycloalkyl group contains 3 to 20 ring atoms and wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O))_t(wherein t is an integer from 0 to 2) heteroatoms, excluding the ring moieties of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon); more preferably 3-to 10-membered heterocycloalkyl group, wherein 1 to 3 ring atoms are heteroatoms; more preferably 3-to 6-membered heterocycloalkyl; more preferably a 5-to 6-membered heterocycloalkyl group. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like. Non-limiting examples of polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

As used herein, "partially unsaturated" refers to a pi-electron system that contains one or more unsaturated bonds but does not have a complete conjugation.

As used herein, "C" is_1-20Alkoxy means-O- (C)_1-20Alkyl) wherein alkyl is as defined above. Preferably C_1-10Alkoxy, more preferably C_1-6Alkoxy, most preferably C_1-3An alkoxy group. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like.

As used herein, "C" is_3-20Cycloalkoxy means-O- (C)_3-20Cycloalkyl), wherein cycloalkyl is as defined above. Preferably C_3-10Cycloalkoxy, preferably C_3-8Cycloalkoxy, more preferably C_3-6A cycloalkoxy group. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

As used herein, "C" is_6-20Aryl "refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, and refers to aryl groups containing from 6 to 20 carbon atoms; more preferably a C6-12 aryl group, more preferably a phenyl group and a naphthyl group, most preferably a phenyl group.

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

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

As used herein, "halo" refers to a group in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogens are replaced with a halogen.

For example, "halo C_1-20Alkyl "means an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein alkyl is as defined above. Preferably a halogen atom_1-10Alkyl, more preferably halogenated C_1-6Alkyl, most preferably halo C_1-3An alkyl group. Halogen substituted C_1-20Examples of alkyl groups include, but are not limited to, monochloroethyl, dichloromethyl, 1, 2-dichloroethyl, monobromoethyl, monofluoroethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, and the like.

Also for example, "halo C_1-20Alkoxy "means an alkoxy group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein the alkoxy group is as defined above. Preferably a halogen atom_1-10Alkoxy, more preferably halo C_1-6Alkoxy, most preferably halo C_1-3An alkoxy group. Including, but not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

Also for example, "halo C_3-20Cycloalkyl "refers to a cycloalkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein cycloalkyl is as defined above. Preferably a halogen atom_3-10Cycloalkyl, more preferably halo C_3-8Cycloalkyl, most preferably halo C_3-6A cycloalkyl group. Including, but not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.

As used herein, "deuterated C_1-20Alkyl "means an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) deuterium atoms, wherein alkyl is as defined above. Preferably deuterated C_1-10Alkyl, more preferably deuterated C_1-6Alkyl, most preferably deuterated C_1-3An alkyl group. Deuterated C_1-20Examples of alkyl groups include (but are not limited to)) Mono-deuterated methyl, mono-deuterated ethyl, di-deuterated methyl, di-deuterated ethyl, tri-deuterated methyl, tri-deuterated ethyl, and the like.

As used herein, "C" is_1-20Hydroxyalkyl "means C substituted by hydroxy_1-20Alkyl, wherein alkyl is as defined above. Preferably C_1-10Hydroxyalkyl, more preferably C_1-6Hydroxyalkyl, most preferably C_1-3A hydroxyalkyl group.

As used herein, "amino" refers to-NH₂"cyano" means-CN, "nitro" means-NO₂"benzyl" means-CH₂-phenyl, "oxo" means ═ O, "carboxy" means-c (O) OH, "thiol" means-SH, "cyclopropylene" structure:

as used herein, "carboxylate group" refers to-C (O) O- (C)_1-20Alkyl) or (C)_3-20Cycloalkyl), wherein alkyl, cycloalkyl are as defined above.

As used herein, "C" is_1-20Alkylthio "means-S- (C)_1-20Alkyl) wherein alkyl is as defined above. Preferably C_1-10Alkylthio, more preferably C_1-6Alkylthio, most preferably C_1-3An alkylthio group.

As used herein, "C" is_1-20Alkylamino means- (C)_1-20Alkyl) -NH₂or-NH₂-(C_1-20Alkyl) wherein alkyl is as defined above. Preferably C_1-10Alkylamino, more preferably C_1-6Alkylamino, most preferably C_1-3An alkylamino group.

As used herein, "C" is_3-20Cycloalkylthio "means-S- (C)_3-20Cycloalkyl), wherein cycloalkyl is as defined above. Preferably C_3-10Cycloalkylthio, more preferably C_3-8Cycloalkylthio radical, most preferably C_3-6A cycloalkylthio group.

As used herein, "3-to 20-membered heterocycloalkylthio" refers to-S- (3-to 20-membered heterocycloalkyl), wherein heterocycloalkyl is defined as described above. Preference is given to 3-to 10-membered heterocycloalkylthio.

As used herein, "3-to 20-membered heterocycloalkyloxy" refers to-O- (3-to 20-membered heterocycloalkyl), wherein heterocycloalkyl is defined as above. Preference is given to 3-to 10-membered heterocycloalkyloxy.

As used herein, "heteroaryl ring" is used interchangeably with "heteroaryl" and refers to a monocyclic heteroaryl group having 5 to 10 ring atoms, preferably 5 or 6 membered or a bicyclic heteroaryl group having 8 to 10 membered ring atoms; 6, 10 or 14 pi electrons are shared in the ring array; and a group having 1 to 5 hetero atoms in addition to carbon atoms. "heteroatom" means nitrogen, oxygen or sulfur.

As used herein, "3-to 7-membered monocyclic ring" refers to a saturated or partially unsaturated all-carbon monocyclic ring containing 3 to 7 ring atoms. Preferably 5 to 6 membered. Examples of monocycles include (but are not limited to): cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

As used herein, "3 to 7 membered monocyclic heterocycle" means that 1, 2 or 3 carbon atoms in the 3 to 7 membered monocyclic ring are substituted by a heteroatom selected from nitrogen, oxygen or sulfur. Preferably 5 to 6 membered. Examples of mono-heterocycles include, but are not limited to, tetrahydrofuran rings, tetrahydrothiophene rings, pyrrolidinyl rings, piperidine rings, pyrroline rings, oxazolidine rings, piperazine rings, dioxolanes, morpholine rings, thiomorpholine rings, homopiperazine rings, pyran rings, and the like.

As used herein, "8-to 10-membered bicyclic ring" refers to a saturated all-carbon bicyclic ring or a partially unsaturated all-carbon bicyclic ring containing 8 to 10 ring atoms, examples of bicyclic rings include (but are not limited to):

as used herein, "8 to 10 membered diheterocycle" means that 1, 2, 3, 4 or 5 carbon atoms in the 8 to 10 membered diheterocycle are substituted with a heteroatom selected from nitrogen, oxygen or sulfur. Examples of bis-heterocycles include, but are not limited to, tetrahydroquinoline rings, tetrahydroisoquinoline rings, decahydroquinoline rings, and the like.

As used herein, "5-to 6-membered monocyclic heteroaryl ring" refers to a monocyclic heteroaryl ring containing 5 to 6 ring atoms, including for example (but not limited to): thiophene ring, N-alkylpyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, etc.

As used herein, "8-to 10-membered bicyclic heteroaryl ring" refers to a bicyclic heteroaryl ring containing 8 to 10 ring atoms, including for example (but not limited to): a benzofuran ring, a benzothiophene ring, an indole ring, an isoindole ring, a quinoline ring, an isoquinoline ring, an indazole ring, a benzothiazole ring, a benzimidazole ring, a quinazoline ring, a quinoxaline ring, a cinnoline ring, a phthalazine ring.

As used herein, "benzo 3-to 7-membered monocyclic or benzo 3-to 7-membered monocyclic ring" refers to a bicyclic structure formed by a monocyclic or monocyclic ring containing 3 to 7 ring atoms fused to a benzene ring, preferably a benzo 5-to 6-membered monocyclic or benzo 5-to 6-membered monocyclic ring. Non-limiting examples include:

as used herein, "5-to 6-membered monocyclic heteroaryl ring and 3-to 7-membered monocyclic or 5-to 6-membered monocyclic heteroaryl ring and 3-to 7-membered monocyclic heterocycle" refers to a bicyclic structure formed by a 3-to 7-membered monocyclic or 3-to 7-membered monocyclic heterocycle fused to a 5-to 6-membered monocyclic heteroaryl ring, non-limiting examples of which include:

as used herein, "substituted" refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are substituted independently of each other with a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are substituted independently of each other with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

As used herein, an alkyl group may be substituted or unsubstituted, an alkenyl group may be substituted or unsubstituted, an alkynyl group may be substituted or unsubstituted, a cycloalkyl group may be substituted or unsubstituted, a heterocyclyl group may be substituted or unsubstituted, an alkoxy group may be optionally substituted or unsubstituted, a cycloalkoxy group may be optionally substituted or unsubstituted, an aryl group may be substituted or unsubstituted, a 3 to 7 membered monocyclic ring may be substituted or unsubstituted, an 8 to 10 membered bicyclic ring may be substituted or unsubstituted, a benzo 3 to 7 membered monocyclic or benzo 3 to 7 membered monocyclic ring may be substituted or unsubstituted, a 5 to 6 membered monocyclic heteroaryl ring and a 3 to 7 membered monocyclic or a 5 to 6 membered monocyclic ring and a 3 to 7 membered monocyclic heteroaryl ring may be substituted or unsubstituted heteroaryl, when the above groups are substituted, the substituents are preferably 1 to 5 or less groups independently selected from C_1-20Alkyl, halo C_1-20Alkyl radical, C_2-20Alkenyl radical, C_2-20Alkynyl, C_1-20Alkoxy radical, C_1-20Alkylthio radical, C_1-20Alkylamino, halogen, thiol, hydroxy, nitro, cyano, C_3-20Cycloalkyl, 3-to 20-membered heterocyclyl, C_6-20Aryl, 5-or 6-membered monocyclic or 8-to 10-membered bicyclic heteroaryl, C_3-20Cycloalkoxy, 3-to 20-membered heterocycloalkyloxy, C_3-20Cycloalkylthio, 3-to 20-membered heterocycloalkylthio, oxo, amino, C_1-20Hydroxyalkyl, carboxyl or carboxylate.

Preparation method

The present invention provides methods for the preparation of compounds of formula (I), which can be readily prepared by a variety of synthetic procedures well known to those skilled in the art. Exemplary methods of preparation of these compounds may include, but are not limited to, the schemes described below.

The compounds of formula (I) according to the invention can be prepared by reference to the following synthetic routes, and the steps in the process can be extended or combined as desired during specific operations.

Route 1

Step 1: the compound of formula (I-c) may be formed by first activating the carboxyl group in the compound of formula (I-a) by a reagent such as oxalyl chloride, Carbonyldiimidazole (CDI), propylphosphonic anhydride, urea-based amide coupling reagent or carbodiimide, followed by a displacement reaction with the sulfonamide group in the compound of formula (I-b) in the presence of an affinity base such as 4-dimethylaminopyridine, N-dimethylaminopropyl-N' -ethylcarbodiimide, 4-dimethylaminopyridine/N, N-diisopropylethylamine.

Step 2: the compound of formula (I-c) is reacted with the compound of formula (I-d) in the presence of a base system, suitable base systems include potassium tert-butoxide in DMSO, sodium hydride in DMF, potassium carbonate in DMF, etc., to produce the compound of formula (I-e) by a substitution reaction (e.g., an affinity substitution reaction, etc.) or a coupling reaction (e.g., a Suzuki coupling, etc.).

And step 3: the compound of formula (I-e) can be subjected to substitution reaction with a compound of formula (I-f) to generate a compound of formula (I), wherein Lev in the formula (I-f) is a leaving group, and the leaving group comprises (but is not limited to) trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate and the like; acyloxy groups such as acetoxy, trifluoroacetyloxy, and the like.

Route 2

The compound of formula (I-d) may be first subjected to substitution reaction with the compound of formula (I-f) to produce the compound of formula (I-g), and then subjected to reaction with the compound of formula (I-c) to produce the compound of formula (I), under the same conditions as in step 3 and step 2 of scheme 1, respectively.

The reactions in the above steps are conventional reactions known to those skilled in the art. Unless otherwise indicated, reagents and starting compounds used in the synthetic routes are either commercially available or prepared by one skilled in the art by reference to known methods based on the structure of the various compounds designed.

Compared with the prior art, the invention has the main advantages that:

provides a series of heterocyclic substituted N-sulfonyl benzamide derivatives with novel structures, which have high selective inhibition activity on Nav1.7 and can be used as medicaments for treating extensive pains.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight. Unless otherwise defined, terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the present invention.

As used herein, DMF is dimethylformamide, DMSO is dimethyl sulfoxide, THF is tetrahydrofuran, DIEA is N, N-diisopropylethylamine, EA is ethyl acetate, PE is petroleum ether, BINAP is (2R, 3S) -2, 2 '-bis-diphenylphosphino-1, 1' -binaphthyl. As used herein, room temperature means about 25 ℃.

A method for preparing compound 1-a:

step a: compound 1-a-1(14.8g, 0.10mol) was added to trifluoromethanesulfonic acid (150ml), and mixedThe material was cooled to 0 ℃ and N-iodosuccinimide (24.75g, 0.110mol) was added in portions. The mixture was stirred at room temperature for 2 h. The reaction solution was slowly poured into ice water and stirred for about 15 minutes. Extraction was performed with petroleum ether (3X100 ml). The organic phase was washed with aqueous sodium thiosulfite (100ml) and dried over sodium sulfate. The filtrate was filtered and spin-dried, and the crude product was purified by column chromatography and eluted with petroleum ether to give compound 1-a-2(14.0g, yield: 55%) as a pink liquid.¹H NMR(400MHz，CDCl₃)：δ：7.78(dd，J＝8.0，6.4Hz，1H)，6.94(dd，J＝8.8，7.2Hz，1H)。

Step b: in N₂Compound 1-a-2(14g, 0.051mol) was dissolved in 1, 4-dioxane (140ml) under protection, and triethylamine (15.6g, 0.153mol), water (10ml), 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) dichloromethane complex (2.08g, 2.55mmol) were added, respectively. The mixture was stirred at 80 ℃ for 18h under a carbon monoxide pressure of 10 kg. The reaction mixture was slowly warmed to room temperature, and a 1N aqueous NaOH solution (250ml) was added thereto, followed by stirring for 10 minutes, followed by extraction with ethyl acetate (250 ml). The aqueous phase was adjusted to pH 2 with 1N aqueous HCl. Extraction was carried out with ethyl acetate (3X100ml), the organic phase was washed with saturated brine (100ml) and the organic phase was dried over sodium sulfate. The filtrate was filtered and spin-dried to obtain compound 1-a-3(7.8g, yield: 80%) as a white solid. MS m/z (ESI): 193[ M + H]⁺. Purity 98% (UV 214).

Step c: in N₂Compound 1-a-3(7.8g, 0.041mol) was dissolved in anhydrous dichloromethane (100ml) under protection, and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (11.65g, 0.061mol), DMAP (11.07g, 0.090mol) were added. The mixture was stirred at room temperature for 10 minutes and methylsulfonamide 2(4.82g, 0.061mol) was added. The mixture was stirred at room temperature for 18 h. To the reaction solution was added 150ml of water, and the mixture was stirred at room temperature for 0.5h, whereupon the aqueous phase was separated. The aqueous phase was adjusted to pH 3 with 1N HCl aqueous solution, extracted with dichloromethane (3X100ml), the organic phase was washed with saturated brine (200ml), dried over sodium sulfate and spin dried at 40 ℃. The crude product was passed through a column (100-mesh 200-mesh silica gel) and eluted with petroleum ether/ethyl acetate (1: 1) to give compound 1-a (3.8g, yield: 35%) as a white solid. MS m/z (ESI): 270[ M + H]⁺. Purity of＝100％(UV214)。¹H NMR(400MHz，CDCl₃)：δ：12.41(s，1H)，8.00(t，J＝7.6Hz，1H)，7.74(t，J＝10.0Hz，1H)，3.37(s，3H)。

A method for preparing compound 6-a:

the method comprises the following steps: to a solution of compound 6-a-1(1g, 10mmol) and triethylamine (1.01g, 10mmol) in 20ml of acetonitrile was added dropwise trifluoromethanesulfonic anhydride (2.82g, 10mmol) at 0 ℃ and stirred at room temperature for 2h, and added 4-bromo-2-chlorophenol (1.25g, 6mmol), potassium carbonate (2.76g, 20mmol) and stirred at 60 ℃ for 5 h. After the reaction is finished, the reaction product is cooled to room temperature, filtered, washed by ethyl acetate, and the filtrate is decompressed and concentrated to obtain a crude product which is purified by Combi-flash column chromatography to obtain a colorless oily compound 6-a (1.4g) which is directly used for the next reaction, and the yield is 80.5%.

A method for preparing compound 9-a:

the method comprises the following steps: to a solution of 9-a-1(400mg, 2.27mmol) in 10ml of 1, 2-dichloroethane were added methylsulfonamide (268mg, 2.73mmol), HATU (2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate) (1.3g, 3.41mmol), DIPEA (N, N-diisopropylethylamine) (880mg, 6.81mmol), DMAP (4-dimethylaminopyridine) (50mg) and stirred at 60 ℃ for 1 h. After the reaction is finished, cooling to room temperature, adding dichloromethane, washing with 3N hydrochloric acid, washing with saturated sodium bicarbonate, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying by Combi-flash column chromatography to obtain a red solid compound 9-a (250mg), wherein the red solid compound is directly used for the next reaction, the purity is 45%, and the yield is 44%. MS m/z (ESI): 252.0[ M-H ]]⁺。

A method for preparing compound 11-a:

step a: compound 11-a-1(5g, 31.6mmol) was dissolved in 20ml of sulfuric acid, cooled to 0 ℃ and 1, 3-dibromo-5, 5-dimethylhydantoin (4.4g, 15.5mmol) was added, and the mixture was stirred at 0 ℃ for 2 hours. After the reaction, the reaction mixture was poured into ice water and filtered to obtain compound 11-a-2(6.62g) as a white solid with a purity of 94.37%, yield of 88.62%, MS m/z (ESI): 237[ M + H ] +.

Step b: to a solution of 11-a-2(3g, 12.7mmol), methylsulfonamide (2.4g, 25.4mmol) in 300ml dichloromethane were added HATU (2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate) (7.2g, 19.1mmol), DIPEA (N, N-diisopropylethylamine) (3.3g, 25.4mmol), DMAP (4-dimethylaminopyridine) (159mg, 1.3mmol), and stirred at room temperature overnight. After the reaction is finished, adding water for washing, separating an organic phase, drying by anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, purifying by Combi-flash column chromatography to obtain a red solid compound 11-a (3.6g), directly using the red solid compound in the next reaction, wherein the purity is 88.2%, the yield is 90%, and the content of MS m/z (ESI): 314[ M + H ] +.

A method for preparing compound 13-a:

step a: compound 13-a-1(50g, 0.40mol) was added to concentrated hydrochloric acid (400ml), the mixture was cooled to 0 ℃ and a solution of sodium nitrite (28.6g, 0.44mol) in water (100ml) was added dropwise. After the mixture was reacted at 0 ℃ for 0.5h, cuprous chloride (91.68g, 0.48mol) was added. After the mixture was stirred at room temperature for 0.5h, it was heated to 100 ℃ and stirred for 1 h. After cooling, filtration was carried out, the filtrate was extracted with petroleum ether (500 ml. times.2), the organic phase was washed with saturated brine (500ml), dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, and the crude product was purified by column chromatography (eluent/PE: EA: 10: 1) to give compound 13-a-2(24.1g, yield: 41%) as a colorless oily compound.¹H NMR(400MHz，DMSO-d₆)δ：14.10(brs，1H)，12.50(brs，1H)，7.87(d，J＝6.0Hz，1H)，7.76(d，J＝10.0Hz，1H)，3.38(s，3H)。

Step b: compound 13-a-2(18.72g, 130mmol) was dissolved in anhydrous THF (200ml), cooled to-78 deg.C, and nitrogen was addedUnder the protection of gas, n-BuLi (62.4ml, 2.4M/L, 248mmol) was added dropwise. The mixture was stirred at-78 ℃ for 1h and then poured onto dry ice. The mixture was stirred at-78 ℃ for 1h, then at room temperature for 1 h. The mixture was poured into a 2N aqueous hydrochloric acid solution (200ml), which was subjected to extraction with ethyl acetate (250 ml). The organic phase was separated and washed with brine (200 ml). Dried over anhydrous sodium sulfate and filtered. The filtrate was spin-dried with a rotary evaporator to give 13-a-3(9.1g, yield: 37%). ESI-MS (M-H)^-: 187. purity 80% (UV 214).

Step c: compound 13-a-3(9.1g, 48mmol) was dissolved in anhydrous DCM (150mL), cooled to 0 deg.C and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (13.76g, 72mmol), DMAP (11.8g, 96mmol), methylsulfonamide (9.12g, 96mmol) was added, respectively. The mixture was stirred at room temperature for 18h, then poured into 2N aqueous hydrochloric acid (100ml), and after stirring the mixture at room temperature for 0.5h, the organic phase was separated and washed with brine (100 ml). Dried over anhydrous sodium sulfate and filtered. The filtrate was spin-dried with a rotary evaporator to give 13-a-4(9.6g, yield: 78%). ESI-MS (M + H)⁺: 266.0. purity 91% (UV 214).

Step d: compound 13-a-4(7.95g, 30mmol) was dissolved in anhydrous DME (100ml), and NBS (12.21g, 69mmol), azobisisobutyronitrile (0.59g, 3mmol) were added. After refluxing the mixture for 18h with stirring, the filtrate was rotary dried on a rotary evaporator. The residue was prepared by HPLC column to give 13-a-5(3.1g, yield: 30%) as a white solid. ESI-MS (M + H)⁺: 343.7. purity 98.2% (UV 214).¹H NMR(400MHz，CDCl₃)δ：8.80(s，1H)，8.12(d，J＝6.8Hz，1H)，7.36(d，J＝12.0Hz，1H)，4.54(s，2H)，3.43(s，3H)。

Step e: compound 13-a-5(0.686mg, 2mmol) was added to 2% dilute sulfuric acid (25ml), and sodium periodate (856mg, 4mmol) was added with stirring. The mixture was reacted at 100 ℃ for 18 h. Extracted with ethyl acetate (3 × 50ml) and the organic phase washed with 10% sodium thiosulfate (50 ml). Dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, and the resulting crude product was purified by column chromatography (DCM: MeOH ═ 10: 1) to give 13-a (266mg, yield: 41.6%) as a white solid. ESI-MS (M + H) +: 295.8. purity 9 ═ 98.5％(UV214)。¹H NMR(400MHz，DMSO-d6)δ：14.10(brs，1H)，12.50(brs，1H)，7.87(d，J＝6.0Hz，1H)，7.76(d，J＝10.0Hz，1H)，3.38(s，3H)。

A method for preparing compound 15-a:

the method comprises the following steps: compound 15-a-1(500mg, 2.4mmol) was dissolved in 2-methylpropan-1-ol (2.7g, 36mmol), and cesium carbonate (1.6g, 4.8mmol) was added. Stirred at 180 ℃ for 30 minutes. After the reaction was completed, it was cooled to room temperature, poured into water, extracted with ethyl acetate (2X 50ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 15-a (400mg, yield: 63.5%) as a colorless oily compound.

A method for preparing compound 17-a:

step a: to a solution of compound 17-a-1(4.5g, 28.8mmol), p-toluenesulfonic acid (499mg, 2.9mmol) in dichloromethane (100ml) was cooled to zero degrees centigrade, N-chlorosuccinimide (4g, 30.3mmol) was slowly added, stirred for 2 hours, and stirred at room temperature overnight. After the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 17-a-2(5g) as a white solid. MS m/z (ESI): 189[ M-1 ]]^-。

Step b: to a solution of compound 17-a-2(5g, 26.3mmol) in methanol (130ml) was added concentrated sulfuric acid (7ml, 1mmol) dropwise, and the mixture was stirred under reflux for 5 hours. After the reaction, it was cooled to room temperature, poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, dichloromethane was added thereto, and stirred at room temperature for 20 minutes, and filtered to obtain compound 17-a (4.2g) as a white solid. MS m/z (ESI): 203[ M-1 ]]^-。

A method for preparing compound 22-a:

step a: the preparation method of reference example 57, step 3, was carried out using compound 17-a (2g) as a starting material, except that the reaction conditions were changed to room temperature and stirring was carried out overnight, to give compound 22-a-2(552mg) with purity of 96.57%, yield of 14%, MS m/z (esi): 322.1[ M + H-56 ]]⁺。

Step b: the preparation method of reference example 4, step 1, starting from compound 22-a-2(552mg) gave compound 22-a (409mg) with 100% purity, 41% yield, MS m/z (esi): 288[ M + H]⁺。

A method of preparing compound 23-a:

step a: the preparation method of reference example 29, step 2, starting from compound 23-a-1(1g) gave compound 23-a-2(683mg) in 83.85% purity in 83% yield, MS m/z (esi): 168.1[ M + H]⁺。

Step b: to a solution of compound 23-a-2(385mg, 2.296mmol) in acetonitrile (5ml) was added p-toluenesulfonic acid (474mg, 2.756mmol), 4-chloroaniline and tert-butyl nitrite (284mg, 2.756mmol), tetrabutylammonium bromide (1479mg, 4.593mmol), cuprous bromide (33mg, 0.23mmol) at zero degrees centigrade, and the mixture was stirred at room temperature for 1 hour. After the reaction is finished, washing with salt water, drying and separating an organic phase, concentrating under reduced pressure to obtain a crude product, and purifying by Combi-flash column chromatography to obtain a colorless oily compound 23-a (394mg), wherein the purity is 73.57% and the yield is 75%.

A method for preparing compound 24-a:

compound 24-a was prepared by the method described for compound 23-a, starting with compound 4-bromoaniline.

A method of preparing compound 25-a:

the method comprises the following steps: to a solution of compound 25-a-1(2.03g, 11.93mmol) in acetic acid (65ml) was added bromine (0.61ml, 11.33mmol), and the mixture was stirred at room temperature overnight. After the reaction is finished, carrying out reduced pressure concentration, washing with salt water, extracting with ethyl acetate, drying and separating an organic phase, carrying out reduced pressure concentration to obtain a crude product, and purifying by Combi-flash column chromatography to obtain the compound 25-a (3g), wherein the purity is 85% and the yield is 100%. MS m/z (ESI): 249[ M + H ]]⁺。

A method of preparing compound 30-a:

the method comprises the following steps: prepared according to the method of example 4, step 1, starting with compound 30-a-1(10g), to give compound 30-a (6.5 g). MS m/z (ESI): 102[ M + H-36 ]]⁺。

A process for preparing compound 32-a, 33-a, 34-a:

compound 32-a was prepared according to the procedure for compound 15-a except that 15-a-1 in step was changed to 5-bromo-3-chloro-2-fluoropyridine, 2-methylpropan-1-ol was changed to propan-2-ol, and the reaction conditions were changed to 100 deg.C and stirred overnight.

Compound 33-a was prepared by following the procedure of Compound 15-a except that 15-a-1 in step was changed to 4-bromo-2-chlorophenol, 2-methylpropan-1-ol was changed to 2-iodopropane, and the reaction conditions were changed to 80 ℃ and stirred for 3 hours.

Compound 34-a was prepared by the method described for compound 15-a except that 15-a-1 in step was changed to 4-bromo-2-chlorophenol, 2-methylpropan-1-ol was changed to 2-chloro-2, 2-difluoroacetic acid sodium salt, and the reaction conditions were changed to 100 ℃ with stirring for 2 hours.

A method of preparing compound 35-a:

step a: compound 13-a-3(23g, 121.7mmol), ethanesulfonamide (19.9g, 182.5mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (46.7g, 243.4mmol), 4-dimethylaminopyridine (14.8g, 121.7mmol), N, N-diisopropylethylamine (47.1g, 365.1mmol) in dichloromethane (250mL) was stirred at room temperature for 48 hours, the reaction was terminated, concentrated under reduced pressure, 300mL of water was added, 4N hydrochloric acid solution was added to adjust the pH to 3 to 4, ethyl acetate was extracted, and the organic phase was washed with brine. Drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and recrystallizing with ethanol to obtain the compound 35-a-2(19.3g, yield: 56.8%), MS m/z (esi): 280.1[ M + H]⁺. The purity was 95.27%.

Step b: a mixed solution of compound 35-a-2(19g, 67.9mmol), N-bromosuccinimide (18.1g, 101.8mmol) and azobisisobutyronitrile (0.56g, 3.4mmol) in acetonitrile (200ml) was prepared. Stirring at 80 ℃ for 2h to complete the reaction. Cooled to room temperature, concentrated under reduced pressure, washed with brine, dried over anhydrous sodium sulfate, filtered, added with diethyl phosphite (4.69g, 34mmol), N, N-diisopropylethylamine (8.7g, 67.9mmol), stirred at room temperature for 5 hours, washed with 2N hydrochloric acid, washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried to give 35-a (18.92g, yield: 77.5%) as a white solid. MS m/z (ESI): 359.9[ M + H]⁺. The purity was 98.61%.

A method of preparing compound 36-a:

step 1: to a 50ml sealed tube were added compound 36-a-1(500mg, 2.23mmol), compound 36-a-2(671mg, 3.35mmol), Pd₂(dba)₃(tris (dibenzylideneacetone) dipalladium) (41mg, 0.045mmol), BINAP ((+ -) -2, 2 '-bis- (diphenylphosphino) -1, 1' -binaphthyl) (56mg, 0.089mmol), potassium tert-butoxide (644mg, 6.7mmol), 7ml of 1, 4-dioxane, stirred at 90 ℃ for 2 h. After the reaction, the mixture was cooled to room temperature, 30ml of water and 30ml of ethyl acetate were added, and the mixture was filtered, extracted with ethyl acetate, and the organic phase was separated and combinedAnd concentrating the filtrate under reduced pressure to obtain a crude product, and purifying by Combi-flash column chromatography to obtain a yellow oily compound 36-a-3(475mg), which is directly used for the next reaction. MS m/z (ESI): 289.1[ M + H-56 ]]⁺。

Step 2: compound HCl (1.5ml, 5.53mmol) was added to a solution of compound 36-a-3(475mg) in methanol, stirred at room temperature for 4 hours and the reaction was concentrated to give the crude compound 36-a. Used without purification.

Example 4: preparation of 5-chloro-4- (1- (3-chloro-4- (trifluoromethoxy) phenyl) azetidin-3-yloxy) -2-fluoro-N- (methylsulfonyl) benzamide (Z-4)

Step 1: to a 50ml single neck round bottom flask was added compound 5-a (517mg, 2.98mmol), hydrochloric acid (4M, 5ml, 20mmol), and 5ml of methanol, and stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated under reduced pressure to give solid compound 4-b (325mg) which was used directly in the next reaction in a yield of 99.4%. MS m/z (ESI): 74[ M + H ]]⁺。

Step 2: to a 50ml sealed tube was added 4-bromo-2-chloro-1- (trifluoromethoxy) benzene (215mg, 0.781mmol), compound 4-b (127mg, 1.159mmol), Pd₂(dba)₃(tris (dibenzylideneacetone) dipalladium) (36mg, 0.039mmol), BINAP ((+ -) -2, 2 '-bis- (diphenylphosphino) -1, 1' -binaphthyl) (51mg, 0.082mmol), potassium tert-butoxide (263mg, 2.344mmol), 7ml of 1, 4-dioxane, stirred at 90 ℃ for 2 h. After the reaction is finished, cooling to room temperature, adding 30ml of water and 30ml of ethyl acetate, filtering, extracting with ethyl acetate, separating and combining organic phases, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying by Combi-flash column chromatography to obtain a yellow oily compound 4-c (215mg), wherein the yellow oily compound is directly used for the next reaction, the purity is 73.3%, and the yield is 89.6%. MS m/z (ESI): 268.0[ M + H]⁺。

And step 3: a mixture of compound 4-c (135mg, 0.504mmol), 5-chloro-2, 4-difluoro-N- (methylsulfonyl) benzamide (107mg, 0.397mmol), cesium carbonate (260mg, 0.798mmol), 6ml dimethyl sulfoxide was heated under microwave conditions to 220 deg.CStirring at deg.C for 30 minutes. After the reaction is finished, cooling to room temperature, adding 30ml of water, adjusting the pH value to 6-7, extracting with ethyl acetate, separating an organic phase, concentrating under reduced pressure to obtain a deep oily substance 300mg, and purifying by Combi-flash column chromatography to obtain a white solid compound Z-4(30mg), wherein the purity is 98.77%, and the yield is 69.0%. MS m/z (ESI): 517.0[ M + H]⁺。¹H NMR(400MHz，DMSO-d₆)：δ12.18(s，1H)，7.86(d，J＝7.8Hz，1H)，7.37(d，J＝8.8Hz，1H)，7.12(d，J＝12Hz，1H)，6.73(d，J＝2.8Hz，1H)，6.51～6.54(dd，J₁＝8.8Hz，J₂＝2.8Hz，1H)，5.31～5.36(m，1H)，4.39～4.44(m，2H)，3.90～3.94(m，2H)，3.36(s，3H)。

Example 5: preparation of 5-chloro-4- (1- (3-chloro-4- (trifluoromethoxy) benzoyl) azetidin-3-yloxy) -2-fluoro-N- (methylsulfonyl) benzamide (Z-5)

The method comprises the following steps: to a 50ml single neck round bottom flask was added 3-chloro-4- (trifluoromethoxy) benzoic acid (31g, 0.129mmol), compound 2-c (65mg, 0.181mmol), HATU (2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate) (99mg, 0.260mmol), DIPEA (N, N-diisopropylethylamine) (56mg, 0.433mmol), and dimethylformamide 3ml, and stirred at room temperature overnight. After the reaction is finished, 20ml of water is added, the pH is adjusted to be 4-5, ethyl acetate is used for extraction (20ml x3), an organic phase is separated, anhydrous sodium sulfate is used for drying, filtration is carried out, a filtrate is decompressed and concentrated to obtain an oily substance (120mg), and a white solid compound Z-5(10mg) is obtained through separation and purification of a preparation liquid phase, wherein the purity is 100%, and the yield is 14.2%. MS m/z (ESI): 545.0[ M + H]⁺。¹HNMR(400MHz，DMSO-d₆)：δ7.96((d，J＝2.0Hz，1H)，7.77～7.83(m，2H)，7.64～7.67(dd，J₁＝8.4Hz，J₂＝1.6Hz，1H)，6.82(d，J＝12Hz，1H)，5.18～5.21(m，1H)，4.79～4.83(m，1H)，4.59～4.64(m，1H)，4.46～4.49(m，1H)，4.07(d，J＝9.6Hz，1H)，2.91(s，3H)。

Example 6: preparation of 5-chloro-4- (1- (3-chloro-4- (trifluoromethoxy) benzyl) azetidin-3-yloxy) -N- (N, N-dimethylsulfamoyl) -2-fluorobenzamide (Z-6)

Step 1: to a 100ml single neck round bottom flask was added compound 1-a-3(1g, 5.19mmol), CDI (N, N' -carbonyldiimidazole) (1.87g, 11.53mmol), 20ml THF, stirred at 75 ℃ for 0.5h, cooled to room temperature, added N, N-dimethylsulfonamide (1.29g, 10.39mmol), DBU (1, 8-diazabicycloundecen-7-ene) (2.37g, 15.57mmol), and stirred at 75 ℃ for 5 h. After the reaction is finished, the reaction solution is subjected to reduced pressure concentration to remove THF, 50ml of water and 50ml of ethyl acetate are added, the pH is adjusted to 5-6, the ethyl acetate is extracted, an organic phase is separated, reduced pressure concentration is carried out, 10ml of petroleum ether and 10ml of ethyl acetate are added, pulping and filtering are carried out, and the off-white solid compound 6-b (1.38g) is obtained and is directly used for the next reaction, wherein the purity is 91.2%, and the yield is 84.7%. MS m/z (ESI): 299.0[ M + H]⁺。

Step 2: compound 6-b (306mg, 1.02mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (215mg, 1.24mmol), cesium carbonate (993mg, 3.05mmol), 10ml of a mixture of 1, 4-dioxane were stirred under microwave conditions at 180 ℃ for 40 minutes. After the reaction is finished, cooling to room temperature, adding 30ml of water, adjusting the pH value to 5-6, extracting with ethyl acetate (30ml x2), separating and combining organic phases, concentrating under reduced pressure to obtain a crude product, and purifying by Combi-flash column chromatography to obtain an oily compound 6-c (170mg), wherein the purity is 69.8%, and the yield is 37% and is directly used for the next reaction. MS m/z (ESI): 474.1[ M + Na]⁺。

And step 3: to a 50ml single neck round bottom flask was added compound 6-c (170mg, 0.376mmol), hydrochloric acid (4M, 2ml, 8mmol), 3ml methanol and stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated under reduced pressure to give 6-d (145mg) as an oily compound, which was used directly in the next reaction with a purity of 69.9% and a yield of 99.3%. MS m/z (ESI): 352.1[ M + H]⁺。

And 4, step 4: to a 50ml single neck round bottom flask was added compound 6-d (145mg, 0.373mmol), 4- (bromomethyl) -2-chloro-1- (trifluoromethoxy) benzene(115mg, 0.397mmol), potassium carbonate (150mg, 1.085mmol), 5ml of dimethylacetamide, and stirred at room temperature for 4 h. And after the reaction is finished, adding 30ml of water, adjusting the pH value to be 5-6, extracting with ethyl acetate (30ml x2), separating and combining organic phases, concentrating under reduced pressure to obtain 270mg of oily matter, and separating and purifying a prepared liquid phase to obtain a white solid compound Z-6(20.2mg), wherein the purity is 97.8% and the yield is 9.7%. MS m/z (ESI): 559.9[ M + H]⁺。¹H NMR(400MHz，DMSO-d₆)：δ7.76(d，J＝7.6Hz，1H)，7.74(d，J＝1.6Hz，1H)，7.52～7.55(dd，J₁＝8.4Hz，J₂＝1.2Hz，1H)，7.41～7.44(dd，J₁＝8.4Hz，J₂＝2.0Hz，1H)，6.95(d，J＝11.6Hz，1H)，5.01(m，1H)，3.86(m，2H)，3.74(s，2H)，3.20(m，2H)，2.81(s，6H)。

Examples 7, 9 to 14, 18 to 21, 165

Compounds Z-7, Z-9, Z-10, Z-11, Z-12, Z-13, Z-14, Z-18, Z-19 and Z-20 starting from compound 4-b are prepared by the method described in example 4, except that 4-bromo-2-chloro-1- (trifluoromethoxy) benzene in step 2 is replaced with 4-bromo-1, 2-dichlorobenzene, 1-bromo-3-chlorobenzene, 1-bromo-3, 5-dichlorobenzene, 1-bromo-4-chlorobenzene, 1-bromo-4- (trifluoromethoxy) benzene, 1-bromo-4-fluorobenzene, compound 6-a, 1-bromo-2- (trifluoromethoxy) benzene, 1-bromo-4- (trifluoromethoxy) benzene, compound 6-a, 4-bromo-2-chloro-1- (trifluoromethyl) benzene, compound 15-a.

Compound Z-21 was prepared by referring to the procedure of example 4 starting from compound 4-c except that compound 1-a in step 3 was replaced with compound 9-a.

Compound Z-165 was prepared analogously with reference to Z-7.

Example 22: preparation of (R) -5-chloro-4- ((1- (3-chloro-4- (trifluoromethoxy) phenyl) pyrrolidin-2-yl) methoxy) -2-fluoro-N- (methylsulfonyl) benzamide (Z-22)

Step 1: the preparation method of reference example 4, step 2, starting from compound 7-a (500mg) gave compound 22-b (220mg) with a purity of 53%, yield 41%, MS m/z (esi): 296[ M + H ]]⁺。

Step 2: the preparation method of step 3 in example 4 was referenced using compound 22-b (200mg) as a starting material to give compound Z-22(60mg) with a purity of 79%, yield 16.3%, MS m/Z (esi): 545[ M + H]⁺。¹H NMR(500MHz，DMSO-d₆)δ12.14(s，1H)，7.78(d，J＝7.5Hz，1H)，7.31(d，J＝9.0Hz，1H)，7.19(d，J＝12.1Hz，1H)，6.91(d，J＝2.5Hz，1H)，6.71(dd，J＝9.5，2.9Hz，1H)，4.25(s，1H)，4.16(m，2H)，3.48(t，J＝8.6Hz，1H)，3.24(s，3H)，3.15(d，J＝6.5Hz，1H)，2.23(d，J＝7.5Hz，1H)，2.12-1.92(m，3H).

Example 23:

compound Z-23 was prepared by the method of example 22 using compound 7-a as the starting material, except that 4-bromo-2-chloro-1- (trifluoromethoxy) benzene in step 1 was changed to 4-bromo-1, 2-dichlorobenzene.

Example 26: preparation of (S) -5-chloro-4- ((1- (3-chloro-4- (trifluoromethoxy) phenyl) azetidin-2-yl) methoxy) -2-fluoro-N- (methylsulfonyl) benzamide (Z-24)

Step 1: to a solution of compound 8-a (333mg, 3.294mmol) in 5ml of THF was added dropwise 6.6ml of borane/THF solution (1M) at zero ℃ and after completion of the addition, the mixture was stirred at 60 ℃ for 5 hours. After the reaction, the reaction mixture was cooled to room temperature, methanol was added thereto, and the mixture was concentrated under reduced pressure, diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to give 24-b (340mg) as a colorless oily compound. The reaction was carried out in the next step without further purification.

Step 2: referring to the preparation method of step 2 in example 4, starting from compound 24-b (340mg), compound 24-c (130mg) was obtained as a yellow solid with a purity of 65% and a yield of 18%.

And step 3: referring to the preparation method of step 3 in example 4, starting from compound 24-c (130mg), compound Z-24(11mg) was obtained as a white solid with a purity of 100%, yield 7%, MS m/Z (esi): 531.0[ M + H]⁺。¹H NMR(400MHz，DMSO-d₆)δ7.81(d，J＝6Hz，1H)，7.33(d，J＝7.2Hz，1H)，7.19(s，1H)，7.02(d，J＝2Hz，1H)，6.69(dd，J＝7.2，2.4Hz，1H)，4.50(d，J＝3.2Hz，1H)，4.39-4.34(m，2H)，4.03-3.99(m，1H)，3.69(d，J＝7.2Hz，1H)，3.32(s，3H)，3.04-3.02(m，2H)。

Example 28: preparation of 5-chloro-4- (4- (3, 4-dichlorophenyl) piperazin-1-yl) -2-fluoro-N- (methylsulfonyl) benzamide (Z-25)

The method comprises the following steps: to a solution of compound 10-a (211.6mg, 0.92mmol) in 2ml of dimethyl sulfoxide were added compound 1-a (250mg, 0.92mmol), potassium carbonate (254mg, 1.84mmol), and the mixture was stirred under microwave at 140 ℃ for 0.5 h. After the reaction is finished, cooling to room temperature, adding ethyl acetate, washing with saturated sodium bicarbonate, separating an organic phase, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product. The white solid compound Z-25(21.2mg) is obtained by separation and purification of the preparation liquid phase, the purity is 100 percent, and the yield is 4.8 percent. MS m/z (ESI): 480.0[ M + H ]]⁺。¹H NMR(400MHz，DMSO-d₆)：δ7.45(d，J＝8.8Hz，1H)，7.40(d，J＝8.8Hz，1H)，7.19(d，J＝3.2Hz，1H)，7.00(m，1H)，6.90(d，J＝12.4Hz，1H)，3.32(m，4H)，3.17(m，4H)，3.09(s，3H).

Example 29: preparation of 4- (1- (3-chloro-4- (trifluoromethoxy) phenyl) azetidin-3-yloxy) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide (Z-26)

Step 1: referring to the preparation method of step 3 in example 4, starting from compound 4-c (240mg), compound 1-a was replaced with compound 11-a to give compound 26-b (160mg) as a yellow solid with a purity of 26.11%, yield 27.8%, MS m/z (esi): 563[ M + H ] +.

Step 2: to a solution of compound 26-b (140mg, 0.25mmol), cyclopropylboronic acid (43mg, 0.5mmol) in 10ml dioxane was added [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (22mg, 0.03mmol), cesium carbonate (163mg, 0.5mmol), under argon, stirred at 100 ℃ overnight. After the reaction, the mixture is cooled to room temperature, filtered, poured into water, extracted by ethyl acetate, and the organic phase is dried by anhydrous sodium sulfate, and then is decompressed and concentrated to obtain a crude product, and a white solid compound Z-26(20mg) is obtained after separation and purification of a preparation liquid phase. MS m/z (ESI): 523[ M + H]⁺。¹H NMR(500MHz，DMSO-d₆)：δ12.00(s，1H)，7.36(d，J＝8.0Hz，1H)，7.21(d，J＝5.5Hz，1H)，6.74(d，J＝3.0Hz，1H)，6.67(d，J＝12.5，1H)，6.53(dd，J＝9.0，2.5Hz，1H)，5.29-5.22(m，1H)，4.42(t，J＝6.5Hz，2H)，3.91(dd，J＝3.5，9.0Hz，2H)，3.06(s，3H)，2.11-2.07(m，1H)，0.93-0.89(m，2H)，0.65-0.64(3m，2H)。

Example 31: preparation of 5-chloro-4- (3- (3-chloro-4- (trifluoromethoxy) phenyl) azetidine-1-carbonyl) -2-fluoro-N- (methylsulfonyl) benzamide (Z-31)

The method comprises the following steps: a mixture of compound 30-c (30mg, 0.104mmol), compound 13-a (30mg, 0.101mmol), DIPEA (N, N-diisopropylethylamine) (36mg, 0.355mmol), HATU (2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate) (67mg, 0.176mmol), and 6ml of dichloromethane was stirred at room temperature for 1 h. After the reaction is finished, washing with 2N hydrochloric acid, extracting with dichloromethane, washing with saturated salt water, concentrating the organic phase under reduced pressure to obtain crude product, and purifying by preparative column chromatography to obtain compound Z-31(24mg) with purity94%, yield 44%. MS m/z (ESI): 529[ M-H]⁺。¹H NMR(500MHz，DMSO-d₆)：δ7.758-7.716(m，2H)，7.587-7.509(m，2H)，7.383(d，J＝9.5Hz，1H)，4.459(s，1H)，4.278(s，1H)，4.01-4.00(m，3H)，2.838(s，3H).

Example 32: preparation of 5-chloro-4- ((3- (3-chloro-4- (trifluoromethoxy) phenyl) azetidin-1-yl) methyl) -2-fluoro-N- (methylsulfonyl) benzamide (Z-32)

The method comprises the following steps: to a 25ml single neck round bottom flask was added compound 30-c (67mg, 0.232mmol), compound 13-a-5(40mg, 0.117mmol), potassium carbonate (64mg, 0.463mmol), 7ml acetonitrile and stirred at room temperature overnight. After the reaction was complete, water (10 ml. times.3) and ethyl acetate were added for extraction (10 ml. times.3), the combined organic phases were separated and concentrated under reduced pressure to give a crude product which was purified by liquid phase preparative purification to give solid compound Z-32(29mg) in 100% purity and 24% yield. MS m/z (ESI): 515[ M + H]⁺。¹H NMR(500MHz，DMSO-d₆)：δ7.731(d，J＝1Hz，1H)，7.684(d，J＝7，1H)，7.518-7.555(m，2H)，7.199(d，J＝11.5Hz，1H)，6.089(s，2H)，3.737-3.681(m，5H)，2.829(s，3H).

Example 33: preparation of (R) -5-chloro-4- (1- (3-chloro-4- (trifluoromethoxy) phenyl) pyrrolidin-3-yloxy) -2-fluoro-N- (methylsulfonyl) benzamide (Z-33)

Step 1: the preparation method of example 4, step 1 was repeated using compound 14-a (644mg) as a starting material to give compound 33-b (425mg) as a yellow solid in 100% yield.

Step 2: the preparation method of step 2 in reference example 4 was repeated, starting from compound 33-b (425mg), to give compound 33-c (520mg) as a yellow oil with a purity of 83.4%, yield 80.7%, MS m/z (ESI): 282[ M + H ]]⁺。

And step 3: to a single portCompound 33-c (288mg, 1.0225mmol), potassium tert-butoxide (344mg, 3.065mmol), THF10ml were added to the round-bottom flask, stirred in an ice bath for 2 minutes, compound 1-a (358mg, 1.327mmol) was added, and stirred for 30 minutes. After the reaction was completed, water (10 ml. times.3) and ethyl acetate were added for extraction (10 ml. times.3), the combined organic phases were separated and concentrated under reduced pressure to give a crude product, which was purified by liquid phase preparative purification to give solid compound Z-33(4.6mg) with 100% purity and 0.7% yield. MS m/z (ESI): 531[ M + H]⁺。¹H NMR(500MHz，DMSO-d₆)δ7.765(d，J＝8Hz，1H)，7.315(d，J＝8Hz，1H)，7.110(d，J＝12Hz，1H)，6.765(d，J＝3Hz，1H)，6.583-6.607(m，1H)，5.312(s，1H)，3.701(dd，J＝11.5，4.5Hz，1H)，3.446-3.410(m，3H)，3.328(s，2H)，2.818(s，3H).

Examples 40 to 41, 43 to 47, 49:

compounds Z-40 to 41, Z-43 to 47 and Z-49 can be prepared analogously to examples 1 to 33 according to the invention.

Example 50: preparation of (R) -5-chloro-2-fluoro-N- (methylsulfonyl) -4- ((1- (4- (trifluoromethoxy) phenyl) pyrrolidin-2-yl) methoxy) benzamide (Z-50)

Step 1: a mixed solution of 1-bromo-4- (trifluoromethoxy) benzene (1g, 4.15mmol), compound 7-a (0.63g, 6.22mmol), (S) -proline (96mg, 0.83mmol), cuprous iodide (79mg, 0.415mmol), potassium carbonate (1.72g, 12.45mmol) in dimethyl sulfoxide (10ml) was stirred at 90 ℃ for 4h under nitrogen. After the reaction is finished, cooling to room temperature, pouring water and ethyl acetate for extraction, washing with salt water, drying and separating an organic phase, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying by Combi-flash column chromatography to obtain a yellow oily compound 50-b (186mg), wherein the purity is 82% and the yield is 17% and the yellow oily compound is directly used for the next reaction. MS m/z (ESI): 262.1[ M + H]⁺。

Step 2: to combine withProduct 50-b (119mg) was used as a starting material, and according to the preparation method in step 3 of example 4, white solid compound Z-50(52.17mg) was obtained with a purity of 100%, MS m/Z (ESI): 509[ M-H]^-。¹H NMR(500MHz，DMSO-d₆)：δ12.11(s，1H)，7.78(d，J＝7.5Hz，1H)，7.16(m，3H)，6.74(d，9.0Hz，2H)，4.18(d，J＝7.0Hz，2H)，4.13-4.08(m，1H)，3.46(t，J＝6.8Hz，1H)，3.20(s，3H)，3.17-3.11(m，1H)，2.27-2.21(m，1H)，2.10-2.04(m，2H)，2.05-2.00(m，1H).

Examples 51 to 52, 58, 67, 69, 71 to 72, 76, 97, 104, 110, 113

Compound Z-51 was synthesized by the method of example 50 starting with compound 7-a, except that 1-bromo-4- (trifluoromethoxy) benzene was changed to 1-bromo-2, 4-dichlorobenzene in step 1, and the reaction conditions were changed to 140 ℃ and stirring was carried out for 30 minutes.

Compound Z-52 was synthesized by the method described in example 50, starting from compound 7-a, except that 1-bromo-4- (trifluoromethoxy) benzene was replaced with 4-bromo-2-chloro-1-fluorobenzene in step 1, and the reaction conditions were changed to 90 ℃ and the mixture was stirred overnight.

Compound Z-58 was synthesized by the method of example 50 starting with compound 7-a, except that 1-bromo-4- (trifluoromethoxy) benzene was replaced with 2-bromo-5-chloropyridine in step 1, and the reaction conditions were changed to 110 ℃ and stirring was carried out for 5 hours. Compound Z-67 was prepared by the method in accordance with example 50, starting from compound 7-a, except that 1-bromo-4- (trifluoromethoxy) benzene was replaced with 1-bromo-4- (trifluoromethyl) benzene in step 1, and the reaction conditions were changed to 100 ℃ and stirring was carried out for 20 hours.

Compound Z-69 was synthesized by the method described in example 50, starting from compound 7-a, except that 1-bromo-4- (trifluoromethoxy) benzene was replaced with 4-bromo-2-fluoro-1- (trifluoromethyl) benzene in step 1, and the reaction conditions were changed to 110 ℃ and the mixture was stirred overnight.

Compound Z-71 was synthesized by the method in accordance with example 50, starting from compound 7-a, except that 1-bromo-4- (trifluoromethoxy) benzene was replaced with 5-bromo-2- (trifluoromethyl) pyridine in step 1, the reaction conditions were changed to 100 ℃ and stirring was carried out overnight, and the reaction conditions in step 2 were changed to 180 ℃ and stirring was carried out for 30 minutes.

Compound Z-72 was prepared by the method described in example 50, starting from compound 7-a, except that 1-bromo-4- (trifluoromethoxy) benzene in step 1 was replaced with 1-bromo-4- (trifluoromethyl) benzene, the reaction conditions were changed to 100 ℃ and stirring was carried out for 20 hours, compound 1-a in step 2 was replaced with compound 9-a, and the reaction conditions were changed to 200 ℃ and stirring was carried out for 30 minutes.

Compound Z-76 was prepared by the method of example 50 starting with compound 7-a, except that 1-bromo-4- (trifluoromethoxy) benzene in step 1 was changed to compound 23-a.

Compound Z-97 was prepared by the method of example 50 except that compound 7-a in step 1 was changed to compound 30-a, 1-bromo-4- (trifluoromethoxy) benzene to 4-bromo-1, 2-dichlorobenzene and the reaction conditions in step 2 were changed to 200 ℃ and stirred for 60 minutes.

Compound Z-104 was synthesized by the method of example 50, except that compound 7-a in step 1 was changed to compound 31-a, 1-bromo-4- (trifluoromethoxy) benzene to 1-bromo-4- (trifluoromethyl) benzene, the reaction conditions were changed to 100 ℃ and stirring was carried out for 20 hours, and in step 2, the reaction conditions were changed to 200 ℃ and stirring was carried out for 60 minutes.

Compound Z-110 was prepared by the method of example 50 except that compound 7-a of step 1 was changed to compound 31-a, 1-bromo-4- (trifluoromethoxy) benzene to 4-bromo-1, 2-dichlorobenzene, the reaction conditions were changed to 100 ℃ and stirred for 16h, compound 1-a in step 2 was changed to compound 9-a, and the reaction conditions were changed to 200 ℃ and stirred for 30 minutes.

Compound Z-113 was synthesized by the method of example 50, except that compound 7-a in step 1 was changed to compound 31-a, 1-bromo-4- (trifluoromethoxy) benzene and compound 34-a, and the reaction conditions were changed to 100 ℃ and stirring was carried out overnight and 200 ℃ in step 2 and stirring was carried out for 60 minutes.

Example 53: preparation of (R) -5-chloro-4- (((1- (3-chloro-4- (trifluoromethoxy) phenyl) pyrrolidin-2-yl) methyl) thio) -2-fluoro-N- (methylsulfonyl) benzamide (Z-53)

Step 1: a mixed solution of compound 22-b (504mg, 1.704mmol), p-toluenesulfonyl chloride (415mg, 2.045mmol), triethylamine (350mg, 3.239mmol) and 4-dimethylaminopyridine (25mg, 0.17mmol) in 10ml of dichloromethane was stirred at room temperature for 6 hours. After the reaction, 1M hydrochloric acid solution and sodium bicarbonate solution are added for washing, the organic phase is dried and separated, and the crude compound 53-b (754mg) is obtained by decompression and concentration. MS m/z (ESI): 450.1[ M + H]⁺。

Step 2: to a solution of compound 53-b (424mg, 0.942mmol) in dimethylformamide (5ml) was added potassium thioacetyl (548mg, 4.807mmol), and the mixture was stirred at 140 ℃ for 1 hour. After the reaction is finished, cooling to room temperature, adding water and ethyl acetate for extraction, drying and separating an organic phase, concentrating under reduced pressure to obtain a crude product, and purifying by Combi-flash column chromatography to obtain a yellow oily compound 53-c (156mg), wherein the purity is 100 percent and the yield is 49 percent. MS m/z (ESI): 354.1[ M + H]⁺。

And step 3: using compound 53-c (150mg) as a starting material, according to the preparation method in step 3 of example 4, compound Z-53(144mg) was obtained as a white solid with a purity of 96.65%, yield of 38%, MS m/Z (ESI): 561[ M + H ]]⁺。¹H NMR(DMSO-d₆，400MHz)：＝7.74(d，J＝7.2Hz，1H)，7.25-7.35(m，2H)，6.69(d，J＝2.8Hz，1H)，6.57(dd，J＝9.2，2.8Hz，1H)，4.04(br.s.，1H)，3.39-3.49(m，1H)，3.08-3.28(m，3H)，2.96(s，3H)，2.10-2.22(m，1H)，1.90-2.10ppm(m，3H)。

Example 54: preparation of (R) -4- ((1- (3-chloro-4- (trifluoromethoxy) phenyl) pyrrolidin-2-yl) methoxy) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide (Z-54)

Step 1: starting from compound 22-b (200mg), the preparation process was carried out in step 3 of example 4, except that compound 1-a was changed to compound 11-a, to give compound 54-b (110mg) as a white solid with a purity of 72%, yield 18.39%, MS m/z (ESI): 589[ M + H]⁺。

Step 2: compound 54-b (100mg, 0.17mmol), cyclopropylboronic acid (29.13mg, 0.34mmol), potassium carbonate (46.87mg, 0.34mmol), palladium acetate (7.613mg, 0.034mmol) were added to toluene (20ml) and water (2ml), tricyclohexylphosphine (47.55mg, 0.17mmol) was added, and stirring was carried out overnight at 100 ℃ under nitrogen. After the reaction is finished, cooling to room temperature, washing with water, washing with salt water, separating an organic phase, concentrating under reduced pressure to obtain a crude product, and purifying by Combi-flash column chromatography to obtain a compound Z-54(32 mg). MS m/z (ESI): 551[ M + H ]]⁺。¹H NMR(DMSO-d₆，500MHz)：＝11.92(br.s.，1H)，7.30(d，J＝8.0Hz，1H)，7.14(d，J＝8.0Hz，1H)，6.84-6.95(m，2H)，6.72(dd，J＝9.5，3.0Hz，1H)，4.30(d，J＝5.5Hz，1H)，4.07(d，J＝5.5Hz，2H)，3.50(t，J＝8.0Hz，1H)，3.10-3.25(m，4H)，2.12-2.25(m，1H)，1.90-2.11(m，4H)，0.83-0.94(m，1H)，0.54-0.76ppm(m，3H)

Example 55: preparation of (R) -4- ((1- (3-chloro-4- (trifluoromethoxy) phenyl) pyrrolidin-2-yl) methoxy) -3-cyano-N- (methylsulfonyl) benzamide (Z-55)

Step 1: a mixed solution of compound 16-a (3g, 13.7mmol), methanesulfonamide (1.95g, 20.5mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (5.73g, 15.07mmol) and triethylamine (2.77mg, 27.4mmol) in methylene chloride (30ml) was stirred at room temperature for 16 hours. After the reaction, washing with 2N hydrochloric acid solution, washing with water, washing with salt water, drying to separate organic phase, and concentrating under reduced pressure to obtain crude productPurifying by Combi-flash column chromatography to obtain compound, adding ethyl acetate and petroleum ether, filtering, and washing with petroleum ether to obtain white solid compound 55-b (1.5 g). MS m/z (ESI): 295.9[ M + H]⁺。

Step 2: a mixed solution of compound 55-b (1g, 3.38mmol), zinc cyanide (237mg, 2.03mmol), tris (dibenzylideneacetone) dipalladium (31mg, 0.034mmol), 1, 1' -bis (diphenylphosphino) ferrocene (38mg, 0.068mmol), zinc (9mg, 0.135mmol), zinc acetate (25mg, 0.135mmol) in dioxane (15ml) was stirred at 110 ℃ for 5 hours. After the reaction is finished, cooling to room temperature, filtering, washing with ethyl acetate, concentrating under reduced pressure, adding ethyl acetate and petroleum ether, filtering, washing with petroleum ether, drying, and purifying by Combi-flash column chromatography to obtain a yellow solid compound 55-c (238 mg). MS m/z (ESI): 241[ M-H]^-。

And step 3: starting from compound 22-b (100mg), the preparation process was carried out in step 3 of example 4, except that compound 1-a was changed to compound 55-c to give compound Z-55(44mg) as a yellow solid, MS m/Z (esi): 518[ M + H]⁺。

¹H NMR(DMSO-d₆，500MHz)：＝8.21(d，J＝2.5Hz，1H)，8.16(dd，J＝9.0，2.0Hz，1H)，7.29(dd，J＝9.0，2.0Hz，2H)，6.83(d，J＝3.0Hz，1H)，6.75(dd，J＝9.5，2.5Hz，1H)，4.25(d，J＝7.0Hz，2H)，4.11-4.23(m，1H)，3.49(t，J＝8.5Hz，1H)，3.12-3.21(m，1H)，3.08(s，3H)，2.22-2.35(m，1H)，2.05-2.15(m，2H)，2.01ppm(br.s.，1H)

Example 57: preparation of (R) -5-chloro-4- (1- (1- (3-chloro-4- (trifluoromethoxy) phenyl) pyrrolidin-2-yl) ethoxy) -2-fluoro-N- (methylsulfonyl) benzamide (Z-57)

Step 1: to a solution of compound 22-b (600mg, 2.029mmol) in dichloromethane (20ml) was added dess-martin oxidant (1.033g, 2.435mmol) at 0 ℃ and stirred at 0 ℃ for 30 minutes. After the reaction is finished, adding sodium bicarbonate solution, sodium thiosulfate solution and dichloromethane for extraction,the organic phase was dried and separated by washing with sodium bicarbonate solution and concentrated under reduced pressure to give crude 57-b (575mg) as a yellow oil. MS m/z (ESI): 294[ M + H]⁺。

Step 2: to a solution of compound 57-b (0.575g, 1.958mmol) in tetrahydrofuran (5ml) was added dropwise methylmagnesium bromide (1ml, 2.937mmol) at 0 ℃ and allowed to warm to room temperature naturally, followed by stirring for 1 hour. After the reaction, ammonium chloride solution was added, followed by extraction with ethyl acetate, washing with brine, drying to separate the organic phase, and concentration under reduced pressure to obtain crude yellow oily compound 57-c (339 mg). MSm/z (ESI): 310.1[ M + H]⁺。

And step 3: to a solution of compound 57-c (339mg, 1.094mmol), compound 17-a (224mg, 1.094mmol), and triphenylphosphine (576mg, 2.189mmol) in toluene (5ml) was added diisopropyl azodicarboxylate (443mg, 2.189mmol) under argon, and the mixture was stirred at 60 ℃ under argon overnight. After the reaction, cooling to room temperature, pouring into water, extracting with ethyl acetate, washing with brine, drying, separating an organic phase, and concentrating under reduced pressure. Purification by Combi-flash column chromatography gave 57-d (276mg) as a yellow oil. MS m/z (ESI): 496.1[ M + H]⁺。

And 4, step 4: to a solution of compound 57-d (276mg, 0.556mmol) in methanol (10ml) was added a solution of sodium hydroxide (89mg, 2.224mmol) in water (1ml), and the mixture was stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated under reduced pressure, water was added thereto, pH was adjusted to 1 with 1N hydrochloric acid, extraction was carried out with ethyl acetate, washing was carried out with brine, the organic phase was dried and separated, and concentration under reduced pressure was carried out to give 57-e (266mg) as a yellow oily compound. MS m/z (ESI): 482[ M + H ]]⁺。

And 5: the compound was synthesized according to the method of example 5 using 57-e (266mg) and methanesulfonamide as starting materials to give compound Z-57(57mg) as a yellow oily substance. MS m/z (ESI): 559[ M + H ]]⁺。¹H NMR(500MHz，DMSO-d₆)：δ12.06-12.02(br.s.，1H)，7.75(d，J＝7.5Hz，1H)，7.30(d，J＝9.0Hz，1H)，7.07(d，J＝7.0Hz，1H)，6.78(d，J＝2.5Hz，1H)，6.64(dd，J＝2.5Hz，9.0Hz，1H)，4.99-4.95(m，1H)，4.01(d，J＝8.5Hz，1H)，3.37-3.34(m，1H)，3.16(s，3H)，3.14-3.09(m，1H)，2.37-2.31(m，1H)，2.28-2.23(m，1H)，2.06-1.99(m，1H)，1.98-1.92(m，1H)，1.32(d，J＝6.0Hz，3H).

Example 60: preparation of (R) -4- ((1- (3-chloro-4- (trifluoromethyl) phenyl) pyrrolidin-2-yl) methoxy) -2, 5-difluoro-N- (methylsulfonyl) benzamide (Z-60)

Step 1: starting from compound 7-a (2.92g), the preparation was carried out by the method described in example 50, except that 1-bromo-4- (trifluoromethoxy) benzene in step 1 was changed to 4-bromo-2-chloro-1- (trifluoromethyl) benzene, and the reaction conditions were changed to 100 ℃ and stirring was carried out for 16 hours. Compound 60-b (2.076g) was obtained as a yellow oil and used directly in the next reaction, 91.7% pure in 31% yield. MS m/z (ESI): 280.1[ M + H]⁺。

Step 2: to a solution of compound 60-b (55mg, 0.197mmol) in tetrahydrofuran (10ml) was added potassium tert-butoxide (66mg, 0.592mmol) at 0 ℃ and stirred at 0 ℃ for 10 minutes, compound 9-a (50mg, 0.197mmol) was added and the mixture was allowed to warm to room temperature and stirred for 2 hours. After the reaction, ethyl acetate was used for extraction, the mixture was washed with a hydrochloric acid solution to pH 5 to 6, and the organic phase was dried and separated and purified by prep-HPLC to obtain compound Z-60(22mg) as a white solid. MS m/z (ESI): 511.1[ M-H]^-。¹H NMR(500MHz，DMSO-6)：δ12.08(s，1H)，7.60-7.57(m，1H)，7.53(d，J＝9.0Hz，1H)，7.28-7.25(m，1H)，6.92(d，J＝2.0Hz，1H)，6.73(dd，J＝9.0Hz，4.0Hz，1H)，4.34-4.33(m，1H)，4.20-4.13(m，2H)，3.52-3.49(m，1H)，3.35(s，3H)，3.24-3.21(m，1H)，2.18-2.15(m，1H)，2.11-2.05(m，3H).

Example 61: preparation of 5-chloro-4- ((1- (4-chlorophenyl) -1H-imidazol-2-yl) methoxy) -2-fluoro-N- (methylsulfonyl) benzamide (Z-61)

Step 1: compound 18-a (1g, 10.407mmol), 1-bromo-4-chlorobenzene (1.992g, 10.407mmol), 4, 7-dimethoxy-1, 10-phenanthroline (500mg, 2.081mmol), N1,a mixed solution of N2-dimethylethane-1, 2-diamine (183mg, 2.081mmol), cuprous iodide (396mg, 2.081mmol), and potassium carbonate (4.315g, 31.221mmol) in thionyl chloride (20ml) was stirred under argon at 100 ℃ overnight. After the reaction, cooling to room temperature, pouring into water, extracting with ethyl acetate, washing with brine, drying, separating an organic phase, and concentrating under reduced pressure. Purification by Combi-flash column chromatography gave compound 61-b as a yellow solid (257 mg). MS m/z (ESI): 207.1[ M + H]⁺。

Step 2: to a solution of compound 61-b (257mg, 1.244mmol) in methanol (10ml) was added sodium borohydride (25mg, 0.622mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction, ammonium chloride solution was added, followed by extraction with dichloromethane, and the organic phase was dried and separated, and concentrated under reduced pressure to give 61-c (267mg) as a yellow oil. MS m/z (ESI): 209.1[ M + H]⁺。

And step 3: to a solution of compound 61-c (267mg, 1.28mmol) and triethylamine (259mg, 2.559mmol) in methanol (10ml) was added acetyl chloride (151mg, 1.919mmol) at 0 ℃ and the mixture was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was washed with brine, extracted with dichloromethane, dried to separate the organic phase, and concentrated under reduced pressure to give compound 61-d (300mg) as a green solid. MS m/z (ESI): 251.1[ M + H]⁺。

And 4, step 4: using compound 61-d (300mg) as a starting material, according to the preparation method in step 3 of example 4, compound Z-61(10mg) was obtained as a yellow solid with a purity of 99%, MS m/Z (ESI): 456[ M-H ]]^-。¹H NMR(500MHz，DMSO-d₆)：δ7.79(d，J＝8.0Hz，1H)，7.73(s，1H)，7.63(m，5H)，7.39(s，1H)，5.35(s，2H)，3.32(s，3H).

Example 62: preparation of (R) -5-chloro-4- ((1- (4-chlorophenyl) -5-oxopyrrolidin-2-yl) methoxy) -2-fluoro-N- (methylsulfonyl) benzamide (Z-62)

Step 1: using compound 19-a (1.5g) as a starting material, the reaction conditions were changed to 140 ℃ and microwave stirring was carried out for 30 minutes in accordance with the preparation method of step 1 in example 61, whereby compound 62-b (350mg) was obtained as a yellow oily substance.

Step 2: using compound 62-b (130mg) as a starting material, the preparation process was carried out in step 3 of example 57 to give compound 62-c (364mg) as a yellow oil, MS m/z (ESI): 412.1[ M + H]⁺。

And step 3: using compound 62-c (264mg) as a starting material, the preparation process was carried out in accordance with step 4 of example 57 to give compound 62-d (109mg) as a yellow oil, MS m/z (ESI): 398.1[ M + H]⁺。

And 4, step 4: using compound 62-d (109mg) as a starting material, according to the production method of step b in compound 11-a, compound Z-62(32.01mg) was obtained as a white solid, MS m/Z (ESI): 474.8[ M + H]⁺。¹H NMR(500MHz，DMSO-d₆)：δ12.09(br.s.，1H)，7.76(d，J＝7.0Hz，1H)，7.53(d，J＝9.0Hz，2H)，7.43(d，J＝9.0Hz，2H)，7.16(d，J＝12.0Hz，1H)，4.83-4.80(m，1H)，4.23(dd，J＝3.0Hz，10.5Hz，1H)，4.16(dd，J＝3.0Hz，10.0Hz，1H)，3.35(s，3H)，2.84-2.78(m，1H)，2.49-2.37(m，2H)，2.12-2.06(m，1H).

Examples 81, 122, 137, 152, 153

Compounds Z-81, Z-122, Z-137, Z-152 and Z-153 were prepared starting from compound 7-a by the method described for compound 62. Except that 1-bromo-4-chlorobenzene in step 1 is replaced by 1-bromo-4- (trifluoromethyl) benzene, 2-bromo-5- (trifluoromethyl) pyridine, respectively, and methylsulfonamide in step 4 is replaced by ethanesulfonamide, isopropanesulfonamide, respectively, according to their structures.

Example 63: preparation of (R) -4- ((1- (3-chloro-4-fluorophenyl) pyrrolidin-2-yl) methoxy) -5-cyclopropyl-2-fluoro-N- (methylsulfonyl) benzamide (Z-63)

Step 1: starting with compound 7-a (728mg), the preparation was carried out by the method described in step 1 of example 50, except that 1-bromo-4- (trifluoromethoxy) benzene was changed to 4-bromo-2-chloro-1-fluorobenzene, the reaction conditions were changed to 90 ℃ and stirring was carried out overnight to give compound 63-b (120mg), MS m/z (esi), as a white solid: 230[ M + H [ ]]⁺。

Step 2: starting with compound 63-b (110mg), the preparation was carried out by the method described in step 3 of example 4, except that compound 1-a in step was changed to compound 11-a, and the reaction conditions were changed to 180 ℃ and stirring was carried out for 1 hour to give compound 63-c (120mg) as a white solid, MS m/z (esi): 523[ M + H]⁺。

Step 3 preparation of the title compound was carried out in the same manner as in step 2 of example 29, starting from compound 63-c (110mg), and yielded compound Z-63(10mg) as a white solid, MS m/Z (ESI): 485[ M + H]⁺。¹H NMR(500MHz，DMSO-d₆)：δ11.907(s，1H)，7.218-7.192(m，2H)，6.836-6.818(m，1H)，6.759(d，J＝12.5Hz，1H)，6.673-6.648(m，1H)，4.187(s，1H)，4.020-3.989(m，2H)，3.466(t，J＝8.0Hz，1H)，3.127-3.077(m，1H)，2.902(s，3H)，2.169-2.054(m，1H)，2.036-1.956(m，4H)，0.910-0.862(m，1H)，0.795-0.770(m，1H)，0.555-0.545(m，2H)，

Examples 65, 73, 115

Compound Z-65 was prepared by the method of example 63, starting with compound 7-a, except that 4-bromo-2-chloro-1-fluorobenzene in step 1 was changed to 1-bromo-4-chlorobenzene.

Compound Z-73 was synthesized by the method described in example 63, starting from compound 7-a, except that 4-bromo-2-chloro-1-fluorobenzene in step 1 was changed to 1-bromo-4- (trifluoromethyl) benzene, the reaction conditions were changed to 100 ℃ and stirring was carried out for 16 hours, that in step 2 was changed to 200 ℃ and stirring was carried out for 30 minutes, and that in step 3 was changed to 80 ℃ and stirring was carried out for 16 hours.

Compound Z-115 was prepared by the method described in example 63, except that compound 7-a in step 1 was changed to compound 31-a, 4-bromo-2-chloro-1-fluorobenzene to 4-bromo-1, 2-dichlorobenzene, the reaction conditions were changed to 100 ℃ and stirred for 16 hours, that in step 2 was changed to 200 ℃ and stirred for 30 minutes, and that in step 3 was changed to 80 ℃ and stirred for 16 hours.

Example 64: preparation of (R) -5-chloro-4- ((1- (6-chloropyridin-2-yl) pyrrolidin-2-yl) methoxy) -2-fluoro-N- (methylsulfonyl) benzamide (Z-64)

Step 1: a mixed solution of 2-chloro-6-fluoropyridine (2.20g, 16.72mmol), compound 7-a (1.27g, 12.54mmol) and potassium carbonate (2.31g, 16.72mmol) in dimethylformamide (22ml) was stirred at 80 ℃ for 5 hours. After the reaction, cooling to room temperature, pouring into water, extracting with ethyl acetate, washing with water, washing with salt water, drying, separating the organic phase, and concentrating under reduced pressure. Purification by Combi-flash column chromatography gave compound 64-b (2g) as a yellow solid. MS m/z (ESI): 213[ M + H]⁺。

Step 2: starting with compound 64-b (500mg), the preparation was carried out by the method described in step 3 of example 4, except that the reaction conditions were changed to 200 ℃ and stirring was carried out for 1 hour to obtain compound Z-64(80mg) as a white solid, MS m/Z (esi): 462[ M + H ]]⁺。¹H NMR(DMSO-d₆，400MHz)：δ7.78(d，J＝7.6Hz，1H)，7.53(d，J＝7.5Hz，1H)，7.18(d，J＝12.4Hz，1H)，6.64(d，J＝7.2Hz，1H)，6.54(d，J＝8.4Hz，1H)，4.37-4.26(m，2H)，4.06-4.10(m，1H)，3.42-3.52(m，2H)，2.81(s，3H)，2.09-2.05(m，4H).

Example 70

Compound Z-70 was prepared by the method in accordance with example 64, starting from compound 7-a, except that 2-chloro-6-fluoropyridine in step 1 was changed to 2-bromo-5- (trifluoromethyl) pyridine, and the reaction conditions in step 2 were changed to 180 ℃ and stirring was carried out for 30 minutes.

Example 66: preparation of (R) -5-chloro-4- ((1- (5-chloro-6-cyclopropoxypyridin-3-yl) pyrrolidin-2-yl) methoxy) -2-fluoro-N- (methylsulfonyl) benzamide (Z-66)

Step 1: to a solution of compound 20-a (1.5g, 7.128mmol), cyclopropanol (0.621g, 10.692mmol) and N-methylpyrrolidone (20ml) was added a solution of potassium tert-butoxide (1.2g, 10.692mmol) in tetrahydrofuran (20ml), and the mixture was stirred at room temperature for 1 hour. After the reaction is finished, adding water, separating an organic phase, washing with salt water, drying and separating the organic phase, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying by Combi-flash column chromatography to obtain a colorless oily compound 66-b (1.58g), wherein the purity is 99.01 percent, and the yield is 89 percent. MS m/z (ESI): 250[ M + H ]]⁺。

Step 2: starting with compound 7-a (407mg), the preparation was carried out by the method described in step 1 of example 50, except that 1-bromo-4- (trifluoromethoxy) benzene was changed to compound 66-b in the step, and the reaction conditions were changed to 95 ℃ and stirring was carried out overnight to obtain compound 66-c (194mg), MS m/z (esi): 269.1[ M + H]⁺。

And step 3: starting with compound 66-c (164mg), the preparation was carried out by the method described in step 3 of example 4, except that the reaction conditions in step were changed to 200 ℃ and stirring was carried out for 30 minutes, to obtain compound Z-66(33.06mg), MSm/Z (esi): 518.1[ M + H]⁺。¹H NMR(500MHz，DMSO-d₆)：δ12.12(br.s.，1H)，7.77(d，J＝7.5Hz，1H)，7.62(d，J＝2.5Hz，1H)，7.40(d，J＝2.5Hz，1H)，7.25(d，J＝12.0Hz，1H)，4.20-4.17(m，4H)，3.49(t，J＝7.5Hz，1H)，3.36(s，3H)，3.10(q，J＝8.5Hz，1H)，2.20(q，J＝10.0Hz，1H)，2.10-1.97(m，3H)，0.75-0.71(m，2H)，0.65-0.62(m，2H).

Example 74: preparation of (R) -5-chloro-4- ((1- (4-chlorobenzyl) pyrrolidin-2-yl) methoxy) -2-fluoro-N- (methylsulfonyl) benzamide (Z-74)

Step 1: prepared by the method of example 61, step 2 using compound 21-a (1g) as a starting material, to give compound 74-b (984mg) as a white solid.

Step 2: starting from compound 74-b (100mg), the preparation was carried out according to the method of example 61, step 3, except that acetyl chloride in the step was changed to methanesulfonyl chloride, to give compound 74-c (146mg) as a yellow oil.

And step 3: a mixed solution of compound 74-c (124mg, 0.563mmol), compound 22-a (162mg, 0.563mmol), potassium carbonate (156mg, 1.127mmol) in acetonitrile (10ml) was stirred at 60 ℃ for 2 hours. After the reaction is finished, cooling to room temperature, washing with water, drying and separating an organic phase, and concentrating under reduced pressure. Purification by Combi-flash column chromatography gave compound 74-d (147mg) as a colourless oil. MS m/z (ESI): 412[ M + H]⁺。

And 4, step 4: using compound 74-d (147mg) as a starting material, the preparation process was carried out in step 4 of example 57 to give compound 74-e (136mg) as a white solid, MS m/z (ESI): 398.1[ M + H]⁺。

And 5: starting with compound 74-e (97mg), according to the preparation method of step b of compound 11-a, compound Z-74(21.04mg) was obtained as a white solid, MS m/Z (esi): 475.1[ M + H]⁺。¹H NMR(500MHz，DMSO-d₆)：δ7.80(d，J＝7.5Hz，1H)，7.43(br.s.，4H)，7.15(d，J＝12.0Hz，1H)，4.47-4.36(m，1H)，4.21(s，2H)，3.89-3.61(m，1H)，3.34(m，2H)，3.10(s，3H)，2.99-2.93(m，1H)，2.14-2.07(m，1H)，1.84-1.72(m，3H)

Example 77: preparation of (R) -5-chloro-4- ((1- (4-chlorobenzoyl) pyrrolidin-2-yl) methoxy) -2-fluoro-N- (methylsulfonyl) benzamide (Z-77)

Step 1: using the compound (R) -tert-butyl-2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.19g) as a starting material, the reaction conditions were changed to 180 ℃ and stirred with a microwave for 20 minutes in accordance with the preparation method of step 3 in example 4, to obtain compound 77-b (375mg), MS m/z (esi): 351[ M + H-100 ]]⁺。

Step 2: using compound 77-b (375mg) as a starting material, and by referring to the preparation method in step 3 of example 6, the reaction conditions were changed to 40 ℃ and microwave stirring was carried out overnight to obtain compound 77-c (120mg), MS m/z (ESI): 351[ M + H-36 ]]⁺。

And step 3: to a 50ml single neck round bottom flask was added 4-chlorobenzoic acid (16mg, 0.102mmol), compound 77-c (40mg, 0.102mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (118mg, 0.306mmol), N, N-diisopropylethylamine (40mg, 0.306mmol), and dichloromethane (10ml), and stirred at room temperature for 1.5 h. After the reaction, ethyl acetate and water were extracted, the organic phase was separated, concentrated under reduced pressure, and purified by preparative liquid phase separation to give compound Z-77(5.26mg) with a purity of 92% and a yield of 10%. MS m/z (ESI): 489[ M + H ]]⁺。¹H NMR(500MHz，DMSO)：δ7.799(d，J＝6Hz，1H)，7.509-7.502m，4H)，7.135(d，J＝11.5Hz，1H)，4.487-4.453(m，1H)，4.318-4.299(m，2H)，3.513-3.497(m，1H)，2.906(s，3H)，2.125-2.022(m，3H)，1.796-1.784(m，1H)，1.252-1.250(m，1H).

Example 82: preparation of (R) -2-fluoro-5-methyl-N- (methylsulfonyl) -4- ((1- (4- (trifluoromethyl) phenyl) pyrrolidin-2-yl) methoxy) benzamide (Z-82)

Step 1: starting with compound 7-a (6.08g), the preparation was carried out by the method described in step 1 of example 50, except that 1-bromo-4- (trifluoromethoxy) benzene was changed to 1-bromo-4- (trifluoromethyl) benzene in step, and the reaction conditions were changed to 100 ℃ and stirred for 16 hours to give compound 82-b (3.98g), MS m/z (esi), as a yellow oil: 246.1[M+H]⁺。

Step 2: prepared by the method of example 57, step 3, starting with compound 82-b (490mg) except that compound 17-a in step was changed to compound 25-a and the reaction conditions were changed to room temperature, followed by stirring for 2 hours, to give compound 82-c (650mg), MS m/z (esi): 478.1[ M + H]⁺。

And step 3: starting with compound 82-c (650mg), the preparation was carried out by the method described in step 4 of example 57, except that the reaction conditions were changed to 60 ℃ and stirring was carried out for 2 hours, to give compound 82-d (509mg) as a white solid, MS m/z (esi): 462.1[ M + H]⁺。

And 4, step 4: using compound 82-d (500mg) as a starting material, according to the production method in step b of compound 11-a, compound 82-e (150mg) was obtained as a white solid, MS m/z (ESI): 539[ M + H ]]⁺。

And 5: a mixed solution of compound 82-e (50mg, 0.093mmol), methylboronic acid (7mg, 0.111mmol), 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (7mg, 0.009mmol) and sodium carbonate (30mg, 0.278mmol) in dioxane (15ml) was stirred at 100 ℃ overnight. After the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by liquid phase preparative purification to give Compound Z-82(7.39mg) as a brown solid. MS m/z (ESI): 475.2[ M + H]⁺。¹H NMR(500MHz，DMSO-d₆)：δ7.51(d，J＝8.5Hz，1H)，7.46(d，J＝9.0Hz，2H)，6.85(d，J＝13.0Hz，1H)，6.81(d，J＝8.5Hz，2H)，4.33-4.24(br.s.，1H)，4.09-4.01(m，2H)，3.51(m，1H)，3.24-3.20(m，1H)，3.13(s，3H)，2.22-2.16(m，1H)，2.10-1.94(m，6H)

Examples 120, 143, 155, 167, 168

Compounds Z-120, Z-143 to Z-144, Z-154, Z-155, Z-167 and Z-168 were prepared starting from compound 7-a by the method described in example 82, except that 1-bromo-4- (trifluoromethyl) benzene or 2-bromo-5- (trifluoromethyl) pyridine in step 1 was replaced, methylsulfonamide in step 4 was replaced with ethanesulfonamide, cyclopropanesulfonamide or isopropanesulfonamide, respectively, and methylboronic acid in step 5 was replaced with ethylboronic acid, isopropylboronic acid or cyclopropylboronic acid, depending on the respective structures.

Example 86: preparation of 5-chloro-4- ((4- (3-chloro-4- (trifluoromethoxy) phenyl) piperazin-1-yl) methyl) -2-fluoro-N- (methylsulfonyl) benzamide (Z-86)

Step 1: to a solution of 4-bromo-2-chloro-1- (trifluoromethoxy) benzene (1.63g, 8.76mmol), compound 27-a (2g, 7.3mmol), cesium carbonate (4.76g, 14.6mmol) in dioxane (25ml) was added (tris (dibenzylideneacetone) dipalladium) (334mg, 0.37mmol), (±) -2, 2 '-bis- (diphenylphosphino) -1, 1' -binaphthyl (227mg, 0.37mmol), under argon and stirred at 100 ℃ for 5 h. After the reaction is finished, cooling to room temperature, pouring water, extracting with ethyl acetate, drying and separating an organic phase, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying by Combi-flash column chromatography to obtain a yellow solid compound 86-b (1.3g), wherein the purity is 97.21% and the yield is 46.93%. MS m/z (ESI): 325[ M + H-56 ]]⁺。

Step 2: the preparation method according to step 1 of example 4 was carried out using compound 86-b (1.3g) as a starting material to obtain compound 86-c (1g), MS m/z (ESI): 281[ M + H-36 ]]⁺。

And step 3: the preparation method of step 3 in example 4 was referenced starting from compound 86-c (100mg) except that compound 1-a was changed to compound 13-a-5 and the reaction conditions were changed to 70 ℃ to stir for 4 hours, to give compound Z-86(40.41mg) as a white solid with a purity of 99.15%, yield of 22.99%, MS m/Z (esi): 544[ M + H]⁺。¹H NMR(500MHz，DMSO-d₆)：δ12.149(s，1H)，7.689(d，J＝6.5Hz，1H)，7.351(d，J＝10.5Hz，1H)，7.286(d，J＝9.0Hz，1H)，7.080(d，＝3.0Hz，1H)，6.919(dd，J＝2.9Hz，J＝9.0Hz，1H)，3.605(s，2H)，3.187(s，4H)，3.078(s，3H)，2.542(s，4H).

Examples 85, 88, 145

Compounds Z-85, Z-88 and Z-145 were prepared by the method of example 86 starting with compound 27-a except that 4-bromo-2-chloro-1- (trifluoromethoxy) benzene in step 1 was replaced with the corresponding substituted bromobenzene.

Example 162: preparation of (R) -5-chloro-4- ((4- (3, 4-dichlorophenyl) -2-methylpiperazin-1-yl) methyl) -N- (ethylsulfonyl) -2-fluorobenzene (Z-162)

Compound 36-a and compound 35-a were synthesized by the procedure of step 3 in example 86 to give compound Z-162. MS m/z (ESI): 522[ M + H]⁺。

Example 87: preparation of 5-cyclopropyl-4- ((4- (3, 4-dichlorophenyl) piperazin-1-yl) methyl) -2-fluoro-N- (methylsulfonyl) benzamide (Z-87)

Step 1: a solution of compound 28-a (50g, 324.7mmol), iron (10.9g, 194.8mmol) in dichloromethane (500ml) was stirred at room temperature for a while, heated to 40 ℃ and stirred, bromine (153.9g, 974.1mmol) was added dropwise and stirred at room temperature overnight. After the reaction, the reaction mixture was poured into a sodium thiosulfate solution, filtered, and the filtrate was concentrated under reduced pressure to give 87-b (70g) as a yellow solid. MSm/z (ESI): 231[ M-1 ]]^-。

Step 2: using the compound 87-b (17.5g) as a starting material, with reference to the preparation method in step 1 of example 55, the compound 87-c(15.3g)，MS m/z(ESI)：309.9[M+H]⁺。

And step 3: a solution of compound 87-c (6.109g, 0.0197mol), N-bromosuccinimide (5.259g, 0.0295mol) and azobisisobutyronitrile (1.617g, 0.0098mol) in acetonitrile (40ml) was stirred at 80 ℃ for 4 hours. After the reaction, the reaction mixture was cooled to room temperature, washed with a sodium thiosulfate solution, washed with brine, dried to separate an organic phase, and the filtrate was concentrated under reduced pressure to give compound 87-d (12.4 g). MS m/z (ESI): 467.8[ M-1 ]]^-。

And 4, step 4: to a solution of compound 87-d (12.4g, 0.0229mol) in ethyl acetate (50ml) was added N, N-diisopropylethylamine (4.871g, 0.0382mol), diethyl phosphite (1.39g, 0.01mol), and the mixture was stirred at room temperature for 4 hours under argon shield. After the reaction, the organic phase was separated by drying and washing with hydrochloric acid, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by Combi-flash column chromatography to give 87-e (6.613g) as a yellow solid with a purity of 94.5% and a yield of 74%. MS m/z (ESI): 387.9[ M-1 ]]^-。

And 5: the preparation method of example 28 was referenced using compound 87-e (336mg) as a starting material, except that compound 1-c was changed to compound 10-a, and the reaction conditions were changed to 80 ℃ to stir for 2 hours, thereby obtaining compound 87-f (335mg) with a purity of 97%, yield of 72%, MS m/z (ESI): 540[ M + H ]]⁺。

Step 6: starting with compound 87-f (235mg), the procedure of preparation of step 5 of example 82 was followed, except that in step (ii), methyl boronic acid was replaced with cyclopropylboronic acid, and the reaction conditions were changed to 80 ℃ under argon atmosphere and stirred overnight, to give compound Z-87(23.93mg) with 98% purity and 8% yield, MS m/Z (esi): 500[ M + H ]]⁺。¹H NMR(500MHz，DMSO)：δ7.320(d，J＝9Hz，1H)，7.187(d，J＝7Hz，1H)，7.151(d，J＝11.5Hz，1H)，7.060(d，J＝2.5Hz，1H)，6.865(dd，J＝2.5，9Hz，1H)，3.652(s，2H)，3.147(t，J＝4Hz，4H)，3.110(s，3H)，2.508(m，4H)，2.036-1.982(m，1H)，0.883-0.846(m，2H)，0.583-0.573(m，2H).

Examples 146-

Compounds No. Z-146 to Z-148, Z-157, Z-158, Z-160, Z-161, Z-170 and Z-171 were prepared by starting with compound No. 7-a and following the procedure of example 87, except that, according to the respective structures, the methylsulfonamide in step 2 was replaced with ethanesulfonamide, the compound No. 10-a in step 5 was replaced with the corresponding phenyl-substituted piperazine and the cyclopropylboronic acid in step 6 was replaced with methylboronic acid and ethylboronic acid.

Example 91: preparation of 5-chloro-4- ((4- (3, 4-dichlorophenyl) piperazin-1-yl) methyl) -2-fluoro-N- (isopropylsulfonyl) benzamide (Z-91)

Step 1: reference was made to the preparation of compound 17-a in step b starting from compound 13-a-3(11.219g) except that the reaction conditions were changed to 80 ℃ and stirring was carried out for 7 hours to give compound 91-b (11.144g), MS m/z (esi): 203[ M + H]⁺。

Step 2: the preparation of compound 91-c (12.907g), MS m/z (esi), was carried out according to the method for preparing compound 91-b (11.144g) using the compound 91-b (11.144g) as a starting material, referring to step 3 of example 87: 281[ M + H]⁺。

And step 3: the preparation method of reference example 28 using compound 91-c (4.067g) as a starting material, except that compound 1-c was changed to compound 10-a and the reaction conditions were changed to 80 ℃ and stirring was carried out for 2 hours, gave compound 91-d (4.722g) with a purity of 94.63%, yield of 77%, MS m/z (ESI): 433.1[ M + H ]]⁺。

And 4, step 4: starting from compound 91-d (4.722g), the preparation was carried out in the same manner as in step 4 of example 57 except that the reaction conditions were changed to 60 ℃ and the mixture was stirred for 3 hours. Compound 91-e (4.163g) was obtained as a white solid, MS m/z (ESI): 419.1[ M + H]⁺。

And 5: the preparation method of compound 91-e (100mg) was referenced to step 1 of example 55, except that methanesulfonamide was replaced with isopropane-2-sulfonamide to obtain compound Z-91(10.36mg), MS m/Z (esi): 524.1[ M + H]⁺。¹HNMR(400MHz，DMSO-d₆)：δ12.52(br.s.，1H)，7.65(d，J＝6.8Hz，1H)，7.35(d，J＝9.2Hz，1H)，7.31(d，J＝11.2Hz，1H)，7.09(d，J＝2.8Hz，1H)，6.91(dd，J＝2.8Hz，9.2Hz，1H)，3.60(s，2H)，3.57-3.53(m，1H)，3.20-3.17(m，4H)，2.56-2.53(m，4H)，1.18(d，J＝6.8Hz，6H).

Examples 90, 93, 129, 131, 133, 136, 138, 139, 140, 149, 151, 156, 163, 169

Compounds Z-90, Z-93, Z-129 to Z-131, Z-133, Z-136, Z-138, Z-139, Z-140, Z-149, Z-151, Z-156, Z-163 and Z-169 were prepared according to the method of example 91, except that the compound 10-a in step 3 was replaced with various types of phenyl-or pyridyl-substituted piperazines and the isopropane-2-sulfonamide or ethanesulfonamide in step 5 was replaced according to its structure.

Example 99: preparation of 5-chloro-4- ((1- (5-chloropyridin-3-yl) piperidin-4-yl) oxy) -2-fluoro-N- (methylsulfonyl) benzamide (Z-99)

Step 1: a solution of the compound 3-bromo-5-chloropyridine (500mg, 2.6mmol), the compound 31-a (394mg, 3.9mmol), (tris (dibenzylideneacetone) dipalladium) (59mg, 0.065mmol), (2-biphenyl) di-tert-butylphosphine (39mg, 0.129mmol), and sodium tert-butoxide (749mg, 7.79mmol) in toluene (15ml) was stirred at 40 ℃ overnight. After the reaction, the mixture is cooled to room temperature, poured into water, extracted by ethyl acetate, separated from an organic phase and concentrated under reduced pressure. Purification by Combi-flash column chromatography gave 99-b (70mg) as a yellow oil, MS m/z (esi): 213.1[ M + H]⁺。

Step 2: using compound 99-b (70mg) as a starting material, the preparation process was carried out in step 3 of example 57 to give compound 99-c (120mg), MS m/z (ESI): 399.1[ M + H]⁺。

And step 3: using compound 99-c (120mg) as a starting material, the preparation process was carried out in step 4 of example 57 to give compound 99-d (110mg), MS m/z (ESI): 383.1[ M-H]^-。

And 4, step 4: using compound 99-d (110mg) as a starting material, according to the production method in step b of compound 11-a, compound Z-99(12mg) was obtained as a white solid, MS m/Z (ESI): 462.0[ M + H]⁺。¹H NMR(500MHz，DMSO-6)：12.10(s，1H)，8.32(d，J＝2.5Hz，1H)，7.97(d，J＝2.0Hz，1H)，7.80(d，J＝7.5Hz，1H)，7.50-7.49(m，1H)，7.45(d，J＝12.5Hz，1H)，4.92-4.91(m，1H)，3.60-3.58(m，2H)，3.36(s，3H)，3.34-3.31(m，2H)，2.06-2.04(m，2H)，1.77-1.75(m，2H).

Examples 100, 101, 103, 105, 106, 114

Compound Z-100 was prepared by the method in accordance with example 99, starting from compound 31-a, except that 3-bromo-5-chloropyridine in step 1 was changed to compound 32-a, the reaction conditions were changed to 46 ℃ and stirring was carried out for 5 hours, and the reaction conditions in step 4 were changed to room temperature and stirring was carried out for 3 days.

Compound Z-101 was prepared by the method in accordance with example 99, starting from compound 31-a, except that 3-bromo-5-chloropyridine in step 1 was changed to compound 33-a, and the reaction conditions were changed to 40 ℃ and stirring was carried out for 5 hours.

Compound Z-103 was prepared by the method in accordance with example 99, starting from compound 31-a, except that 3-bromo-5-chloropyridine in step 1 was changed to 1-bromo-2, 4-dichlorobenzene, and the reaction conditions in step 3 were changed to 50 ℃ and stirred for 3 hours.

Compound Z-105 was prepared by the method of example 99, starting with compound 31-a, except that 3-bromo-5-chloropyridine in step 1 was changed to 4-bromo-2-chloro-1- (trifluoromethyl) benzene and the reaction conditions were changed to 40 ℃ and stirred for 5 hours.

Compound Z-106 was prepared by the method of example 99 starting with compound 31-a, except that 3-bromo-5-chloropyridine in step 1 was changed to 4-bromo-2-chloro-1-fluorobenzene.

Compound Z-114 was prepared by the method in accordance with example 99, starting from compound 31-a, except that 3-bromo-5-chloropyridine in step 1 was changed to compound 23-a, and the reaction conditions were changed to 40 ℃ and stirring was carried out for 4 hours.

Example 132: preparation of 4- ((4- (3, 4-dichlorophenyl) piperazin-1-yl) methyl) -2-fluoro-N- (isopropylsulfonyl) benzamide (Z-132)

Step 1: to a solution of compound 28-a (500mg, 3.24mmol), propane-2-sulfonamide (799mg, 6.49mmol) in dichloromethane (5ml) was added triethylamine (985mg, 9.73mmol), carbodiimide (1.24g, 6.49mmol), 4-dimethylaminopyridine (396mg, 3.24mmol) dropwise, and the mixture was stirred at room temperature overnight. After the reaction, 10ml of water was added, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was separated and concentrated under reduced pressure. Purification by Combi-flash column chromatography gave compound 132-b (560mg) as a white solid, MS m/z (esi): 260[ M + H ] +.

Step 2: to a solution of compound 132-b (510mg, 1.97mmol) in acetonitrile (5ml) was added N-bromosuccinimide (455mg, 2.56mmol), azobisisobutyronitrile (32mg, 0.20mmol), under argon, and stirred at 80 ℃ for 3 hours. After the reaction, the reaction mixture was cooled to room temperature, poured into water, adjusted to pH 3 with hydrochloric acid (4N), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was separated and concentrated under reduced pressure to give compound 132-c (665mg) as a yellow oily substance, MS m/z (ESI): 338[ M + H ] +.

And step 3: to a solution of compound 10-a (68mg, 0.30mmol), compound 132-c (100mg, 0.30mmol) in dimethylformamide (3ml) was added potassium carbonate (102mg, 0.75mmol), and the mixture was stirred at 85 ℃ for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was separated, concentrated under reduced pressure, and purified by Pre-HPLC to give a white solid compound Z-132(33.66mg), MS m/Z (esi): 488.1[ M + H]+。¹H NMR(400MHz，DMSO-d₆)：δ7.59(t，J＝8.0Hz，1H)，7.36(d，J＝8.0Hz，1H)，7.21(d，J＝8.0Hz，2H)，7.09(d，J＝4.0Hz，1H)，6.89-6.92(m，1H)，3.64-3.71(m，1H)，3.58(s，2H)，3.17-3.19(m，4H)，2.47-2.51(m，4H)，1.26(s，3H)，1.25(s，3H).

Comparative example 1: preparation of 5-cyclopropyl-4- ((4- (3, 4-dichlorobenzyl) piperazin-1-yl) methyl) -2-fluoro-N- (methylsulfonyl) benzamide (C1)

Step 1: a mixed solution of 4- (bromomethyl) -1, 2-dichlorobenzene (1.0g, 4.17mmol), compound 27-a (0.78g, 4.17mmol) and potassium carbonate (1.15g, 8.34mmol) in acetonitrile (10ml) was stirred at 80 ℃ for 5 hours. After the reaction is finished, cooling to room temperature, concentrating under reduced pressure, adding water, extracting with ethyl acetate, washing the organic phase with saline, drying and separating the organic phase, concentrating the filtrate under reduced pressure to obtain a crude product, and purifying by Combi-flash column chromatography to obtain a colorless oily compound 166-b (1.23g), wherein the purity is 100 percent, and the yield is 85.4 percent. MS m/z (ESI): 345.2[ M +H]⁺。

Step 2: to a solution of compound 166-b (1.23g, 3.57mmol) in methanol (10ml) was added hydrochloric acid/dioxane (4M, 4ml, 14.28mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to give 166-c (1.1g) as a white solid, which was used directly in the next reaction, purity was 96.91%, yield was 100%. MS m/z (ESI): 245.1[ M + H]⁺。

And step 3: a mixed solution of compound 166-c (200mg, 0.71mmol), compound 87-e (276mg, 0.71mmol), potassium carbonate (196mg, 1.42mmol) and acetonitrile (5ml) was stirred at 80 ℃ for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, added with water to adjust pH to 7, extracted with ethyl acetate, the organic phase was washed with brine, dried and separated, and the filtrate was concentrated under reduced pressure to give 166-d (285mg) as a yellow solid compound with a purity of 89.3% and a yield of 72.5%. MS m/z (ESI): 554.0[ M + H]⁺。

And 4, step 4: a mixed solution of compound 166-d (283mg, 0.51mmol), cyclopropylboronic acid (88mg, 1.02mmol), 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (37mg, 0.051mmol) and cesium carbonate (333mg, 1.02mmol) in dioxane (5ml) was stirred at 80 ℃ for 24 hours. After the reaction, the mixture is cooled to room temperature, filtered, and the filtrate is concentrated under reduced pressure, and the required product is collected by Combi-flash column chromatography, concentrated, and added with methanol and treated with ultrasound for 2 minutes and 2 times to obtain a light yellow solid compound C1(80 mg). Purity 91.36%, yield 30.5%. MS m/z (ESI): 514.2[ M + H ] +. 1H NMR (DMSO-d6, 400 MHz): 11.29(br.s., 1H), 7.49-7.64(m, 2H), 7.30(d, J ═ 8.0Hz, 1H), 7.05-7.25(m, 2H), 3.72(s, 2H), 3.62(s, 2H), 3.16(s, 3H), 2.55(br.s., 8H), 1.92-2.09(m, 1H), 0.85-0.93(m, 2H), 0.57-0.65ppm (m, 2H).

Preparation of Positive control drug 2(Z-0)

Step 1: compound Z-0-1(20.0g, 155mmol) was dissolved in t-butanol (150mL), cooled to 0 deg.C, and diphenyl phosphorazidate (47g, 170mmol) and triethylamine (17.3g, 170mmol) were added under nitrogen protection). The mixture was stirred under reflux for 18h and then spin dried on a rotary evaporator. The residue was dissolved in dichloromethane (400mL) and washed with water (200 mL. times.2), brine (200 mL). Drying with anhydrous sodium sulfate, and vacuum filtering. The filtrate was spin-dried using a rotary evaporator and the residue was purified by column chromatography (PE: EA ═ 3: 1) to give Z-0-2(15.2g, yield: 49%) as a pale yellow solid, ESI-MS (M-55) +: 145, 97% purity (UV 214).¹HNMR(400MHz，CDCl₃)δ：8.85(brs，1H)，8.61(d，1H)，7.32(s，1H)，1.55(s，9H)。

Step 2: in N₂Z-0-2(8.0g, 0.04mol) was dissolved in anhydrous THF (80ml) with protection, the mixture was cooled to-78 ℃ and a solution of LiHMDS (1M, 48ml, 0.048mol) in THF was added dropwise. After the addition was complete, the mixture was stirred at-78 ℃ for 0.5 h. The reaction was slowly warmed to room temperature, stirred for 1h, then cooled to-78 ℃ and a solution of 5-chloro-2, 4-difluorobenzenesulfonyl chloride (11.11g, 0.048mol) in THF (50ml) was added dropwise to the reaction. The mixture was stirred at-78 ℃ for 1h, then warmed to room temperature and stirred at room temperature for 16 h. To the reaction mixture was added saturated aqueous ammonium chloride (250ml), extracted with ethyl acetate (3X100ml), and the organic phases were combined, washed with saturated brine (200ml), dried and spin-dried at 40 ℃. The crude product was passed through a column (100-mesh 200-mesh silica gel) and the eluent was petroleum ether and ethyl acetate (4: 1) to give Z-0-3(5.11g, yield: 31.8%) as a white solid. ESI-MS (M + Na) +: 434.0, purity: 95.9% (UV 214).

And step 3: compound Z-0-4(50.8g, 254mmol) was dissolved in THF (600mL), cooled to 0 deg.C in an ice bath with stirring, and lithium aluminum hydride (8.4g, 220mmol) was added portionwise. After the mixture was stirred at 0 ℃ for 2 hours, water was added to quench the reaction, hydrochloric acid (6N) was added to adjust PH 3, the aqueous phase was separated, the organic phase was dried over anhydrous sodium sulfate, and suction filtration was performed. The filtrate was spin-dried using a rotary evaporator to obtain Z-0-5(32.0g, yield: 73.5%) as a white solid.¹H NMR(400MHz，CDCl₃)δ7.22-7.16(m，1H)，6.77(d，J＝8.7Hz，1H)，4.61(d，J＝3.7Hz，2H)，3.82(s，3H)，2.63(s，1H).

And 4, step 4: compound Z-0-5(32.0g, 190mmol) was dissolved in dichloromethane (400mL) and thionyl chloride (50mL) was added. The mixture is heated to reflux and stirred under the protection of nitrogenStirring for 3 h. The mixture was cooled to room temperature, the reaction was quenched with water (200mL), the organic phase was separated, and the aqueous phase was extracted with dichloromethane (200X 2 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and filtered with suction. The filtrate was spin-dried using a rotary evaporator to obtain Z-0-6 as a red solid (33.0g, yield: 92.2%).¹H NMR(400MHz，CDCl₃)δ7.34(d，J＝2.6Hz，1H)，7.25(dd，J＝8.7，2.7Hz，1H)，6.81(d，J＝8.8Hz，1H)，4.59(s，2H)，3.86(s，3H).

And 5: compound Z-0-6(32g, 168mmol) was dissolved in DMSO (200mL), and sodium cyanide (29g, 606mmol) was added. The mixture was heated to 80 ℃ under nitrogen blanket and stirred for 3 h. The reaction mixture was cooled to room temperature, dispersed in water and filtered with suction. The filter cake was washed with a small amount of water. Air-dried to obtain orange solid Z-0-7(31g, yield: 98.3%).¹H NMR(400MHz，CDCl₃)δ7.35(d，J＝2.5Hz，1H)，7.28(dd，J＝8.5，2.3Hz，1H)，6.82(d，J＝8.7Hz，1H)，3.86(s，3H)，3.66(s，2H).

Step 6: compound Z-0-7(32g, 177mmol) was dissolved in methyl formate (400mL), and sodium (8.14g, 354mmol) was added. The mixture was heated under reflux with stirring for 24h under nitrogen. The reaction mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate (400 × 2mL), the combined organic phases washed with water (200 × 2mL), dried over anhydrous sodium sulfate and filtered with suction. Then, the residue was evaporated to dryness under reduced pressure to give yellow solid Z-0-8(10.5g, yield: 28.4%).¹H NMR(400MHz，DMSO)δ11.91(s，1H)，7.71(d，J＝93.3Hz，1H)，7.40-7.32(m，1H)，7.29(dd，J＝12.2，2.6Hz，1H)，7.08(dd，J＝8.7，3.1Hz，1H)，3.82(s，3H)。

And 7: compound Z-0-8(10.5g, 50.2mmol) was dissolved in ethanol (150mL), and tert-butylhydrazine (7.5g, 60.3mmol) was added. The mixture was heated under reflux with stirring for 3.5h under nitrogen. The reaction mixture was cooled to room temperature, evaporated to dryness under reduced pressure to give a yellow solid (15g), and subjected to flash column chromatography to give Z-0-9(14.0g, yield: 99.9%) as a yellow solid.

And 8: compound Z-0-9(13.5g, 48.4mmol) was dissolved in dichloromethane (300mL), cooled to 0 ℃ in an ice bath and trifluoroacetic anhydride (30.5g, 145.2mmol), triethylamine (14.7g, 145.2mmol) were added. The mixture was warmed to room temperature under nitrogen and stirred for 4 h. The reaction mixture was quenched to neutrality by the addition of sodium carbonate, the aqueous phase was separated, the organic phase was washed with saturated brine (100X 2mL), dried over anhydrous sodium sulfate and filtered with suction. Evaporated under reduced pressure to dryness to give brown solid Z-0-10(12.0g, yield: 66.1%). ESI-MS (M-H): 376 purity 89.23% (UV254).

And step 9: compound Z-0-10(11.0g, 29.3mmol) was dissolved in dichloromethane (200mL), cooled to 0 ℃ in an ice bath and boron tribromide (36.7g, 146.6mmol) was added. The mixture was warmed to room temperature under nitrogen and stirred for 4 h. The reaction mixture was slowly added with ice water (100mL), the aqueous phase was separated, the organic phase was washed with saturated brine (100X 2mL), dried over anhydrous sodium sulfate, and filtered with suction. The residue was evaporated to dryness under reduced pressure to give brown solid Z-0-11(6.3g, yield: 68.9%). ESI-MS (M-H): 362, purity 80.83% (UV254).

Step 10: compound Z-0-11(25.0g, 69mmol) was dissolved in methanol (100mL) and dioxane hydrochloride solution (4M/L, 100 mL). The mixture was stirred at 70 ℃ for 18 h. After cooling to room temperature, spin-dry. A solution of ammonia in methanol (50mL) was slowly added to the residue (100mL) and spun dry at 40 ℃. The crude product was passed through a column (100-200 mesh silica gel) and the eluent was dichloromethane: methanol (10: 1) to give Z-0-12 as a gray solid (8.0g, yield: 38%). ESI-MS (M-H): 210.1, purity 90% (UV 214).

Step 11: compound Z-0-12(4.18g, 20mmol), Z-0-3(8.20g, 20mmol), potassium carbonate (8.28g, 60mmol) were dissolved in DMF (100mL) and the mixture was heated to 40 ℃ under nitrogen and stirred for 18 h. The reaction mixture was added with water (500mL), extracted with dichloromethane (200mL x3), and the combined organic phases were washed with water (100mL x2), washed with saturated brine (100x 2mL), dried over anhydrous sodium sulfate, and filtered with suction. Reduced pressure evaporation to dryness to obtain red solid Z-0-13(15.1g, yield > 100%). ESI-MS (M + H) +: 600.1, purity 28% (UV254).

Step 12: compound Z-0-13(12.0g, 20mmol) was dissolved in dichloromethane (40mL) and trifluoroacetic acid (20mL) was added. The mixture was stirred at room temperature for 24h under nitrogen. The crude product was evaporated to dryness under reduced pressure to give a yellow solid, which was prepared by HPLC to give off-white solid powder Z-0(3.04mg, yield:31%). ESI-MS (M + H) +: 499.8, purity 100% (UV254).¹H NMR(400MHz，DMSO)δ11.56(s，2H)，8.91(d，J＝2.4Hz，1H)，7.90(d，J＝6.8Hz，1H)，7.69(s，1H)，7.43(s，1H)，7.32(dd，J＝8.8，2.4Hz，1H)，7.22(dd，J＝8.4Hz，1H)，7.07(d，J＝2.0Hz，1H)，6.73(d，J＝10.8Hz，1H)，4.92(s，2H)。

Electrophysiological assay

Test example 1 Manual patch-Clamp experiments for the hNav1.7 and hNav1.5 channels

Patch voltage clamp electrophysiology can directly measure and quantify the current blockade of voltage-gated sodium channels (various navs) and can determine the time and voltage dependence of blockade, which has been explained as a binding difference to the resting, open and inactive states of sodium channels to reflect the inhibitory or activating effect of compounds (hill, b., Journal of General Physiology (1977), 69: 497-.

Representative compounds of the invention were tested using manual patch clamp experiments, and the aim of this study was to test the effect of compounds on the ion channel current on stable cell lines transfected with specific ion channels using manual patch clamp methods. The stable cell lines CHO-hNav1.7 and HEK-hNav1.5 used therein were from Genionics and Wuxi Aptecte, Shanghai, respectively.

The manual patch clamp experimental protocol was as follows:

preparing a solution and a compound: the hNav1.7 and hNav1.5 currents were recorded using whole-cell patch-clamp techniques. In the experiment, the composition (mM) of the extracellular fluid: HEPES (high efficiency particulate air): 5, NaCl: 40, KCl: 3, CaCl₂：1，MgCl₂：1，CdCl₂: 0.1, TEA-Cl: 20. adjusting pH value to 7.3 with NaOH, adjusting osmotic pressure to 310-320mOsm with sucrose, filtering, and storing at 4 deg.C. Composition of intracellular fluid (mM): HEPES (high efficiency particulate air): 10, NaCl: 10, CsOH: 5, CsF: 140, EGTA: 1. adjusting pH to 7.3 with CsOH, adjusting osmotic pressure to 280-290mOsm with sucrose, filtering, and storing at-20 deg.C.

Positive control and test compounds were first dissolved in 100% DMSO (Sigma-Aldrich, D2650, prepared as stock solutions at a concentration (100nM, 1000 nM.) the stock solutions were serially diluted with DMSO prior to the experiment and then further diluted with extracellular fluid to give test solutions at the desired concentration, the final concentration of DMSO in the extracellular fluid did not exceed 0.30%.

(II) manual patch clamp experiment: the cell suspension was taken in a 35mm petri dish and placed on an inverted microscope stage. After the cells adhere to the wall, the cells are perfused by extracellular fluid with the flow rate of 1-2 mL/min. The glass microelectrode is drawn by a microelectrode drawing instrument in two steps, and the water inlet resistance value of the glass microelectrode is 2-5M omega. Stimulation and signal acquisition are carried out through Digidata 1440(Molecular Devices) and pCLAMP software (10.2 edition, Molecular Devices) A/D-D/A digital-to-analog conversion; the signals were amplified by a patch clamp amplifier (multiclad 700B, Molecular Devices) and filtered at 4 KHz.

Two different voltage stimulation programs were used in the hNav1.7 and hNav1.5 manual patch clamp experiments.

One is a deactivation stimulation program, clamping the V with potential set in the corresponding channel_1/2I.e. about 50% of the channels are in an inactive state. Then a voltage was applied to-120 mV for 50 ms. Depolarized to-10 mV, and withdrawn sodium current for 20ms, and finally returned to the clamp potential. Such a stimulation program may also be referred to as a channel state dependent voltage stimulation program.

The other is a non-inactivating stimulation program, the clamping potential is kept at-120 mV, voltage stimulation is given to-10 mV, sodium current is led out for 20ms, and finally the clamping potential is returned. That is, under such stimulation program conditions, all channels have not experienced an inactivated state, but have been directly activated from a resting state.

The time interval of the two voltage stimulation programs is 10 s. The inhibitory effect of the compounds was calculated from the current change before and after dosing, and IC₅₀The values were fitted by the Hill equation. A compound is state-dependent on a channel if it exhibits a fold difference in channel effect under the two different voltage stimuli. The results are shown in tables 1 and 2, respectively.

TABLE 1 inhibition of Nav1.7 by representative compounds of the invention at two concentrations

TABLE 2 inhibition of Nav1.7 and Nav1.5 by representative compounds of the invention

TABLE 3 IC of representative compounds of the invention for Nav1.7 and Nav1.5₅₀Value of

Compound (I)	Nav1.7(IC₅₀/nM)	Nav1.5(IC₅₀/nM)	Nav1.5/Nav 1.7
				Z-4	30.62	5340	174
Z-22	5.17	600	116
				Z-23	24.6	2380	97
Z-41	6.66	4290	644
				Z-45	10.55	1530	145
Z-47	8.23	1500	182
				Z-67	5.95	10380	1745
Z-73	5.61	780	139
				Z-85	29.98	29120	971
Z-86	13.76	8360	608
				Z-97	14.35	3330	232

As can be seen from tables 1, 2 and 3, representative compounds of the present invention have high inhibitory activity against Nav1.7, and significantly weak inhibitory activity against Nav1.5, and thus have significant selective inhibitory activity against Nav1.7.

As can be seen from the table above, the different substitution positions on the pyrrole ring carbons have a significant effect on selectivity. The selectivity of the 2-substituted compound is much improved over that of the 3-substituted compound.

The difference of the substituent groups and the substituent positions on the nitrogen and carbon atoms on the four-membered, five-membered and six-membered (piperidine ring, piperazine ring) nitrogen-containing heterocycles have obvious influence on the inhibitory activity of Nav1.7, and research shows that when the nitrogen atom is not directly connected with the ring A (such as benzene ring or pyridine ring), namely the ring A (such as benzene ring or pyridine ring) is connected with the nitrogen atom through methylene, carbonyl and other groups, the inhibitory activity is obviously reduced; and the positions of the substituents (such as 2-position and 3-position) and substituents (such as-O-, -CH) on carbon atoms on the four-membered or six-membered nitrogen heterocyclic rings are found₂The difference of-O-) has a more obvious influence on the inhibitory activity.

Test example 2 pain model (formalin) test

The experimental animal is a male Wistar rat with the weight of 250 +/-30 g. The experimental animals were purchased from Beijing Wittiulihua laboratory animals GmbH, and bred in the barrier facility of Shanghai Ruizi chemical research GmbH (2-3 animals/cage, temperature 21.0 + -2 deg.C, humidity 40-70%, light control started from early morning at 5 o' clock, and period 12 h). The experiment was started at least 5 days after the animals were acclimated to the breeding environment.

Detection compound:

negative control: compound solvent, 5% DMAC (dimethylacetamide) + 5% Solutol (polyethylene glycol-12-hydroxystearate) + 90% physiological saline;

positive control drug 1: morphine (Mor), 5mg/kg group: 2ml/kg, i.p., n ═ 7;

positive control drug 2: HYC00012 (also known as compound Z-0), 10mg/kg group: 10ml/kg, p.o., n ═ 10;

the drug to be tested: compound Z-4.

Grouping:

negative control group (Veh): 10ml/kg, animal gavage (p.o.);

positive control drug 1: morphine (Mor-5 mpk): 2.5mg/ml, 2ml/kg, i.p.);

positive control drug 2: compound Z-0(Z-0-10 mpk): 1mg/ml, 10ml/kg, gavage animal (p.o.);

test drug groups:

10mg/kg group (Z-4-10 mpk): 1mg/ml, 10ml/kg, gavage animal (p.o.);

30mg/kg group (Z-4-30 mpk): 3mg/ml, 10ml/kg, gavage animal (p.o.);

150mg/kg group (Z-4-150 mpk): 15mg/ml, 10ml/kg, gavage animal (p.o.);

all drug solutions were prepared on the day of the experiment.

The experimental method comprises the following steps:

introduction to the Laboras System: LABORASTM System, purchased from METRIS, Netherlands. The experimental system comprises an experimental cage and a bottom plate. The experimental cage box is 880 square centimeters in area and 17.5 centimeters in height, consists of a top cover, food and a water bottle groove, is placed on a frame with adjustable height, and is 2-3 millimeters away from a bottom flat plate. The bottom plate is placed on a platform equipped with a vibro-susceptor. The animal behavior is transmitted to a computer through a vibration sensor, the behavior is automatically recorded and stored in a computer system, and computer software generates final experimental data by recognizing and analyzing the animal behavior original data.

2. Formalin acute pain model: 5%, 50 microliters of formalin solution was injected into the subcutaneous tissue of the rat's left hind paw and the Laboras system recorded the pain behavior (paw licking times and total time) of the animal after 60 minutes. The pain behavior of animals is divided into two phases:

positive control 1(Mor) was administered 10 minutes after the test compound Z-4, positive control 2, and compound solvent were administered to rats;

formalin was administered 25 minutes after the test compound Z-4, positive control 2, and compound solvent were administered to rats;

the first phase (phase I) represents the time from 25 minutes after the test compound Z-4, the positive control 2 and the compound solvent are administered to the rat (i.e., the time at which formalin injection is started) to 30 minutes (i.e., 5 minutes after formalin injection), i.e., 25-30min in fig. 1 and 3; corresponding to 0-5 minutes after formalin injection.

The second phase (phase II) represents the time period from 40 minutes after administration of test compound Z-4, positive control 2 and compound solvent to rats (i.e., 15 minutes after formalin injection) to 55 minutes (i.e., 30 minutes after formalin injection), i.e., 40-55min in fig. 1 and 3; corresponding to 15-30 minutes after formalin injection.

3. The animals are firstly adapted to the experimental environment, namely are put into an experimental cage box, are taken out after 60 minutes and are put back into a feeding cage box, and are adapted for 3 days continuously;

4. the compound solvent and the compound Z-4 are administrated 25 minutes before the subcutaneous injection of formalin, and morphine is administrated 10 minutes in advance;

5. starting a Laboras system immediately after the administration of the experimental animal, and starting recording;

6. the formalin solution is injected into the left hind paw subcutaneously and then the animal is quickly placed back into a Laboras experimental cage box, and the Laboras records the pain behavior (paw licking times and total time) of the animal for 60 minutes;

7. statistical analysis: data are expressed as mean ± sem, with statistically significant differences at P values less than 0.05 compared to negative solvent group data using Two way ANOVA test and unpaired t-test provided by the Graph pad Prism version 5.0 statistical analysis software package.

The graphs of the time-dependent change of the number of hind limbs licked by rats corresponding to the test compound in Two way ANOVA test and the area under the curves of the number of hind limbs licking by rats corresponding to the test compound in unpaired t-test are shown in fig. 1 and fig. 2, respectively.

The area under the curve of the time change graph of the time taken for the rat corresponding to the test compound in Two way ANOVA test to lick the hind limb and the time taken for the rat corresponding to the test compound in unpaired t-test to lick the hind limb are shown in fig. 3 and fig. 4, respectively, for each dose.

As can be seen from FIGS. 1 to 4, compound Z-4 inhibits pain behavior in rats in one and two phases in the formalin inflammation model, and has analgesic effect.

Test example 3 Cold stimulation allodynia method SNL

The experimental animals were male Sprague-Dawley rats weighing 140-. The experimental animals are purchased from Silik company, and after being purchased, food and water are supplied in a free feeding mode, the animals are raised in cages, 4 animals are placed in each cage, and the animals are marked by an animal tail marking method.

Test compounds and groups:

solvent group (Vehicle): 5% Dimethylacetamide (national medicine technology), 5% solutol (Sigma) and 90% physiological saline

Positive control: HYC00012 (also known as compound Z-0);

the drug to be tested: the compound Z-22, Z-40, Z-97, Z-85, Z-73;

the solvent components of the positive control and the drug to be tested are 5% of dimethylacetamide, 5% of solutol and 90% of normal saline.

Positive control and test substance were administered orally at a dose of 100mg/kg for 2 hours to inhibit cold allodynia caused by spinal nerve ligation in rats, as shown in Table 4

Table 4 Compound Chinese medicinal efficacy test group in spinal nerve ligation rats

100mg/kg compound Z-85: weighing 295.4mg of Z-85, adding 0.73mL of dimethylacetamide, adding 0.73mL of solutol after complete dissolution, shaking and uniformly mixing, adding 90% physiological saline to fix the volume to 14.54mL, and fully and uniformly mixing for oral administration.

100mg/kg of compound Z-73: 289.9mg of Z-73 is weighed, 0.71mL of dimethylacetamide is added, 0.71mL of solutol is added after complete dissolution, 90% physiological saline is added after shaking and mixing uniformly to fix the volume to 14.24mL, and oral administration is carried out after mixing uniformly and fully.

100mg/kg positive control: 278.6mg of positive control is weighed, 0.68mL of dimethylacetamide is added, 0.68mL of solutol is added after complete dissolution, 90% physiological saline is added after shaking and uniform mixing to fix the volume to 13.52mL, and oral administration is carried out after complete dissolution.

The experimental method comprises the following steps:

1.1. spinal nerve ligation model

The surgical procedure performs a sterile procedure.

Surgical instruments (scissors, forceps, scalpel, surgical cotton, suture, distractor) have been sterilized prior to surgery.

Animals were anesthetized with pentobarbital (50mg/kg, i.p.). The animal's toes were compressed to confirm that the animal had been completely anesthetized prior to surgery. Applying eye ointment on animal eyes to prevent cornea drying.

The hair of the lower body of the animal was shaved and the skin of the operation area was disinfected three times with iodophor and 70% ethanol. The operation is started after the skin is dry.

A longitudinal incision was made in the back of the sacrum at the waist of the animal using a scalpel, the left paraspinal muscles were exposed, and the muscle tissue was separated using a spreader to expose the vertebra.

Left spinal nerves L5 and L6 were isolated and ligated using 6-0 silk thread.

Suture wound.

Clean surgical instruments and sterilize using a hot bead sterilizer.

Post-surgery animals were placed on an electric blanket and injected subcutaneously with 5mL of saline to prevent dehydration. The animals were returned to their cages after they fully recovered (freely movable).

1.2. Baseline testing and grouping of cold allodynia

Two days prior to dosing, rats were subjected to a baseline test for cold allodynia and 100 μ l of acetone was applied to the skin of the hind paw on the operative side of the animal using a pipette. The time of the animal to pat, contract, raise, lick the affected foot was recorded within one minute. The acetone test was performed twice with a 10 minute interval. The sum of the two times was recorded as the cold allodynic hypersensitivity time of the rats. Animals were randomized according to the results of the cold allodynic hypersensitivity test the day prior to dosing.

1.3. Cold allodynia hypersensitivity test

Two hours after dosing, 100 μ l of acetone was applied to the skin of the hindtoe on the animal's side using a pipette. The time for the animal to flap, contract, raise, lick the affected foot within one minute was recorded. The acetone test was performed twice with a 10 minute interval. The sum of the two times was recorded as the cold allodynic hypersensitivity time of the rats.

1.4. Administration of drugs

Cold stimulation pain test was administered orally 2 hours prior to.

1.5. Data collection and analysis

Data were collected using Excel software. Data were analyzed using Prism software.

And (4) conclusion:

TABLE 5 rat cold allodynia test results (Z-22)

TABLE 6 rat cold allodynia test results (Z-73, Z-85)

TABLE 7 rat cold allodynia test results (Z-97)

TABLE 8 rat cold allodynia test results (Z-40)

The results are shown in FIG. 6, FIG. 8, FIG. 10 and FIG. 12, and show that the exemplary compounds Z-22, Z-40, Z-73, Z-85 and Z-97 of the present invention have the effect of inhibiting cold allodynia induced by rat spinal nerve ligation in rat models of spinal nerve ligation and the effect of statistically significant inhibition in rat models of in vivo neuralgia after 2 hours of oral administration.

In figure 6, compound Z-97 was shown to have efficacy in spina nerve-ligated rats, p < 0.001 compared to solvent group, using one-way anova with Dunnett's multiple comparison test. Compound Z-97 and positive control, 100mg/kg, were administered orally to inhibit cold allodynia induced by spinal nerve ligation in rats two hours each.

In figure 8, compound Z-40 inhibited the effect of cold-stimulated allodynia in the spinal nerve ligation rat model with p < 0.05 and p < 0.001 compared to the solvent group using a one-way anova plus Dunnett multiple comparison test. Compound Z-40 and positive control, 100mg/kg, were each administered orally to inhibit cold allodynia induced by spinal nerve ligation in rats two hours.

In figure 10, compound Z-73, 85, was shown to have efficacy in spina nerve-ligated rats, p < 0.01, p < 0.001 compared to the solvent group, using one-way variance analysis with an additional Dunnett multiple comparison test. Compound Z-73, 85 and positive control, 100mg/kg, were each administered orally to inhibit cold allodynia induced by spinal nerve ligation in rats two hours.

In figure 12 p < 0.01, p < 0.001 was compared to the solvent set, using one-way anova with an additional Dunnett multiple comparison test. Compound Z-22 and positive control, 100mg/kg, were each administered orally to inhibit cold allodynia induced by spinal nerve ligation in rats two hours.

Test example 4: in vivo test in rats

The LC/MS/MS method is used for measuring the drug concentration in the blood plasma of rats at different times after the rats are gavaged with the compound of the embodiment, researching the pharmacokinetic behavior of the compound in the rats and evaluating the pharmacokinetic characteristics of the compound.

The experimental scheme is as follows:

test animals: healthy adult male SD rats (weight 200-;

administration mode and dose: SD rats are administered by intragastric administration, and the administration dose and the concentration and the formula of oral solution are as follows:

TABLE 9

Blood sample collection: animals meeting experimental requirements are first selected before administration and weighed and labeled. Before blood sampling, rats were bound, and each dosed rat was bled at a predetermined bleeding time point (gavage: 0.083, 0.25, 0.5, 1, 2, 4, 8, 24h, total 9 time points before dosing, respectively, and after dosing), via the tail vein, at approximately 150 μ L. Blood transfer to Pre-addition K₂EDTA in 1.5mL tubes. The collected blood sample is placed on wet ice, centrifuged for 5min (2000g, 4 ℃), and plasma is taken out, and the whole process is completed within 15min after blood collection. All samples were stored in a-70 ℃ freezer until sample analysis.

The pharmacokinetic properties of the compounds of some examples of the invention in rats in the same administration mode were measured by LC/MS/MS method and are shown in Table 10:

TABLE 10 Compound pharmacokinetic parameters in rats

	Z-73	Z-85	Z-4	Z-97
					Tmax(hr)	2.0	1.0	0.5	0.83
Half-life T1/2(hr)	9.73	2.52	1.89	1.37
					Oral relative bioavailability F	90.3％	83.4％	66.1％	87.5％
Maximum blood concentration Cmax (ng/mL)	5695	2377	861	949
					Area under the curve AUC (hr. ng/mL)	67357	10878	1963	3190

As can be seen from table 10, the compounds of the present invention have good drug absorption, significant drug absorption effect, and good bioavailability. The compound has more excellent performance, can be administrated in lower dosage, and therefore has better safety or lower toxic and side effects.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A compound of formula (II), or a pharmaceutically acceptable salt thereof:

in the formula (I), the compound is shown in the specification,

R₁、R₃each independently is halogen, C_1-3Alkyl, or C_3-6A cycloalkyl group;

R₂、R₄is hydrogen;

R₅is hydrogen;

R₆is C_1-3An alkyl group;

is composed of

L₁Is- (CR)^yR^x)_r1(O)_r2(CR^yR^x)_r3-; wherein R is^y、R^xIs hydrogen; r1 is 0; r2 is 0; r3 is 1;

R₀is hydrogen;

a is phenyl(ii) a The phenyl is substituted or unsubstituted; and said substitution means that 1 to 5 hydrogens in the group are substituted with a substituent selected from the group consisting of: halogen, C_1-20Alkyl, halo C_1-20Alkyl, halo C_1-20Alkoxy radical, C_1-20Alkoxy radical, C_3-20Cycloalkyl and C_3-20A cycloalkoxy group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof,

R₁、R₃each independently is fluoro, chloro, methyl, ethyl, n-propyl, isopropyl or cyclopropyl;

R₆is methyl, ethyl, n-propyl or isopropyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a is phenyl; the phenyl is substituted or unsubstituted; and said substitution means that 1 to 5 hydrogens in the group are substituted with a substituent selected from the group consisting of: halogen, C_1-3Alkyl, halo C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy radical, C_3-6Cycloalkyl, and C_3-6A cycloalkoxy group.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the phenyl is

Wherein R is₁’、R₂’、R₃’、R₄’、R₅' are each independently hydrogen, fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, difluoromethoxy, methoxy, ethoxy, isopropoxy, or cyclopropyl.

5. A pharmaceutical composition comprising a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

6. Use of a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 5, in the manufacture of a medicament for treating a disease or condition selected from pain, depression, cardiovascular disease, respiratory disease, psychiatric disease, or a combination thereof.