CN107207430B - Heterocyclic substituted N-sulfonyl benzamide derivative, preparation method and medical application thereof - Google Patents

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 (II) 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 (II), 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;

L₁attached at any different position on the ring, a 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 heteroaryl ringA monocyclic ring, a benzo 3-to 7-membered monocyclic heterocycle, a 5-to 6-membered monocyclic heteroaryl ring and a 3-to 7-membered monocyclic ring, or a 5-to 6-membered monocyclic heteroaryl ring and a 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_6-20An aryl group;

and the number of the first and second electrodes,

selected from:

wherein, A, L₁、R₀As defined above.

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, 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 preferred embodiment, 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, L₁Is- (CR)^yR^x)_r1(O)_r2(CR^yR^x)_r3-; wherein R is^y、R^xEach independently is hydrogen; r1 is 1 or 2; r2 is 1; r3 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 above.

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 another preferred embodiment, W₂Is N.

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

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、R₀As defined above.

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 1; 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, halo C_1-20Alkoxy radicalBase, 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;

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; and/or

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, in the compounds represented by the formulas (II) to (V),

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(ii) a Wherein R is_a、R_bEach independently is hydrogen, C_1-20An alkyl group;

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, the phenyl is

Wherein R is₁’、R₂’、R₃’、R₄’、R₅' independently of each otherIs 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:

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.

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; and/or

R₆Is C_1-20Alkyl, -NR_aR_b(ii) a Wherein R is_a、R_bEach independently is hydrogen, or C_1-20An alkyl group.

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, 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 II in the examples.

In another preferred embodiment, the compounds of formula II according to the invention are each of the specific compounds mentioned in the examples section, in particular any of the compounds Z-22 to Z-168.

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 so forth, 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 the baseline cold pain test in rats of Compound Z-40 in the spinal nerve ligation rat model.

FIG. 2 shows the effect of Compound Z-40 in inhibiting cold-stimulated allodynia in a spinal nerve ligation rat model.

FIG. 3 shows the baseline cold pain test in rats of Compound Z-73 in the spinal nerve ligation rat model.

FIG. 4 shows the effect of Compound Z-73 in inhibiting cold-stimulated allodynia in a spinal nerve ligation rat model.

FIG. 5 shows the baseline cold pain test in rats of Compound Z-22 in the spinal nerve ligation rat model.

FIG. 6 shows the effect of compound Z-22 in inhibiting cold-stimulated allodynia in a rat model of spinal nerve ligation

FIG. 7 shows the baseline for the rat cold pain test in the spinal nerve ligation rat model for compounds Z-47 and Z-54.

FIG. 8 shows the effect of compounds Z-47 and Z-54 in inhibiting 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-dimethylhexylEthylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 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 "heterocyclyl" are used interchangeably and refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon radical, preferably a 3-to 20-membered heterocycloalkyl (meaning that the heterocycloalkyl 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 C_6-12Aryl, more preferably phenyl and naphthyl, most preferably phenyl.

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_3-20A cycloalkylthio group,3-to 20-membered heterocycloalkylthio, oxo, amino, C_1-20Hydroxyalkyl, carboxyl or carboxylate.

Preparation method

The present invention provides methods for preparing compounds of formula (II), 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 (II) of the present invention may be prepared by reference to the following synthetic routes, and the steps in the process may 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 (II), 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 (II), 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), the mixture was cooled to 0 deg.C 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 with petroleum ether (3 × 100 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), sodium sulfateDrying and spin-drying 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 100% (UV 214).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 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 n-BuLi (62.4ml, 2.4M/L, 248mmol) was added dropwise under nitrogen. 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: the compound13-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), and methylsulfonamide (9.12g, 96mmol) were 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 98.5% (UV 214).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 (2 × 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: to a 50ml single neck round bottom flask was added compound 22-a-2(552mg), hydrochloric acid (4M, 5ml, 20mmol), and 5ml of methanol, and stirred at room temperature overnight. After the reaction, the reaction solutionConcentration under reduced pressure gave compound 22-a (409mg) as a solid in 100% purity and 41% yield, MS m/z (ESI): 288[ M + H]⁺And directly used for the next reaction.

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, concentrating under reduced pressure, washing with salt water, extracting with ethyl acetate, drying and separating an organic phase, concentrating under reduced pressure to obtain a crude product, and purifying by Combi-flash column chromatography to obtain the compound 25-a (3g), wherein the purity is 85 percent, and the yield is 100％。MS m/z(ESI)：249[M+H]⁺。

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: to a 50ml sealed tube was added 4-bromo-2-chloro-1- (trifluoromethoxy) benzene (215mg, 0.781mmol), compound 7-a (117mg), 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), 7ml1, 4-dioxane, and 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 22-b (51.5mg), wherein the yellow oily compound is directly used for the next reaction, and the purity is 53%, the yield is 41%, and the MS m/z (ESI): 296[ M + H ]]⁺。

Step 2: a mixture of compound 22-b (148.6mg), 5-chloro-2, 4-difluoro-N- (methylsulfonyl) benzamide (107mg, 0.397mmol), cesium carbonate (260mg, 0.798mmol), 6ml dimethyl sulfoxide was stirred under microwave conditions at 220 ℃ 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-22(69mg) with the purity of 79%, the yield of 16.3%, and the mass ratio of 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).

Examples 23 to 25:

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.

Compound Z-28 was prepared by referring to the method of example 22, except that compound 7-a in step 1 was changed to (S) -pyrrolidin-2-ylmethanol.

Compound Z-29 was prepared by referring to the method of example 22, except that compound 7-a in step 1 was changed to (S) -pyrrolidin-2-ylmethanol and 4-bromo-2-chloro-1- (trifluoromethoxy) benzene was changed to 4-bromo-1, 2-dichlorobenzene.

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: to a 50ml single neck round bottom flask was added compound 14-a (644mg), 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 33-b (425mg) as a yellow solid, which was used directly in the next reaction in 100% yield.

Step 2: the preparation method of reference example 22, step 1, starting from compound 33-b (425mg) gave compound 33-c (520mg) as a yellow oil, purity 83.4%, yield 80.7%, MS m/z (ESI): 282[ M + H ]]⁺。

And step 3: to a single neck round bottom flask was added compound 33-c (288mg, 1.0225mmol), potassium tert-butoxide (344mg, 3.065mmol), THF10ml, 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 38 to 49:

compounds Z-38 to Z-41, Z-43, Z-44, Z-46, Z-47, Z-49 can be prepared by analogous methods to those of examples 22 to 33 of 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: using compound 50-b (119mg) as a starting material, according to the preparation method of step 2 in example 22, compound Z-50(52.17mg) was obtained as a white solid 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, 56, 58 to 59, 67 to 69, 71 to 72, 76, 79

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-56 was prepared by the method of example 50 starting with compound 7-a, except that 1-bromo-4- (trifluoromethoxy) benzene was changed to 4-bromo-2-chlorobenzonitrile in step 1, and the reaction conditions were changed to 140 ℃ and stirring was carried out for 30 minutes.

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-59 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 3-bromo-5-chloropyridine in step 1, and the reaction conditions were changed to 110 ℃ and stirring was carried out overnight.

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-68 was prepared by the method of example 50 starting with compound 7-a, except that 1-bromo-4- (trifluoromethoxy) benzene was changed to 4-bromo-1-chloro-2-fluorobenzene in step 1, and the reaction conditions were changed to 90 ℃ and stirred for 8 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 and Z-79 was prepared by starting from compound 7-a and following the procedure of example 50, except that 1-bromo-4- (trifluoromethoxy) benzene in step 1 was replaced with compound 23-a and 24-a, respectively, the reaction conditions were changed to 140 ℃ and stirring was carried out for 30 minutes, and the reaction conditions in step 2 were changed to 200 ℃ and stirring was carried out for 30 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: compound 22-b (504mg, 1.704mmol), p-toluenesulfonyl chloride (415mg, 2.045mmol), triethylamine (350mg, 3.239mmol), 4-dimethylaminopyridine (25mg, 0.17mmol) of dichloromethane 10ml, stirring 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 2 of example 22, 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 method was conducted in accordance with step 2 of example 22, 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), and tricyclohexyl was addedPhosphine (47.55mg, 0.17mmol), stirred 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 is finished, washing with 2N hydrochloric acid solution, washing with water, washing with salt water, drying, separating an organic phase, concentrating under reduced pressure to obtain a crude product, purifying by Combi-flash column chromatography to obtain a compound, adding ethyl acetate and petroleum ether, filtering, and washing with petroleum ether to obtain a 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. Cooling to room temperature after the reaction is finished, filtering, washing with ethyl acetate, decompressing and concentrating, adding ethyl acetate and petroleum ether, filtering, washing with petroleum ether, drying, and purifying by Combi-flash column chromatography to obtain the compoundThis gave compound 55-c (238mg) as a yellow solid. MS m/z (ESI): 241[ M-H]^-。

And step 3: starting from compound 22-b (100mg), the preparation process was carried out in accordance with step 2 of example 22, 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, sodium bicarbonate solution, sodium thiosulfate solution and dichloromethane are added for extraction, the organic phase is dried and separated, and crude yellow oily compound 57-b (575mg) is obtained by decompression and concentration. 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), triphenylphosphine (576mg, 2.189mmol) in toluene (5ml) under an argon shieldDiisopropyl azodicarboxylate (443mg, 2.189mmol) was added and stirred overnight at 60 ℃ under argon. 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: to a 50ml single neck round bottom flask was added 3-chloro-4- (trifluoromethoxy) benzoic acid (31g, 0.129mmol), compound 57-e (87mg), methanesulfonamide, HATU (2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate) (99mg, 0.260mmol), DIPEA (N, N-diisopropylethylamine) (56mg, 0.433mmol), dimethylformamide 3ml and stirred at room temperature overnight. And after the reaction is finished, adding 20ml of water, adjusting the pH value to be 4-5, extracting with ethyl acetate (20ml x3), separating an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain an oily substance (120mg), and separating and purifying a prepared liquid phase to obtain a yellow oily compound Z-57(19 mg). 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 81: preparation of (R) -5-chloro-N- (ethylsulfonyl) -2-fluoro-4- ((1- (4- (trifluoromethyl) phenyl) pyrrolidin-2-yl) methoxy) benzamide (Z-81)

Step 1: a mixed solution of compound 7-a (6.08g), 1-bromo-4- (trifluoromethyl) benzene (9g, 40mmol), 4, 7-dimethoxy-1, 10-phenanthroline (920mg, 8mmol), cuprous iodide (764mg, 4mmol), potassium carbonate (16.56g, 120mmol) in dimethyl sulfoxide (20ml) was stirred under argon protection at 140 ℃ for 30 minutes with microwave. 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 81-b as a yellow oil (3.98 g).

Step 2: starting from compound 81-b (956mg), according to the preparation method of step 3 in example 57, compound 81-c (1.1g) was obtained as a yellow oil, MS m/z (esi): 432.2[ M + H]⁺。

And step 3: using compound 81-c (1.1g) as a starting material and in accordance with the preparation method of step 4 in example 57, compound 81-d (0.84g) was obtained as a yellow oil, MS m/z (ESI): 398.1[ M + H]⁺。

And 4, step 4: using compound 81-d (100mg) and ethanesulfonamide (52mg) as starting materials, and referring to the preparation method in step b of compound 11-a, compound Z-81(50mg) was obtained as a white solid, MS m/Z (ESI): 509.2[ M + H]⁺。¹H NMR(DMSO-d6，400MHz)：＝7.72(d，J＝7.6Hz，1H)，7.42(d，J＝8.8Hz，2H)，6.96(d，J＝12.4Hz，1H)，6.78(d，J＝8.8Hz，2H)，4.23(br.s.，1H)，4.02-4.15(m，2H)，3.47(t，J＝8.8Hz，1H)，3.12-3.23(m，1H)，3.05(q，J＝7.2Hz，2H)，2.13-2.31(m，1H)，1.91-2.11(m，3H)，1.08ppm(t，J＝7.2Hz，3H).

Examples 121, 122, 126, 127, 135, 137, 141, 152, 153

Compounds Z-121, Z-122, Z-126, Z-127, Z-135, Z-137, Z-141, Z-152 and Z-153 were prepared starting from compound 7-a by a method similar to that for compound Z-81. Except that 1-bromo-4-chlorobenzene in step 1 was replaced with 5-bromo-2- (trifluoromethyl) pyridine, bromobenzene, 2-bromopyrimidine, 2-bromo-5-chloropyrimidine, 4 bromopyrimidine, 2-bromo-5- (trifluoromethyl) pyridine, respectively, and ethanesulfonamide in step 4 was replaced with methylsulfonamide or isopropanesulfonamide, respectively, according to the respective 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 2 of example 22, 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 to a solution of compound 63-c (130.5mg), 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 reaction mixture was cooled to room temperature, filtered, poured into water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was separated and purified by preparative liquid phase to give a white solid compound Z-63(12mg), 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 and 73

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.

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 2 of example 22, except that the reaction conditions were changed to 200 ℃ and stirring was carried out for 1 hour to give 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 2 of example 22, except that the reaction conditions in step (ii) were changed to 200 ℃ and stirring was carried out for 30 minutes, to give compound Z-66(33.06mg), MS m/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 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 118, 120, 123, 124, 143, 144, 154, 155, 167, 168

Compounds Z-118, Z-120, Z-123 to Z-124, 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 was used in step 1, methylsulfonamide or ethanesulfonamide, cyclopropanesulfonamide or isopropanesulfonamide, respectively, was used in step 4, and methylboronic acid or ethylboronic acid, isopropylboronic acid or cyclopropylboronic acid, respectively, was used in step 5, according to the respective structures.

Example 84

Compound Z-84 was synthesized by the method described in example 82, starting from compound 82-e, except that in step 5, phenylboronic acid was replaced with methylboronic acid and the reaction conditions were changed to 100 ℃ and the mixture was stirred under argon atmosphere for 4 hours.

Example 83: preparation of (R) -2-fluoro-N- (methylsulfonyl) -4- ((1- (4- (trifluoromethyl) phenyl) pyrrolidin-2-yl) methoxy) benzamide (Z-83)

Step 1: starting with compound 82-b (250mg), according to the procedure of example 573, except that compound 17-a in step (a) was changed to compound 25-a-1, and the reaction conditions were changed to room temperature and stirred for 2 hours, to give compound 83-c (373mg) as a yellow oil, MS m/z (esi): 398.2[ M + H]⁺。

Step 2: prepared by the method of step 4 of example 57, starting with compound 83-c (373mg), to give compound 83-d (354mg) as a white solid, MS m/z (esi): 384.2[ M + H]⁺。

And step 3: starting with compound 83-d (100mg), compound 83-d (49mg), methanesulfonamide (65mg, 0.181mmol), HATU (2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate) (99mg, 0.260mmol), DIPEA (N, N-diisopropylethylamine) (56mg, 0.433mmol), and dimethylformamide (3 ml) were added to a 50ml single-neck round-bottom flask and stirred at room temperature overnight. After the reaction is finished, adding 20ml of water, adjusting the pH value to 4-5, extracting with ethyl acetate (20ml x3), separating an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain an oily substance (120mg), and separating and purifying a prepared liquid phase to obtain a white solid compound Z-83(3.4mg), MS m/Z (ESI): 461.2[ M + H ]]⁺。

Comparative example 1: preparation of (R) -5-chloro-4- ((1- (4-chlorobenzoyl) pyrrolidin-2-yl) methoxy) -2-fluoro-N- (methylsulfonyl) benzamide (compound C1)

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 ℃ by microwave stirring for 20 minutes in accordance with the preparation method in step 2 of example 22, to obtain compound 77-b (375mg), MS m/z (esi): 351[ M + H-100 ]]⁺。

Step 2: to a 50ml single neck round bottom flask was added compound 77-b (169mg), hydrochloric acid (4M, 2ml, 8mmol), 3ml methanol, and stirred overnight with microwave at 40 ℃. After the reaction, the reaction mixture was concentrated under reduced pressure to give 77-c (54mg), MS m/z (ESI): 351[ M + H-36 ]]⁺Directly used for the next reaction step,

and step 3: to the direction ofA50 ml single neck round bottom flask was charged with 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 separated and purified by preparative liquid phase to give compound C1(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).

Comparative example 2: preparation of (R) -5-chloro-2-fluoro-N- (methylsulfonyl) -4- ((1- (4- (trifluoromethyl) benzoyl) pyrrolidin-2-yl) methoxy) benzamide (Compound C2)

Compound C2 was prepared starting from compound 77-C by the method of comparative example 1, except that 4-chlorobenzoic acid was replaced with 4- (trifluoromethyl) benzoic acid in step 3.

Comparative example 3: preparation of (R) -5-chloro-4- ((1- (4-chlorobenzyl) pyrrolidin-2-yl) methoxy) -2-fluoro-N- (methylsulfonyl) benzamide (C3)

Step 1: to a solution of compound 21-a (174mg) 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, drying to separate the organic phase, and concentration under reduced pressure to obtain compound 74-b (984mg) as a white solid.

Step 2: to a solution of compound 74-b (182mg) and triethylamine (259mg, 2.559mmol) in methanol (10ml) was added methanesulfonyl chloride (151mg, 1.919mmol) at 0 ℃ and stirred at room temperature for 3 hours. After the reaction, the reaction mixture was washed with brine, extracted with dichloromethane, and the organic phase was separated by drying and concentrated under reduced pressure to give 74-c (265mg) as a yellow oily compound.

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 from compound 74-e (97mg), according to the preparation method of step b of compound 11-a, compound C3(21.04mg), 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)

Comparative example 4: preparation of (R) -4- ((1- (4- (trifluoromethyl) benzyl) pyrrolidin-2-yl) methoxy) -5-chloro-2-fluoro-N- (methylsulfonyl) benzamide (C4)

Compound C4 was prepared starting from compound 4- (trifluoromethyl) benzaldehyde by the method of comparative example 3.

Preparation of Positive control drug 2(Z-0)

Step 1: compound Z-0-1(20.0g, 155mmol) was dissolved in t-butanol (150mL) and cooledThen, the mixture was cooled to 0 ℃ and diphenyl phosphorazidate (47g, 170mmol) and triethylamine (17.3g, 170mmol) were added thereto 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 dichloromethaneTo an alkane (400mL), then thionyl chloride (50mL) was added. The mixture was heated to reflux with nitrogen 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 (200X2 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 (400x2mL), the combined organic phases washed with water (200x2mL), 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 (100X2mL), 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 to ice water (100mL), the aqueous phase was separated, the organic phase was washed with saturated brine (100X2mL), 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 x 2), washed with saturated brine (100x2mL), 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. Reduced pressure steamingThe crude product was dried to give a yellow solid, and prepared by HPLC as 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 inhibitory Selectivity of representative compounds of the invention for Nav1.7 and Nav1.5

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-22	5.17	600	116
Z-23	24.6	2380	97
				Z-41	6.66	4290	644
Z-47	8.23	1500	182
				Z-67	5.95	10380	1745
Z-73	5.61	780	139

As can be seen from Table 2, the different substitution positions on the pyrrole ring carbons have a clear effect on selectivity. The selectivity of the 2-substituted compound is much improved over that of the 3-substituted compound. Meanwhile, research shows that when the nitrogen atom is not directly connected with the A ring (such as a benzene ring or a pyridine ring), namely the A ring (such as a benzene ring or a pyridine ring) is connected with the nitrogen atom through a methylene group, a carbonyl group or other groups, the inhibition activity is obviously reduced.

As can be seen from Table 3, representative compounds of the present invention (e.g., Z-22, Z-23, Z-41, Z-47, Z-67, Z-73) have a high inhibitory activity against Nav1.7, a significantly weaker inhibitory activity against Nav1.5, and thus a significantly selective inhibitory activity against Nav1.7.

Test example 2 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-47, Z-54, 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 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 Z-0: 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)

TABLE 7 rat cold allodynia test results (Z-40)

TABLE 8 rat cold allodynia test results (Z-47, Z-54)

The experimental results are as follows: in comparison with FIGS. 1, 3, 5 and 7, as shown in FIGS. 2, 4, 6 and 8, exemplary compounds Z-40, Z-73, Z-22, Z-47 and Z-54 of the present invention had inhibitory effects on rat spinal nerve ligation-induced cold allodynia in rat models of spinal nerve ligation and statistically significant inhibitory effects in rat in vivo neuropathic pain models after oral administration for 2 hours.

In figure 2, compound Z-40 inhibited the cold-stimulated allodynic effect in the spinal nerve ligation rat model with p < 0.05 and p < 0.001. Compared to the solvent group, one-way anova was used with Dunnett's multiple comparison test attached. 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 4, compound Z-73 was shown to have efficacy in spina nerve-ligated rats, # p < 0.01, # p < 0.001 compared to the solvent group, using one-way anova with an additional Dunnett multiple comparison test. Compound Z-73 and positive control, 100mg/kg, were administered orally to inhibit cold allodynia induced by spinal nerve ligation in rats two hours each.

In figure 6, p < 0.001 was compared to the solvent group, 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.

In figure 8, compounds Z-47 and Z-54 were tested for efficacy in spina nerve-ligated rats, p < 0.05, p < 0.01, p < 0.001 in comparison to the solvent group, using a one-way anova plus Dunnett's multiple comparison test. Z-47, Z-54 and positive control 100mg/kg were taken orally to inhibit cold allodynia induced by spinal nerve ligation in rats two hours respectively.

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

Note: the compound C5 is prepared similarly to compound Z-22, and has the following structural formula:

blood sample collection: animals meeting experimental requirements are first selected before administration and weighed and labeled. Before blood sampling, the rats were bound and each dose was administeredRats were bled at predetermined blood sampling time points (gavage: 0.083, 0.25, 0.5, 1, 2, 4, 8, 24h blood collection before administration, respectively, and 9 time points total) 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	C5
			Tmax(hr)	2.0	0.5
Half life T1/2(hr)	9.73	1.89
			Oral relative bioavailability F	90.3％	66.1％
Maximum blood concentration Cmax(ng/mL)	5695	861
			Area under the curve AUC (hr. ng/mL)	67357	1963

As can be seen from table 10, the compound of the present invention has good absorption, significant absorption effect, and better bioavailability (better than the control compounds such as C5). The compound of the present invention represented by Z-73 has more excellent properties and can be administered at a lower dose, and therefore, is more safe or has less 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 (8)

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 hydrogen, CN, halogen, C_1-3Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, or C_1-3An alkoxy 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^xEach independently is hydrogen or C_1-3An alkyl group; r1 is 1; r2 is 1; r3 is 0;

R₀is hydrogen;

a is phenyl; the phenyl is substituted or unsubstituted; 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.

2. 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.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is₁Is- (CR)^yR^x)_r1(O)_r2(CR^yR^x)_r3-; wherein R is^y、R^xEach independently is hydrogen; r1 is 1; r2 is 1; r3 is 0.

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

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

R₆is methyl, ethyl, n-propyl or isopropyl.

5. 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, propoxy, isopropoxy, cyclopropyl, or cyclopropyloxy.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

7. a pharmaceutical composition comprising a compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

8. Use of a compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 7, 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.

Images