CN114437062A

CN114437062A - Compound capable of being used as sodium channel regulator and application thereof

Info

Publication number: CN114437062A
Application number: CN202110476034.8A
Authority: CN
Inventors: 刘冠锋; 任俊峰; 易守兵; 张国彪; 杜楠; 李彭武; 原晨光; 李英富
Original assignee: Shenzhen Haibowei Pharmaceutical Co ltd; Chengdu Haibowei Pharmaceutical Co ltd
Current assignee: Shenzhen Haibowei Pharmaceutical Co ltd; Chengdu Haibowei Pharmaceutical Co ltd
Priority date: 2020-04-30
Filing date: 2021-04-29
Publication date: 2022-05-06

Abstract

The invention discloses a compound capable of being used as a sodium channel regulator and application thereof, wherein the compound has obvious inhibiting and blocking effects on the activity of a voltage-gated sodium ion channel subtype Nav1.8 ion channel, can be used as a Nav1.8 specific inhibitor, can be used for preparing medicaments for treating diseases such as Nav1.8 mediated intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, multiple sclerosis, summer-horse-Tourette syndrome, incontinence, arrhythmia and the like, and has wide application prospect.

Description

Compound capable of being used as sodium channel regulator and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a compound used as a voltage-gated sodium ion channel subtype Nav1.8 specific inhibitor and application thereof.

Background

With the coming of the global aging society, the range of the influence of chronic pain diseases is gradually expanded, and more than one third of people in the world suffer from chronic pain; in addition, cancer will eventually become a chronic disease, cancer pain will accompany the patient for a long time, and more than half of cancer patients in China have been reported to have not received cancer pain treatment. Pain is a mechanism for self-protection of animals or human bodies, however, many persistent pains exceed the usefulness of the pain, great pains are brought to the physical or mental health of patients, the treatment of pain is an important factor for improving the life quality of patients, and the market prospect is very huge.

In 2005, the total number of analgesic markets worldwide was over 800 billion dollars, and the sales of prescribed drugs were about 200 billion dollars. According to statistical estimates of the National Institutes of Health (NIH), up to 2500 million people in the united states struggle against pain each day, with 2300 million adults suffering from severe pain. However, abuse of opioid analgesics has caused a dramatic impact on society, and it is estimated by the WHO that 6.9 million people die of opioid overdose every year worldwide, and 1500 million people depend on opioid (i.e., opioid addiction), and the importance of developing new safe and effective analgesics is self-evident.

The inward current of voltage-gated sodium ion channels (Nav) is an important link in the generation and conduction of action potentials in central and peripheral neurons, while increased neuronal excitability or increased responsiveness to stimuli is an important mechanism for the development of various pain generations. Thus, the role of voltage-gated sodium ion channels in pain transduction pathways, particularly in peripheral sensory neurons, has been a focus of pain research.

The human sodium ion channels are 9, Nav1.1-Nav1.9, Nav1.5, Nav1.8 and Nav1.9 are tetrodotoxin (TTX) insensitive sodium channels, wherein Nav1.8 is an important ion channel participating in chronic pain, atrial fibrillation and Bulgar syndrome, and is a high-selectivity action target point for treating pain. Nav1.8 is mainly expressed in small diameter pain sense neurons, involved in sensory neurons action potential and rhythm discharge. Nav1.8 is under the regulation of inflammatory mediators, and the expression of the Nav1.8 is up-regulated in a sciatic nerve injury model, and gene knockout and silencing studies of Nav1.8 show that the Nav1.8 is involved in the regulation of neuropathic and inflammatory pain. Since Nav1.8 is primarily localized to pain-sensing neurons, selective Nav1.8 blockers are unlikely to induce adverse effects common to non-selective Nav blockers. Therefore, specific inhibitor screening research aiming at Nav1.8 pain target has been the focus in pain field, however, the known Nav inhibitors mainly have the defects of poor therapeutic window band, and the like, which is probably caused by the lack of subtype selectivity.

Currently known Nav1.8 inhibitors include PF-01247324, A803467, PF-06305591, and VX 150. Among them, the first three compounds are terminated in preclinical stage due to problems of poor selectivity, poor pharmacokinetic data, low bioavailability, etc. VX-150 is currently in the second clinical stage and has reached its primary clinical endpoint in clinical studies including post-operative acute pain, osteoarthritic chronic pain, and neuropathic pain. The VX-150 has good tolerance and no serious adverse reaction. The FDA has granted VX-150 a breakthrough therapy for the treatment of moderate to severe pain. However, the activity of VX-150 is expected to be further improved when the clinical dosage is as large as 1500mg for the first dose and then 750 mg every 12 hours. Meanwhile, the dissolution and absorption of the compound have a great problem, and although the problem is partially solved by a prodrug method, the prodrug method is still not ideal.

Therefore, the development of higher affinity, high specificity and better pharmacokinetics Nav1.8inhibitors has great social and economic value.

Disclosure of Invention

The invention mainly solves the technical problem of providing a compound which has strong selective inhibition effect on Nav1.8.

In order to solve the technical problems, the invention adopts a technical scheme that:

the invention relates to a compound which has a structure shown in a formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form, a pharmaceutically acceptable hydrate, a solvate or a salt thereof:

wherein:

A₁、A₂are each independently selected from CR₇Or N, or A₁、A₂The atoms connected with the substituted or unsubstituted C3-C10 naphthenic base, substituted or unsubstituted 3-10 membered heterocyclic alkyl, substituted or unsubstituted C3-C10 aryl and substituted or unsubstituted 3-10 membered heteroaryl;

R₇independently at each occurrence, is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ester, amide, sulfonyl, boronic acid, boronic ester, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;

q is selected from substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted 3-15 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the substituent is selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester group, amide group, guanidine group, acyl guanidine group, carbamido, aryl, heteroaryl, sulfonyl, boric acid group, borate group, phosphoryl group and imino;

w is selected from the group consisting of a bond, CR₈R₉、O、NR₁₀Carbonyl group, C (O) NR₁₁、C(S)NR₁₂、S(O)、S(O)NR₁₃、 S(O)₂、S(O)₂NR₁₄The connecting end of W and Q is not limited; r₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄Are respectively and independently selected from hydrogen or C1-C6 alkyl;

R₁、R₂each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, andsubstituted OR unsubstituted heteroalkyl, substituted OR unsubstituted heterocycloalkyl, OR₁₅、NR₁₆R₁₇、C(O)R₁₈、SR₁₉Hydroxy, cyano, amino, ester, amide, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, sulfonyl, or R₁、R₂And the atoms connected with the compound form substituted or unsubstituted C3-C10 naphthenic base, substituted or unsubstituted 3-10 membered heterocyclic alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R₁₅、R₁₆、R₁₇、R₁₈、R₁₉selected from hydrogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxyl, amido, sulfonyl, wherein the substituents are selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, sulfonyl, boronic acid, boronic ester, phosphoryl, alkenyl, alkynyl;

A₁、A₂、R₇、R₁、R₂wherein said substituted substituents are each independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, sulfonyl;

the cycloalkyl or heterocycloalkyl group is a monocyclic, bicyclic, tricyclic, bridged, or spiro ring structure.

Further, W is selected from the group consisting of a bond, C (O) NR₁₁、C(S)NR₁₂、S(O)NR₁₃、S(O)₂NR₁₄。

Further, R₁Selected from hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted cycloalkyl, substituted OR unsubstituted heteroalkyl, substituted OR unsubstituted heterocycloalkyl, OR₁₅、NR₁₆R₁₇、C(O)R₁₈、SR₁₉Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or R₁、R₂And the atomic composition to which they are attachedSubstituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, wherein the substituted substituent is selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino;

R₂is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, wherein the substituents are independently selected from halogen, alkyl, heteroalkyl, hydroxy, cyano, amino;

R₁₅、R₁₆、R₁₇、R₁₈、R₁₉is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, cyano, amino, ester, amide, alkenyl, and alkynyl.

Further, R₁Selected from OR₁₅、NR₁₆R₁₇、C(O)R₁₈、SR₁₉Or R is₁、R₂And atoms connected with the compound form substituted or unsubstituted C3-C6 naphthenic base, substituted or unsubstituted 3-6 membered heterocyclic alkyl, wherein the substituted substituent is selected from halogen, alkyl, naphthenic base, heteroalkyl, heterocyclic alkyl, hydroxyl, cyano and amino;

R₂selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, wherein the substituents are selected from halogen, alkyl, heteroalkyl, hydroxy, cyano, amino;

R₁₅、R₁₆、R₁₇、R₁₈、R₁₉is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the substituent is selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, cyano, amino, ester group, amido, alkenyl, alkynyl.

Further, the compound of the present invention is a compound having a structure represented by formula II or III, or an isomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt thereof:

wherein R is₃、R₄Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, sulfonyl, boronic acid, borate, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, wherein the substituent is selected from halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 heteroalkyl, cyano, ester, amide, aryl, heteroaryl, sulfonyl;

q is selected from substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, wherein the substituent is selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester group, amide group, guanidino, acyl guanidino, ureido, aryl, heteroaryl, sulfonyl, boronic acid group, boronic ester group, phosphoryl group and imino;

x is selected from O, S, NR₂₀Carbonyl group, CR₂₁R₂₂；

R₂₀、R₂₁、R₂₂Are respectively and independently selected from hydrogen, hydroxyl and alkyl of C1-C6;

A_rselected from substituted or unsubstituted aryl, substituted or unsubstituted N-containing heteroaryl, wherein the substituent is selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, cyano, amino, ester, amido, alkenyl, alkynyl.

Further, Q is selected from substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted N-containing heteroaryl, wherein the substituent is selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester group, amide group, guanidine group, acyl guanidine group, urea group, aryl group, heteroaryl, sulfonyl, boronic acid group, boronic ester group, phosphoryl group, imino group, or two adjacent substituents together form C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl group, heteroaryl group, diimide ring, lactam ring, sultam ring, boronic acid lactone ring;

further, Q is selected from the group consisting of substituted or unsubstituted:

phenyl, 2-pyridonyl, pyridyl, pyrimidyl, imidazolyl, 2-pyrimidonyl, 2-pyridoimidazolyl, cyclohexyl and valerolactam.

Further, X is selected from O, S, CR₂₁R₂₂A carbonyl group; r₂₁、R₂₂Are respectively and independently selected from hydrogen, hydroxyl and alkyl of C1-C6;

ar is selected from substituted or unsubstituted phenyl, wherein the substituent is selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, cyano, amino, ester, amido, alkenyl, alkynyl;

further, X is selected from O, S.

Further, the compounds of the present invention have the structure shown in formula IV or a tautomer, mesomer, ectomer, enantiomer, diastereomer or mixture form, pharmaceutically acceptable hydrate, solvate or salt thereof:

wherein R is₃、R₄Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxy, cyano, amino, ester, amide, sulfonyl, boronic acid, boronic ester, phosphoryl, substituted or unsubstituted alkeneThe substituent is selected from halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 heteroalkyl, cyano, ester group, amido, aryl, heteroaryl and sulfonyl.

Q is selected from the following substituted or unsubstituted groups:

phenyl, 2-pyridonyl, pyridyl, pyrimidyl, imidazolyl, 2-pyrimidonyl, 2-pyridoimidazolyl, cyclohexyl, valerolactam, indazole, benzo [ d ] isoxazole, imidazo [1,2-a ] pyridine, imidazo [1,5-a ] pyridine, [1,2,4] triazolo [4,3-a ] pyridine, wherein the substituents are selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, guanidino, ureido, aryl, heteroaryl, sulfonyl, sulfonamide, boronic acid, boronic ester, phosphoryl, imino, or two adjacent substituents together form a C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl, diimide ring, lactam ring, or a mixture thereof, Internal sulfonamide rings, boronic acid lactone rings.

R₅Independently at each occurrence, is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxyl, cyano, amino, ester, amide, alkenyl, alkynyl, wherein the substituents are selected from deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, hydroxyl, cyano, amino;

n is an integer of 1 to 5.

Further, the compounds of the present invention have the structure shown in formula V or VI or VII or formula VIII or IX or X or XI, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable hydrate, solvate or salt thereof:

A₃、A₄、A₅、A₆each independently selected from C, CR₃₈、N、NR₃₉Or O, and A₃、A₄、A₅、A₆At least one of which is selected from N, NR₃₉Or O.

R₃₇、R₃₈、R₃₉Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxyl, cyano, amino, ester, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acyl guanidino, substituted or unsubstituted guanidino, urea, aryl, heteroaryl, sulfonyl, borate, substituted or unsubstituted phosphoryl, alkenyl, alkynyl, substituted or unsubstituted imine, wherein the substituents are selected from C1-C6 alkyl, C1-C6 heteroalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heteroaryl, halogen, hydroxyl, cyano, amino, ester, amide, sulfonamide, guanidino, acyl guanidino.

Further, the air conditioner is provided with a fan,

selected from the group consisting of:

preference is given to

Further, R₃₇Selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, ester, acyl, carboxy, amide, sulfonyl, sulfonamide, boronic acid, borate, ester, carboxyl, amide, sulfonyl, sulfonamide, boronic acid, ester, carboxylic acid, amide, sulfonic acid, ester, sulfonic acid,Phosphoryl, wherein the substituent is selected from halogen, hydroxyl, amino, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cyano, ester, acyl, carboxyl, amido, aryl, heteroaryl, sulfonyl, sulfonamide.

Further, R₃₇Selected from hydrogen, halogen, hydroxyl, cyano, amino, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, ester, acyl, carboxyl, amide, wherein the substituent is selected from halogen, hydroxyl, amino, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cyano, ester, acyl, carboxyl, amide, sulfonyl, sulfonamide.

Further, R₃₇Selected from hydrogen, hydroxyl, amino, carboxyl and amido, preferably amino and amido.

R₃、R₄Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxy, cyano, amino, ester, acyl, amide, sulfonyl, boronic acid, boronic ester, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R of formula V or VI₃、R₄At least one of them is one of substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl, and R of formulas VIII and IX₃、R₄At least one of the substituent groups is one of substituted or unsubstituted naphthenic base, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl, wherein the substituent group is selected from halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 heteroalkyl, cyano, ester group, amido, aryl, heteroaryl and sulfonyl;

said "R of formula V or VI₃、R₄When at least one of the alkyl groups is one of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, and a substituted or unsubstituted alkynyl group, "the formula: r in the formula V₃、R₄With at least one being substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkeneOne of the radicals, substituted or unsubstituted alkynyl, R in the formula VI₃、R₄At least one is one of substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; the same applies to the rest of similar cases.

Further, R₃、R₄Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, ester, acyl, amide, sulfonyl, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R of formula V or VI₃、R₄At least one of them is one of substituted or non-substituted cycloalkyl, substituted or non-substituted alkenyl, substituted or non-substituted alkynyl, and R of formula VIII and IX₃、R₄At least one of the substituent groups is one of substituted or unsubstituted naphthenic base, alkenyl and alkynyl, wherein the substituent group is selected from halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 heteroalkyl, cyano, ester group, amide group, aryl, heteroaryl and sulfonyl.

Further, R₃、R₄Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, acyl, amido, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R of formula V or VI₃、R₄At least one of R is one of substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R is of the formula VIII or IX₃、R₄At least one of the substituent groups is one of substituted or unsubstituted naphthenic base, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl, wherein the substituent group is selected from halogen, hydroxyl, amino, C1-C6 alkyl and C1-C6 heteroalkyl.

Further, R₃、R₄Are respectively and independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl and substituted or unsubstituted heteroalkylA group, a substituted or unsubstituted N-containing heterocycloalkyl, acyl, amido, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R of formula V or VI₃、R₄At least one of them is one of substituted or non-substituted cycloalkyl, substituted or non-substituted alkenyl, substituted or non-substituted alkynyl, and R of formula VIII and IX₃、R₄At least one of the substituent groups is one of substituted or unsubstituted C3-C6 naphthenic base, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl, wherein the substituent group is selected from halogen, hydroxyl, amino, C1-C6 alkyl substituted or unsubstituted by halogen and C1-C6 heteroalkyl.

Further, R₃、R₄Each independently selected from hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted cyclopropyl, cyclopentyl, substituted or unsubstituted alkoxy, substituted or unsubstituted N-containing heterocycloalkyl, acyl, amido, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R of formula V or VI₃、R₄Each having at least one of substituted or unsubstituted cyclopropyl, cyclopentyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R of formulas VIII and IX₃、R₄At least one of the R, R and R is one of substituted or unsubstituted cyclopropyl, cyclopentyl, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl₃、R₄Not H at the same time.

Further, R₃、R₄Each independently selected from hydrogen, halogen, trifluoromethyl, pentafluoroethyl, substituted or unsubstituted cyclopropyl, cyclopentyl, substituted or unsubstituted heteroalkyl, acetyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, trifluoromethyl, cyclopentyl, substituted or unsubstituted heteroalkyl, acetyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyclopentyl, or substituted or unsubstituted heteroalkyl, acetyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyclopentyl, or substituted or unsubstituted alkynyl,

And R of formulae VIII and IX₃、R₄At least one of the compounds is one of substituted or unsubstituted cyclopropyl, cyclopentyl, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl, R₃、R₄Not H at the same time;

the substituted or unsubstituted cyclopropyl is:

R₃₁selected from hydrogen, halogen, hydroxyl, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, wherein the substituent is selected from alkyl and halogen; a is an integer of 0-5;

the substituted or unsubstituted alkenyl is:

the substituted or unsubstituted alkynyl is:

R₃₂、R₃₃、R₃₄、R₃₅are respectively and independently selected from hydrogen, halogen and alkyl of C1-C6.

Further, R₃₁Selected from hydrogen, halogen, hydroxyl, amino, C1-C3 alkyl substituted or not by 0-3 halogens, and C1-C3 alkoxy substituted or not by 0-3 halogens; a is an integer of 0 to 3;

R₃₂、R₃₃、R₃₄、R₃₅are respectively and independently selected from hydrogen, halogen and alkyl of C1-C3.

Further, R₅Independently at each occurrence, is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxyl, cyano, amino, ester, amido, alkenyl, alkynyl, wherein the substituents are selected from deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, hydroxyl, cyano, amino, sulfonamide;

said "R" of the present invention₅Independently selected for each occurrence "means when defining R₅Number ofWhen n is greater than 1, different R₅May be selected from the same or different groups. For example, n is 2, one R₅May be selected from substituted or unsubstituted alkyl, another R₅May be selected from halogens; or, n is 2, two R₅May each be selected from substituted or unsubstituted alkyl groups; the same applies to the rest of similar cases.

Further, R₆Independently at each occurrence, is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxy, cyano, amino, ester, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acyl guanidino, substituted or unsubstituted guanidino, urea, aryl, heteroaryl, sulfonyl, boronic acid, boronic ester, substituted or unsubstituted phosphoryl, alkenyl, alkynyl, substituted or unsubstituted imine, or two adjacent R₆The compound is a substituted or unsubstituted C3-C10 naphthenic base, substituted or unsubstituted 3-10 membered heterocyclic alkyl, a lactam ring, a sultam ring, a boric acid lactone ring, an aryl and a heteroaryl, wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heteroaryl, halogen, hydroxyl, cyano, amino, ester group, amido, sulfonamide, guanidino and acyl guanidino;

m and n are respectively independently selected from integers of 1-5.

Further, R₆Independently at each occurrence, is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxy, cyano, amino, ester, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acyl guanidino, substituted or unsubstituted guanidino, urea, aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted imine, sulfonyl, boronic acid, boronic ester, substituted or unsubstituted phosphoryl, or two adjacent R₆Jointly form an internal imide ring, a lactam ring, a sultam ring and boric acidA lactone ring, wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heteroaryl, halogen, hydroxyl, cyano, amino, ester, amide, sulfonamide and guanidino;

m is an integer of 1-3, and n is 1 or 2.

Further, R₆Independently at each occurrence, is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted imine, hydroxyl, ester, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acyl guanidino, substituted or unsubstituted guanidino, urea, sulfonyl, borate, substituted or unsubstituted phosphoryl, or two adjacent R₆The compound is a lactam ring, a sulflactam ring and a boric acid lactone ring, wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heteroaryl, halogen, hydroxyl, cyano, amino, ester group, amide group, sulfonamide group and guanidino;

m is an integer of 1-3, and n is 2.

Further, R₆Independently at each occurrence, is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, boronic acid, boronic ester, hydroxyl, ester, or from substituted or unsubstituted:

R₂₇、R₂₈、R₂₉、R₃₀each independently selected from hydrogen, alkyl, heteroalkyl, cyano, acyl, or R₂₇And R₂₉And the atoms to which they are attached form a 3-to 10-membered heterocycloalkyl, or R₂₈And R₃₀And the atoms to which they are attached form a 3-to 10-membered heterocycloalkyl group, or R₂₇And R₂₈And atoms to which they are attachedConstituting a 5-membered heteroaryl group, Y being selected from a bond, CH₂、C(O)、 -CH₂NH-、-C(O)NH-、-CH＝N-、-S(O)₂-、-CH₂O-；R₃₆Is selected from-NH₂、-CH₂NH₂、

Or two adjacent R₆Together form the following substituted or unsubstituted groups:

wherein, the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxyl, cyano, amino, ester, amido and guanidyl.

The order of the attachment of the two attachment sites to the benzene ring is not limited, e.g.

After substitution, can be

Structure, can also be formed

The structure and the like of the structure are the same.

In a particular embodiment of the present invention,

can be selected from the following substituted or unsubstituted groups:

further, R₆Independently at each occurrence, selected from hydrogen, halogen, andsubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, boronic acid, boronic ester, hydroxyl, ester, or substituted or unsubstituted groups as follows:

or two adjacent R₆Together form substituted or unsubstituted

Wherein, the substituent is selected from alkyl of C1-C6, heteroalkyl of C1-C6, halogen, hydroxyl, cyano-group, amino-group, ester-group, amido-group and guanidyl group.

Further, R₆Independently at each occurrence, is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, boronic acid, boronic ester, hydroxyl, ester, or substituted or unsubstituted:

wherein, the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxyl, cyano, amino, ester group, amido group and guanidyl.

Further, Y is selected from a bond, CH₂、C(O)、-CH₂NH-、-CH＝N-、-S(O)₂-、-CH₂O-, preferably a bond, c (O), -CH ═ N-.

Further, R₂₇、R₂₈、R₂₉、R₃₀Each independently selected from hydrogen, alkyl, heteroalkyl, cyano, acyl, or R₂₇And R₂₉And the atoms to which they are attached form a 3-to 10-membered heterocycloalkyl group, or R₂₈And R₃₀And the atoms to which they are attached form a 3-to 10-membered heterocycloalkyl, or R₂₇And R₂₈And the atoms to which they are attached form a 5-membered heteroaryl group.

Further, R₂₇、R₂₈、R₂₉、R₃₀Each independently selected from hydrogen, alkyl, heteroalkyl, cyano, acyl, or R₂₇And R₂₉And the atoms to which they are attached form a 4-to 6-membered heterocycloalkyl group, or R₂₈And R₃₀And the atoms to which they are attached form a 4-to 6-membered heterocycloalkyl, or R₂₇And R₂₈And the atoms to which they are attached form a 5-membered heteroaryl group.

Further, R₂₇、R₂₈、R₂₉、R₃₀Each independently selected from hydrogen, alkyl, heteroalkyl, cyano, acyl, or R₂₇And R₂₉And the atoms to which they are attached form a 4-to 6-membered heterocycloalkyl group.

Further, R₂₇、R₂₈、R₂₉、R₃₀Are respectively and independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, cyano, or R₂₇And R₂₉And the atoms to which they are attached form a 4-to 6-membered heterocycloalkyl group.

In a particular embodiment of the present invention,

can be selected from the following substituted or unsubstituted groups:

further, the air conditioner is provided with a fan,

selected from the following substituted or unsubstituted groups:

further, the air conditioner is provided with a fan,

selected from the following substituted or unsubstituted groups:

Further, R₂₃、R₂₄Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxyl, cyano, amino, ester, amide, alkenyl, alkynyl, wherein the substituents are selected from deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, hydroxyl, cyano, amino, amide.

Further, R₂₃、R₂₄Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxyl, cyano, amino, ester group, amido, alkenyl, alkynyl, wherein the substituent is selected from deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, hydroxyl, cyano, amino, amido.

Further, R₂₃、R₂₄Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, wherein the substituents are selected from deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, hydroxy, amido; the heteroatom in the heteroalkyl or heterocycloalkyl group is one or more of O, N, S.

Further, R₂₃、R₂₄Are respectively and independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, wherein the substituent is selected from deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, acylamino(ii) a Further, when the substituent is deuterium or halogen, the number of substitution of deuterium or halogen is 0 to 3.

Further, R₂₃Selected from halogen, methyl, trifluoromethyl, substituted or unsubstituted alkoxy; r₂₄Selected from halogen, substituted or unsubstituted C1-C3 alkyl, CD₃Substituted or unsubstituted C1-C3 alkoxy; wherein the substituent is selected from C1-C3 alkyl, C1-C3 heteroalkyl, halogen, hydroxyl and amino.

Further, R₂₃Selected from the group consisting of F, Cl, Br, methyl, trifluoromethyl, methoxy, trifluoromethoxy, preferably F, Cl, Br, trifluoromethoxy, more preferably F, trifluoromethoxy; r₂₄Selected from F, Cl, Br, methyl, CD₃Trifluoromethyl, methoxy, trifluoromethoxy,

Preferably F, Cl, Br, methyl, CD₃A methoxy group,

More preferably F, methyl, CD₃A methoxy group,

Further, R₂₅、R₂₆Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxyl, cyano, amino, ester, substituted or unsubstituted amide, substituted or unsubstituted acyl guanidino, ureido, aryl, heteroaryl, sulfonyl, boronic acid, boronic ester, substituted or unsubstituted phosphoryl, alkenyl, alkynyl, wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxyl, cyano, amino, ester, amido, guanidino, acyl guanidino;

further, R₂₅、R₂₆Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstitutedUnsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxyl, cyano, amino, ester group, boronic acid group, wherein the substituent is selected from the group consisting of C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxyl, cyano, amino, ester group, amide group, sulfonyl;

further, R₂₅、R₂₆Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxyl, and boronic acid, wherein the substituents are selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxyl, and amino; the heteroatom in the heteroalkyl or heterocycloalkyl group is one or more of O, N, S.

Further, R₂₅、R₂₆Are respectively and independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl and hydroxyl, wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxyl and amino.

Further, R₂₅Selected from halogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy and hydroxyl; r₂₆Selected from hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl; wherein, the substituent is selected from C1-C3 alkyl, C1-C3 heteroalkyl, halogen, hydroxyl and amino.

Further, R₂₅Selected from F, Cl, Br, methyl, methoxy, hydroxyl, preferably F, Cl, Br, more preferably F; r₂₆Selected from hydrogen, F, Cl, Br, C1-C3 alkyl, preferably hydrogen.

The invention also provides a medicinal composition, which is characterized in that the active ingredient of the medicinal composition is selected from one or the combination of more than two of the compounds or the stereoisomer, the solvate, the hydrate, the pharmaceutically acceptable salt or the eutectic crystal thereof.

The invention also provides the use of the compound or the stereoisomer, the solvate, the hydrate, the pharmaceutically acceptable salt or the eutectic crystal thereof in the preparation of sodium ion channel regulators; further, the sodium channel modulator is a Nav1.8 inhibitor.

The invention also provides the application of the compound or the stereoisomer, the solvate, the hydrate, the pharmaceutically acceptable salt or the eutectic crystal thereof in preparing a medicament for treating diseases causing over expression of Nav1.8.

The invention also provides the application of the compound or the stereoisomer, the solvate, the hydrate, the pharmaceutically acceptable salt or the eutectic crystal thereof in preparing a medicament for treating diseases caused by over-expression of Nav1.8.

The invention also provides the use of a compound as described above, or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof, in the manufacture of a medicament for use in the treatment of any one or more of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, multiple sclerosis, Charcot-Marie-tooth syndrome, incontinence and arrhythmia.

Further, the neuropathic pain is selected from one or more of postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, mouth burn syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve crush injury, spinal canal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, neuralgia caused by drug therapy, neuralgia caused by cancer chemotherapy, neuralgia caused by anti-retroviral therapy, pain after spinal cord injury, primary small-fiber neuropathy, primary sensory neuropathy, trigeminal autonomic headache;

the musculoskeletal pain is selected from one or more of osteoarthritis pain, back pain, cold pain, burn pain, and toothache;

the inflammatory pain is selected from rheumatoid arthritis pain and/or vulvodynia;

the primary pain is selected from fibromyalgia.

The pharmaceutical composition containing the compound of the invention or the stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or cocrystal thereof can contain pharmaceutically acceptable auxiliary materials.

As used herein, "pharmaceutically acceptable" is intended to include any material which is effective in not interfering with the biological activity of the active ingredient and which is not toxic to the host to which it is administered.

The pharmaceutically acceptable auxiliary material is a general name of all additional materials except the main medicine in the medicine, and the auxiliary material has the following properties: (1) no toxic effect on human body and few side effects; (2) the chemical property is stable and is not easily influenced by temperature, pH, storage time and the like; (3) has no incompatibility with the main drug, and does not influence the curative effect and quality inspection of the main drug; (4) does not interact with the packaging material. The auxiliary materials in the invention include, but are not limited to, filling agent (diluting agent), lubricating agent (glidant or anti-adhesion agent), dispersing agent, wetting agent, adhesive, regulator, solubilizer, antioxidant, bacteriostatic agent, emulsifier, disintegrating agent and the like. The binder comprises syrup, acacia, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethylcellulose, ethyl cellulose or hydroxypropyl methylcellulose), gelatin slurry, syrup, starch slurry or polyvinylpyrrolidone; the filler comprises lactose, sugar powder, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salt (such as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; the lubricant comprises micropowder silica gel, magnesium stearate, pulvis Talci, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; the disintegrating agent comprises starch and its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinylpyrrolidone or microcrystalline cellulose, etc.; the wetting agent comprises sodium lauryl sulfate, water or alcohol, etc.; the antioxidant comprises sodium sulfite, sodium bisulfite, sodium pyrosulfite, dibutylbenzoic acid, etc.; the bacteriostatic agent comprises 0.5% of phenol, 0.3% of cresol, 0.5% of chlorobutanol and the like; the regulator comprises hydrochloric acid, citric acid, potassium (sodium) hydroxide, sodium citrate, and buffer (including sodium dihydrogen phosphate and disodium hydrogen phosphate); the emulsifier comprises polysorbate-80, sorbitan laurate, pluronic F-68, lecithin, soybean lecithin, etc.; the solubilizer comprises tween-80, bile, glycerol, etc. The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. The acid base is a generalized Lewis acid base. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, and oils, especially cottonseed, groundnut, corn germ, olive, castor, and sesame oils, or mixtures of such materials, and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The compounds of the invention can likewise be used in injectable preparations. Wherein the injection is selected from liquid injection (water injection), sterile powder for injection (powder injection) or tablet for injection (refers to impression tablet or machine pressing tablet prepared by aseptic operation method of medicine, and is dissolved with water for injection for subcutaneous or intramuscular injection when in use).

Wherein the powder for injection contains at least an excipient in addition to the above compound. The excipients described herein are components that are intentionally added to a drug and should not have pharmacological properties in the amounts used, however, excipients may aid in the processing, dissolution or dissolution of the drug, delivery by a targeted route of administration, or stability.

"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

"element" means the number of skeleton atoms constituting a ring.

The term "one bond" as used herein means only one bond, and may be understood as "none".

"alkyl" refers to an aliphatic hydrocarbon group and to a saturated hydrocarbon group. The alkyl moiety may be a straight chain or branched chain alkyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

C1-Cn used in the invention comprises C1-C2 and C1-C3 … … C1-Cn, wherein n is an integer more than one; the prefix as a substituent denotes the minimum and maximum number of carbon atoms in the substituent, e.g., "C1-C6 alkyl" means a straight or branched chain alkyl group containing one to 6 carbon atoms.

"heteroalkyl" refers to an alkyl group containing a heteroatom.

"alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl groups may be straight-chain or branched.

"alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group may be linear or branched.

"amido" is a chemical structure having the formula-C (O) NHR or-NHC (O) R, wherein R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.

"Sulfonyl" is a compound having the formula-S (═ O)₂The chemical structure of R, including sulfonamide, wherein R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, and the like;

"phosphoryl" is a chemical structure having the formula-P (═ O) RR ', where R, R' may each be independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, amino, and the like;

"ester group" means having the chemical structure of the formula-C (O) OR OR-OC (O) R, wherein R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.

"acyl" refers to a chemical structure having the formula-C (O) R, wherein R is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.

"acyl guanidino" refers to compounds having the formula

Wherein R is selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and the like.

"cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent such as "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3-6 carbon atoms in the ring skeleton.

"Heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom in the ring backbone.

Heteroatoms include, but are not limited to O, S, N, P, Si and the like.

"Ring" refers to any covalently closed structure, including, for example, carbocycles (e.g., aryl or cycloalkyl), heterocycles (e.g., heteroaryl or heterocycloalkyl), aryls (e.g., aryl or heteroaryl), nonaromatic (e.g., cycloalkyl or heterocycloalkyl). The "ring" in the present invention may be a monocyclic ring or a polycyclic ring, and may be a fused ring, a spiro ring or a bridged ring.

Typical heterocycloalkyl groups include, but are not limited to:

"aryl" means a planar ring having a delocalized pi-electron system and containing 4n +2 pi electrons, where n is an integer. The aryl ring may be composed of five, six, seven, eight, nine or more than nine atoms. Aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracyl, fluorenyl, indenyl, and the like.

Typical heteroaryl groups include, but are not limited to:

"halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

"deuterium" refers to an isotope of hydrogen (H), also known as deuterium, the symbol of the element being generally D or²H。

As used herein, alkyl, heteroalkyl, cyclic, heterocyclic, amino, ester, carbonyl, amide, sulfonyl, phosphoryl, boronic acid, boronic ester, guanidino, acylguanidino, aryl, heteroaryl, imine and the like are unsubstituted alkyl, heteroalkyl, cyclic, heterocyclic, amino, ester, carbonyl, amide, sulfonyl, phosphoryl, boronic acid, boronic ester, guanidino, acylguanidino, aryl, heteroaryl, imine and the like are substituted alkyl, heteroalkyl, cyclic, heterocyclic, amino, ester, carbonyl, amide, sulfonyl, phosphoryl, boronic acid, boronic ester, guanidino, acylguanidino, aryl, heteroaryl, imine and the like.

Hereinbefore, unless already indicated, the term "substituted" means that the group referred to may be substituted by one or more additional groups each and independently selected from alkyl, cycloalkyl, aryl, carboxy, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, alkylthio, aryloxy, O ═ guanidino, cyano, nitro, acyl, halogen, haloalkyl, amino and the like.

The invention has the beneficial effects that: the invention provides a series of compounds with obvious inhibiting effect on Nav1.8 ion channel activity, provides a new scheme for treating diseases taking Nav1.8 as a treatment target, such as chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, multiple sclerosis, Charcot-Marie-tooth syndrome, incontinence or arrhythmia diseases and the like, can be used for preparing medicaments for treating related diseases, and has wide application prospect.

Drawings

FIG. 1 is a schematic view of voltage test in test example 1.

Detailed Description

The technical solutions of the present invention are described clearly and completely below, and it is obvious that the described embodiments are some, not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

In the present invention, the structure of the compound is determined by Mass Spectrometry (MS) and/or nuclear magnetic resonance (1HNMR) equipment. The abbreviations have the following meanings:

DMF: n, N-dimethylformamide

THF: tetrahydrofuran (THF)

The DIAD: diisopropyl azodicarboxylate

DIPEA: n, N-diisopropylethylamine

PE: petroleum ether

EA: ethyl acetate

DCM: methylene dichloride

HATU: o- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea

DMSO, DMSO: dimethyl sulfoxide

Example 1

2- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -1, 5-dihydro-6H-imidazo [4,5-c ] pyridin-6-one

Step 1: synthesis of methyl 2-fluoro-4- (trifluoromethyl) benzoate

2-fluoro-4- (trifluoromethyl) benzoic acid (2.08g, 10mmol), potassium carbonate (2.76g, 20mmol) and 20mL acetonitrile were added to the reaction flask, methyl iodide (1.70g, 12mmol) was added at room temperature, the reaction mixture was heated to reflux and stirred for 6 hours, TLC indicated completion of the reaction. Cooling the reaction system to room temperature, filtering, and spin-drying the filtrate to obtain 2.10g of a target product, wherein the yield is as follows: 95 percent.

Step 2: synthesis of methyl 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate

Methyl 2-fluoro-4- (trifluoromethyl) benzoate (1.11g, 5mmol), 4-fluoro-2-methylphenol (0.63g, 5mmol), potassium carbonate (1.38g, 10mmol) and 10mL of N-methylpyrrolidone were added to the reaction flask, the reaction mixture was heated to 120 ℃ and stirred for 20 hours, TLC indicated completion of the reaction. After the reaction system was cooled to room temperature, it was poured into 50mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 20/1), yielding 1.3g of the target product, yield: 79 percent.

And step 3: synthesis of 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid

To the reaction flask was added methyl 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (656mg, 2mmol), sodium hydroxide (320mg, 8mmol), 10mL of water and 10mL of methanol, the reaction mixture was stirred at room temperature for 8 hours, and TLC showed completion of the reaction. The reaction was poured into 50mL of water, pH adjusted to 5 with 1M hydrochloric acid, extracted with ethyl acetate, the organic phase dried and spun dry to yield 620mg of the target product, yield: 99 percent.

And 4, step 4: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxy-5-nitropyridin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (314mg, 1mmol), 2-methoxy-5-nitropyridin-4-amine (167mg, 1mmol), DIPEA (258mg, 2mmol) and 5mL tetrahydrofuran, HATU (569mg, 1.5mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction system was poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 3/1) to give 350mg of the target product in yield: 75 percent.

And 5: synthesis of 2- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -6-methoxy-1H-imidazo [4,5-c ] pyridine

2- (4-fluoro-2-methylphenoxy) -N- (2-methoxy-5-nitropyridin-4-yl) -4- (trifluoromethyl) benzamide (233mg, 0.5mmol) was dissolved in 5mL of acetic acid, iron powder (112mg, 2mmol) was added at room temperature, and the mixture was stirred at 70 ℃ for 2 hours. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC chromatography (PE/EA ═ 1/1) to give 150mg of the target product in yield: 75 percent.

Step 6: synthesis of 2- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -1, 5-dihydro-6H-imidazo [4,5-c ] pyridin-6-one

2- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -6-methoxy-1H-imidazo [4,5-c ] pyridine (83mg, 0.2mmol) is dissolved in 5mL acetonitrile, potassium iodide (166mg, 1mmol) and TMSCl (109mg, 1mmol) are added at room temperature, and the mixture is stirred at 70 ℃ overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 20/1) to give 45mg of the title product as a white solid in yield: 56 percent.

LC/MS:m/z＝404.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.16(3H,s),6.46(1H,s),6.79(1H,s),7.22-7.24 (1H,m),7.32-7.37(2H,m),7.60(1H,d,J＝9.2Hz),8.29(1H,s),8.57(1H,d,J＝9.2 Hz),12.28(1H,brs).

Example 2

5- (2- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -1H-imidazol-5-yl) pyridin-2 (1H) -one

Step 1: synthesis of 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzonitrile

2-fluoro-4- (trifluoromethyl) benzonitrile (0.95g, 5mmol), 4-fluoro-2-methylphenol (0.63g, 5mmol), potassium carbonate (1.38g, 10mmol) and 10mL of N-methylpyrrolidone were added to the reaction flask, the reaction mixture was heated to 100 deg.C and stirred for 10 hours, TLC indicated completion of the reaction. The reaction system was cooled to room temperature and poured into 50mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 20/1) to give 1.2g of the target product, yield: 81 percent.

Step 2: synthesis of 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamidine

2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzonitrile (1.2g, 4.1mmol) was dissolved in 15mL of tetrahydrofuran, nitrogen blanketed, LiHMDS (1M in THF, 8.2mL, 8.2mmol) was added dropwise at 0 deg.C, after addition the reaction mixture was stirred at room temperature for 12 hours and TLC indicated completion of the reaction. The reaction was poured into 50mL of water, extracted with ethyl acetate, and the organic phase was dried and spin dried to give 1.2g of crude product, yield: 96 percent.

And step 3: synthesis of 2-bromo-1- (2-methoxypyridin-4-yl) ethan-1-one

1- (6-methoxypyridin-3-yl) ethan-1-one (1.5g, 10mmol) was dissolved in 15mL of toluene, followed by 2mL of acetic acid and Br₂(1.6g, 10mmol), after the addition the reaction mixture was stirred at room temperature for 3 hours, the reaction was poured into 50mL of water, the pH was adjusted to 8 with sodium bicarbonate, extracted with ethyl acetate, the organic phase was dried and spin dried to give 1.8g of crude product, yield: 78 percent.

And 4, step 4: synthesis of 5- (2- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -1H-imidazol-5-yl) -2-methoxypyridine

To a reaction flask was added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamidine (312mg, 1mmol), 2-bromo-1- (2-methoxypyridin-4-yl) ethan-1-one (230mg, 1mmol), sodium bicarbonate (168mg, 2mmol), 5mL of water and 5mL of tetrahydrofuran, and the reaction mixture was heated to 60 ℃ and stirred for 10 hours, TLC showed completion of the reaction. The reaction system was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 8/1) to give 250mg of the target product, yield: 56 percent.

And 5: synthesis of 5- (2- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -1H-imidazol-5-yl) pyridin-2 (1H) -one

5- (2- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -1H-imidazol-5-yl) -2-methoxypyridine (88mg, 0.2mmol) was dissolved in 5mL acetonitrile, potassium iodide (166mg, 1mmol) and TMSCl (109mg, 1mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 20/1) to give 65mg of the title product as a white solid in yield: 76 percent.

LC/MS:m/z＝430.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.15(3H,s),6.42(1H,d,J＝8.8Hz),6.74(1H,s), 7.17-7.26(2H,m),7.30-7.34(1H,m),7.52(1H,d,J＝8.0Hz),7.63(1H,s),7.86(1H,s), 8.00(1H,d,J＝8.8Hz),8.48(1H,d,J＝8.0Hz),11.70(1H,brs),12.33(1H,brs).

Example 3

6- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -3- (trifluoromethyl) imidazo [1,5-a ] pyridine-7-carboxamide

Step 1: synthesis of 2-cyano-5-fluoroisonicotinic acid methyl ester

Methyl 2-bromo-5-fluoroisonicotinate (4.68g, 20mmol), cuprous cyanide (8.96g, 100mmol), and 50mL of N-methylpyrrolidinone were added to a reaction flask and the reaction mixture was heated to 120 ℃ under nitrogen and stirred for 10 hours. The reaction system was cooled to room temperature and poured into 200mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 3/1) to give 3.10g of the target product, yield: 86 percent.

Step 2: synthesis of methyl 2-cyano-5- (4-fluoro-2-methylphenoxy) isonicotinate

Methyl 2-cyano-5-fluoroisonicotinate (2.70g, 15mmol), 4-fluoro-2-methylphenol (1.89 g, 15mmol), potassium carbonate (4.14g, 30mmol) and 30mL of N-methylpyrrolidone were added to the reaction flask, the reaction mixture was heated to 100 ℃ and stirred for 10 hours, TLC showed completion of the reaction. The reaction system was cooled to room temperature and poured into 100mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 5/1) to give 3.17g of the target product, yield: 74 percent.

And step 3: synthesis of methyl 2- (aminomethyl) -5- (4-fluoro-2-methylphenoxy) isonicotinate

To a reaction flask was added methyl 2-cyano-5- (4-fluoro-2-methylphenoxy) isonicotinate (2.86g, 10mmol), 10% Pd/C (0.29g), 3mL acetic acid and 30mL methanol, and the reaction mixture was incubated at 1MPa H₂The reaction was heated to 60 ℃ under pressure and stirred for 20 hours, TLC showed completion of the reaction. Cooling the reaction system to room temperature, filtering, and spin-drying the filtrate to obtain 2.82g of a target product, wherein the yield is as follows: 97 percent.

And 4, step 4: synthesis of methyl 6- (4-fluoro-2-methylphenoxy) -3- (trifluoromethyl) imidazo [1,5-a ] pyridine-7-carboxylate

To a solution of methyl 2- (aminomethyl) -5- (4-fluoro-2-methylphenoxy) isonicotinate (2.32g, 8mmol) in 30mL of toluene was added 4mL of trifluoroacetic anhydride and the reaction mixture was heated to 80 ℃ and stirred for 6 hours. The reaction system was cooled to room temperature and poured into 100mL of water, the pH was adjusted to 8 with sodium carbonate, extracted with ethyl acetate, the organic phase was dried and purified by silica gel column chromatography (PE/EA ═ 8/1) after spin-drying to give 1.44g of the target product, yield: 49 percent.

And 5: synthesis of 6- (4-fluoro-2-methylphenoxy) -3- (trifluoromethyl) imidazo [1,5-a ] pyridine-7-carboxylic acid

To a reaction flask was added methyl 6- (4-fluoro-2-methylphenoxy) -3- (trifluoromethyl) imidazo [1,5-a ] pyridine-7-carboxylate (736mg, 2mmol), sodium hydroxide (320mg, 8mmol), 10mL of water and 10mL of methanol, and the reaction mixture was stirred at room temperature for 8 hours, TLC showed completion of the reaction. The reaction was poured into 50mL of water, pH adjusted to 5 with 1M hydrochloric acid, extracted with ethyl acetate, the organic phase dried and spun to yield 690mg of the target product, yield: 97 percent.

Step 6: synthesis of 6- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -3- (trifluoromethyl) imidazo [1,5-a ] pyridine-7-carboxamide

To a reaction flask was added 6- (4-fluoro-2-methylphenoxy) -3- (trifluoromethyl) imidazo [1,5-a ] pyridine-7-carboxylic acid (354mg, 1mmol), 2-methoxypyridin-4-amine (124mg, 1mmol), DIPEA (258mg, 2mmol) and 5mL tetrahydrofuran, HATU (569mg, 1.5mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction system was poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spun-dried and purified by silica gel column chromatography (PE/EA ═ 2/1) to give 270mg of the target product, yield: 59 percent.

And 7: synthesis of 6- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -3- (trifluoromethyl) imidazo [1,5-a ] pyridine-7-carboxamide

6- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -3- (trifluoromethyl) imidazo [1,5-a ] pyridine-7-carboxamide (230mg, 0.5mmol) is dissolved in 5mL acetonitrile, potassium iodide (332mg, 2.0mmol) and TMSCl (218mg, 2.0mmol) are added at room temperature and the mixture is stirred at 70 ℃ overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 20/1) to give 70mg of the title product as a white solid in yield: 30 percent.

LC/MS:m/z＝447.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.24(3H,s),6.33(1H,d,J＝8.0Hz),6.65(1H,s), 7.02-7.04(2H,m),7.18(1H,d,J＝8.8Hz),7.30(1H,d,J＝7.2Hz),7.87(1H,s),7.92 (1H,s),8.28(1H,s),10.64(1H,s),11.28(1H,brs).

Example 4

2- (4-fluoro-2-methylphenoxy) -N- (2-oxopiperidin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (31mg, 0.1mmol), 4-amino-2-piperidone (12mg, 0.1mmol), DIPEA (26mg, 0.2mmol) and 2mL tetrahydrofuran, HATU (76mg, 0.2mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction system was poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 26mg of the target product in yield: and 63 percent.

LC/MS:m/z＝411.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.61-1.85(2H,m),2.20(3H,s),2.33-2.47(2H, m),3.27-3.41(2H,m),3.71-3.77(1H,m),6.24(1H,brs),6.83(1H,s),7.00-7.13(2H,m), 7.24-7.29(1H,m),7.55(1H,d,J＝8.2Hz),7.69(1H,d,J＝7.8Hz),8.20(1H,d,J＝8.0 Hz).

Example 5

4- (4- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -1H-imidazol-2-yl) pyridin-2 (1H) -one

Step 1: synthesis of 1- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) ethan-1-one

To a reaction flask were added 1- (2-fluoro-4- (trifluoromethyl) phenyl) ethan-1-one (2.06g, 10mmol), 4-fluoro-2-methylphenol (1.26g, 10mmol), potassium carbonate (2.76g, 20mmol) and 20mL of N-methylpyrrolidinone, and the reaction mixture was heated to 120 ℃ and stirred for 20 hours. The reaction system was cooled to room temperature and poured into 100mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 20/1) to give 2.20g of the target product, yield: 71 percent.

Step 2: synthesis of 2-bromo-1- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) ethan-1-one

1- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) ethan-1-one (1.56g, 5mmol) was dissolved in 15mL of toluene, followed by 2mL of acetic acid and Br₂(0.80g, 5mmol), stirring the reaction mixture at room temperature for 3 hours after the addition is finished, pouring the reaction system into 50mL of water, adjusting the pH value to 8 by sodium bicarbonate, extracting by ethyl acetate, and carrying out organic extractionThe phases were dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 20/1) to give 0.43g of crude product, yield: 22 percent.

And step 3: synthesis of 4- (4- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -1H-imidazol-2-yl) -2-methoxypyridine

To a reaction flask was added 2-bromo-1- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) ethan-1-one (391mg, 1mmol), 2-methoxypyridine-4-carboxamidine (151mg, 1mmol), sodium bicarbonate (168mg, 2mmol), 5mL of water and 5mL of tetrahydrofuran, and the reaction mixture was heated to 60 ℃ and stirred for 10 hours, TLC showed completion of the reaction. The reaction system was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, dried and spun-dried, and purified by silica gel column chromatography (PE/EA ═ 2/1) to give 210mg of the target product, yield: and 47 percent.

And 4, step 4: synthesis of 4- (4- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -1H-imidazol-2-yl) pyridin-2 (1H) -one

4- (4- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -1H-imidazol-2-yl) -2-methoxypyridine (89mg, 0.2mmol) was dissolved in 5mL acetonitrile, and potassium iodide (166mg, 1.0mmol) and TMSCl (109mg, 1.0mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 20/1) to give 62mg of the title product as a white solid in yield: 72 percent.

LC/MS:m/z＝430.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.19(3H,s),6.82(1H,s),6.88(1H,d,J＝8.0Hz), 6.95(1H,s),7.06-7.13(2H,m),7.30(1H,d,J＝8.0Hz),7.48(1H,d,J＝7.6Hz),7.53 (1H,d,J＝8.0Hz),7.87(1H,s),8.48(1H,d,J＝7.2Hz),11.63(1H,brs),13.12(1H, brs).

Example 6

7-bromo-2- (4-fluoro-2-methylphenyl) -3-oxo-N- (2-oxo-1, 2-dihydropyridin-4-yl) isoindoline-4-carboxylic acid amide

Step 1: synthesis of 7-bromo-2- (4-fluoro-2-methylphenyl) -3-oxoisoindoline-4-carbonitrile

7-bromo-3-oxoisoindoline-4-carbonitrile (948mg, 4mmol), 4-fluoro-1-iodo-2-methylbenzene (944mg, 4mmol), cesium carbonate (2608mg, 8mmol), N, N' -dimethylethylenediamine (44mg, 0.5mmol), cuprous iodide (95mg, 0.5mmol), and 10mL of DMSO were added to a reaction flask, and the reaction mixture was heated to 120 ℃ under nitrogen and stirred for 10 hours. The reaction system was cooled to room temperature and poured into 50mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 5/1) to give 740mg of the target product, yield: 54 percent.

Step 2: synthesis of 7-bromo-2- (4-fluoro-2-methylphenyl) -3-oxoisoindoline-4-carboxylic acid

To a reaction flask was added 7-bromo-2- (4-fluoro-2-methylphenyl) -3-oxoisoindoline-4-carbonitrile (688mg, 2mmol), sodium hydroxide (400mg, 10mmol), 10mL water and 10mL ethanol, and the reaction mixture was stirred at 80 ℃ overnight. The reaction was poured into 50mL of water, extracted with ethyl acetate to remove impurities, the aqueous phase was adjusted to pH 4 with 1M hydrochloric acid, extracted again with ethyl acetate, the organic phase was dried and spun dry to give 470mg of the target product, yield: 65 percent.

And step 3: synthesis of 7-bromo-2- (4-fluoro-2-methylphenyl) -N- (2-methoxypyridin-4-yl) -3-oxoisoindoline-4-carboxamide

To a reaction flask was added 7-bromo-2- (4-fluoro-2-methylphenyl) -3-oxoisoindoline-4-carboxylic acid (364mg, 1mmol), 2-methoxypyridin-4-amine (124mg, 1mmol), DIPEA (258mg, 2mmol) and 5mL tetrahydrofuran, HATU (569mg, 1.5mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 2/1) to give 255mg of the target product, yield: 54 percent.

And 4, step 4: synthesis of 7-bromo-2- (4-fluoro-2-methylphenyl) -3-oxo-N- (2-oxo-1, 2-dihydropyridin-4-yl) isoindoline-4-carboxamide

7-bromo-2- (4-fluoro-2-methylphenyl) -N- (2-methoxypyridin-4-yl) -3-oxoisoindoline-4-carboxamide (235mg, 0.5mmol) was dissolved in 5mL acetonitrile, potassium iodide (332mg, 2.0mmol) and TMSCl (218mg, 2.0mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 20/1) to give 130mg of the title product as a white solid in yield: 57 percent.

LC/MS:m/z＝456.0[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.10(3H,s),4.93(2H,s),6.41(1H,d,J＝8.4Hz), 7.00-7.10(2H,m),7.24(1H,d,J＝8.8Hz),7.33-7.35(1H,m),7.46(1H,d,J＝7.4Hz), 7.91(1H,d,J＝8.0Hz),8.40(1H,d,J＝8.0Hz),10.94(1H,s),13.28(1H,brs).

Example 7

2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (2-oxopyrrolidin-1-yl) benzamide

Step 1: synthesis of methyl 2- (4-fluoro-2-methylphenoxy) -4-nitrobenzoate

To a reaction flask were added methyl 2-fluoro-4-nitrobenzoate (1.99g, 10mmol), 4-fluoro-2-methylphenol (1.26g, 10mmol), potassium carbonate (2.76g, 20mmol) and 20mL of N-methylpyrrolidone, and the reaction mixture was heated to 120 ℃ and stirred for 20 hours. The reaction system was cooled to room temperature and poured into 100mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 20/1) to give 2.64g of the target product, yield: 86 percent.

Step 2: synthesis of methyl 4-amino-2- (4-fluoro-2-methylphenoxy) benzoate

To a reaction flask were added methyl 2- (4-fluoro-2-methylphenoxy) -4-nitrobenzoate (1.53g, 5mmol), 10% Pd/C (0.20g) and 30mL of methanol, and the reaction mixture was H/C at 0.2MPa₂TLC showed the reaction was complete when stirred at room temperature under pressure for 20 hours. Cooling the reaction system to room temperature, filtering, spin-drying the filtrate to obtain 1.30g of target product,yield: 95 percent.

And step 3: synthesis of methyl 2- (4-fluoro-2-methylphenoxy) -4- (2-oxopyrrolidin-1-yl) benzoate

4-Bromobutyryl chloride (557mg, 3mmol) was added dropwise to a 20mL tetrahydrofuran solution containing methyl 4-amino-2- (4-fluoro-2-methylphenoxy) benzoate (825mg, 3mmol) and potassium carbonate (1104mg, 8mmol) at 0 ℃ and, after the addition was completed, the reaction mixture was stirred at room temperature for 1 hour and then heated to 60 ℃ and stirred overnight. The reaction system was cooled to room temperature, filtered, and the filtrate was spin-dried and purified by silica gel column chromatography (PE/EA ═ 2/1) to give 350mg of the target product in yield: 37 percent.

And 4, step 4: synthesis of 2- (4-fluoro-2-methylphenoxy) -4- (2-oxopyrrolidin-1-yl) benzoic acid

To a reaction flask was added methyl 2- (4-fluoro-2-methylphenoxy) -4- (2-oxopyrrolidin-1-yl) benzoate (343 mg,1mmol), sodium hydroxide (160mg, 4mmol), 5mL of water and 5mL of methanol, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 20mL of water, the pH adjusted to 4 with 1M hydrochloric acid, extracted with ethyl acetate, the organic phase dried and spun dry to give 317mg of the target product, yield: 96 percent.

And 5: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (2-oxopyrrolidin-1-yl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -4- (2-oxopyrrolidin-1-yl) benzoic acid (165mg, 0.5mmol), 2-methoxypyridin-4-amine (62mg, 0.5mmol), DIPEA (129mg, 1mmol) and 5mL tetrahydrofuran, HATU (379mg, 1mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 140mg of the target product in yield: and 64 percent.

Step 6: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (2-oxopyrrolidin-1-yl) benzamide

2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (2-oxopyrrolidin-1-yl) benzamide (44mg, 0.1mmol) was dissolved in 2mL acetonitrile, potassium iodide (83mg, 0.5mmol) and TMSCl (55mg, 0.5mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 20/1) to give 12mg of the title product as a white solid in yield: 29 percent.

LC/MS:m/z＝422.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.03(2H,t,J＝8.2Hz),2.18(3H,s),2.45-2.52 (2H,m),3.78(2H,t,J＝8.2Hz),6.40(1H,d,J＝8.4Hz),6.78(1H,s),6.97-7.08(2H,m), 7.19(1H,d,J＝8.4Hz),7.27-7.29(2H,m),7.44(1H,s),7.67(1H,d,J＝8.0Hz),10.30 (1H,s),11.21(1H,brs).

Example 8

2- (4-fluoro-2-methylphenoxy) -5- ((2-hydroxyethyl) amino) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 5-bromo-2-fluoro-4- (trifluoromethyl) benzoic acid

2-fluoro-4- (trifluoromethyl) benzoic acid (20.8g, 100mmol) was dissolved in 100mL of trifluoroacetic acid, 10mL of concentrated sulfuric acid and NBS (17.8g, 100mmol) were added sequentially at room temperature, and the mixture was stirred at 50 ℃ for 24 hours. The reaction was poured into 500mL of water, extracted with ethyl acetate, and the organic phase was back-washed once with saturated brine, dried and spin-dried and purified by silica gel column chromatography (DCM/MeOH ═ 20/1) to give 22.6g of the desired product, yield: 79 percent.

Step 2: synthesis of methyl 5-bromo-2-fluoro-4- (trifluoromethyl) benzoate

5-bromo-2-fluoro-4- (trifluoromethyl) benzoic acid (14.4g, 50mmol) is dissolved in 150mL of methanol, 5mL of concentrated sulfuric acid is added at room temperature, and the mixture is heated to reflux and stirred for 6 hours. The reaction was poured into 500mL of water, extracted with ethyl acetate, and the organic phase was back-washed once with 1M aqueous sodium hydroxide solution, dried and spin-dried to give 13.9g of the target product, yield: 92 percent.

And step 3: synthesis of methyl 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate

To a reaction flask were added methyl 5-bromo-2-fluoro-4- (trifluoromethyl) benzoate (12.0g, 40mmol), 4-fluoro-2-methylphenol (5.0g, 40mmol), potassium carbonate (11.0g, 80mmol) and 150mL of N-methylpyrrolidinone, and the reaction mixture was heated to 100 ℃ and stirred for 20 hours. The reaction system was cooled to room temperature and poured into 500mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 20/1) to give 14.2g of the target product, yield: 87 percent.

And 4, step 4: synthesis of 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid

To a reaction flask was added methyl 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (8.14 g, 10mmol), sodium hydroxide (3.2g, 80mmol), 100mL of water and 100mL of methanol, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 500mL of water, pH adjusted to 4 with 1M hydrochloric acid, extracted with ethyl acetate, the organic phase dried and spun dry to yield 7.60g of the target product, yield: 97 percent.

And 5: synthesis of 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask was added 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (3.93g, 10mmol), 2-methoxypyridin-4-amine (1.24g, 10mmol), DIPEA (2.58g, 20mmol) and 50mL tetrahydrofuran, HATU (5.69g, 15mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 200mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 3.90g of the target product, yield: 78 percent.

Step 6: synthesis of 2- (4-fluoro-2-methylphenoxy) -5- ((2-hydroxyethyl) amino) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask was added 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (499mg, 1mmol), cesium carbonate (652mg, 2mmol), N, N' dimethylethylenediamine (18mg, 0.2mmol), cuprous iodide (38mg, 0.2mmol), and 5mL of DMSO, and the reaction mixture was heated to 120 ℃ under nitrogen blanket and stirred for 10 hours. The reaction system was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 70mg of the target product, yield: 15 percent.

And 7: synthesis of 2- (4-fluoro-2-methylphenoxy) -5- ((2-hydroxyethyl) amino) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

2- (4-fluoro-2-methylphenoxy) -5- ((2-hydroxyethyl) amino) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (48mg, 0.1mmol) was dissolved in 2mL acetonitrile, potassium iodide (83mg, 0.5mmol) and TMSCl (55mg, 0.5mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 10/1) to give 23mg of the title product as a white solid in yield: 49 percent.

LC/MS:m/z＝466.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.20(3H,s),3.27-3.30(2H,m),3.59-3.63(2H, m),4.89(1H,t,J＝4.8Hz),5.37(1H,t,J＝4.8Hz),6.36(1H,d,J＝8.0Hz),6.70(1H, s),6.70-6.76(1H,m),6.94-7.12(4H,m),7.28(1H,d,J＝8.4Hz),10.50(1H,s),11.23 (1H,brs).

Example 9

N- (3- (dimethylphosphoryl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-iodophenyl) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (314mg, 1mmol), 4-fluoro-3-iodoaniline (237mg, 1mmol), DIPEA (258mg, 2mmol) and 5mL tetrahydrofuran, HATU (569mg, 1.5mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 385mg of the target product in yield: 72 percent.

Step 2: synthesis of N- (3- (dimethylphosphoryl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-iodophenyl) -4- (trifluoromethyl) benzamide (267mg, 0.5mmol), dimethylphosphine oxide (78mg, 1mmol), triethylamine (101mg, 1mmol), xanthphos (29mg, 0.05mmol) and 5mL dioxane, and after replacement of nitrogen, Pd was added₂(dba)₃(27mg, 0.03mmol) and the reaction mixture was heated to 110 ℃ under nitrogen and stirred for 6 hours. The reaction system was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spun-dried and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 160mg of the target product as a white solid in yield: 66 percent.

LC/MS:m/z＝484.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.63(3H,s),1.66(3H,s),2.16(3H,s),6.31(1H, d,J＝8.0Hz),6.69-6.72(2H,m),6.81(1H,s),7.01-7.07(2H,m),7.24-7.26(1H,m), 7.55(1H,d,J＝7.6Hz),8.21(1H,d,J＝8.4Hz),10.31(1H,s).

Example 10

5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of methyl 5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate

To a reaction flask were added methyl 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (407mg, 1mmol), cyclopropylboronic acid (344mg, 4mmol), sodium carbonate (530mg, 5mmol) and 10mL of DMF, and after replacement of nitrogen, Pd (dppf) Cl was added₂(37mg, 0.05mmol) and the reaction mixture was heated under nitrogen blanketStir to 90 ℃ overnight. The reaction system was cooled to room temperature and poured into 40mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 10/1) to give 280mg of the target product, yield: 76 percent.

Step 2: synthesis of 5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid

To a reaction flask was added methyl 5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (184mg, 0.5mmol), sodium hydroxide (80mg, 2mmol), 3mL of water and 3mL of methanol, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 10mL of water, pH adjusted to 4 with 1M hydrochloric acid, extracted with ethyl acetate, the organic phase dried and spun dry to yield 165mg of the target product, yield: 93 percent.

And step 3: synthesis of 5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask were added 5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (71mg, 0.2mmol), 2-methoxypyridin-4-amine (25mg, 0.2mmol), DIPEA (52mg, 0.4mmol) and 2mL tetrahydrofuran, HATU (114mg, 0.3mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (PE/EA ═ 1/1) to give 58mg of the target product in yield: and 63 percent.

And 4, step 4: synthesis of 5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (46mg, 0.1mmol) was dissolved in 2mL acetonitrile, potassium iodide (83mg, 0.5mmol) and TMSCl (55mg, 0.5mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 10/1) to give 30mg of the title product as a white solid in yield: 67%.

LC/MS:m/z＝447.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ0.85-0.89(2H,m),1.00-1.05(2H,m),2.05-2.11 (1H,m),2.16(3H,s),6.36(1H,dd,J＝7.2Hz,1.6Hz),6.74(1H,s),6.94(1H,s), 7.00-7.09(2H,m),7.20(1H,dd,J＝9.2Hz,2.8Hz),7.30(1H,d,J＝7.2Hz),8.13(1H, s),10.56(1H,s),11.25(1H,brs).

Example 11

N- (3- (guanidinocarbamoyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Step 1: synthesis of methyl 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoate

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (63mg, 0.2mmol), methyl 5-amino-2-fluorobenzoate (34mg, 0.2mmol), DIPEA (52mg, 0.4mmol) and 2mL tetrahydrofuran, HATU (114mg, 0.3mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by TLC (PE/EA ═ 1/1) to give 65mg of the desired product in 70% yield.

Step 2: synthesis of 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoic acid

Methyl 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoate (47mg, 0.1mmol), sodium hydroxide (16mg, 0.4mmol), 2mL of water and 2mL of methanol were added to a reaction flask, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 10mL of water, pH adjusted to 4 with 1M hydrochloric acid, extracted with ethyl acetate, the organic phase dried and spun dry to yield 45mg of the target product, yield: 100 percent.

And step 3: synthesis of N- (3- (guanidinoformyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoic acid (45mg, 0.1mmol), CDI (16mg, 0.1mmol) and 2mL tetrahydrofuran, and after stirring at room temperature for 1 hour, DIPEA (103mg, 0.8mmol) and guanidine hydrochloride (48mg, 0.5mmol) were added in this order, and the reaction mixture was stirred at 50 ℃ overnight. The reaction system was directly purified by reverse phase preparation to obtain 12mg of the target product as a white solid with a yield of 24%.

LC/MS:m/z＝493.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.17(3H,s),6.70(2H,brs),6.95(1H,s), 7.10-7.15(3H,m),7.23(1H,d,J＝8.8Hz),7.59-7.65(2H,m),7.85(1H,d,J＝8.0Hz), 7.95(2H,brs),8.02(1H,dd,J＝8.0Hz,2.0Hz),10.58(1H,s).

Example 12

4- (dimethylphosphoryl) -2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) benzamide

Step 1: synthesis of 4-bromo-2-fluoro-N- (2-methoxypyridin-4-yl) benzamide

To a reaction flask were added 4-bromo-2-fluorobenzoic acid (219mg, 1.0mmol), 2-methoxypyridin-4-amine (124mg, 1.0mmol), DIPEA (258mg, 2.0mmol) and 5mL tetrahydrofuran, HATU (569mg, 1.5mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 280mg of the target product in yield: 86 percent.

Step 2: synthesis of 4- (dimethylphosphoryl) -2-fluoro-N- (2-methoxypyridin-4-yl) benzamide

To a reaction flask were added 4-bromo-2-fluoro-N- (2-methoxypyridin-4-yl) benzamide (163mg, 0.5mmol), dimethylphosphine oxide (78mg, 1mmol), triethylamine (101mg, 1mmol), xanthphos (29mg, 0.05mmol) and 5mL dioxane, and after replacement of nitrogen gas, Pd was added₂(dba)₃(27mg, 0.03mmol) and the reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. Cooling the reaction system to roomAfter warming, the mixture is poured into 20mL of water, extracted with ethyl acetate, the organic phase is dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 1/1) to yield 100mg of the desired product: 62 percent.

And step 3: synthesis of 4- (dimethylphosphoryl) -2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) benzamide

To a reaction flask were added 4- (dimethylphosphoryl) -2-fluoro-N- (2-methoxypyridin-4-yl) benzamide (65mg, 0.2mmol), 4-fluoro-2-methylphenol (25mg, 0.2mmol), potassium carbonate (55mg, 0.4mmol) and 3mL of N-methylpyrrolidone, and the reaction mixture was heated to 100 ℃ and stirred for 20 hours. The reaction was cooled to room temperature and poured into 15mL of water, extracted with ethyl acetate, the organic phase dried and spun-dried and purified by TLC (PE/EA ═ 1/1) to give 45mg of the target product, yield: 52 percent.

And 4, step 4: synthesis of 4- (dimethylphosphoryl) -2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) benzamide

4- (Dimethylphosphoryl) -2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) benzamide (43mg, 0.1mmol) was dissolved in 2mL acetonitrile, potassium iodide (83mg, 0.5mmol) and TMSCl (55mg, 0.5mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 10/1) to give 30mg of the title product as a white solid in yield: 73 percent.

LC/MS:m/z＝415.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.61(3H,s),1.65(3H,s),2.17(3H,s),6.40(1H, d,J＝8.0Hz),6.78(1H,s),7.07-7.23(3H,m),7.31(1H,d,J＝7.4Hz),7.56-7.59(1H, m),7.71-7.73(1H,m),10.59(1H,s),11.27(1H,brs).

Example 13

N- (3- (guanidinocarbamoyl) -4-fluorophenyl) -5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Step 1: synthesis of methyl 5- (5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) -2-fluorobenzoate

To a reaction flask were added 5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (71mg, 0.2mmol), methyl 5-amino-2-fluorobenzoate (34mg, 0.2mmol), DIPEA (52mg, 0.4mmol) and 2mL tetrahydrofuran, HATU (114mg, 0.3mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and dried by rotary drying and purified by TLC (PE/EA-1/1) to yield 70mg of the desired product in 69% yield.

Step 2: synthesis of 5- (5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) -2-fluorobenzoic acid

To a reaction flask was added methyl 5- (5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) -2-fluorobenzoate (51mg, 0.1mmol), sodium hydroxide (16mg, 0.4mmol), 2mL of water and 2mL of methanol, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 10mL of water, pH adjusted to 4 with 1M hydrochloric acid, extracted with ethyl acetate, the organic phase dried and spun dry to yield 45mg of the target product, yield: 92 percent.

And step 3: synthesis of N- (3- (guanidinoformyl) -4-fluorophenyl) -5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

To a reaction flask were added 5- (5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) -2-fluorobenzoic acid (39mg, 0.08mmol), CDI (13mg, 0.08mmol) and 2mL of tetrahydrofuran, and after stirring at room temperature for 1 hour, DIPEA (78mg, 0.6mmol) and guanidine hydrochloride (38mg, 0.4mmol) were sequentially added, and the reaction mixture was stirred at 50 ℃ overnight. The reaction system was directly purified by reverse phase preparation to give 15mg of the target product as a white solid with a yield of 35%.

LC/MS:m/z＝533.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ0.86-0.90(2H,m),1.01-1.04(2H,m),2.07-2.09 (1H,m),2.17(3H,s),6.72(2H,brs),6.93(1H,s),7.01-7.13(3H,m),7.20(1H,dd,J＝ 8.8Hz,3.2Hz),7.37(1H,s),7.60-7.64(1H,m),7.96(2H,brs),7.99(1H,dd,J＝8.0Hz, 3.6Hz),10.50(1H,s).

Example 14

5-cyclopentyl-2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 5- (cyclopent-1-en-1-yl) -2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask was added 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (499mg, 1mmol), cyclopenten-1-ylboronic acid (224mg, 2mmol), sodium carbonate (424mg, 4mmol) and 10mL DMF, and after displacement of nitrogen, Pd (dppf) Cl was added₂(37mg, 0.05mmol) and the reaction mixture was heated to 90 ℃ under nitrogen and stirred overnight. The reaction system was cooled to room temperature and poured into 40mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 10/1) to afford 360mg of the target product, yield: 74 percent.

And 2, step: synthesis of 5-cyclopentyl-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask was added 5- (cyclopent-1-en-1-yl) -2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (243mg, 0.5mmol), 10% Pd/C (20mg) and 10mL methanol, and the reaction mixture was taken up at 0.2MPa H₂Stir at room temperature under pressure overnight and TLC showed the reaction was complete. Directly filtering the reaction system, and spin-drying the filtrate to obtain 230mg of a target product, wherein the yield is as follows: 94 percent.

And step 3: synthesis of 5-cyclopentyl-2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

5-cyclopentyl-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (49mg, 0.1mmol) was dissolved in 2mL acetonitrile, potassium iodide (83mg, 0.5mmol) and TMSCl (55mg, 0.5mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by TLC (DCM/MeOH ═ 10/1) to give 24mg of the title product as a white solid in yield: 51 percent.

LC/MS:m/z＝475.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.66(4H,brs),1.86(2H,brs),1.99(2H,brs),2.17 (3H,s),3.20(1H,brs),6.37(1H,dd,J＝8.0Hz,3.2Hz),6.76(1H,s),6.88(1H,s), 7.07-7.09(2H,m),7.20(1H,d,J＝8.8Hz),7.31(1H,d,J＝7.2Hz),7.82(1H,s),10.60 (1H,s),11.27(1H,brs).

Example 15

N- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) phenyl) -4-methylpiperazine-1-carboxamide

Step 1: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-nitrophenyl) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (63mg, 0.2mmol), 4-fluoro-3-nitroaniline (31mg, 0.2mmol), DIPEA (52mg, 0.4mmol) and 2mL tetrahydrofuran, HATU (114mg, 0.3mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction system was poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by TLC (PE/EA-1/1) to give 75mg of the target product in 83% yield.

Step 2: synthesis of N- (3-amino-4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

To a reaction flask was added 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-nitrophenyl) -4- (trifluoromethyl) benzamide (45mg, 0.1mmol), 10% Pd/C (5mg) and 5mL methanol, and the reaction mixture was H at 1MPa₂Stir at room temperature under pressure overnight and TLC showed the reaction was complete. Inverse directionThe reaction system was directly filtered and the filtrate was spin dried to give 42mg of the target product in yield: 100 percent.

And step 3: synthesis of N- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) phenyl) -4-methylpiperazine-1-carboxamide

N- (3-amino-4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide (42mg, 0.1mmol) and DIPEA (52mg, 0.4mmol) were dissolved in 2mL of tetrahydrofuran, 4-nitrophenyl chloroformate (20mg, 0.1mmol) was added at room temperature, and after the reaction system was stirred at room temperature for 1 hour, 1-methylpiperazine (10mg, 0.1mmol) was added, and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 20/1) to give 30mg of the target product as a white solid in yield: and 55 percent.

LC/MS:m/z＝549.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.16(3H,s),2.19(3H,s),2.30(4H,t,J＝6.4Hz), 3.42(4H,t,J＝6.4Hz),6.94(1H,s),7.09-7.11(2H,m),7.16(1H,d,J＝8.4Hz),7.22 (1H,d,J＝8.8Hz),7.33-7.35(1H,m),7.59(1H,d,J＝8.0Hz),7.82-7.84(2H,m),8.34 (1H,s),10.54(1H,s).

Examples 16, 17 and 18

(3- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) phenyl) (methyl) phosphinic acid

N- (3- (amino (methyl) phosphoryl) phenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

(3- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) phenyl ] (methyl) phosphinic acid methyl ester

Step 1: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (3-iodophenyl) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (314mg, 1mmol), 3-iodoaniline (319mg, 1mmol), DIPEA (258mg, 2mmol) and 5mL tetrahydrofuran, HATU (569mg, 1.5mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 20/1) to give 430mg of the target product in yield: 83 percent.

Step 2: synthesis of ethyl (3- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) phenyl ] (methyl) phosphinate

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -N- (3-iodophenyl) -4- (trifluoromethyl) benzamide (258mg, 0.5mmol), diethyl methylphosphonite (136mg, 1mmol), triethylamine (101mg, 1mmol), xanthphos (29mg, 0.05mmol) and 5mL dioxane, and after replacement of nitrogen, Pd was added₂(dba)₃(27mg, 0.03mmol) and the reaction mixture was heated to 110 ℃ under nitrogen and stirred for 6 hours. After the reaction system is cooled to room temperature, the reaction system is poured into 20mL of water, extracted with ethyl acetate, and the organic phase is dried and spun-dried and then purified by silica gel column chromatography (PE/EA: 10/1), yielding 172mg of the target product: and 69 percent.

And step 3: synthesis of (3- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) phenyl) (methyl) phosphinic acid

To a reaction flask was added ethyl (3- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) phenyl ] (methyl) phosphinate (149mg, 0.3mmol), sodium hydroxide (40mg, 1.0mmol), 5mL of water and 5mL of methanol, and the reaction mixture was stirred at room temperature overnight, the reaction was poured into 20mL of water, the pH was adjusted to 4 with 1M hydrochloric acid, extracted with ethyl acetate, and the organic phase was dried and spun dry to give 90mg of the desired product as a white solid in 96% yield.

LC/MS:m/z＝468.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.41-1.45(3H,m),2.16(3H,s),6.94(1H,s), 7.07-7.13(2H,m),7.21(1H,d,J＝8.2Hz),7.42-7.43(2H,m),7.59(1H,d,J＝8.2Hz), 7.79(1H,s),7.85(1H,d,J＝8.0Hz),8.10(1H,d,J＝13.0Hz),10.74(1H,brs).

And 4, step 4: synthesis of (3- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) phenyl) (methyl) phosphinic acid chloride

(3- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) phenyl) (methyl) phosphinic acid (47mg, 0.1mmol) was dissolved in 1mL phosphorus oxychloride and the reaction mixture was stirred at 80 ℃ for 1 hour. The reaction was spin dried and the solid obtained after twice washing with chloroform was used directly in the next reaction.

And 5: synthesis of N- (3- (amino (methyl) phosphoryl) phenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide and methyl (3- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) phenyl) (methyl) phosphinate

The solid obtained in the above step was added to 5mL of a 7M ammonia methanol solution, and the reaction mixture was stirred at room temperature overnight. The reaction was spun dry and purified directly by reverse phase preparative purification to afford example 17(20mg, white solid, yield 42%) and example 18(14mg, white solid, yield 30%).

Example 17 analytical data: LC/MS, M/z 467.1[ M + H ]]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.41-1.44(3H,m),2.17(3H,s),4.49(2H,s),6.94 (1H,s),7.10-7.12(2H,m),7.21(1H,d,J＝8.8Hz),7.43-7.53(2H,m),7.60(1H,d,J＝ 8.0Hz),7.84-7.87(2H,m),8.13(1H,d,J＝13.0Hz),10.78(1H,s).

Example 18 analytical data: LC/MS M/z 482.1[ M + H ]]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.62-1.66(3H,m),2.17(3H,s),3.48-3.51(2H, m),6.97(1H,s),7.10-7.11(2H,m),7.22(1H,d,J＝8.2Hz),7.44-7.48(2H,m),7.59(1H, d,J＝8.0Hz),7.77-7.86(2H,m),8.11(1H,d,J＝12.8Hz),10.68(1H,s).

Example 19

4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

Step 1: synthesis of 4-bromo-2-fluoro-5- (trifluoromethyl) aniline

2-fluoro-5- (trifluoromethyl) aniline (3.58g, 20mmol) was dissolved in 50mL DMF and NBS (3.56g, 20mmol) was added at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 200mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 2/1) to give 4.80g of the target product, yield: 93 percent.

Step 2: synthesis of 4-cyclopropyl-2-fluoro-5- (trifluoromethyl) aniline

To a reaction flask were added 4-bromo-2-fluoro-5- (trifluoromethyl) aniline (2.58g, 10mmol), cyclopropylboronic acid (3.44g, 40mmol), sodium carbonate (5.30g, 50mmol) and 30mL of DMF, and after displacement of nitrogen, Pd (dppf) Cl was added₂(220mg, 0.3mmol) and the reaction mixture was heated to 90 ℃ under nitrogen and stirred overnight. The reaction system was cooled to room temperature and poured into 200mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 2/1) to give 1.62g of the target product, yield: 74 percent.

And step 3: synthesis of 1-iodo-4-cyclopropyl-2-fluoro-5- (trifluoromethyl) benzene

4-cyclopropyl-2-fluoro-5- (trifluoromethyl) aniline (1.10g, 5mmol) was dissolved in 15mL of acetonitrile, isoamyl nitrite (0.70g, 6mmol) was added dropwise at 0 ℃ and the system was stirred at room temperature for 1 hour after the addition was completed. A5 mL aqueous solution of potassium iodide (1.66g, 10mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. The reaction system is poured into 50mL of water, ethyl acetate is used for extraction, the organic phase is backwashed by using 1M dilute hydrochloric acid, 1M sodium carbonate aqueous solution and saturated saline water in sequence, and after drying and spin-drying, 1.05g of target product is obtained, and the yield is as follows: 61 percent.

And 4, step 4: synthesis of 4-cyclopropyl-2-fluoro-5- (trifluoromethyl) benzoic acid

1-iodo-4-cyclopropyl-2-fluoro-5- (trifluoromethyl) benzene (660mg,2mmol) and triethylamine (404mg, 4mmol) were dissolved in DMF/H₂O (10mL/1mL), Pd (dppf) Cl₂(73mg, 0.1mmol), after replacing the air in the system with carbon monoxide, the reaction mixture was heated to 90 ℃ under carbon monoxide at a pressure of 1M Pa and stirred overnight. Cooling the reaction system to room temperature, pouring the cooled reaction system into 50mL of water, extracting with ethyl acetate, drying and spin-drying the organic phasePurification by silica gel column chromatography (DCM/MeOH ═ 10/1) afforded 190mg of the title product in yield: 38 percent.

And 5: synthesis of 4-cyclopropyl-2-fluoro-N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide

To a reaction flask were added 4-cyclopropyl-2-fluoro-5- (trifluoromethyl) benzoic acid (124mg, 0.5mmol), 2-methoxypyridin-4-amine (62mg, 0.5mmol), DIPEA (129mg, 1.0mmol) and 3mL tetrahydrofuran, HATU (303mg, 0.8mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (PE/EA ═ 1/1) to give 140mg of the target product in yield: 49 percent.

Step 6: synthesis of 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide

To a reaction flask were added 4-cyclopropyl-2-fluoro-N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (35mg, 0.1mmol), 4-fluoro-2-methylphenol (13mg, 0.1mmol), potassium carbonate (28mg, 0.2mmol) and 1mL of N-methylpyrrolidone, and the reaction mixture was heated to 80 ℃ and stirred for 8 hours. The reaction was cooled to room temperature and poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun-dried and purified by TLC (PE/EA ═ 1/1) to give 37mg of the target product in yield: 80 percent.

And 7: synthesis of 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (23mg, 0.05mmol) was dissolved in 1mL acetonitrile, potassium iodide (33mg, 0.2mmol) and TMSCl (22mg, 0.2mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was filtered directly and the filtrate was spun dry and purified by TLC (DCM/MeOH ═ 10/1) to give 8mg of the title product as a white solid in yield: 36 percent.

LC/MS:m/z＝467.1[M+H]⁺.

1H NMR(400MHz,CDCl₃)δ0.49-0.53(2H,m),1.02-1.07(2H,m),2.15-2.20(1H, m),2.22(3H,s),6.19(1H,s),6.66(1H,d,J＝2.0Hz),6.86(1H,dd,J＝7.2Hz,2.0Hz), 7.00-7.02(2H,m),7.08-7.10(1H,m),7.30(1H,d,J＝7.2Hz),8.57(1H,s),9.68(1H,s), 12.01(1H,brs).

Example 20

2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) -5-vinylbenzamide

Step 1: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) -5-vinylbenzamide

To a reaction flask was added 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (100mg, 0.2mmol), vinylboronic acid pinacol ester (62mg, 0.4mmol), sodium carbonate (63mg, 0.6mmol) and 2mL of DMF, and after replacement of nitrogen, Pd (dppf) Cl was added₂(7mg, 0.01mmol) and the reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction system was cooled to room temperature and poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and spun-dried and purified by silica gel column chromatography (PE/EA ═ 2/1) to give 44mg of the target product, yield: 49 percent.

Step 2: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) -5-vinylbenzamide

2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) -5-vinylbenzamide (22mg, 0.05mmol) was dissolved in 1mL acetonitrile, and potassium iodide (33mg, 0.2mmol) and TMSCl (22mg, 0.2mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was directly filtered, the filtrate was spun dry and purified by TLC (DCM/MeOH — 10/1) to give 12mg of the title product as a white solid in yield: 54 percent.

LC/MS:m/z＝433.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.17(3H,s),5.54(1H,d,J＝11.6Hz),6.07(1H, d,J＝17.2Hz),6.38(1H,d,J＝7.0Hz),6.77(1H,s),6.89-6.94(2H,m),7.09(1H,s), 7.10(1H,s),7.23(1H,d,J＝8.6Hz),7.32(1H,d,J＝7.2Hz),8.10(1H,s),10.66(1H,s), 11.28(1H,brs).

Example 21

5-ethynyl-2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) -5- ((trimethylsilyl) ethynyl) benzamide

To a reaction flask, 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (100mg, 0.2mmol), trimethylethynylsilicon (196mg, 2mmol), triethylamine (101mg, 1mmol), cuprous iodide (4mg, 0.02mmol) and 2mL of DMF were added, nitrogen was replaced, Pd (PPh)₂Cl₂(7mg, 0.01mmol) and the reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction system was cooled to room temperature and poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 60mg of the target product, yield: 58 percent.

Step 2: synthesis of 5-ethynyl-2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) -5- ((trimethylsilyl) ethynyl) benzamide (52mg, 0.1mmol) was dissolved in 2mL of 40% HBr in acetic acid and the mixture was stirred at 70 ℃ overnight. The reaction was cooled to room temperature and poured into 10mL of water, pH adjusted to 8 with sodium carbonate, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 10/1) to give 10mg of the target product as a white solid in yield: 23 percent.

LC/MS:m/z＝431.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.16(3H,s),4.47(1H,s),6.38(1H,d,J＝7.2Hz), 6.79(1H,s),6.91-6.93(1H,m),7.10-7.13(2H,m),7.23(1H,d,J＝8.4Hz),7.31(1H,d, J＝7.2Hz),8.24(1H,s),10.61(1H,s),11.27(1H,brs).

Example 22

2- (4-fluoro-2-methylphenoxy) -5- (1-fluorocyclopropyl) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (4-fluoro-2-methylphenoxy) -5- (1-fluorovinyl) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide

Triethylamine trihydrofluoride (483mg, 3mmol) was added dropwise to a solution of 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) -5-vinylbenzamide (446mg, 1mmol) in 10mL of dichloromethane at 0 ℃ for 5 minutes, followed by addition of NBS (178mg, 1mmol), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 20mL of water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried and spin-dried. The resulting solid was dissolved in 10mL of tetrahydrofuran, and after adding potassium tert-butoxide (224mg, 2mmol), the reaction was stirred at 50 ℃ for 2 hours. The reaction solution was cooled to room temperature and poured into 30mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA-1/1) to give 185mg of the target product in yield: 40 percent.

Step 2: synthesis of 2- (4-fluoro-2-methylphenoxy) -5- (1-fluorocyclopropyl) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide

Diethyl zinc (1M in N-hexane, 1mL, 1mmol) was added dropwise to a solution of diiodomethane (268mg, 1mmol) in 5mL of dry dichloromethane at 0 deg.C under nitrogen, after stirring the reaction system at 0 deg.C for 0.5 hour, trifluoroacetic acid (114mg, 1mmol) was added dropwise slowly, after stirring for 0.5 hour, a solution of 2- (4-fluoro-2-methylphenoxy) -5- (1-fluoroethyl) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (185mg, 0.4mmol) in 2mL of dichloromethane was added slowly, and after addition the system was stirred at room temperature overnight. The reaction solution was poured into 20mL of water, the pH was adjusted to 8 with sodium carbonate, extracted with dichloromethane, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 50mg of the target product, yield: 26 percent.

And step 3: synthesis of 2- (4-fluoro-2-methylphenoxy) -5- (1-fluorocyclopropyl) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

2- (4-fluoro-2-methylphenoxy) -5- (1-fluorocyclopropyl) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (48mg, 0.1mmol) was dissolved in 2mL acetonitrile, potassium iodide (83mg, 0.5mmol) and TMSCl (55mg, 0.5mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 10/1) to give 30mg of the title product as a white solid in yield: 65 percent.

LC/MS:m/z＝465.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.20-1.30(2H,m),1.33-1.46(2H,m),2.16(3H, s),6.37(1H,d,J＝7.2Hz),6.76(1H,s),7.00(1H,s),7.12-7.14(2H,m),7.25(1H,d,J＝ 8.0Hz),7.32(1H,d,J＝7.6Hz),7.99(1H,s),10.67(1H,s),11.29(1H,s).

Example 23

5- (2, 2-Difluorocyclopropyl) -2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 5- (2, 2-difluorocyclopropyl) -2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide

A mixture of 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) -5-vinylbenzamide (446mg, 1mmol), 2- (fluorosulfonyl) difluoroacetic acid trimethylsilyl ester (500mg, 2mmol) and sodium fluoride (8mg, 0.2mmol) was heated to 110 ℃ and stirred for 6 hours. After cooling to room temperature, 30mL of water was poured into the system, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 260mg of the target product in yield: 52 percent.

Step 2: synthesis of 5- (2, 2-difluorocyclopropyl) -2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

5- (2, 2-Difluorocyclopropyl) -2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (50mg, 0.1mmol) was dissolved in 2mL acetonitrile, potassium iodide (83mg, 0.5mmol) and TMSCl (55mg, 0.5mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 10/1) to give 25mg of the title product as a white solid in yield: 52 percent.

LC/MS:m/z＝483.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.03-2.10(1H,m),2.16(3H,s),2.29-2.37(1H, m),3.06-3.13(1H,m),6.37(1H,dd,J＝7.2Hz,1.6Hz),6.76(1H,s),7.00(1H,s), 7.08-7.10(2H,m),7.22(1H,d,J＝8.8Hz),7.31(1H,d,J＝7.2Hz),7.75(1H,s),10.65 (1H,s),11.28(1H,brs).

Example 24

2- (4-fluoro-2-methylphenoxy) -5- ((1-methylpiperidin-4-yl) oxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -5- ((1-methylpiperidin-4-yl) oxy) -4- (trifluoromethyl) benzamide

To a reaction flask was added 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (100mg, 0.2mmol), 1-methylpiperidin-4-ol (115mg, 1mmol), potassium phosphate (85mg, 0.4mmol), L-proline (12mg, 0.1mmol), cuprous iodide (19mg, 0.1mmol) and 2mL toluene, and the reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. The reaction was cooled to room temperature and poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun-dried and purified by silica gel column chromatography (DCM/MeOH ═ 20/1) to give 12mg of the desired product in yield: 11 percent.

Step 2: synthesis of 2- (4-fluoro-2-methylphenoxy) -5- ((1-methylpiperidin-4-yl) oxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -5- ((1-methylpiperidin-4-yl) oxy) -4- (trifluoromethyl) benzamide (11mg, 0.02mmol) was dissolved in 2mL acetonitrile, potassium iodide (17mg, 0.1mmol) and TMSCl (11mg, 0.1mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 10/1) to give 3mg of the title product as a white solid in yield: 29 percent.

LC/MS:m/z＝520.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.62-1.66(2H,m),2.01-2.08(2H,m),2.17(3H, s),2.39(3H,s),2.73-2.85(4H,m),3.98-4.02(1H,m),6.39(1H,d,J＝7.2Hz),6.79(1H, s),6.90-6.93(1H,m),7.08-7.12(2H,m),7.17(1H,s),7.20(1H,d,J＝8.8Hz),7.32(1H, d,J＝7.2Hz),10.64(1H,s),11.27(1H,brs).

Example 25

N- (4- (2-aminoethoxy) -3-formylguanidino-phenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Step 1: synthesis of methyl 2- (2- (((tert-butoxycarbonyl) amino) ethoxy) -5-nitrobenzoate

Methyl 2-hydroxy-5-nitrobenzoate (1.97g, 10mmol), (tert-butyl 2-bromoethyl) carbamate (2.24g, 10mmol), potassium carbonate (2.76g, 20mmol) and 20mL of DMF were added to a reaction flask and the reaction mixture was heated to 80 ℃ and stirred overnight. The reaction system was cooled to room temperature and poured into 100mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 2.40g of the target product, yield: 70 percent.

Step 2: synthesis of methyl 5-amino-2- (2- (((tert-butoxycarbonyl) amino) ethoxy) benzoate

To a reaction flask was added methyl 2- (2- (((tert-butoxycarbonyl) amino) ethoxy) -5-nitrobenzoate (2.40g, 7.1mmol), 10% Pd/C (200mg) and 50mL methanol, and the reaction mixture was H at 0.2MPa₂Stir at room temperature under pressure overnight and TLC showed the reaction was complete. The reaction system was directly filtered and the filtrate was spin dried to obtain 2.10g of the target product, yield: 96 percent.

And step 3: synthesis of methyl 2- (2- ((tert-butoxycarbonyl) amino) ethoxy) -5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoate

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (628mg, 2mmol), methyl 5-amino-2- (2- (((tert-butoxycarbonyl) amino) ethoxy) benzoate (620mg, 2mmol), DIPEA (516mg, 4mmol) and 10mL of tetrahydrofuran, HATU (1137mg, 3mmol) was added at room temperature, the reaction mixture was stirred at room temperature overnight, the reaction was poured into 40mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 865mg of the objective product with a yield of 71%.

And 4, step 4: synthesis of 2- (2- ((tert-butoxycarbonyl) amino) ethoxy) -5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoic acid

To a reaction flask was added methyl 2- (2- ((tert-butoxycarbonyl) amino) ethoxy) -5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoate (607mg, 1mmol), sodium hydroxide (160mg, 4mmol), 10mL of water and 10mL of methanol, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 40mL of water, pH adjusted to 5 with 1M dilute hydrochloric acid, extracted with ethyl acetate, the organic phase dried and spun dry and purified by silica gel column chromatography (DCM/MeOH ═ 10/1) to give 466mg of the desired product, yield: 79 percent.

And 5: synthesis of tert-butyl (2- (2-formylguanidino-4- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) phenoxy) ethyl) carbamate

To a reaction flask were added 2- (2- ((tert-butoxycarbonyl) amino) ethoxy) -5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoic acid (296mg, 0.5mmol), CDI (81mg, 0.5mmol) and 5mL tetrahydrofuran, and after stirring at room temperature for 1 hour, DIPEA (258mg, 2.0mmol) and guanidine hydrochloride (96mg, 1.0mmol) were successively added, and the reaction mixture was stirred at 50 ℃ overnight. The reaction system is directly prepared and purified by reverse phase to obtain 90mg of target product with the yield of 28 percent.

Step 6: synthesis of N- (4- (2-aminoethoxy) -3-formylguanidino-phenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Tert-butyl (2- (2-formylguanidino-4- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) phenoxy) ethyl) carbamate (66mg, 0.1mmol) was dissolved in 2mL trifluoroacetic acid and the reaction mixture was stirred at room temperature for 2 hours. After the reaction system was spin dried, 2mL of methanol was added, the pH was adjusted to 8 with 1M aqueous sodium carbonate solution and the mixture was directly purified by reverse phase preparative purification to give 20mg of the target product as a white solid with yield: 38 percent.

LC/MS:m/z＝534.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.16(3H,s),3.03(2H,t,J＝7.2Hz),4.24(2H,t, J＝7.2Hz),6.94(1H,s),7.10-7.14(3H,m),7.22(1H,d,J＝8.4Hz),7.55-7.63(3H,m), 7.81-7.83(2H,m),8.35(3H,brs),10.50(1H,s)

Example 26

N-amidino-3- ((dimethylamino) methyl) -2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzamide

Step 1: synthesis of methyl 3- (bromomethyl) -2-fluoro-5-nitrobenzoate

To a reaction flask were added methyl 2-fluoro-3-methyl-5-nitrobenzoate (2.13g, 10mmol), NBS (1.78g, 10mmol), BPO (485mg, 2mmol) and 30mL acetonitrile, and the reaction mixture was stirred at 70 ℃ overnight. The reaction system was cooled to room temperature and poured into 100mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 10/1) to give 1.55g of the target product, yield: 53 percent.

Step 2: synthesis of methyl 3- ((dimethylamino) methyl) -2-fluoro-5-nitrobenzoate

To a reaction flask was added methyl 3- (bromomethyl) -2-fluoro-5-nitrobenzoate (1.46g, 5mmol), dimethylamine (450mg, 10mmol), potassium carbonate (1.38g, 10mmol) and 20mL DMF, and the reaction mixture was heated to 50 ℃ and stirred overnight. The reaction system was cooled to room temperature and poured into 100mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 3/1) to give 870mg of the target product, yield: 68 percent.

And step 3: synthesis of methyl 5-amino-3- (((dimethylamino) methyl) -2-fluorobenzoate

To a reaction flask was added methyl 3- ((dimethylamino) methyl) -2-fluoro-5-nitrobenzoate (870mg, 3.4 mmol), 10% Pd/C (100mg) and 20mL methanol, and the reaction mixture was H at 0.2MPa₂Stir at room temperature under pressure overnight and TLC showed the reaction was complete. Directly filtering the reaction system, and spin-drying the filtrate to obtain 770mg of a target product, wherein the yield is as follows: 100 percent.

And 4, step 4: synthesis of methyl 3- ((dimethylamino) methyl) -2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoate

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (628mg, 2mmol), methyl 5-amino-3- (((dimethylamino) methyl) -2-fluorobenzoate (452mg, 2mmol), DIPEA (516mg, 4mmol) and 10mL tetrahydrofuran, HATU (1137mg, 3mmol) was added at room temperature, the reaction mixture was stirred at room temperature overnight, the reaction was poured into 40mL water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 630mg of the objective product with a yield of 60%.

And 5: synthesis of 3- ((dimethylamino) methyl) -2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoic acid

To a reaction flask was added methyl 3- ((dimethylamino) methyl) -2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoate (522mg, 1mmol), sodium hydroxide (160mg, 4mmol), 10mL water and 10mL methanol, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 40mL of water, the pH was adjusted to 5 with 1M dilute hydrochloric acid, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by column chromatography on silica gel (DCM/MeOH ═ 10/1) to give 440mg of the desired product, yield: 87 percent.

Step 6: synthesis of N-amidino-3- ((dimethylamino) methyl) -2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzamide

To a reaction flask were added 3- ((dimethylamino) methyl) -2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoic acid (254mg, 0.5mmol), CDI (81mg, 0.5mmol) and 5mL tetrahydrofuran, and after stirring at room temperature for 1 hour, DIPEA (258mg, 2.0mmol) and guanidine hydrochloride (96mg, 1.0mmol) were sequentially added, and the reaction mixture was stirred at 50 ℃ overnight. The reaction system was directly purified by reverse phase preparation to obtain 45mg of the target product as a white solid with yield: 16 percent.

LC/MS:m/z＝550.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.17(3H,s),2.71(6H,s),3.84(2H,s),6.73(2H, brs),6.96(1H,s),7.10-7.16(3H,m),7.22(1H,d,J＝8.8Hz),7.85(1H,d,J＝8.4Hz), 7.95(2H,brs),8.04(1H,dd,J＝8.0Hz,2.0Hz),8.36(1H,s),10.57(1H,s).

Examples 27 and 28

2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (2-iminoimidazolidine-1-carbonyl) phenyl) -4- (trifluoromethyl) benzamide

N- (3- ((4, 5-dihydro-1H-imidazol-2-yl) carbamoyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoic acid (226mg, 0.5mmol), CDI (81mg, 0.5mmol) and 5mL tetrahydrofuran were added to a reaction flask, and after stirring at room temperature for 1 hour, DIPEA (258mg, 2.0mmol) and imidazolidinyl-2-imine hydrochloride (122mg, 1.0mmol) were sequentially added, and the reaction mixture was stirred at 50 ℃ overnight. The reaction was directly purified by reverse phase preparative purification to give example 27(15mg, white solid, yield 6%) and example 28(66mg, white solid, yield 25%).

Example 27 analytical data: LC/MS M/z 519.2[ M + H ]]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.17(3H,s),3.73(2H,t,J＝7.6Hz),3.86(2H,t, J＝7.6Hz),6.94(1H,s),7.11-7.15(3H,m),7.22(1H,d,J＝8.8Hz),7.59-7.65(2H,m), 7.83(1H,d,J＝8.0Hz),8.02(1H,d,J＝8.4Hz),8.33(2H,brs),10.57(1H,s).

Example 28 analytical data: LC/MS M/z 519.2[ M + H ]]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.16(3H,s),3.97(4H,brs),6.94(1H,s), 7.10-7.14(3H,m),7.23(1H,d,J＝8.8Hz),7.59-7.65(2H,m),7.83(1H,d,J＝8.0Hz), 8.02(1H,d,J＝8.4Hz),8.29(1H,brs),10.62(1H,s).

Example 29

2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (guanidinomethyl) phenyl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (bromomethyl) -1-fluoro-4-nitrobenzene

To a reaction flask were added 1-fluoro-2-methyl-4-nitrobenzene (1.55g, 10mmol), NBS (1.78g, 10mmol), BPO (485mg, 2mmol) and 30mL acetonitrile, and the reaction mixture was stirred at 70 ℃ overnight. The reaction system was cooled to room temperature and poured into 100mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 10/1) to give 2.00g of the target product, yield: 85 percent.

Step 2: synthesis of 1- (2-fluoro-5-nitrobenzyl) guanidine

Guanidine hydrochloride (955mg, 10mmol) is dissolved in 20mL DMF and potassium tert-butoxide (2.24g, 20mmol) is added at RT and after stirring for 0.5 h, 2- (bromomethyl) -1-fluoro-4-nitrobenzene (1.17g, 5mmol) is added and the reaction mixture is heated to 50 ℃ and stirred overnight. The reaction was cooled to room temperature and poured into 100mL of water, extracted with ethyl acetate, the organic phase dried and spun-dried and purified by silica gel column chromatography (DCM/MeOH ═ 10/1) to afford 560mg of the target product, yield: 53 percent.

And 3, step 3: synthesis of 1- (5-amino-2-fluorobenzyl) guanidine

1- (2-fluoro-5-nitrobenzyl) guanidine (424mg, 2mmol) was dissolved in 5mL of acetic acid, iron powder (560mg, 10mmol) was added at room temperature, and the mixture was stirred at 70 ℃ for 2 hours. Filtering a reaction system, drying the filtrate by spinning, and then performing reversed-phase preparation and purification to obtain 230mg of a target product, wherein the yield is as follows: and 63 percent.

And 4, step 4: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (guanidinomethyl) phenyl) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (314mg, 1mmol), 1- (5-amino-2-fluorobenzyl) guanidine (182mg, 1mmol), DIPEA (258mg, 2mmol) and 5mL tetrahydrofuran, HATU (570mg, 1.5mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by silica gel column chromatography (DCM/MeOH ═ 10/1) to give 30mg of the title product as a white solid in yield: 6 percent.

LC/MS:m/z＝479.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.16(3H,s),4.88(2H,s),5.16(4H,brs),6.94 (1H,s),7.07-7.14(3H,m),7.23(1H,d,J＝8.8Hz),7.29-7.31(1H,m),7.42(1H,d,J＝ 8.0Hz),7.50-7.53(1H,m),7.81(1H,d,J＝8.0Hz),10.50(1H,s).

Example 30

2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-guanidinophenyl) -4- (trifluoromethyl) benzamide

To a reaction flask were added N- (3-amino-4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide (42mg, 0.1mmol), cyanamide (21mg, 0.5mmol) and 3mL ethanol, and the reaction mixture was stirred at 80 ℃ for 2 days. The reaction system was directly purified by reverse phase preparation to obtain 8mg of the target product as a white solid with yield: 17 percent.

LC/MS:m/z＝465.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.17(3H,s),5.50(4H,brs),6.92(1H,s), 6.99-7.04(1H,m),7.10-7.12(2H,m),7.21-7.26(3H,m),7.57(1H,d,J＝8.0Hz),7.80 (1H,d,J＝7.6Hz),10.37(1H,s).

Example 31

N- (3- ((N- (4-aminobutyl) carbamimidoyl) carbamoyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Step 1: synthesis of tert-butyl (4- (3- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoyl) guanidino) butyl) carbamate

2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoic acid (226mg, 0.5mmol), CDI (81mg, 0.5mmol) and 5mL tetrahydrofuran were added to a reaction flask, and after stirring at room temperature for 1 hour, DIPEA (258mg, 2.0mmol) and tert-butyl (4-guanidinobutyl) carbamate (230mg, 1.0mmol) were added in this order, and the reaction mixture was stirred at 50 ℃ overnight. The reaction system is directly subjected to reverse phase preparation and purification to obtain 85mg of target product with the yield of 26%.

Step 2: synthesis of N- (3- ((N- (4-aminobutyl) carbamimidoyl) carbamoyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Tert-butyl (4- (3- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoyl) guanidino) butyl) carbamate (66mg, 0.1mmol) was dissolved in 2mL of trifluoroacetic acid and the reaction mixture was stirred at room temperature for 2 hours. After the reaction system was spin dried, 2mL of methanol was added, the pH was adjusted to 8 with 1M aqueous sodium carbonate solution and the mixture was directly purified by reverse phase preparative purification to give 30mg of the target product as a white solid with yield: 54 percent.

LC/MS:m/z＝564.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.63-1.70(4H,m),2.17(3H,s),2.77-2.79(2H, m),3.50-3.54(2H,m),5.25(2H,brs),6.68(1H,brs),6.95(1H,s),7.10-7.14(3H,m), 7.23(1H,d,J＝8.8Hz),7.59-7.63(2H,m),7.82(1H,brs),7.84(1H,d,J＝8.0Hz),7.90 (1H,brs),8.02(1H,dd,J＝8.0Hz,2.0Hz),10.61(1H,s).

Example 32

N- (3- (guanidinoformyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (1-hydroxycyclopropyl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of methyl 5-acetyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate

To a reaction flask were added methyl 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (4.07 g, 10mmol), tributyl (1-ethoxyethylene) tin (3.61g, 10mmol) and 50mL DMF, and after replacement of nitrogen, Pd (PPh) was added₂Cl₂(351mg, 0.5mmol) and the reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. After the reaction system was cooled to room temperature, it was poured into 100mL of water, 10mL of concentrated hydrochloric acid was added, the mixture was stirred for 1 hour, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 6/1), yielding 2.80g of the target product, yield: 76 percent.

Step 2: synthesis of methyl 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilyl) oxy) ethenyl) benzoate

To a reaction flask, 5-acetyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid methyl ester (1.85g, 5mmol), triethylamine (1.01g, 10mmol) and 20mL of dichloromethane were added, and after cooling to 0 deg.C, trimethylsilyl trifluoromethanesulfonate (1.11g, 5mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was poured into 100mL of water, extracted with dichloromethane, and the organic phase was dried and spun to give 2.25g of crude product, which was used directly in the next reaction.

And step 3: synthesis of methyl 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilyl) oxy) cyclopropyl) benzoate

Diethyl zinc (1M in n-hexane, 15mL, 15mmol) was added dropwise to a solution of diiodomethane (4.02g, 15mmol) in 50mL of dry dichloromethane at 0 ℃ under nitrogen protection, after the reaction system was stirred at 0 ℃ for 0.5 h, a solution of methyl 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilanyl) oxy) vinyl) benzoate (2.21g, 5mmol) in 10mL of dichloromethane was slowly added dropwise, after which the system was stirred at room temperature overnight, the reaction solution was poured into 200mL of water, extracted with dichloromethane, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA 10/1) to give 1.05g of the desired product in 46% yield.

And 4, step 4: synthesis of 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilyl) oxy) cyclopropyl) benzoic acid

To a reaction flask were added methyl 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilyl) oxy) cyclopropyl) benzoate (912mg, 2mmol), lithium hydroxide monohydrate (168mg, 4mmol), 10mL of water and 10mL of methanol, and the reaction mixture was stirred at room temperature overnight after which the reaction system was poured into 40mL of water, the starting material for the reaction was removed by extraction with diethyl ether, the aqueous phase was adjusted to pH 7 with 1M dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was dried and spun dry to give 745mg of the desired product in 84% yield.

And 5: synthesis of methyl 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilyl) oxy) cyclopropyl) benzamido) benzoate

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilyl) oxy) cyclopropyl) benzoic acid (442mg, 1mmol), methyl 5-amino-2-fluorobenzoate (169mg, 1mmol), DIPEA (258mg, 2mmol) and 8mL tetrahydrofuran, HATU (569mg, 1.5mmol) was added at room temperature, the reaction mixture was stirred at room temperature overnight, the reaction was poured into 30mL water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 4/1) to give 390mg of the desired product in 66% yield.

Step 6: synthesis of 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilyl) oxy) cyclopropyl) benzamido) benzoic acid

To a reaction flask were added methyl 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsily) oxy) cyclopropyl) benzamido) benzoate (297mg, 0.5mmol), lithium hydroxide monohydrate (42mg, 1mmol), 5mL of water and 5mL of methanol, and the reaction mixture was stirred at room temperature overnight, the reaction system was poured into 20mL of water, after removing unreacted starting materials by extraction with diethyl ether, the aqueous phase was adjusted to pH 7 with 1M dilute hydrochloric acid, extracted with ethyl acetate, the organic phase was dried and spun dry to give 215mg of the desired product in 74% yield.

And 7: synthesis of N- (3- (guanidinoformyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (1-hydroxycyclopropyl) -4- (trifluoromethyl) benzamide

To a reaction flask was added 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilyl) oxy) cyclopropyl) benzamido) benzoic acid (116mg, 0.2mmol), CDI (32mg, 0.2mmol) and 3mL tetrahydrofuran, and after stirring at room temperature for 1 hour, DIPEA (129mg, 1.0mmol) and guanidine hydrochloride (48mg, 0.5mmol) were added in sequence, and the reaction mixture was stirred at 50 ℃ overnight, 0.5mL water and 0.5mL acetic acid were added to the reaction and after stirring for 0.5 hour, the reaction was directly purified by reverse phase preparation to give 18mg of the desired product as a white solid in 16% yield.

LC/MS:m/z＝549.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ0.95-0.98(2H,m),1.01-1.05(2H,m),2.18(3H, s),5.88(1H,s),6.73(2H,brs),6.89(1H,s),7.08-7.13(2H,m),7.23(1H,dd,J＝9.2Hz, 2.4Hz),7.33(1H,d,J＝7.2Hz),7.64(1H,d,J＝8.0Hz),7.79(1H,s),7.96(2H,brs), 8.12(1H,s),10.53(1H,s).

Example 33

N- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -2-oxo-1, 2-dihydropyridine-4-carboxamide

Step 1: synthesis of 4-fluoro-2-methyl-1- (2-nitro-5- (trifluoromethyl) phenoxy) benzene

To a reaction flask were added 3-fluoro-4-nitrobenzotrifluoride (209mg, 1mmol), 4-fluoro-2-methylphenol (126 mg,1mmol), potassium carbonate (276mg, 2mmol) and 5mL acetonitrile, and the reaction mixture was heated to 60 ℃ and stirred overnight. The reaction was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun-dried and purified by TLC (PE/EA ═ 10/1) to give 280mg of the target product in yield: 89 percent.

Step 2: synthesis of 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) aniline

To a reaction flask was added 4-fluoro-2-methyl-1- (2-nitro-5- (trifluoromethyl) phenoxy) benzene (158mg,0.5mmol), 10% Pd/C (20mg) and 5mL methanol, and the reaction mixture was H/C at 0.2MPa₂Stir overnight at room temperature under pressure and TLC showed the reaction was complete. The reaction system was directly filtered and the filtrate was spin dried to give 140mg of the target product, yield: 98 percent.

And step 3: synthesis of N- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) -2-oxo-1, 2-dihydropyridine-4-carboxamide

To a reaction flask were added 2-oxo-1, 2-dihydropyridine-4-carboxylic acid (14mg, 0.1mmol), 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) aniline (29mg, 0.1mmol), DIPEA (39mg, 0.3mmol) and 2mL tetrahydrofuran, HATU (76mg, 0.2mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 20/1) to give 26mg of the title product as a white solid in 63% yield.

LC/MS:m/z＝407.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.17(3H,s),6.65-6.68(2H,m),6.85(1H,s), 7.05-7.11(2H,m),7.21-7.27(2H,m),7.35(1H,d,J＝7.6Hz),8.00(1H,d,J＝8.0Hz), 10.06(1H,s),11.16(1H,brs).

Example 34

2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) -5- (1- (trifluoromethyl) cyclopropyl) benzamide

Step 1: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) -5- (3,3, 3-trifluoroprop-1-en-2-yl) benzamide

To a reaction flask was added 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (100mg, 0.2mmol), (3,3, 3-trifluoroprop-1-en-2-yl) boronic acid (56mg, 0.4mmol), sodium carbonate (63mg, 0.6mmol) and 2mL DMF, and after displacement of nitrogen, Pd (dppf) Cl was added₂(7mg, 0.01mmol) and the reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction system was cooled to room temperature and poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 2/1) to give 65mg of the target product, yield: and 63 percent.

Step 2: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) -5- (1- (trifluoromethyl) cyclopropyl) benzamide

Diethyl zinc (1M in N-hexane, 0.3mL, 0.3mmol) was added dropwise to a solution of diiodomethane (80mg, 0.3mmol) in 3mL of dry dichloromethane at 0 deg.C under nitrogen, and after stirring the reaction system at 0 deg.C for 0.5 h, a solution of 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) -5- (3,3, 3-trifluoroprop-1-en-2-yl) benzamide (51M g,0.1 mmol) in 10mL of dichloromethane was slowly added dropwise, and after addition the system was stirred at room temperature overnight. The reaction solution was poured into 10mL of water, extracted with dichloromethane, the organic phase was dried and spun dry and purified by TLC (PE/EA ═ 2/1) to give 28mg of the target product in yield: 53 percent.

And step 3: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) -5- (1- (trifluoromethyl) cyclopropyl) benzamide

2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) -5- (1- (trifluoromethyl) cyclopropyl) benzamide (11mg, 0.02mmol) was dissolved in 2mL acetonitrile and potassium iodide (17mg, 0.1mmol) and TMSCl (11mg, 0.1mmol) were added at room temperature and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 10/1) to give 6mg of the title product as a white solid in yield: 60 percent.

LC/MS:m/z＝515.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.24-1.27(2H,m),1.86-1.89(2H,m),2.16(3H, s),6.35(1H,dd,J＝7.2Hz,1.6Hz),6.74(1H,s),6.93(1H,s),7.00-7.07(2H,m),7.23 (1H,dd,J＝9.2Hz,2.8Hz),7.32(1H,d,J＝7.2Hz),8.13(1H,s),10.52(1H,s),11.20 (1H,brs).

Example 35

Step 1: synthesis of 4-amino-5-bromo-2-fluorobenzoic acid methyl ester

Methyl 4-amino-2-fluorobenzoate (1.69g, 10mmol) was dissolved in 20mL acetonitrile, NBS (1.78g, 10mmol) was added at room temperature, and the mixture was stirred at room temperature overnight. The reaction was spun down and purified by silica gel column chromatography (DCM/MeOH ═ 20/1) to afford 1.90g of the title product in yield: 77 percent.

Step 2: synthesis of methyl 5-bromo-2-fluoro-4-iodobenzoate

Methyl 4-amino-5-bromo-2-fluorobenzoate (1.24g, 5mmol) was dissolved in 15mL acetonitrile, isoamyl nitrite (0.70g, 6mmol) was added dropwise at 0 deg.C, and the system was stirred at room temperature for 1 hour after the addition was completed. A5 mL aqueous solution of potassium iodide (1.66g, 10mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. The reaction system was poured into 50mL of water, extracted with ethyl acetate, and the organic phase was backwashed with 1M dilute hydrochloric acid, 1M aqueous sodium carbonate solution and saturated brine in this order, dried and spin-dried and then purified by FCC (PE/EA ═ 20/1) to give 1.20g of the desired product, yield: 67%.

And step 3: synthesis of methyl 5-bromo-2-fluoro-4- (perfluoroethyl) benzoate

Methyl 5-bromo-2-fluoro-4-iodobenzoate (718mg, 2mmol), sodium pentafluoropropionate (272mg, 2mmol) and cuprous iodide (191mg, 1mmol) were added to a reaction flask, nitrogen was replaced, 10mL of anhydrous NMP was added, and the reaction mixture was heated to 150 ℃ under nitrogen and stirred overnight. The reaction system was cooled to room temperature and poured into 50mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA-20/1) to yield 330mg of the target product: and 47 percent.

And 4, step 4: synthesis of methyl 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (perfluoroethyl) benzoate

To a reaction flask were added methyl 5-bromo-2-fluoro-4- (perfluoroethyl) benzoate (70mg, 0.2mmol), 4-fluoro-2-methylphenol (25mg, 0.2mmol), potassium carbonate (55mg, 0.4mmol) and 3mL of N-methylpyrrolidone, and the reaction mixture was heated to 80 ℃ and stirred overnight. The reaction was cooled to room temperature and poured into 15mL of water, extracted with ethyl acetate, the organic phase dried and spun-dried and purified by TLC (PE/EA ═ 10/1) to give 60mg of the target product in yield: 66 percent.

And 5: synthesis of methyl 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (perfluoroethyl) benzoate

Example 35 was obtained according to the same protocol as example 10, starting from the corresponding substrate

LC/MS:m/z＝497.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ0.85-0.88(2H,m),1.00-1.05(2H,m),2.06-2.11 (1H,m),2.17(3H,s),6.36(1H,dd,J＝7.2Hz,1.6Hz),6.56(1H,s),6.93(1H,s), 7.02-7.09(2H,m),7.20(1H,dd,J＝8.8Hz,2.8Hz),7.32(1H,d,J＝7.2Hz),8.03(1H, s),10.56(1H,s),11.22(1H,brs).

Example 36

5-cyclopropyl-2- (4-fluoro-2- (methyl-d 3) phenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 4-fluoro-2- (methyl-d 3) phenol

5-fluoro-2-hydroxybenzoic acid (156mg, 1mmol) and triethylamine (303mg, 3mmol) were dissolved in 5mL of dry tetrahydrofuran, and methyl chloroformate (190mg, 2mmol) was added dropwise at 0 ℃ and the mixture was stirred at room temperature for 1 hour after the addition. Suction filtration, spin drying the filtrate, dissolving in 5mL dry tetrahydrofuran, adding NaBD₄(168mg, 4mmol) of 2mL of deuterated aqueous solution, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 20mL of water, the pH was adjusted to 5 with 1M dilute hydrochloric acid, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 3/1) to give 90mg of the desired product, yield: 70 percent.

Step 2: synthesis of methyl 5-bromo-2- (4-fluoro-2- (methyl-d 3) phenoxy) -4- (trifluoromethyl) benzoate

To a reaction flask were added methyl 5-bromo-2-fluoro-4- (trifluoromethyl) benzoate (150mg, 0.5mmol), 4-fluoro-2- (methyl-d 3) phenol (65mg, 0.5mmol), potassium carbonate (138mg, 1.0mmol) and 3mL of N-methylpyrrolidone, and the reaction mixture was heated to 100 ℃ and stirred overnight. The reaction was cooled to room temperature and poured into 15mL of water, extracted with ethyl acetate, the organic phase dried and spun-dried and purified by TLC (PE/EA ═ 10/1) to give 125mg of the target product, yield: 61 percent.

And step 3: synthesis of 5-cyclopropyl-2- (4-fluoro-2- (methyl-d 3) phenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

Example 36 was obtained according to the same protocol as example 10 starting from the corresponding substrate

LC/MS:m/z＝450.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ0.86-0.89(2H,m),1.01-1.05(2H,m),2.05-2.11 (1H,m),2.17(3H,s),6.36(1H,dd,J＝7.2Hz,1.6Hz),6.75(1H,s),6.94(1H,s), 7.03-7.09(2H,m),7.22(1H,dd,J＝8.8Hz,2.8Hz),7.31(1H,d,J＝7.6Hz),8.13(1H, s),10.62(1H,s),11.28(1H,brs).

Example 37

2- (4-fluoro-2-methylphenoxy) -4- (1-fluorocyclopropyl) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

Step 1: synthesis of 2-fluoro-5- (trifluoromethyl) -4-vinylaniline

To a reaction flask were added 4-bromo-2-fluoro-5- (trifluoromethyl) aniline (258mg, 1mmol), vinyl boronic acid pinacol ester (310mg, 2mmol), sodium carbonate (318mg, 3mmol) and 5mL of DMF, and after displacement of nitrogen, Pd (dppf) Cl was added₂(37mg, 0.05mmol) and the reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction system was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 2/1) to give 175mg of the target product, yield: 85 percent.

Step 2: synthesis of 1-iodo-2-fluoro-5- (trifluoromethyl) -4-vinylbenzene

2-fluoro-5- (trifluoromethyl) -4-vinylaniline (164mg, 0.8mmol) was dissolved in 3mL of acetonitrile, isoamyl nitrite (93mg, 0.8mmol) was added dropwise at 0 ℃ and the mixture was stirred at room temperature for 1 hour after the addition. A1 mL aqueous solution of potassium iodide (332mg, 2mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. Pouring the reaction system into 10mL of water, extracting with ethyl acetate, backwashing the organic phase with 1M dilute hydrochloric acid, 1M sodium carbonate aqueous solution and saturated salt solution in sequence, drying and spin-drying to obtain 160mg of a target product, and obtaining the yield: and 63 percent.

And step 3: synthesis of 2-fluoro-5- (trifluoromethyl) -4-vinylbenzoic acid

1-iodo-2-fluoro-5- (trifluoromethyl) -4-vinylbenzene (158mg,0.5mmol) and triethylamine (101mg, 1mmol) were dissolved in DMF/H₂O (3mL/0.3mL), Pd (dppf) Cl₂(37mg, 0.05mmol), after replacing the air in the system with carbon monoxide, the reaction mixture was heated to 90 ℃ under carbon monoxide at a pressure of 0.2M Pa and stirred overnight. The reaction was cooled to room temperature and poured into 10mL of water, extracted with ethyl acetate, dried and spun-dried and purified by TLC (PE/EA-10/1) to give 65mg of the target product, yield: 56 percent.

And 4, step 4: synthesis of 2-fluoro-N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) -4-vinylbenzamide

To a reaction flask were added 2-fluoro-5- (trifluoromethyl) -4-vinylbenzoic acid (47mg, 0.2mmol), 2-methoxypyridin-4-amine (25mg, 0.2mmol), DIPEA (52mg, 0.4mmol) and 2mL tetrahydrofuran, HATU (114mg, 0.3mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by TLC (PE/EA-1/1) to yield 50mg of the desired product in 74% yield.

And 5: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) -4-vinylbenzamide

To a reaction flask was added 2-fluoro-N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) -4-vinylbenzamide (34mg, 0.1mmol), 4-fluoro-2-methylphenol (13mg, 0.1mmol), potassium carbonate (28mg, 0.2mmol) and 1mL acetonitrile and the reaction mixture was heated to 60 ℃ and stirred overnight. The reaction was cooled to room temperature and poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun-dried and purified by TLC (PE/EA ═ 10/1) to give 35mg of the target product, yield: 78 percent.

Step 6: synthesis of 2- (4-fluoro-2-methylphenoxy) -4- (1-fluorocyclopropyl) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

Example 37 was obtained according to the same protocol as example 22, starting from the corresponding substrate

LC/MS:m/z＝465.1[M+H]⁺.

1H NMR(400MHz,CDCl₃)δ0.67-0.71(2H,m),0.93-0.96(2H,m),2.23(3H,s), 6.22(1H,s),6.64(1H,d,J＝2.0Hz),6.86(1H,dd,J＝7.6Hz,2.0Hz),6.99-7.02(2H, m),7.08-7.10(1H,m),7.32(1H,d,J＝7.2Hz),8.65(1H,s),9.60(1H,s),12.15(1H, brs).

Example 38

2- (4-fluoro-2-methylphenoxy) -4- (1-hydroxycyclopropyl) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

Step 1: synthesis of 1- (4-amino-5-fluoro-2- (trifluoromethyl) phenyl) ethan-1-one

To a reaction flask were added 4-bromo-2-fluoro-5- (trifluoromethyl) aniline (2.58g, 10mmol), tributyl (1-ethoxyethylene) tin (3.61g, 10mmol) and 50mL DMF, and after nitrogen substitution, Pd (PPh) was added₂Cl₂(351mg, 0.5mmol) and the reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. After the reaction system was cooled to room temperature, it was poured into 100mL of water, 10mL of concentrated hydrochloric acid was added, the mixture was stirred for 1 hour, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 2/1), yielding 1.60g of the target product: 72 percent.

Step 2: synthesis of 1- (4-iodo-5-fluoro-2- (trifluoromethyl) phenyl) ethan-1-one

2-fluoro-5- (trifluoromethyl) -4-vinylaniline (884mg, 4mmol) was dissolved in 10mL acetonitrile, isoamyl nitrite (465mg, 4mmol) was added dropwise at 0 ℃ and the system was stirred at room temperature for 1 hour after the addition was completed. A3 mL aqueous solution of potassium iodide (1328mg, 8mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. Pouring the reaction system into 30mL of water, extracting with ethyl acetate, backwashing the organic phase with 1M of dilute hydrochloric acid, 1M of sodium carbonate aqueous solution and saturated salt water in sequence, drying and spin-drying to obtain 576mg of a target product, and obtaining the yield: 33 percent.

And step 3: synthesis of methyl 4-acetyl-2-fluoro-5- (trifluoromethyl) benzoate

1-iodo-2-fluoro-5- (trifluoromethyl) -4-vinylbenzene (b)332mg,1mmol) and triethylamine (202mg, 2mmol) were dissolved in DMF/MeOH (5mL/1mL) and Pd (dppf) Cl was added₂(37mg, 0.05mmol), after replacing the air in the system with carbon monoxide, the reaction mixture was heated to 90 ℃ under carbon monoxide at a pressure of 0.2M Pa and stirred overnight. The reaction system was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, dried and spun-dried, and purified by silica gel column chromatography (PE/EA ═ 10/1) to give 200mg of the target product, yield: 76 percent.

And 4, step 4: synthesis of methyl 4-acetyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoate

To a reaction flask were added methyl 4-acetyl-2-fluoro-5- (trifluoromethyl) benzoate (132mg, 0.5mmol), 4-fluoro-2-methylphenol (63mg, 0.5mmol), potassium carbonate (138mg, 1.0mmol) and 3mL acetonitrile, and the reaction mixture was heated to 60 ℃ and stirred overnight. The reaction was cooled to room temperature and poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun-dried and purified by TLC (PE/EA ═ 10/1) to give 120mg of the target product in yield: 65 percent.

And 5: synthesis of 2- (4-fluoro-2-methylphenoxy) -4- (1-hydroxycyclopropyl) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

Example 38 was obtained according to the same protocol as example 32 starting from the corresponding substrate

LC/MS:m/z＝463.1[M+H]⁺.

1H NMR(400MHz,CDCl₃)δ0.78-0.82(2H,m),1.05-1.09(2H,m),2.22(3H,s), 6.21(1H,s),6.67(1H,d,J＝2.0Hz),6.86(1H,dd,J＝7.2Hz,2.0Hz),6.99-7.02(2H, m),7.07-7.10(1H,m),7.30(1H,d,J＝7.2Hz),8.71(1H,s),9.67(1H,s),12.08(1H, brs).

Example 39

N- (3- (3-acetylguanidino) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-guanidinophenyl) -4- (trifluoromethyl) benzamide (46mg, 0.1mmol) and potassium carbonate (28mg, 0.2mmol) were dissolved in 2mL acetonitrile, acetic anhydride (10mg, 0.1mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. Suction filtration, spin-drying the filtrate, and performing reverse-phase preparation and purification to obtain 17mg of a target product, wherein the yield is as follows: 33 percent.

LC/MS:m/z＝507.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.96(3H,s),2.16(3H,s),6.95(1H,s),7.12-7.17 (3H,m),7.23(1H,d,J＝8.4Hz),7.37(2H,brs),7.59-7.63(2H,m),7.84(1H,d,J＝8.0 Hz),8.03(1H,dd,J＝8.0Hz,2.2Hz),10.65(1H,s).

Example 40

N- (3- (guanidinoformyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (1-fluorocyclopropyl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of methyl 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5-vinylbenzoate

To a reaction flask, methyl 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (407mg, 1mmol), vinyl boronic acid pinacol ester (310mg, 2mmol), sodium carbonate (318mg, 3mmol) and 5mL of DMF were added, and after replacement of nitrogen gas, Pd (dppf) Cl was added₂(37mg, 0.05mmol) and the reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. The reaction system was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA-20/1) to give 210mg of the target product in yield: 59 percent.

Step 2: synthesis of methyl 2- (4-fluoro-2-methylphenoxy) -5- (1-fluorovinyl) -4- (trifluoromethyl) benzoate

Triethylamine trihydrofluoride (242mg, 1.5mmol) was added dropwise to a solution of methyl 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5-vinylbenzoate (177mg, 0.5mmol) in 5mL of dichloromethane at 0 ℃ for 5 minutes, followed by addition of NBS (89mg, 0.5mmol), and the mixture was stirred at room temperature for 1 hour after the addition was completed. The reaction mixture was poured into 20mL of water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried and spun-dried. The resulting solid was dissolved in 5mL of tetrahydrofuran, and after addition of potassium tert-butoxide (112mg, 1mmol), the reaction was stirred at 50 ℃ for 2 hours. The reaction was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun-dried and purified by TLC (PE/EA ═ 20/1) to give 80mg of the target product, yield: and 43 percent.

And step 3: synthesis of methyl 2- (4-fluoro-2-methylphenoxy) -5- (1-fluorocyclopropyl) -4- (trifluoromethyl) benzoate

Diethyl zinc (1M in n-hexane, 0.5mL, 0.5mmol) was added dropwise to a solution of diiodomethane (134mg, 0.5mmol) in 2mL of dry methylene chloride under nitrogen at 0 deg.C, after stirring the reaction system at 0 deg.C for 0.5 hour, trifluoroacetic acid (57mg, 0.5mmol) was slowly added dropwise, after stirring for 0.5 hour, a solution of methyl 2- (4-fluoro-2-methylphenoxy) -5- (1-fluoroethyl) -4- (trifluoromethyl) benzoate (75mg, 0.2mmol) in 2mL of methylene chloride was slowly added, and after the addition was complete, the system was stirred at room temperature overnight. The reaction solution was poured into 10mL of water, extracted with dichloromethane, the organic phase was dried and spun dry and purified by TLC (PE/EA ═ 20/1) to give 45mg of the target product in yield: 58 percent.

And 4, step 4: synthesis of 2- (4-fluoro-2-methylphenoxy) -5- (1-fluorocyclopropyl) -4- (trifluoromethyl) benzoic acid

To a reaction flask were added methyl 2- (4-fluoro-2-methylphenoxy) -5- (1-fluorocyclopropyl) -4- (trifluoromethyl) benzoate (39mg, 0.1mmol), lithium hydroxide monohydrate (21mg, 0.5mmol), 2mL of water and 2mL of methanol, and the reaction mixture was stirred at room temperature overnight. The reaction system was poured into 10mL of water, after unreacted starting materials were removed by extraction with diethyl ether, the aqueous phase was adjusted to pH 7 with 1M dilute hydrochloric acid, extracted with ethyl acetate, the organic phase was dried and spin dried to give 35mg of the target product, yield: 94 percent.

And 5: synthesis of N- (3- (guanidinoformyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (1-fluorocyclopropyl) -4- (trifluoromethyl) benzamide

Example 40 was obtained according to the same protocol as example 11 starting from the corresponding substrate

LC/MS:m/z＝551.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.21-1.25(2H,m),1.37-1.43(2H,m),2.16(3H, s),6.72(2H,brs),6.97(1H,s),7.5-7.13(3H,m),7.23(1H,dd,J＝8.8Hz,3.2Hz),7.37 (1H,s),7.60-7.64(1H,m),7.96(2H,brs),8.10(1H,dd,J＝8.0Hz,3.6Hz),10.64(1H, s).

EXAMPLE 41

N- (3- (guanidinocarbamoyl) -4-fluorophenyl) -5- (2, 2-difluorocyclopropyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Step 1: synthesis of methyl 5- (2, 2-difluorocyclopropyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate

A mixture of methyl 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5-vinylbenzoate (354mg, 1mmol), trimethylsilyl 2- (fluorosulfonyl) difluoroacetate (500mg, 2mmol) and sodium fluoride (8mg, 0.2mmol) was heated to 110 ℃ and stirred for 6 hours. After cooling to room temperature, 30mL of water was poured into the system, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 20/1) to give 315mg of the target product in yield: 78 percent.

Step 2: synthesis of 5- (2, 2-difluorocyclopropyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid

To a reaction flask was added methyl 5- (2, 2-difluorocyclopropyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (202mg, 0.5mmol), lithium hydroxide monohydrate (84mg, 2.0mmol), 5mL of water and 5mL of methanol, and the reaction mixture was stirred at room temperature overnight. Pouring the reaction system into 20mL of water, extracting with diethyl ether to remove unreacted raw materials, adjusting the pH value of the water phase to 7 with 1M dilute hydrochloric acid, extracting with ethyl acetate, drying the organic phase and spin-drying to obtain 190mg of a target product, wherein the yield is as follows: 97 percent.

And step 3: synthesis of N- (3- (guanidinocarbamoyl) -4-fluorophenyl) -5- (2, 2-difluorocyclopropyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Example 41 was obtained according to the same protocol as example 11, starting from the corresponding substrate

LC/MS:m/z＝569.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.03-2.08(1H,m),2.15(3H,s),2.29-2.35(1H, m),3.06-3.13(1H,m),6.72(2H,brs),6.94(1H,s),7.01-7.08(2H,m),7.14-7.21(2H,m), 7.37(1H,s),7.60-7.63(1H,m),7.93(2H,brs),7.97-8.00(1H,m),10.56(1H,s).

Example 42

N- (3-carbamimidoyl-4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Step 1: synthesis of N- (3-cyano-4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (314mg, 1.0mmol), 5-amino-2-fluorobenzonitrile (136mg, 1.0mmol), DIPEA (258mg, 2.0mmol) and 10mL of tetrahydrofuran, HATU (570mg, 1.5mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 50mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA-2/1) to yield 265mg of the desired product in 61% yield.

Step 2: synthesis of N- (3-carbamimidoyl-4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

A solution of N- (3-cyano-4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide (216mg, 0.5mmol) in 10mL of ethanolic hydrogen chloride (6M) was stirred at room temperature overnight. The reaction was spin dried and redissolved in 5mL of absolute ethanol, ammonium carbonate (48mg, 0.5mmol) was added, and the reaction mixture was stirred at room temperature for 6 hours. The reaction system was directly purified by reverse phase preparation to obtain 60mg of the target product as hydrochloride, white solid, yield: 25 percent.

LC/MS:m/z＝450.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.17(3H,s),6.94(1H,s),7.11-7.15(3H,m),7.23 (1H,d,J＝8.8Hz),7.41(2H,brs),7.59-7.63(2H,m),7.85(1H,d,J＝8.0Hz),8.09(1H, dd,J＝8.0Hz,2.0Hz),10.66(1H,s).

Example 43

N- (3- (guanidinoformyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (prop-1-yn-1-yl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of methyl 2- (4-fluoro-2-methylphenoxy) -5- (prop-1-yn-1-yl) -4- (trifluoromethyl) benzoate

To butynoic acid (84mg, 1mmol), Pd (PPh)₂Cl₂To a 10mL DMSO solution of (70mg, 0.1mmol) and dppb (83mg, 0.2mmol) were added methyl 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (407mg, 1mmol) and DBU (0.44mL, 3 mmol). After nitrogen displacement, the reaction mixture was heated to 80 ℃ under nitrogen blanket and stirred overnight. The reaction system was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 20/1) to give 190mg of the target product, yield: 52 percent.

And 2, step: synthesis of 2- (4-fluoro-2-methylphenoxy) -5- (prop-1-yn-1-yl) -4- (trifluoromethyl) benzoic acid

To a reaction flask was added methyl 2- (4-fluoro-2-methylphenoxy) -5- (prop-1-yn-1-yl) -4- (trifluoromethyl) benzoate (183mg, 0.5mmol), lithium hydroxide monohydrate (84mg, 2.0mmol), 5mL of water and 5mL of methanol, and the reaction mixture was stirred at room temperature overnight. The reaction system was poured into 20mL of water, after unreacted starting materials were removed by extraction with diethyl ether, the aqueous phase was adjusted to pH 7 with 1M dilute hydrochloric acid, extracted with ethyl acetate, the organic phase was dried and spin dried to yield 170mg of the target product, yield: 97 percent.

And step 3: synthesis of N- (3- (guanidinocarbamoylformyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (prop-1-yn-1-yl) -4- (trifluoromethyl) benzamide

Example 43 was obtained according to the same protocol as example 11 starting from the corresponding substrate

LC/MS:m/z＝531.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.95(3H,s),2.17(3H,s),6.75(2H,brs), 7.08-7.15(3H,m),7.23(1H,d,J＝8.8Hz),7.59-7.65(2H,m),7.94(2H,brs),8.02(1H, dd,J＝8.4Hz,2.4Hz),8.30(1H,s),10.66(1H,s).

Example 44

N- (3- (3-cyano-2-methylguanidino) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

To a reaction flask were added N- (3-amino-4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide (42mg, 0.1mmol), triethylamine (20mg, 0.2mmol), N-cyanocarboximidodiphenyl ester (24mg, 0.1mmol) and 2mL acetonitrile, and after stirring at room temperature for 6 hours, a methanol solution of methylamine (2M, 0.5mL, 1.0mmol) was added, and the reaction mixture was heated to 60 ℃ and stirred overnight. The reaction was cooled to room temperature and poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 10/1) to give 15mg of the target product as a white solid in yield: 30 percent.

LC/MS:m/z＝504.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.16(3H,s),2.86(3H,s),6.91(1H,s),6.99-7.04 (1H,m),7.09-7.12(2H,m),7.21-7.27(3H,m),7.29(2H,brs),7.57(1H,d,J＝8.0Hz), 7.81(1H,d,J＝7.6Hz),10.44(1H,s).

Example 45

N- (3- ((2-carbamimidoyl hydrazono) methyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-formylphenyl) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (314mg, 1.0mmol), 5-amino-2-fluorobenzaldehyde (139mg, 1.0mmol), DIPEA (258mg, 2.0mmol) and 10mL tetrahydrofuran, HATU (570mg, 1.5mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 50mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA-2/1) to give 280mg of the desired product in 64% yield.

Step 2: synthesis of N- (3- ((2-carbamimidoyl hydrazono) methyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

A mixed solution of 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-formylphenyl) -4- (trifluoromethyl) benzamide (218mg, 0.5mmol), aminoguanidine hydrochloride (55mg, 0.5mmol), sodium acetate (41mg, 0.5mmol) and 5mL of ethanol was heated to 80 ℃ and stirred for 6 hours. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 10/1) to give 160mg of the title product as a white solid in yield: and 63 percent.

LC/MS:m/z＝492.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.17(3H,s),6.95(1H,s),7.10-7.12(2H,m),7.17 (4H,brs),7.21-7.29(2H,m),7.60(1H,d,J＝8.0Hz),7.63-7.66(1H,m),7.85(1H,d,J＝ 8.0Hz),8.26-8.29(2H,m),10.63(1H,s).

Example 46

2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) -4-vinylbenzamide

2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) -4-vinylbenzamide (9mg, 0.02mmol) was dissolved in 2mL of acetonitrile, and potassium iodide (17mg, 0.1mmol) and TMSCl (11mg, 0.1mmol) were added at room temperature, and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 10/1) to give 6mg of the title product as a white solid in yield: 67%.

LC/MS:m/z＝433.1[M+H]⁺.

1H NMR(400MHz,CDCl₃)δ2.24(3H,s),5.58(1H,d,J＝11.2Hz),6.09(1H,d,J ＝17.2Hz),6.36(1H,s),6.41(1H,d,J＝7.2Hz),6.66(1H,d,J＝2.0Hz),6.85(1H,dd, J＝7.6Hz,2.4Hz),7.00-7.04(2H,m),7.09-7.13(1H,m),7.30(1H,d,J＝7.2Hz),8.55 (1H,s),9.73(1H,s),12.26(1H,brs).

Example 47

2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (prop-1-yn-1-yl) -5- (trifluoromethyl) benzamide

Step 1: synthesis of 2-fluoro-4- (prop-1-yn-1-yl) -5- (trifluoromethyl) aniline

To butynoic acid (84mg, 1mmol), Pd (PPh)₂Cl₂To a 10mL DMSO solution of (70mg, 0.1mmol) and dppb (83mg, 0.2mmol) were added 4-bromo-2-fluoro-5- (trifluoromethyl) aniline (258mg, 1mmol) and DBU (0.44mL, 3 mmol). After nitrogen displacement, the reaction mixture was heated to 80 ℃ under nitrogen blanket and stirred overnight. The reaction system was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 20/1) to give 85mg of the target product, yield: 39 percent.

Step 2: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (prop-1-yn-1-yl) -5- (trifluoromethyl) benzamide

Example 47 was obtained according to the same protocol as example 37, starting from the corresponding substrate

LC/MS:m/z＝445.1[M+H]⁺.

1H NMR(400MHz,CDCl₃)δ1.95(3H,s),2.24(3H,s),6.64-6.66(1H,m),6.86 (1H,dd,J＝7.6Hz,2.8Hz),6.99-7.04(2H,m),7.09-7.13(1H,m),7.30(1H,d,J＝7.2 Hz),7.78(1H,s),8.55(1H,s),9.73(1H,s),12.26(1H,brs).

Example 48

N- (3- (3-amino-1H-1, 2, 4-triazol-5-yl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (hydrazinoformyl) phenyl) -4- (trifluoromethyl) benzamide

A solution of methyl 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoate (47mg, 0.1mmol) and hydrazine hydrate (0.2mL) in 1mL of methanol was stirred at room temperature for 6 hours. Pouring the reaction system into 10mL of water, performing suction filtration, and spin-drying the obtained solid to obtain 47mg of a target product, wherein the yield is as follows: 100 percent.

Step 2: synthesis of N- (3- (3-amino-1H-1, 2, 4-triazol-5-yl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (hydrazinoformyl) phenyl) -4- (trifluoromethyl) benzamide (47mg, 0.1mmol), S-methylisothiourea sulfate (19mg, 0.1mmol) and 2mL of water, and the reaction mixture was heated to 100 ℃ and stirred for 6 hours. After cooling to room temperature, 100mg of sodium hydroxide was added to the system, and the reaction system was heated again to 100 ℃ and stirred for 6 hours. After the temperature is reduced to room temperature, the reaction solution is directly prepared and purified by reversed phase to obtain 8mg of target product which is white solid, and the yield is as follows: 16 percent.

LC/MS:m/z＝490.1[M+H]⁺.

1H NMR(400MHz,CDCl₃)δ2.25(3H,s),4.17(2H,s),6.86(1H,s),7.06-7.11(3H, m),7.25-7.30(1H,m),7.48(1H,d,J＝8.4Hz),7.97-8.01(1H,m),8.22(1H,dd,J＝6.0 Hz,2.8Hz),8.49(1H,d,J＝8.0Hz),9.68(1H,s),12.85(1H,s).

Example 49

N- (3- (3-amino-1, 2, 4-oxadiazol-5-yl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Step 1: synthesis of N- (3- (cyanocarbamoyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoic acid (45mg, 0.1mmol), cyanamide (9mg, 0.2mmol), DIPEA (26mg, 0.2mmol) and 2mL tetrahydrofuran, HATU (76mg, 0.2mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by TLC (PE/EA ═ 1/1) to give 20mg of the desired product in 42% yield.

Step 2: synthesis of N- (3- (3-amino-1, 2, 4-oxadiazol-5-yl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

A solution of N- (3- (cyanocarbamoyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide (20mg, 0.04mmol) and hydroxylamine hydrochloride (7mg, 0.1mmol) in 1mL of pyridine was heated to 80 ℃ and stirred overnight. The reaction was cooled to room temperature and poured into 50mL of water, extracted with ethyl acetate, the organic phase dried and spun-dried and purified by TLC (DCM/MeOH ═ 10/1) to give 6mg of the target product, yield: 29 percent.

LC/MS:m/z＝491.1[M+H]⁺.

1H NMR(400MHz,CDCl₃)δ2.26(3H,s),4.53(2H,s),6.86(1H,s),7.07-7.11(3H, m),7.25-7.29(1H,m),7.48(1H,d,J＝8.4Hz),7.97-8.01(1H,m),8.21(1H,dd,J＝6.0 Hz,2.8Hz),8.49(1H,d,J＝8.0Hz),9.75(1H,s).

Table one: the following compounds were prepared starting from the corresponding reagents in a similar procedure to that described in the above example.

Example 96

N- (3- (carbamoylcarbamoyl) -4-fluorophenyl) -5-chloro-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 5-chloro-2-fluoro-4- (trifluoromethyl) benzoic acid

Under the protection of nitrogen, n-butyllithium (1.6M, 1mL) was added dropwise to a solution of 2,2,6, 6-tetramethylpiperidine (212 mg, 1.5mmol) in 3mL of anhydrous tetrahydrofuran at 0 ℃ and stirred for 1 hour, after which the system was cooled to-70 ℃ and 1-chloro-4-fluoro-2- (trifluoromethyl) benzene (198mg, 1.0mmol) was added dropwise and stirring was continued for 1 hour after the addition was completed. The system was poured over excess dry ice, stirred for 10 minutes, then 10mL water was added, pH adjusted to acidic with hydrochloric acid and extracted with ethyl acetate, the organic phase was dried and spun dry and purified by Prep-TLC (DCM/MeOH ═ 10/1) to give 155mg of a light yellow solid, yield: and 64 percent.

Step 2: synthesis of N- (3- (carbamoylcarbamoyl) -4-fluorophenyl) -5-chloro-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Example 96 was obtained according to the same protocol as examples 1 and 11, starting from the corresponding substrate

LC/MS:m/z＝527.1[M+H]⁺.

Example 97

2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (sulfamoylcarbamoyl) phenyl) -4- (trifluoromethyl) benzamide

2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamido) benzoic acid (50mg, 0.11mmol), triethylamine (56mg, 0.55mmol) and sulfonamide (21mg, 0.22mmol) were dissolved in 5ml DFF, HATU (57mg, 0.15mmol) was added at room temperature and stirred for 3 hours. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by Prep-TLC (PE/EA ═ 1/1) to give 15mg of white solid, yield: 29 percent.

LC/MS:m/z＝530.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.16(3H,s),6.94(1H,s),7.10-7.16(2H,m), 7.21-7.23(2H,m),7.59(1H,d,J＝8.0Hz),7.74-7.75(1H,m),7.84(1H,s),7.97-7.98 (1H,m),10.67(1H,s),11.98(1H,brs).

Example 98

2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-ureidophenyl) -4- (trifluoromethyl) benzamide

N- (3-amino-4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide (120mg, 0.28mmol) was dissolved in 4mL of acetic acid and 1mL of water, and sodium isocyanate (36mg, 0.56mmol) was added thereto at room temperature and stirred for 5 hours. The reaction was poured into 30mL of water, extracted with ethyl acetate, and the organic phase was dried and purified by silica gel column chromatography (PE/EA ═ 3/1) to obtain 90mg of a white solid in yield: and 69 percent.

LC/MS:m/z＝466.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.17(3H,s),6.20(2H,s),6.93(1H,s),7.09-7.11 (2H,m),7.13-7.16(1H,m),7.20-7.22(1H,m),7.35-7.39(1H,m),7.56(1H,d,J＝7.6 Hz),7.81(1H,d,J＝7.6Hz),8.34(1H,d,J＝2.0Hz),8.38(1H,dd,J＝7.6Hz,2.4Hz), 10.53(1H,s).

Example 99

2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- ((guanidinooxy) methyl) phenyl) -5- (trifluoromethyl) benzamide

Step 1: synthesis of methyl 2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoate

Step 2: synthesis of 2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid

And step 3: synthesis of methyl 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) benzoate

The intermediate of step 3 was obtained according to the same protocol as example 1, starting from the corresponding substrate.

And 4, step 4: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (hydroxymethyl) phenyl) -5- (trifluoromethyl) benzamide

To a reaction flask were added methyl 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) benzoate (500mg, 1.08mmol), anhydrous lithium chloride (4.2mg, 0.1mmol) and 20mL of methanol, sodium borohydride (205mg, 5.4mmol) was added portionwise at room temperature, and the reaction was stirred at room temperature for 3 hours. Adding dilute hydrochloric acid to quench the reaction, extracting with ethyl acetate, drying the organic phase, and concentrating to dryness to obtain 430mg of gray solid, wherein the yield is as follows: 91 percent.

And 5: synthesis of N- (3- (chloromethyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (hydroxymethyl) phenyl) -5- (trifluoromethyl) benzamide (430mg, 0.98mmol) and 6mL phosphorus oxychloride and the reaction mixture was stirred at 100 ℃ for 3 hours. After the reaction system was concentrated to dryness, an aqueous sodium bicarbonate solution was added under ice bath to quench the reaction, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 3/1) to give 360mg of a pale yellow solid in yield: 80 percent.

Step 6: synthesis of N- (3- ((((1, 3-dioxoisoindolin-2-yl) oxy) methyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

To a reaction flask was added N- (3- (chloromethyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide (200mg, 0.44mmol), 2-hydroxyisoindoline-1, 3-dione (108mg, 0.66mmol), potassium tert-butoxide (148mg, 1.32mmol) and 8mL of DMF, and the reaction mixture was stirred at 90 ℃ overnight. The reaction was poured into 40mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by gel column chromatography (PE/EA ═ 2/1) to give 180mg of a grey solid in yield: 70 percent.

And 7: synthesis of N- (3- ((aminooxy) methyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

To a reaction flask was added N- (3- ((((1, 3-dioxoisoindolin-2-yl) oxy) methyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide (180mg, 0.31mmol), 3mL hydrazine hydrate and 10mL ethanol, the reaction mixture was stirred at room temperature overnight, the reaction was poured into 30mL water, ethyl acetate extracted, the organic phase dried and spun dry, purified by Prep-TLC (DCM/MeOH ═ 30/1) to give 80mg gray solid in 57% yield.

And 8: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- ((guanidinooxy) methyl) phenyl) -5- (trifluoromethyl) benzamide

Example 99 was obtained according to the same protocol as example 30 starting from the corresponding substrate

LC/MS:m/z＝495.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.15(3H,s),4.39(2H,s),4.69(2H,s),5.04(2H, s),6.81(1H,d,J＝8.4Hz),7.12-7.26(4H,m),7.69-7.71(1H,m),7.75-7.78(2H,m), 7.97(1H,d,J＝1.6Hz),10.55(1H,s).

Example 100

N- (3- ((4, 5-dihydro-1H-imidazol-2-yl) amino) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

To a reaction flask was added N- (3-amino-4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide (50mg, 0.12mmol), tert-butyl 2- (methylthio) -4, 5-dihydro-1H-imidazole-1-carboxylate (78mg, 0.36mmol), 2mL of acetic acid and 8mL of ethanol, and the reaction was stirred at 90 ℃ overnight. The reaction was poured into 30mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by Prep-TLC (DCM/MeOH ═ 10/1) to give 12mg of white solid, yield: 21 percent.

LC/MS:m/z＝491.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.15(3H,s),3.31(4H,s),6.13(2H,brs),6.80 (1H,d,J＝8.4Hz),6.96-6.99(1H,m),7.01-7.26(5H,m),7.76(1H,dd,J＝8.8Hz,2.0 Hz),7.90(1H,d,J＝2.0Hz),10.31(1H,s).

Example 101

N- (3- (3-acetylguanidino) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-guanidinophenyl) -5- (trifluoromethyl) benzamide (23mg, 0.05mmol), triethylamine (10mg, 0.1mmol) and 2mL of dichloromethane, and acetic anhydride (7.5mg, 0.075mmol) was added under ice bath and stirred for 1 hour. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by Prep-TLC (DCM/MeOH ═ 20/1) to give 6mg of a white solid, yield: 24 percent.

LC/MS:m/z＝507.2[M+H]⁺.

Example 102

2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- ((4-oxo-4, 5-dihydro-1H-imidazol-2-yl) amino) phenyl) -5- (trifluoromethylbenzamide

Example 102 was obtained according to the same protocol as example 100, starting from the corresponding substrate

LC/MS:m/z＝505.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.15(3H,s),4.07(2H,s),6.82(1H,d,J＝8.0Hz), 7.21-7.30(3H,m),7.33-7.34(1H,m),7.70-7.73(1H,m),7.80(1H,d,J＝8.4Hz),7.85 (1H,dd,J＝8.0Hz,2.0Hz),7.96(1H,d,J＝1.6Hz),10.70(1H,s).

Example 103

N- (3- (3-cyanoguanidino) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

Example 103 was obtained according to the same protocol as example 30, starting from the corresponding substrate

LC/MS:m/z＝490.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.16(3H,s),6.83(1H,d,J＝8.7Hz),7.10-7.31 (6H,m),7.53-7.59(1H,m),7.78(1H,dd,J＝8.8Hz,1.9Hz),7.97(1H,d,J＝1.8Hz), 8.08(1H,dd,J＝7.3Hz,2.4Hz),8.88(1H,s),10.60(1H,s).

Example 104

N- (3- (N-carbamoylsulfamoyl) phenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

Step 1: synthesis of N-carbamoylamino-3-nitrobenzenesulfonamide

To the reaction flask was added 3-nitrobenzenesulfonyl chloride (500mg, 2.26mmol), guanidine hydrochloride (216mg, 4.52 mmol), sodium hydroxide (271mg, 6.78mmol) dissolved in 5mL of water and 20mL of ethanol, the reaction mixture was stirred at room temperature for 2 hours, and TLC indicated completion of the reaction. After the reaction system is concentrated, water is added for dilution, ethyl acetate is used for extraction, an organic phase is dried and concentrated to be dried, and the yellow solid of about 280mg is obtained through silica gel column chromatography purification, and the yield is as follows: 51 percent.

Step 2: synthesis of 3-amino-N-carbamoylbenzenesulfonamide

Adding 280mg of N-carbamoylamino-3-nitrobenzenesulfonamide (1.15 mmol) and 10mL of ethanol into a reaction bottle, replacing hydrogen in a reaction system, adding Pd/C (56mg, 20% wt) at room temperature, stirring the reaction mixture for 3 hours under a hydrogen atmosphere, directly filtering and spin-drying the reaction system to obtain 210mg of light yellow solid, and obtaining the yield: 85 percent.

And step 3: synthesis of N- (3- (N-carbamoylsulfamoyl) phenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (50mg, 0.16mmol), 3-amino-N-carbamoylbenzenesulfonamide (43mg, 0.2mmol), DIPEA (62mg, 0.48mmol) and 10mL tetrahydrofuran, HATU (76mg, 0.2mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction system was poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spun-dried and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 10mg of the target product in yield: 12 percent. LC/MS M/z 511.2 [ M + H ]]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.16(3H,s),6.73(4H,brs),6.82(1H,d,J＝8.4 Hz),7.14-7.27(3H,m),7.47-7.52(2H,m),7.77-7.80(2H,m),8.02(1H,d,J＝2.6Hz), 8.26(1H,s),10.76(1H,s).

Example 105

5-cyano-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-guanidinophenyl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 5-cyano-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid

To a reaction flask was added 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (500mg, 1.28mmol), CuCN (229mg, 2.56mmol), and 10mL NMP, the reaction mixture was heated to 120 ℃ and stirred overnight, the reaction was cooled to room temperature and 50mL water was added, ethyl acetate was extracted, the organic phase was dried and concentrated to dryness and purified by PE/EA (5/1) slurrying to give about 300mg yellow solid, yield: and 69 percent.

Step 2: synthesis of 5-cyano-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-guanidinophenyl) -4- (trifluoromethyl) benzamide

Example 105 was obtained according to the same protocol as examples 15 and 30, starting from the corresponding substrate

LC/MS:m/z＝490.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.15(3H,s),6.05(4H,brs),7.05(1H,s), 7.11-7.18(2H,m),7.24-7.40(4H,m),8.48(1H,s),10.61(1H,s).

Example 106

N- (3- ((2-amino-1H-imidazol-1-yl) methyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

To a reaction flask was added N- (3- (chloromethyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide (50mg, 0.11mmol), 1H-imidazol-2-amine (18mg, 0.22mmol), potassium carbonate (61mg, 0.44mmol) dissolved in 5mL DMF, the reaction was heated to 100 ℃ and stirred overnight, the reaction was cooled to room temperature and poured into 30mL water, extracted with ethyl acetate, the organic phase dried and spun dried and purified by Prep-TLC (DCM/MeOH ═ 12/1) to give 15mg of the desired product, yield: and 27 percent.

LC/MS:m/z＝503.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.14(3H,s),5.00(2H,s),5.38(2H,s),6.41(1H, d,J＝1.3Hz),6.51(1H,d,J＝1.1Hz),6.81(1H,d,J＝8.7Hz),7.12-7.17(2H,m), 7.22-7.25(2H,m),7.31(1H,dd,J＝6.7Hz,2.5Hz),7.71-7.78(2H,m),7.94(1H,d,J＝ 2.0Hz),10.59(1H,s).

Example 107

2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (sulfamoylamino) phenyl) -5- (trifluoromethyl) benzamide

N- (3-amino-4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide (50mg, 0.12mmol) was dissolved in 5mL of dichloromethane, chlorosulfonyl isocyanate (51mg, 0.36mmol) was added under ice bath, and the reaction was stirred at room temperature for 2 hours. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by Prep-TLC (DCM/MeOH ═ 15/1) to give 36mg of a white solid, yield: 60 percent.

LC/MS:m/z＝502.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.15(3H,s),6.80(1H,d,J＝8.7Hz),7.03(2H,s), 7.10-7.27(4H,m),7.47-7.54(1H,m),7.77(1H,dd,J＝8.8Hz,2.0Hz),7.84(1H,dd,J＝ 7.3Hz,2.4Hz),7.94(1H,d,J＝1.9Hz),9.09(1H,s),10.57(1H,s).

Example 108

N- (3- (2-amino-1H-imidazol-5-yl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

Step 1: synthesis of 2-bromo-1- (2-fluoro-5-nitrophenyl) ethan-1-one

1- (2-fluoro-5-nitrophenyl) ethan-1-one (500mg, 2.73mmol) and 20mL chloroform were added to the reaction flask, phenyltrimethylammonium tribromide (2052mg, 5.46mmol) was added to the reaction mixture in portions, the reaction was stirred at room temperature overnight, water was added to the reaction system, the organic phase was extracted with ethyl acetate, dried and concentrated to dryness to give about 800mg of a yellow solid, which was used directly in the next reaction.

Step 2: synthesis of tert-butyl (5- (2-fluoro-5-nitrophenyl) -1H-imidazol-2-yl) carbamate

To a reaction flask was added 2-bromo-1- (2-fluoro-5-nitrophenyl) ethan-1-one (500mg, crude), dissolved in 10ml dmf, tert-butoxycarbonylguanidine (318mg, 2mmol) was added, the reaction mixture was stirred at room temperature overnight, the reaction system was added water, extracted with ethyl acetate, the organic phase was concentrated by drying and purified by silica gel column chromatography (DCM/MeOH ═ 50/1) to give 150mg of a pale yellow solid in two-step yield: 23 percent.

And step 3: synthesis of tert-butyl (5- (5-amino-2-fluorophenyl) -1H-imidazol-2-yl) carbamate

To a reaction flask were added tert-butyl (5- (2-fluoro-5-nitrophenyl) -1H-imidazol-2-yl) carbamate (150mg, 0.47mmol) and 10mL ethanol, the reaction was purged with hydrogen, Pd/C (30mg, 20% wt) was added at room temperature, the reaction mixture was stirred under hydrogen atmosphere for 3 hours, the reaction was directly filtered and dried to give 120mg of a pale yellow solid, yield: 88 percent.

And 4, step 4: synthesis of tert-butyl (5- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) phenyl) -1H-imidazol-2-yl) carbamate

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (100mg, 0.32 mmol), (5- (5-amino-2-fluorophenyl) -1H-imidazol-2-yl) carbamic acid tert-butyl ester (120mg, 0.41mmol), DIPEA (83mg, 0.64mmol) and 15mL tetrahydrofuran, HATU (144mg, 0.38mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 30mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 1/1) to yield 120mg of the desired product: 64 percent

And 5: synthesis of N- (3- (2-amino-1H-imidazol-5-yl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

To a reaction flask were added tert-butyl (5- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) phenyl) -1H-imidazol-2-yl) carbamate (120mg, 0.2mmol) and 8mL of ethyl acetate hydrochloride solution, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 30mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by Prep-TLC (DCM/MeOH ═ 15/1) to give 60mg of white solid, yield: 61 percent.

LC/MS:m/z＝489.1[M+H]⁺.

Examples 109,110

2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (hydrazinocarbonyl) phenyl) -5- (trifluoromethyl) benzamide

N- (3- (5-amino-4H-1, 2, 4-triazol-3-yl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (hydrazinocarbonyl) phenyl) -5- (trifluoromethyl) benzamide

To a reaction flask was added methyl 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) benzoate (300mg, 0.65mmol), hydrazine hydrate (3mL) and 10mL methanol, the reaction mixture was stirred at room temperature overnight, the reaction was directly filtered, the filter cake was washed 2 times with ethanol/water (3/1), and the resulting solid was dried by spinning to give about 125mg of a white solid, yield: 42 percent.

LC/MS:m/z＝466.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.14(3H,s),4.56(2H,s),6.82(1H,d,J＝8.2Hz), 7.18-7.27(4H,m),7.78-7.80(2H,m),7.94(1H,dd,J＝8.0Hz,2.6Hz),7.99(1H,d,J＝ 2.4Hz),9.53(1H,s),10.62(1H,s).

Step 2: synthesis of N- (3- (5-amino-4H-1, 2, 4-triazol-3-yl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

Example 110 was obtained according to the same protocol as example 30, starting from the corresponding substrate

LC/MS:m/z＝490.1[M+H]⁺.

Example 111

6-amino-5- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) phenyl) -N-methylpyridinamide

Step 1: synthesis of 6-amino-5-bromo-N-methylpyridinemethylamide

To the reaction flask was added methyl 5-bromo-6-aminopyridine-2-carboxylate (458mg, 2mmol) and 20mL of methylamine methanol solution, the reaction mixture was heated to 50 ℃ and stirred overnight, TLC indicated complete reaction. The reaction system was directly concentrated to dryness and purified by silica gel flash column chromatography to give about 400mg of off-white solid, yield: 88 percent.

Step 2: synthesis of 6-amino-5- (2-fluoro-5-nitrophenyl) -N-methylpyridine formamide

To a reaction flask was added 6-amino-5-bromo-N-methylpyridinemethylamide (400mg, 1.75mmol), (2-fluoro-5-nitrophenyl) boronic acid (389mg, 2.1mmol), potassium carbonate (483mg, 3.5mmol), Pd (dppf) Cl₂(132mg, 0.18mmol) and 3mL of water and 10mL of 1, 4-dioxane, the reaction mixture was stirred overnight at 90 ℃ under nitrogen, the reaction was spun dry directly and purified by silica gel column chromatography (DCM/MeOH ═ 20/1) to give 230mg of a pale yellow solid in yield: 45 percent.

And step 3: synthesis of 6-amino-5- (5-amino-2-fluorophenyl) -N-methylpyridine carboxamide

6-amino-5- (2-fluoro-5-nitrophenyl) -N-methylpyridine-carboxamide (130mg, 0.45mmol), and 15mL of methanol were added to a reaction flask, and after hydrogen gas was replaced, Pd/C (26mg, 20% wt) was added, and the reaction mixture was stirred under hydrogen atmosphere at room temperature overnight. The reaction was directly filtered and spun dry to give 106mg of an off-white solid in yield: 91 percent.

And 4, step 4: synthesis of 6-amino-5- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) phenyl) -N-methylpyridinamide

2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (50mg, 0.16mmol), 6-amino-5- (5-amino-2-fluorophenyl) -N-methylpyridine-carboxamide (50mg, 0.19mmol), DIPEA (41mg, 0.32 mmol) were dissolved in 3mL DMF and HATU (72mg, 0.19mmol) was added at room temperature and stirred overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by Prep-TLC (DCM/MeOH ═ 15/1) to give 15mg of white solid, yield: 17 percent.

LC/MS:m/z＝557.2[M+H]⁺.

Example 112

N- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) phenyl) pyrrolidine-2-carboxamide

Step 1: synthesis of tert-butyl 2- ((2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) phenyl) carbamoyl) pyrrolidine-1-carboxylate

(tert-Butoxycarbonyl) proline (26mg, 0.12mmol), N- (3-amino-4-fluorophenyl) -2- (4-fluorophenoxy) -5- (trifluoromethyl) benzamide (50mg, 0.12mmol), DIPEA (46mg, 0.36mmol) were dissolved in 3mL DMF, HATU (57mg, 0.15mmol) was added at room temperature and stirred overnight. Pouring the reaction system into 20mL of water, extracting with ethyl acetate, backwashing the organic phase with saturated sodium chloride solution twice, drying and spin-drying to obtain 80mg of crude product, and directly using the crude product in the next reaction.

Step 2: synthesis of N- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) phenyl) pyrrolidine-2-carboxamide

Tert-butyl 2- ((2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) phenyl) carbamoyl) pyrrolidine-1-carboxylate (80mg, crude) was dissolved in 5mL of ethyl acetate hydrochloride solution and stirred at room temperature for 2 hours. The reaction was concentrated to dryness, water was added to adjust the pH to basic with sodium carbonate, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by Prep-TLC (DCM/MeOH ═ 15/1) to give 23mg of a white solid, yield: 37% (2 steps).

LC/MS:m/z＝520.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.62-1.68(2H,m),1.80-1.83(2H,m),1.99-2.09 (1H,m),2.15(3H,s),2.91-3.01(2H,m),3.76(1H,dd,J＝9.2Hz,5.6Hz),6.82(1H,d,J ＝6.8Hz),7.13-7.28(4H,m),7.49-7.51(1H,m),7.77(1H,d,J＝8.5Hz),7.96(1H,s), 8.56(1H,d,J＝7.3Hz),10.16(1H,s),10.59(1H,s)

Example 113

N- (3- (3- (2- (2-amino-2-oxoethyl) ureido) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

N- (3-amino-4-fluorophenyl) -2- (4-fluorophenoxy) -5- (trifluoromethyl) benzamide (50mg, 0.12mmol), triethylamine (61mg, 0.6mmol) and p-nitrophenyl chloroformate (48mg, 0.24mmol) were dissolved in 5mL of tetrahydrofuran, and after stirring at room temperature for 2 hours, glycinamide hydrochloride (26mg, 0.24mmol) was added to the solution, and the reaction was heated to 50 ℃ and stirred overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by Prep-TLC (DCM/MeOH ═ 20/1) to give 20mg of a white solid, yield: 32 percent.

LC/MS:m/z＝523.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.15(3H,s),3.71(2H,d,J＝5.2Hz),6.79(1H,d, J＝8.7Hz),6.88-6.90(1H,m),7.06(1H,s),7.10-7.26(4H,m),7.35-7.41(1H,m),7.43 (1H,s),7.76(1H,d,J＝8.9Hz),7.94(1H,s),8.42(1H,dd,J＝7.5Hz,2.4Hz),8.60(1H, s),10.49(1H,s).

Example 114

N- (3- ((2-amino-3, 4-dioxocyclobut-1-en-1-yl) amino) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

N- (3-amino-4-fluorophenyl) -2- (4-fluorophenoxy) -5- (trifluoromethyl) benzamide (50mg, 0.12mmol), DIPEA (46mg, 0.36mmol), 3, 4-dimethoxy-3-cyclobutene-1, 2-dione (51mg, 0.36mmol) were dissolved in 5mL of methanol, and after stirring at room temperature for 2 hours, the system was concentrated to dryness, followed by addition of 5mL of methanolic ammonia and stirring at room temperature overnight. The reaction was directly spun dry and purified by Prep-TLC (DCM/MeOH ═ 20/1) to give 16mg of a white solid, yield: 26 percent.

LC/MS:m/z＝518.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.16(3H,s),6.81(1H,d,J＝8.0Hz),7.14-7.30 (4H,m),7.50-7.54(1H,m),7.79(1H,d,J＝9.2Hz),7.90-7.92(1H,m),7.96(1H,s), 9.63(1H,brs),10.60(1H,s).

Example 115

N- (3- ((2-amino-2-oxoethyl) amino) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

N- (3-amino-4-fluorophenyl) -2- (4-fluorophenoxy) -5- (trifluoromethyl) benzamide (50mg, 0.12mmol), potassium carbonate (50mg, 0.36mmol), 2-bromoacetamide (50mg, 0.36mmol) were dissolved in 5mL DMF, the reaction was stirred at 90 ℃ for 3 hours, quenched with water and extracted with ethyl acetate, and the organic phase was dried and concentrated to dryness. Purification by Prep-TLC (DCM/MeOH ═ 30/1) gave 30mg of white solid, yield: 52 percent.

LC/MS:m/z＝480.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.15(3H,s),4.30(2H,s),5.23(1H,s),6.42-6.49 (2H,m),6.75-6.89(3H,m),7.05-7.11(1H,m),7.18(1H,s),7.25(1H,dd,J＝8.2Hz,2.2 Hz),7.45(1H,s),7.50(1H,dd,J＝8.0Hz,2.4Hz),7.64(1H,d,J＝2.0Hz).

Example 116

5-acetyl-2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 5-acetyl-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask was added 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (250mg, 0.5mmol), tributyl (1-ethoxyvinyl) stannane (272mg, 0.75mmol), bis triphenylphosphine palladium dichloride (35mg, 0.05mmol) and 5mL toluene, heated to 100 ℃ under nitrogen for overnight reaction, and TLC showed completion. Cooling the reaction system to room temperature, adding dilute hydrochloric acid, stirring for 30min, extracting with ethyl acetate, drying the organic phase, and spin-drying to obtain about 300mg of crude target product for the next reaction.

Step 2: synthesis of 5-acetyl-2- (4-fluoro-2-methylphenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask was added 5-acetyl-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (300mg, 0.65mmol), chlorotrimethylsilane (424mg, 3.9mmol), potassium iodide (216mg, 1.3mmol) and 8mL acetonitrile, the reaction mixture was heated to 75 ℃ and stirred for 2 hours, TLC showed completion of the reaction. The reaction was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, the organic phase was back-washed once with sodium bisulfite solution, dried and spin-dried and purified by silica gel column chromatography (DCM/MeOH ═ 20/1) to give 80mg of the target product, yield: 36% (2 steps).

LC/MS:m/z＝449.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.16(3H,s),2.63(3H,s),6.37(1H,d,J＝7.2Hz), 6.77(1H,s),6.98(1H,s),7.08-7.21(2H,m),7.25(1H,d,J＝9.2Hz),7.33(1H,d,J＝ 7.2Hz),8.21(1H,s),10.73(1H,s),11.30(1H,s).

Example 117

2- (4-fluoro-2-methylphenoxy) -5- (2-methylpropan-1-en-1-yl) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethylbenzamide

Step 1: synthesis of 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -5- (2-methylpropan-1-en-1-yl) -4- (trifluoromethyl) benzamide

To a reaction flask were added 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (100mg, 0.2mmol), 4,4,5, 5-tetramethyl-2- (2-methylpropan-1-en-1-yl) -1,3, 2-dioxaborane (73mg, 0.4mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (15mg, 0.02mmol), potassium carbonate (83mg, 0.6mmol) and 6mL of ethylene glycol dimethyl ether, the reaction mixture was heated to 80 ℃ and stirred for 3 hours, TLC showed completion of the reaction. The reaction system was cooled to room temperature and poured into 50mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 3/1) to give 60mg of the target product, yield: and 63 percent.

Step 2: synthesis of 2- (4-fluoro-2-methylphenoxy) -5- (2-methylpropan-1-en-1-yl) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethylbenzamide

To a reaction flask was added 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -5- (2-methylpropan-1-en-1-yl) -4- (trifluoromethyl) benzamide (60mg, 0.13mmol), chlorotrimethylsilane (85mg, 0.78mmol), potassium iodide (43mg, 0.26mmol) and 4mL acetonitrile, and the reaction mixture was stirred at 75 ℃ for 2 hours and TLC showed completion of the reaction. The reaction was poured into 15mL of water, extracted with ethyl acetate, the organic phase was back-washed once with sodium bisulphite solution, dried and spin-dried, preparative TLC purification (DCM-MeOH ═ 15/1) afforded 22mg of pure product, yield: 37 percent.

LC/MS:m/z＝461.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.72(3H,s),1.90(3H,s),2.17(3H,s),6.30(1H,s), 6.37(1H,dd,J＝7.2,2.0Hz),6.74(1H,d,J＝1.6Hz),6.97(1H,s),7.08(2H,dd,J＝7.2, 2.0Hz),7.21(1H,d,J＝8.6Hz),7.30(1H,d,J＝7.2Hz),7.53(1H,s),10.60(1H,s), 11.27(1H,s).

Example 118

4-cyclopropyl-2- (4-fluoro-2- (1-hydroxycyclopropyl) phenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

Step 1: synthesis of 1- (5-fluoro-2- (((4-methoxybenzyl) oxy) phenyl) ethan-1-one

To a reaction flask were added 1- (5-fluoro-2-hydroxyphenyl) ethan-1-one (3.08g, 20mmol), 4-methoxybenzyl chloride (4.7g, 30mmol), potassium carbonate (5.52g, 40mmol) and 50mL of N, N-dimethylformamide, and the reaction mixture was heated to 50 ℃ and stirred overnight. The reaction system was cooled to room temperature and poured into 50mL of water, extracted with ethyl acetate, the organic phase was backwashed with saturated sodium chloride solution for 2 times, dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 5/1) to give 4.9g of the target product, yield: 89 percent.

Step 2: synthesis of tert-butyl ((1- (5-fluoro-2- ((4-methoxybenzyloxy) phenyl) vinyl) oxy) dimethylsilane

To a reaction flask were added 1- (5-fluoro-2- (((4-methoxybenzyl) oxy) phenyl) ethan-1-one (4.5g, 16.4 mmol), triethylamine (3.3g, 32.8mmol) and 50mL of dichloromethane, and to the reaction mixture was added dropwise tert-butyldimethylsilyl trifluoromethanesulfonate (6.5g, 24.6mmol) in an ice-water bath, after completion of the addition, the reaction was stirred at room temperature for 3 hours, TLC showed completion of the reaction, the reaction system was cooled to room temperature, poured into 100mL of water, extracted with dichloromethane, the organic phase was dried and spin-dried, and then purified by silica gel column chromatography (PE/EA ═ 15/1) to obtain 5.4g of the objective product with a yield of 85%.

And step 3: synthesis of 2- (1- ((tert-butyldimethylsilyl) oxy) cyclopropyl) -4-fluorophenol

Diethyl zinc (1M in n-hexane, 18mL, 18mmol) was added dropwise to a solution of diiodomethane (4.82g, 18mmol) in 60mL of dry dichloromethane at 0 ℃ under nitrogen protection, the reaction system was stirred at 0 ℃ for 1 hour, a solution of tert-butyl ((1- (5-fluoro-2- ((4-methoxybenzyloxy) phenyl) vinyl) oxy) dimethylsilane (2.33g, 6mmol) in 10mL of dichloromethane was slowly added dropwise, the mixture was stirred overnight at room temperature, the reaction mixture was poured into 200mL of water, dichloromethane was extracted, the organic phase was dried and spin-dried, and then purified by silica gel column chromatography (PE/EA ═ 5/1) to give 900mg of the target product in 53% yield.

And 4, step 4: synthesis of 4-fluoro-2- (1-hydroxycyclopropyl) phenol

To the reaction flask were added 2- (1- ((tert-butyldimethylsilyl) oxy) cyclopropyl) -4-fluorophenol (282 mg,1mmol), tetrabutylammonium fluoride (313mg, 1.2mmol) and 5mL of tetrahydrofuran, and the reaction mixture was stirred at room temperature for 1 hour. The reaction system was poured into 20mL of water, extracted with ethyl acetate, the organic phase was reacted 1 time with dilute hydrochloric acid, dried and spin-dried to give 130mg of the target product, yield: 77 percent.

LC/MS:m/z＝169.1[M+H]⁺.

4-cyclopropyl-2-fluoro-5- (trifluoromethyl) benzoic acid (5g, 20mmol), 2-methoxypyridin-4-amine (3g, 24mmol), pyridine (7.9g, 100mmol) and 100mL dichloromethane were added to the reaction flask, the reaction mixture was cooled in an ice-water bath, and phosphorus oxychloride (9.2g, 60mmol) was added dropwise to the system, and the mixture was stirred at room temperature for 2 hours. The reaction system was cooled to room temperature and poured into 100mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by beating (PE/EA ═ 20/1) to give 5.6g of the target product, yield: 79 percent.

Step 6: synthesis of 4-cyclopropyl-2- (4-fluoro-2- (1-hydroxycyclopropyl) phenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide

To a reaction flask were added 4-cyclopropyl-2-fluoro-N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (70mg, 0.2mmol), 4-fluoro-2- (1-hydroxycyclopropyl) phenol (101mg, 0.6mmol), potassium carbonate (138mg, 1mmol) and 2mL of N-methylpyrrolidone, after the addition was complete the reaction mixture was stirred at 100 ℃ for 5 hours, the reaction was poured into 10mL of water, extracted with ethyl acetate, back-washed 2 times with saturated brine, the organic phase was dried and spin-dried to give 50mg of crude product, yield: 50 percent.

And 7: synthesis of 4-cyclopropyl-2- (4-fluoro-2- (1-hydroxycyclopropyl) phenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

To a reaction flask were added 4-cyclopropyl-2- (4-fluoro-2- (1-hydroxycyclopropyl) phenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (50mg, 0.1mmol), chlorotrimethylsilane (108mg, 1mmol), potassium iodide (83mg, 0.5mmol), and 3mL acetonitrile, the reaction mixture was heated to 75 ℃ and stirred for 3 hours, TLC showed completion of the reaction. The reaction was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and dried to afford preparative TLC purification (DCM/MeOH ═ 15/1) to afford 3mg of the target product, yield: 6 percent.

LC/MS:m/z＝489.1[M+H]⁺.

Example 119

4-cyclopropyl-2- (4-fluoro-2- (2-hydroxyethoxy) phenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

Step 1: synthesis of 4-cyclopropyl-2- (4-fluoro-2- ((4-methoxybenzyl) oxy) phenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide

To a reaction flask was added 4-cyclopropyl-2-fluoro-N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (1.78g, 5mmol), 4-fluoro-2- ((4-methoxybenzyl) oxy) phenol (1.49g, 6mmol), potassium carbonate (1.38g, 10mmol) and 20mL of N-methylpyrrolidinone and the reaction mixture was heated to 100 ℃ and stirred overnight. Cooling the reaction system to room temperature, pouring the reaction system into 100mL of water, extracting with ethyl acetate, backwashing an organic phase saturated sodium chloride solution for 2 times, drying and spin-drying the organic phase saturated sodium chloride solution, and then carrying out impurity removal to obtain 3.2g of a crude product, wherein the yield is as follows: it was not purified.

Step 2: 4-cyclopropyl-2- (4-fluoro-2-hydroxyphenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide

4-cyclopropyl-2- (4-fluoro-2- ((4-methoxybenzyl) oxy) phenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (3.2g, crude from the above step) was dissolved in 25mL of dichloromethane, 5mL of trifluoroacetic acid was added, and after the addition was completed, the reaction mixture was stirred at room temperature for 30 minutes, the reaction system was concentrated to dryness, 50mL of water was added to quench, ethyl acetate was extracted, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 2/1) to give 1.62g of crude product, yield: 70 percent.

And step 3: synthesis of 4-cyclopropyl-2- (4-fluoro-2- (2-hydroxyethoxy) phenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide

To a reaction flask was added 24-cyclopropyl-2- (4-fluoro-2-hydroxyphenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (100mg, 0.22mmol), 2-bromoethane-1-ol (83mg, 0.66mmol), potassium carbonate (138mg, 1mmol), and 2mL of N-methylpyrrolidone, and the reaction mixture was heated to 100 ℃ with stirring for 3 hours and TLC indicated completion of the reaction. The reaction system was cooled to room temperature and poured into 10mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 2/1) to give 70mg of the target product, yield: and 63 percent.

And 4, step 4: synthesis of 4-cyclopropyl-2- (4-fluoro-2- (2-hydroxyethoxy) phenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

4-cyclopropyl-2- (4-fluoro-2- (2-hydroxyethoxy) phenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (70mg, 0.14mmol) was dissolved in 5mL acetonitrile and potassium iodide (117 mg, 0.7mmol) and TMSCl (151mg, 1.4mmol) were added at room temperature and the mixture was stirred at 70 ℃ overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by TLC (DCM/MeOH ═ 15/1) to give 25mg of the title product as a white solid in yield: 37 percent.

LC/MS:m/z＝493.1[M+H]⁺.

Example 120

2- (2- (5-cyclopropyl-2- ((2-oxo-1, 2-dihydropyridin-4-yl) carbamoyl) -4- (trifluoromethyl) phenoxy) -5-fluorophenoxy) acetic acid

Step 1: synthesis of ethyl 2- (2- (5-cyclopropyl-2- ((2-methoxypyridin-4-yl) carbamoyl) -4- (trifluoromethyl) phenoxy) -5-fluorophenoxy) acetate

To a reaction flask were added 4-cyclopropyl-2- (4-fluoro-2-hydroxyphenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (231mg, 0.5mmol), ethyl 2-bromoacetate (166mg, 1mmol), potassium carbonate (207mg, 1.5mmol), and 4mL of N-methylpyrrolidone, and the reaction mixture was stirred at 90 ℃ for 3 hours. The reaction system was cooled to room temperature and poured into 15mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 5/1) to give 200mg of the target product, yield: 73 percent.

Step 2: synthesis of 2- (2- (5-cyclopropyl-2- ((2-methoxypyridin-4-yl) carbamoyl) -4- (trifluoromethyl) phenoxy) -5-fluorophenoxy) acetic acid

To a reaction flask was added ethyl 2- (2- (5-cyclopropyl-2- ((2-methoxypyridin-4-yl) carbamoyl) -4- (trifluoromethyl) phenoxy) -5-fluorophenoxy) acetate (200mg, 0.36mmol), sodium hydroxide (43mg, 1.08mmol), 2mL water and 8mL ethanol, and the reaction mixture was stirred at room temperature overnight. Pouring the reaction system into 30mL of water, extracting with ethyl acetate to remove impurities, adjusting the pH value of the water phase to 4 with 1M hydrochloric acid, extracting with ethyl acetate again, drying and spin-drying the organic phase to obtain 120mg of a target product, wherein the yield is as follows: and 63 percent.

And step 3: synthesis of 2- (2- (5-cyclopropyl-2- ((2-oxo-1, 2-dihydropyridin-4-yl) carbamoyl) -4- (trifluoromethyl) phenoxy) -5-fluorophenoxy) acetic acid

To a reaction flask was added 2- (2- (5-cyclopropyl-2- ((2-methoxypyridin-4-yl) carbamoyl) -4- (trifluoromethyl) phenoxy) -5-fluorophenoxy) acetic acid (120mg, 0.23mmol), trimethylchlorosilane (248mg, 2.3mmol), potassium iodide (192mg, 1.15mmol) and 5mL acetonitrile, and the reaction mixture was stirred at 70 ℃ for 3 hours. The reaction system was poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by preparative HPLC to give 80mg of the target product, yield: 68 percent.

LC/MS:m/z＝507.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ0.53-0.54(2H,m),0.95-0.97(2H,m),1.95-2.01 (1H,m),3.95(2H,s),6.28(1H,s),6.50-6.53(1H,m),6.60(1H,brs)6.75-6.76(1H,m), 6.79-6.93(2H,m),7.21-7.28(1H,m),7.30-7.32(1H,m),7.66(1H,s),11.11(1H,s), 11.90(1H,s).

Example 121

2- (2- (2-amino-2-oxoethoxy) -4-fluorophenoxy) -4-cyclopropyl-N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (2- (2-amino-2-oxoethoxy) -4-fluorophenoxy) -4-cyclopropyl-N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide

To a reaction flask were added 2- (2- (5-cyclopropyl-2- ((2-methoxypyridin-4-yl) carbamoyl) -4- (trifluoromethyl) phenoxy) -5-fluorophenoxy) acetic acid (60mg, 0.12mmol), ammonium chloride (32mg, 0.6mmol), N, N-diisopropylethylamine (155mg, 1.2mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (137mg, 0.36mmol) and 2mL of N, N-dimethylformamide, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by preparative TLC (DCM/MeOH ═ 50/1) to give 45mg of the target product in yield: 75 percent.

Step 2: synthesis of 2- (2- (2-amino-2-oxoethoxy) -4-fluorophenoxy) -4-cyclopropyl-N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

To a reaction flask were added 2- (2- (2-amino-2-oxoethoxy) -4-fluorophenoxy) -4-cyclopropyl-N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (45mg, 0.09mmol), trimethylchlorosilane (97 mg, 0.9mmol), potassium iodide (75mg, 0.45mmol) and 5mL acetonitrile, and the reaction mixture was stirred at 70 ℃ for 2 hours and TLC showed completion of the reaction. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by preparative TLC (DCM/MeOH ═ 15/1) to give 15mg of the target product in yield: 33 percent.

LC/MS:m/z＝506.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ0.62-0.64(2H,m),0.99-1.01(2H,m),1.95-2.01 (1H,m),4.51(2H,s),6.36-6.40(2H,m),6.77(1H,s),6.82-6.84(1H,m),6.98-7.02(1H, m),7.26-7.33(3H,m),7.44(1H,s),7.85(1H,s),10.40(1H,s),11.20(1H,brs).

Example 122

2- (4-fluoro-2- (2- (methylsulfonylamino) ethoxy) phenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (4-fluoro-2- (2- (methylsulfonylamino) ethoxy) phenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2- (2- (2-aminoethoxy) -4-fluorophenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (100mg, 0.22mmol), N, N-diisopropylethylamine (129mg, 1mmol) and 8mL dichloromethane, methanesulfonyl chloride (75mg, 0.66mmol) was added at room temperature and the mixture was stirred at room temperature for 1 hour. The reaction was poured into 20mL of water, extracted with dichloromethane, dried and dried to yield 105mg of the target product, yield: 88 percent.

Step 2: synthesis of 2- (4-fluoro-2- (2- (methylsulfonylamino) ethoxy) phenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2- (2- (methylsulfonamido) ethoxy) phenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (105mg, 0.19mmol), chlorotrimethylsilane (205mg, 1.9mmol), potassium iodide (159mg, 0.95mmol) and 8mL acetonitrile, and the reaction mixture was stirred at 70 ℃ for 2 hours and TLC showed completion of the reaction. The reaction was poured into 30mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by preparative TLC (DCM/MeOH ═ 15/1) to give 65mg of the target product in yield: 65 percent.

LC/MS:m/z＝530.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.81(3H,s),3.16-3.18(2H,m),4.04-4.07(2H,m), 6.41(1H,dd,J＝7.2,2.0Hz),6.79(1H,s),6.87-6.91(1H,m),6.94(1H,s),7.11-7.17 (1H,m),7.18-7.21(1H,m),7.28-7.33(2H,m),7.57(1H,d,J＝7.6Hz),7.82(1H,d,J＝ 8.0Hz),10.55(1H,s),11.29(1H,s).

Example 123

2- (2- (3-amino-3-oxopropyl) -4-fluorophenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (4-fluoro-2-iodophenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2-fluoro-N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (628mg, 2mmol), 4-fluoro-2-iodophenol (711mg, 3mmol), potassium carbonate (828mg, 6mmol) and 10Ml N-methylpyrrolidinone and the reaction mixture was stirred at 100 ℃ overnight. The reaction was poured into 50mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 8/1) to yield 780mg of the desired product: 74 percent.

And 2, step: synthesis of ethyl 3- (5-fluoro-2- (2- (((2-methoxypyridin-4-yl) carbamoyl) -5- (trifluoromethyl) phenoxy) phenyl) propiolate

To a reaction flask were added 2- (4-fluoro-2-iodophenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (600mg, 1.13mmol), ethyl propiolate (332mg, 3.39mmol), triethylamine (685mg, 6.78mmol), cuprous iodide (38mg, 0.2mmol), bis (triphenylphosphine) palladium dichloride (70mg, 0.1mmol) and 10mL of N, N-dimethylformamide, and the reaction mixture was heated to 80 ℃ with replacement of nitrogen and stirred overnight. The reaction system was cooled to room temperature and poured into 50mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 5/1) to give 380mg of the target product, yield: 67%.

And step 3: synthesis of ethyl 3- (5-fluoro-2- (2- (((2-methoxypyridin-4-yl) carbamoyl) -5- (trifluoromethyl) phenoxy) phenyl) propionate

To a reaction flask were added ethyl 3- (5-fluoro-2- (2- (((2-methoxypyridin-4-yl) carbamoyl) -5- (trifluoromethyl) phenoxy) phenyl) propiolate (380mg, 0.76mmol), 10% palladium on carbon (76mg, 20% wt), and 15mL of methanol, and after replacement of hydrogen, the reaction mixture was stirred at 45 ℃ overnight, the reaction was directly filtered with suction and concentrated to dryness to give 280mg of the desired product in 73% yield.

And 4, step 4: synthesis of (2- (2- (3-amino-3-oxopropyl) -4-fluorophenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide

Ethyl 3- (5-fluoro-2- (2- (((2-methoxypyridin-4-yl) carbamoyl) -5- (trifluoromethyl) phenoxy) phenyl) propionate (100mg, 0.2mmol) was dissolved in 10mL of methanolic ammonia and the reaction mixture was stirred at 45 ℃ overnight and the reaction was spun dry to give 95mg of the desired product in 100% yield.

And 5: synthesis of 2- (2- (3-amino-3-oxopropyl) -4-fluorophenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask were added (2- (2- (3-amino-3-oxopropyl) -4-fluorophenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (95mg, 0.2mmol), chlorotrimethylsilane (216mg, 2mmol), potassium iodide (166mg, 1mmol) and 5mL acetonitrile, and the reaction mixture was stirred at 70 ℃ for 2 hours, TLC showed completion the reaction, the reaction was poured into 30mL water, extracted with ethyl acetate, the organic phase was dried and purified by preparative TLC (DCM/MeOH: 15/1) to give 30mg of the desired product in 32% yield.

LC/MS:m/z＝464.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.35(2H,t,J＝8.0Hz),2.78(2H,t,J＝8.0Hz), 6.40(1H,dd,J＝7.2,2.0Hz),6.79-6.81(2H,m),7.03-7.12(3H,m),7.20(1H,dd,J＝ 9.6,3.2Hz),7.30-7.32(2H,m),7.61(1H,d,J＝8.0Hz),7.84(1H,d,J＝8.0Hz),10.70 (1H,s),11.29(1H,s).

Example 124

2- (4-fluoro-2- (3-hydroxypropyl) phenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (4-fluoro-2- (3-hydroxypropyl) phenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide

Adding 3- (5-fluoro-2- (2- (((2-methoxypyridin-4-yl) carbamoyl) -5- (trifluoromethyl) phenoxy) phenyl) propionic acid ethyl ester (100mg, 0.2mmol) and 5mL of methanol into a reaction bottle, adding sodium borohydride (76mg, 2mmol) into the reaction system in batches, adding water to quench the reaction after the TLC detection reaction is completed, and extracting ethyl acetate to obtain 60mg of a target product, wherein the yield is 65%.

Step 2: synthesis of 2- (4-fluoro-2- (3-hydroxypropyl) phenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -4- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2- (3-hydroxypropyl) phenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (60mg, 0.13mmol), chlorotrimethylsilane (140mg, 1.3mmol), potassium iodide (108mg, 0.65mmol) and 5mL acetonitrile, and the reaction mixture was stirred at 70 ℃ for 2 hours and TLC showed completion of the reaction. The reaction was poured into 30mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by preparative TLC (DCM/MeOH ═ 15/1) to give 23mg of the target product in yield: 39 percent.

LC/MS:m/z＝451.1[M+H]⁺.

Example 125

2- (4-fluoro-2- (((6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) oxy) phenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (2- ((6- (((tert-butyldiphenylsilyl) oxy) methyl) tetrahydro-2H-pyran-3-yl) oxy) -4-fluorophenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide

To a reaction flask was added 2- (4-fluoro-2-hydroxyphenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (211mg, 0.5mmol), 6- ((((tert-butyldiphenylsilyl) oxy) methyl) tetrahydro-2H-pyran-3-ol (370mg, 1mmol), triphenylphosphine (393mg, 1.5mmol) and 10mL tetrahydrofuran, and DIAD (505mg, 2.5mmol) was added dropwise at room temperature, the reaction mixture was stirred at room temperature overnight, the reaction was poured into 30mL water, extracted with ethyl acetate, the organic phase was dried and spin dried and purified by column chromatography (PE/EA ═ 3/1) to give 200mg of the desired product in 52% yield.

And 2, step: synthesis of 2- (4-fluoro-2- (((6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) oxy) phenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

To a reaction flask were added 2- (2- ((6- (((tert-butyldiphenylsilyl) oxy) methyl) tetrahydro-2H-pyran-3-yl) oxy) -4-fluorophenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (200mg, 0.26mmol), and 5mL of hydrobromic acid in acetic acid (40% wt), and the reaction mixture was stirred at 100 ℃ for 2 hours. The reaction was poured into 30mL of water, extracted with ethyl acetate, the organic phase dried and dried twice by preparative TLC (DCM/MeOH ═ 12/1) to give 45mg of the desired product, yield: 33 percent.

LC/MS:m/z＝523.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.24-1.29(1H,m),1.62-1.64(1H,m),2.06-2.09 (1H,m),2.95(1H,t,J＝10.4Hz),3.15-3.18(1H,m),3.26-3.33(3H,m),3.84(1H,dd,J ＝10.4,2.8Hz),4.32-4.35(1H,m),4.63(1H,t,J＝7.0Hz),6.43(1H,dd,J＝7.2,2.0Hz), 6.81-6.92(3H,m),7.30-7.36(3H,m),7.78(1H,dd,J＝8.8,2.0Hz),.7.96(1H,d,J＝2.0 Hz),10.48(1H,s),11.28(1H,s).

Example 126

2- (2- (2- (dimethylamino) ethoxy) -4-fluorophenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

Step 1: synthesis of 2- (2- (2-bromoethoxy) -4-fluorophenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide

To a reaction flask was added 2- (4-fluoro-2-hydroxyphenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (422mg, 1mmol), 2-bromoethan-1-ol (250mg, 2mmol), triphenylphosphine (524 mg,2mmol) and 12mL tetrahydrofuran, DIAD (606mg, 3mmol) was added dropwise at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 40mL of water, extracted with ethyl acetate, the organic phase was dried and dried by spin-drying and purified by column chromatography (PE/EA 4/1) to yield 340mg of the desired product in 64% yield.

And 2, step: synthesis of 2- (2- (2- (dimethylamino) ethoxy) -4-fluorophenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide

To a reaction flask was added 2- (2- (2-bromoethoxy) -4-fluorophenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (200mg, 0.38mmol), dimethylamine hydrochloride (62mg, 0.76mmol), potassium carbonate (210mg, 1.52mmol), and 10mL acetonitrile, and the reaction mixture was heated to 80 ℃ and stirred overnight. The reaction system was cooled to room temperature and poured into 30mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 110mg of the target product, yield: 59 percent.

And 3, step 3: synthesis of 2- (2- (2- (dimethylamino) ethoxy) -4-fluorophenoxy) -N- (2-oxo-1, 2-dihydropyridin-4-yl) -5- (trifluoromethyl) benzamide

To a reaction flask were added 2- (2- (2- (dimethylamino) ethoxy) -4-fluorophenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (110mg, 0.22mmol) and 4mL of hydrobromic acid acetic acid solution (40% wt) and the reaction mixture was heated to 100 ℃ and stirred for 2 hours. The reaction was cooled to room temperature and poured into 25mL of water, extracted with ethyl acetate, the organic phase dried and spun-dried and purified by TLC (DCM/MeOH ═ 10/1) to give 30mg of the target product, yield: 28 percent.

LC/MS:m/z＝480.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ1.98(6H,s),2.38(2H,t,J＝5.6Hz),4.04(2H,t,J＝ 5.6Hz),6.40-6.42(1H,m),6.80-6.84(2H,m),6.88-6.89(1H,m),7.18-7.22(1H,m), 7.32-7.39(2H,m),7.76-7.78(1H,m),7.95(1H,d,J＝2.0),10.37(1H,s),11.28(1H, brs).

Table 2: the following compounds were prepared starting from the corresponding reagents in a procedure similar to that described in the above examples.

Example 154

N- (3-amino-1H-indazol-5-yl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

Step 1: synthesis of N- (3-amino-1H-indazol-5-yl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

To a reaction flask were added 2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (314mg, 1mmol), 5-amino-2-fluorobenzonitrile (163mg, 1.2mmol), DIPEA (258mg, 2mmol) and 5mL of N, N-dimethylformamide, HATU (456mg, 1.2mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and spun-dried and purified by column chromatography (PE/EA-2/1) to obtain 355mg of the objective product in 82% yield.

And 2, step: synthesis of N- (3-amino-1H-indazol-5-yl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

To a reaction flask was added N- (3-amino-1H-indazol-5-yl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide (50mg, 0.12mmol), and 4mL of hydrazine hydrate, and the reaction mixture was stirred at 60 ℃ for 2 hours. The reaction was taken up in 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by preparative TLC (DCM/MeOH ═ 15/1) to give 25mg of the desired product in yield: 48.7 percent.

LC/MS:m/z＝445.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.18(3H,s),5.29(2H,s),6.82(1H,d,J＝8.0Hz), 7.20-7.37(5H,m),7.76-7.79(1H,m),7.98(1H,s),8.13(1H,s),10.36(1H,s),11.35(1H, s).

Example 155

N- (3-aminobenzo [ d ] isoxazol-5-yl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

Step 1: synthesis of N- (3-aminobenzo [ d ] isoxazol-5-yl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

To a reaction flask was added N- (3-cyano-4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide (50mg, 0.12mmol), acetohydroxamic acid (27mg, 0.36mmol), potassium carbonate (138mg, 1mmol) and 3 mldff, and the reaction mixture was heated to 100 ℃ under nitrogen blanket and stirred for 6 hours. The reaction was cooled to room temperature and poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun-dried and purified by preparative TLC (DCM/MeOH ═ 12/1) to give 36mg of the target product, yield: and 69 percent.

LC/MS:m/z＝446.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.17(3H,s),6.42(2H,s),6.83(1H,d,J＝8.0Hz), 7.15-7.23(3H,m),7.44(1H,d,J＝7.2Hz),7.59-7.62(1H,m),7.74-7.76(1H,d,J＝7.2 Hz),8.01(1H,d,J＝5.6Hz),8.36(1H,d,J＝5.6Hz),10.64(1H,s)..

Example 156

4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (3-methylbenzo [ d ] isoxazol-5-yl) -5- (trifluoromethyl) benzamide

Step 1: synthesis of tert-butyl (2-acetyl-4-nitrophenoxy) carbamate

To a reaction flask were added 1.0g, 5.5mmol of 1- (2-fluoro-5-nitrophenyl) ethan-1-one, tert-butyl hydroxycarbamate (879mg, 6.6mmol), potassium carbonate (911mg, 6.6mmol) and 20mL of acetonitrile, and the mixture was stirred at room temperature for 3 hours. The reaction was diluted with 30mL of ethyl acetate, filtered, and the organic phase was dried and spun-dried and purified by silica gel column chromatography (PE/EA 3/1) to give 1.35g of the target product in 83% yield.

Step 2: synthesis of 3-methyl-5-nitrobenzo [ d ] isoxazole

To the reaction flask was added tert-butyl (2-acetyl-4-nitrophenoxy) carbamate (592mg, 2mmol), 15mL ethyl acetate hydrochloride solution, the reaction mixture was stirred at room temperature for 1 hour, and TLC showed completion of the reaction. And (3) directly spin-drying a reaction system, adding 30mL of water, adjusting the pH to 9 with sodium carbonate, stirring for 30 minutes, extracting and drying with ethyl acetate, and purifying by silica gel flash column chromatography to obtain 280mg of a target product, wherein the yield is as follows: 79 percent.

And step 3: synthesis of 3-methylbenzo [ d ] isoxazol-5-amine

3-methyl-5-nitrobenzo [ d ] isoxazole (280mg, 1.57mmol) and 10mL of ethanol were added to the reaction flask, hydrogen was replaced and Pd/C (28mg, 10% wt) was added, the reaction stirred at room temperature for 3 hours, direct filtration was carried out after TLC detection of completion of the reaction, the filtrate was spun dry and taken with ethyl acetate 2-3 times to give 220mg of the desired product in yield: 94 percent.

And 4, step 4: synthesis of 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (3-methylbenzo [ d ] isoxazol-5-yl) -5- (trifluoromethyl) benzamide

To a reaction flask were added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (50mg, 0.14mmol), 3-methylbenzo [ d ] isoxazol-5-amine (25mg, 0.17mmol), DIPEA (54mg, 0.42mmol) and 3mLN, N-dimethylformamide, HATU (65mg, 1.7mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 15mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by preparative TLC (PE/EA ═ 2/1) to give 44mg of the target product in 65% yield.

LC/MS:m/z＝485.2[M+H]⁺.

Example 157

5- (4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) benzo [ d ] isoxazole-3-carboxamide

Step 1: synthesis of 5-nitrobenzo [ d ] isoxazole-3-carboxylic acid

3-methyl-5-nitrobenzo [ d ] isoxazole (200mg, 1.12mmol), potassium permanganate (531mg, 3.36mmol), and 15mL pyridine were added to the reaction flask, and the reaction mixture was stirred at 100 ℃ overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and spun to yield 130mg of crude product for the next reaction without further treatment.

Step 2: synthesis of 5-nitrobenzo [ d ] isoxazole-3-carboxamide

To a reaction flask were added 5-nitrobenzo [ d ] isoxazole-3-carboxylic acid (130mg,. about.0.63 mmol), ammonium chloride (170 mg, 3.15mmol), DIPEA (406mg, 3.15mmol) and 8mL of N, N-dimethylformamide, HATU (479mg, 1.26mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 30mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA-2/1) to give 60mg of the target product in 26% yield (2 steps).

And 3, step 3: synthesis of (5-aminobenzo [ d ] isoxazole-3-carboxamide

To a reaction flask was added 5-nitrobenzo [ d ] isoxazole-3-carboxamide (60mg, 0.29mmol) and 5mL of ethanol, hydrogen was replaced and Pd/C (12mg, 20% wt) was added, the reaction stirred at room temperature for 3 hours, direct filtration after TLC detection of completion of the reaction, the filtrate was spun dry and taken up with ethyl acetate 2 times to give 43mg of the desired product, yield: 84 percent.

And 4, step 4: synthesis of 5- (4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) benzo [ d ] isoxazole-3-carboxamide

To a reaction flask were added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (50mg, 0.14mmol), (5-aminobenzo [ d ] isoxazole-3-carboxamide (30mg, 0.17mmol), DIPEA (54mg, 0.42mmol) and 3mL N, N-dimethylformamide, HATU (65mg, 1.7mmol) was added at room temperature, the reaction mixture was stirred at room temperature overnight, the reaction was poured into 15mL water, extracted with ethyl acetate, dried organically and spin-dried and purified by preparative TLC (DCM/MeOH 50/1) to give 42mg of the objective product in 58% yield.

LC/MS:m/z＝514.1[M+H]⁺.

Example 158

N- (3-aminoimidazo [1,2-a ] pyridin-6-yl) -4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

Step 1: synthesis of N- (3-nitroimidazo [1,2-a ] pyridin-6-yl) -1, 1-diphenylazomethine

Adding 6-bromo-3-nitroimidazo [1,2-a ] into a reaction flask]Pyridine (100mg, 0.41mmol), benzophenone imine (89 m)g, 0.49mmol), cesium carbonate (267mg, 0.82mmol), Xphos (19mg, 0.04mmol) dissolved in 8mL of toluene, Pd added under nitrogen at room temperature₂(dba)₃(37mg, 0.04mmol) and the reaction mixture was stirred at 100 ℃ overnight. The reaction was poured into 30mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by silica gel column chromatography (PE/EA ═ 2/1) to give 90mg of the target product in yield: 66 percent.

Step 2: synthesis of 3-nitroimidazo [1,2-a ] pyridin-6-amine

To a reaction flask were added N- (3-nitroimidazo [1,2-a ] pyridin-6-yl) -1, 1-diphenylmethanimine (90mg, 0.26mmol), and 5mL of an ethyl acetate hydrochloride solution, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was directly spun-dried and purified by silica gel column chromatography (PE/EA ═ 1/1) to give 40mg of the target product in yield: 85 percent.

And step 3: synthesis of 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (3-nitroimidazo [1,2-a ] pyridin-6-yl) -5- (trifluoromethyl) benzamide

4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (50mg, 0.14mmol), 3-nitroimidazo [1,2-a ] pyridin-6-amine (30mg, 0.17mmol), pyridine (0.5mL) was dissolved in 15mL dry DCM and phosphorus oxychloride (107mg, 0.7mmol) was added dropwise at 0 deg.C, after addition the system was stirred at room temperature for 1 hour. After the TLC detection reaction is completed, the system is directly dried in a spinning mode and purified through silica gel column chromatography to obtain 55mg of target products, and the yield is as follows: 76 percent.

And 4, step 4: synthesis of N- (3-aminoimidazo [1,2-a ] pyridin-6-yl) -4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (3-nitroimidazo [1,2-a ] pyridin-6-yl) -5- (trifluoromethyl) benzamide (55mg,0.11mmol) was dissolved in 10mL of ethanol, Pd/C (11mg, 20% wt) and after displacement with hydrogen, the reaction mixture was stirred at room temperature for 3 hours. The reaction was filtered directly to dryness and purified by silica prep TLC (DCM/MeOH ═ 15/1) to give 20mg of the desired product in yield: 39 percent.

LC/MS:m/z＝485.2[M+H]⁺.

Table 3: the following compounds were prepared starting from the corresponding reagents in a procedure analogous to that described in the above examples

Example 166

4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (3-hydroxyisoxazol-5-yl) phenyl) -5- (trifluoromethyl) benzamide

Step 1: synthesis of 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-iodophenyl) -5- (trifluoromethyl) benzamide

To a reaction flask were added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (354mg, 1.0mmol), 4-fluoro-3-iodoaniline (237mg, 1.0mmol), DIPEA (258mg, 2mmol) and 5mL of N, N-dimethylformamide, HATU (456mg, 1.2mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spun dry and purified by column chromatography (PE/EA 5/1) to yield 430mg of the desired product in 75% yield.

Step 2: synthesis of ethyl 3- (5- (4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) -2-fluorophenyl) propionate

To a reaction flask, 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-iodophenyl) -5- (trifluoromethyl) benzamide (289mg, 0.50mmol), ethyl acrylate (98mg, 1.00mmol), triethylamine (101mg, 1.00mmol), cuprous iodide (10mg, 0.05mmol) and 5mL of tetrahydrofuran were added, and after replacement of nitrogen, Pd (PPh) was added₃)₂Cl₂(21mg, 0.03mmol), and nitrogen was again replaced. The reaction mixtureThe mixture was stirred at 70 ℃ for 3 hours under nitrogen. The reaction was taken up in 20mL of water, extracted with ethyl acetate, the organic phase dried and purified by preparative TLC (PE/EA ═ 2/1) to give 220mg of the desired product in yield: 81 percent.

And step 3: synthesis of 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (3-hydroxyisoxazol-5-yl) phenyl) -5- (trifluoromethyl) benzamide

To a reaction flask was added ethyl 3- (5- (4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) -2-fluorophenyl) propionate (54mg, 0.1mmol), hydroxylamine hydrochloride (7mg, 0.1mmol), sodium hydrogen carbonate (17mg, 0.2mmol), 2mL of ethanol and 1mL of water. The reaction mixture was stirred at 90 ℃ overnight. The reaction was directly purified by Prep-HPLC to give 10mg of the target product as a white solid, yield: 19 percent.

LC/MS:m/z＝531.1[M+H]⁺.

Example 167

4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (3-hydroxy-1H-pyrazol-5-yl) phenyl) -5- (trifluoromethyl) benzamide

To a reaction flask were added ethyl 3- (5- (4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) -2-fluorophenyl) propionate (54mg, 0.1mmol), hydrazine hydrate (0.1mL) and 2mL ethanol. The reaction mixture was stirred at 90 ℃ overnight. The reaction was directly purified by Prep-HPLC to give 6mg of the target product as a white solid, yield: 11 percent.

LC/MS:m/z＝530.1[M+H]⁺.

Example 168

4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (1H-pyrazol-4-yl) phenyl) -5- (trifluoromethyl) benzamide

To a reaction flask were added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-iodophenyl) -5- (trifluoromethyl) benzamide (57mg, 0.10mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (20mg, 0.10mmol), potassium carbonate (27mg, 0.20mmol) and 2mL DMF, and after replacement of nitrogen, Pd (dppf) Cl was added₂(7mg, 0.01mmol), nitrogen was again replaced. The reaction mixture was stirred at 90 ℃ overnight under nitrogen. The reaction was taken up in 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by preparative TLC (DCM/MeOH ═ 20/1) to give 12mg of the title product as a white solid in yield: 24 percent.

LC/MS:m/z＝514.2[M+H]⁺.

Example 169

4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (1H-pyrrol-2-yl) phenyl) -5- (trifluoromethyl) benzamide

To a reaction flask, 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-iodophenyl) -5- (trifluoromethyl) benzamide (57mg, 0.10mmol), (1H-pyrrol-2-yl) boronic acid (22mg, 0.20mmol), potassium carbonate (41mg, 0.30mmol) and 2mL of DMF were added, and after replacement of nitrogen, Pd (dppf) Cl was added₂(7mg, 0.01mmol), nitrogen was again replaced. The reaction mixture was stirred at 90 ℃ overnight under nitrogen. The reaction was taken up in 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by preparative TLC (DCM/MeOH ═ 20/1) to give 5mg of the title product as a white solid in yield: 10 percent.

LC/MS:m/z＝513.2[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ0.56-0.58(2H,m),1.04-1.06(2H,m),2.12-2.17 (4H,m),6.15-6.18(1H,m),6.36(1H,s),6.46(1H,s),6.90(1H,s),7.09-7.11(2H,m), 7.19-7.24(2H,m),7.39-7.42(1H,m),7.92-7.94(2H,m),10.40(1H,s),11.23(1H,s).

Example 170

4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (3- ((2-hydroxyethyl) amino) benzo [ d ] isoxazol-5-yl) -5- (trifluoromethyl) benzamide

To the reaction flask were added N- (3-aminobenzo [ d ] isoxazol-5-yl) -4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide (49mg, 0.10mmol), 2-bromoethanol (12mg, 0.10mmol), potassium carbonate (41mg, 0.30mmol) and 2mL of DMF. The reaction mixture was stirred at 90 ℃ overnight. The reaction was poured into 10mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by preparative TLC (DCM/MeOH ═ 10/1) to give 15mg of the title product as a white solid in yield: 28 percent.

LC/MS:m/z＝530.2[M+H]⁺.

Example 171

4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (3-hydroxy- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -5- (trifluoromethyl) benzamide

Step 1: synthesis of tert-butyl 2- (5-nitropyridin-2-yl) hydrazine-1-carboxylate

To the reaction flask was added 2-hydrazino-5-nitropyridine (900mg, 5.84mmol), (Boc)₂O (1267mg, 5.84mmol), DIPEA (1507mg, 11.68mmol) and 10mL tetrahydrofuran, the reaction mixture was stirred at room temperature overnight. The reaction was poured into 50mL of water, extracted with ethyl acetate, and the organic phase was back-washed twice with saturated brine, dried and spin-dried to give 1500mg of the target product.

And 2, step: synthesis of tert-butyl 2- (5-aminopyridin-2-yl) hydrazine-1-carboxylate

To a reaction flask was added tert-butyl 2- (5-nitropyridin-2-yl) hydrazine-1-carboxylate (1500mg, 5.91mmol), and 20mL of ethanol, Pd/C (10%, 200mg) was added, and the reaction mixture was stirred under hydrogen atmosphere (0.1MPa) at room temperature overnight. Filtration and spin-drying of the filtrate yielded 1370mg of the desired product.

And step 3: synthesis of tert-butyl 2- (5- (4- (4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) pyridin-2-yl) hydrazine-1-carboxylate

To a reaction flask were added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (354mg, 1.0mmol), tert-butyl 2- (5-aminopyridin-2-yl) hydrazine-1-carboxylate (224mg, 1.0mmol), DIPEA (258mg, 2mmol) and 5mL of N, N-dimethylformamide, HATU (456mg, 1.2mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, dried and spun, and purified by column chromatography (DCM/MeOH-20/1) to give 470mg of the desired product in 84% yield.

And 4, step 4: synthesis of 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (6-hydrazinopyridin-3-yl) -5- (trifluoromethyl) benzamide

To a reaction flask was added tert-butyl 2- (5- (4- (4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamido) pyridin-2-yl) hydrazine-1-carboxylate (470mg, 0.84mmol), and 10mL hydrogen chloride in dioxane (4M), and the reaction mixture was stirred at room temperature for 4 hours, system was spun dry, 1mL water and 1mL methanol were added, 500mg sodium carbonate was added, stirring was continued for 10 minutes, DCM/MeOH (20/1, 20mL) was added, filtration was performed, and the filtrate was spun dry to give 370mg of the desired product.

And 5: synthesis of 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (3-hydroxy- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -5- (trifluoromethyl) benzamide

To a reaction flask were added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (6-hydrazinopyridin-3-yl) -5- (trifluoromethyl) benzamide (46mg, 0.1mmol), CDI (16mg, 0.1mmol), TEA (20mg, 0.2mmol) and 5mL tetrahydrofuran, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, the organic phase dried and spun dry and purified by Prep-HPLC to give 10mg of the target product as a white solid with a yield of 20%.

LC/MS:m/z＝487.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ0.57-0.60(2H,m),1.02-1.07(2H,m),2.10-2.16 (4H,m),6.39(1H,s),7.05-7.09(2H,m),7.21-7.23(2H,m),7.29(1H,d,J＝10.2Hz), 7.95(1H,s),8.52(1H,s),10.49(1H,s),12.51(1H,s).

Example 172

N- (3-amino- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide

To a reaction flask was added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (6-hydrazinopyridin-3-yl) -5- (trifluoromethyl) benzamide (46mg, 0.1mmol), cyanogen bromide (10mg, 0.1mmol), and 3mL of ethanol, and the reaction mixture was stirred overnight at 90 ℃. The reaction was directly purified by Prep-HPLC to give 6mg of the target product as a white solid in 12% yield.

LC/MS:m/z＝486.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ0.56-0.58(2H,m),1.02-1.04(2H,m),2.10-2.16 (4H,m),6.32(2H,s),6.36(1H,s),7.05-7.11(3H,m),7.23(1H,dd,J＝9.6Hz,2.8Hz), 7.47(1H,d,J＝9.6Hz),7.95(1H,s),8.08(1H,s),10.51(1H,s).

Example 173

N- (3-amino- [1,2,4] triazolo [4,3-a ] pyridin-6-yl) -5-chloro-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

The compound of example 173 was prepared by a procedure similar to that described in examples 171 and 172, starting from the corresponding reagents.

LC/MS:m/z＝480.1[M+H]⁺.

1H NMR(400MHz,d₆-DMSO)δ2.18(3H,s),6.01(2H,s),7.08-7.10(2H,m),7.14(1H, s),7.20-7.22(1H,m),7.37(1H,dd,J＝9.0Hz,0.4Hz),7.43(1H,dd,J＝9.6Hz,2.0Hz), 8.09(1H,s),9.06-9.07(1H,m),10.80(1H,s).

Test of drug efficacy

Test example 1: human Na of compound on HEK293 cells_V1.8 inhibition Activity assay for ion channels

1: test compound formulations

Reagents were purchased from Sigma (st. louis, MO) company, except for NaOH and KOH for acid-base titration. The final concentrations of test compounds were all prepared the same day and re-dissolved in extracellular fluid. Extracellular fluid (mM) was: NaCl, 137; KCl, 4; CaCl₂，1.8；MgCl₂1, 1; HEPES, 10; glucose 10; pH 7.4(NaOH titration). Intracellular fluid (mM) is Aspartic acid, 140; MgCl2, 2; EGTA 11; HEPES, 10; pH 7.2(CsOH titration). All test compound solutions contained 1 μ M TTX.

The test compound was stored at a concentration of 3 mM. Dissolved in dimethyl sulfoxide (DMSO). The test day was re-dissolved in extracellular fluid to the desired concentration.

Test compound solvents

2: test method

2.1: cells

All experiments were performed at room temperature. Each cell served as its own control.

2.1.1: testing of Compounds

The compounds are perfused by adopting a perfusion system utilizing the self gravity. At least one cell per concentration was tested. After the current stabilized (or 5 minutes), the blocking effect of the compound was calculated by comparing the change in current level before and after the compound was used.

2.1.2: test cells

HEK293 cells with steady expression of NaV1.8 ion channels.

2.1.3: laboratory apparatus

A patch clamp amplifier: batch Clamp PC-505B (WARNER instruments)/MultiClamp 700A (axon instrument)

A digital-to-analog converter: digidata 1440A (axon CNS)/Digidata 1550A (axon instruments)

A micro-control instrument: MP-225(SUTTER Instrument)

And (3) inverting the microscope: TL4(Olympus)

Glass microelectrode drawing instrument: PC-10(NARISHIGE)

Microelectrode glass capillary: B12024F (Wuhan micro-exploration scientific instruments Co., Ltd.)

2.2: electrophysiology

The cells were transferred to a perfusion chamber and perfused with extracellular fluid. Intracellular fluid (mM) is Aspartic acid, 140; MgCl2, 2; EGTA 11; HEPES, 10; pH 7.2(CsOH titration). The intracellular fluid was stored in small portions in a-80 ℃ freezer and thawed the day of the experiment. The electrode was drawn with PC-10(Narishige, Japan). Whole cell membrane patch clamp recordings and noise was filtered at one fifth of the sampling frequency.

2.3: test voltage equation (restating) and results

Cells were clamped at-80 mV and then depolarized to 10mV with a 10 ms-lasting square wave to give Na_V1.8 current (see fig. 1). This procedure is repeated every 5 seconds. Detecting the maximum current caused by the square wave, perfusing the test compound after the maximum current is stable, and calculating the blocking strength after the reaction is stable.

Table 4: inhibition assay (100nm inhibition/%: A > -80, 80> B > -50, 50> C > -20, D <20)

Examples	Inhibitory Activity	Examples	Inhibitory Activity	Examples	Inhibitory Activity
						1	D	33	B	65	B
2	D	34	B	66	D
						3	C	35	A	67	B
4	D	36	A	68	D
						5	D	37	A	69	B
6	D	38	B	70	A
						7	D	39	B	71	B
8	D	40	A	72	D
						9	C	41	A	73	C
10	A	42	B	74	C
						11	A	43	B	75	A
12	D	44	A	76	A
						13	A	45	A	77	A
14	B	46	A	78	A
						15	D	47	B	79	A
16	C	48	B	80	B
						17	B	49	B	81	B
18	B	50	C	82	A
						19	A	51	C	83	A
20	A	52	D	84	A
						21	A	53	D	85	A
22	A	54	D	86	A
						23	A	55	D	87	A
24	D	56	C	88	B
						25	C	57	B	89	A
26	B	58	C	90	B
						27	A	59	B	91	A
28	B	60	D	92	A
						29	B	61	B	93	B
30	B	62	D	94	A
						31	B	63	D	95	A
32	A	64	D	VX-150	B

Table 5 (continued table 4): inhibition assay (100nm inhibition/%: A > -80, 80> B > -50, 50> C > -20, D <20)

Examples	Inhibitory Activity	Examples	Inhibitory Activity	Examples	Inhibitory Activity
						96	A	115	D	134	A
97	C	116	C	135	A
						98	C	117	A	136	B
99	B	118	B	137	A
						100	C	119	B	138	A
101	C	120	D	139	C
						102	D	121	A	140	A
103	D	122	B	141	C
						104	B	123	D	142	D
105	B	124	C	143	C
						106	B	125	D	144	D
107	C	126	D	145	D
						108	C	127	A	146	B
109	B	128	A	147	C
						110	C	129	D	148	A
111	D	130	C	149	C
						112	D	131	A	150	C
113	D	132	A	151	B
						114	C	133	B	152	B
				153	B

Table 6 (continued table 4): inhibition assay (100nm inhibition/%: A > -80, 80> B > -50, 50> C > -20, D <20)

Examples	Inhibitory Activity	Examples	Inhibitory Activity	Examples	Inhibitory Activity
						154	C	161	A	168	D
155	B	162	B	169	D
						156	/	163	D	170	D
157	A	164	C	171	B
						158	B	165	A	172	B
159	A	166	B	173	A
						160	B	167	D

Table 7: part of Compound IC₅₀Lists

As can be seen from the data in table 7: examples 10, 13, 19, 20, etc. have significant activity advantages over VX-150 (second stage of clinical practice), and the activity of some of the other examples is comparable.

Test example 2: liver microsome stability test

1: adding 10 mu L of a test or control working solution and 80 mu L of microsome working solution (the concentration of liver microsome protein is 0.5mg/mL) into a T0, T5, T10, T20, T30, T60 and NCF60 sample hole site, adding only microsome working solution into a Blank60 hole site, and then placing samples Blank60, T5, T10, T20, T30 and T60 except for the T0 and the NCF60 into a 37 ℃ water bath for preincubation for about 10 minutes;

2: adding 300 mu L of termination solution (acetonitrile solution of conjugation 200ng/mL tolbutamide and 200ng/mL labetalol) into a T0 sample, and then adding 10ul of NADPH regeneration system working solution;

3: after the preincubation of the incubation plates Blank60, T5, T10, T20, T30 and T60 is finished, 10uL of NADPH regeneration system working solution is added into each sample well to start the reaction, and 10uL of 100mM potassium phosphate buffer solution is added into the sample well of NCF 60;

4: after incubation for an appropriate time (e.g., 5, 10, 20, 30, and 60 minutes), 300. mu.L of stop solution was added to each of the test sample wells and the control sample wells of Blank60, T5, T10, T20, T30, T60, and NCF60 plates, respectively, to stop the reaction.

5: all sample plates were shaken up and centrifuged at 4000rpm for 20 minutes, 100. mu.L of test or control supernatant, respectively, was diluted into 300. mu.L of pure water for LC-MS/MS analysis

6: data analysis, calculation of T1/2 and CL based on first order elimination kinetics_int(mic)(μ L/min/mg) value, first order elimination kinetics equation:

TABLE 8 results of the liver microsome stability test for the inventive Compounds

As can be seen from the data in table 8: examples 11, 19, 30, 82 and 154 have comparable or superior stability of liver microsomes relative to VX-150 (second stage of the clinic), i.e., may translate into comparable or superior pharmacokinetics in vivo.

Test example 3: test for inhibitory Activity of Compound on HEK293 cell hERG ion channel

This experiment was used as a compound cardiac safety experiment.

1: testing instrument

Patch clamp instrument: PC-505B, MC-700A

A micro-manipulation instrument: MP-225

Drawing an electrode instrument: PC-10(Narishige, Japan)

2: pharmaceutical formulation

Compounds were purchased from Sigma (st. louis, MO) company, except for NaOH and KOH for acid-base titration. The final concentrations of test compounds were all prepared the same day and re-dissolved in extracellular fluid. The extracellular fluid (mM) is NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose 10; pH 7.4(NaOH titration). All test and control compound solutions contained 0.3% DMSO. Intracellular fluid (mM) was: k asparate, 130; MgCl2, 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2(KOH titration).

3: test method

Cell: all experiments were performed at room temperature. Each cell served as its own control.

Testing of the compounds: the compounds are perfused by adopting a perfusion system utilizing the self gravity. At least two cells were tested per concentration. After the current stabilized (or 5 minutes), the blocking effect of the compound was calculated by comparing the change in current level before and after the compound was used.

Positive control: the concentration of the positive control Cisapride is selected according to the sensitivity test of the Cisapride on cells, and the concentration with the blocking rate of about 90 percent is the optimal concentration of the positive control. The positive control Cisapride was defined as 100nM since Cisapride tested at 100nM, the blocking rate was around 90%. The procedure was the same as for the test compounds.

Electrophysiology: the cells were transferred to a perfusion chamber and perfused with extracellular fluid. Intracellular fluid (mM) was: k asparate, 130; MgCl2, 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2(KOH titration). The intracellular fluid was stored in small batches in a-80 ℃ freezer and thawed the day of the experiment. The electrode was drawn with PC-10(Narishige, Japan). Whole cell patch clamp recordings were made and noise was filtered at one fifth of the sampling frequency.

Test procedure and results: cells were clamped at-80 mV, then depolarized to 40mV with a 4 second duration square wave, and hyperpolarized to-40 mV with a 2 second duration square wave to give the hERG tail current. This procedure was repeated every 20 seconds. The hERG tail current is pure hERG current. And detecting the maximum tail current caused by the second square wave, pouring a test compound after the maximum tail current is stabilized, and calculating the blocking strength after the reaction is stabilized.

TABLE 9 IC50 test results for hERG inhibition by the compounds of the invention

Examples	19	30	131	VX-150
					IC50(uM)	21.74	9.74	23.48	6.98

Strong inhibition of hERG by compounds can create serious cardiac safety risks such as prolongation of cardiac QT interval. As can be seen from the data in table 9: partial compounds of this patent inhibit hERG significantly less than VX-150 (second stage of clinical treatment) and therefore are likely to exhibit better cardiac safety.

Test example 4: compound rat in vivo pharmacokinetic testing

SD rats, male (purchased from shanghai siepal-bika laboratory animals ltd). Each test compound was administered to SD rats in a single dose in two modes of oral (10mg/kg, 3 per group) and intravenous (1mg/kg, 3 per group) for pharmacokinetic studies. Test compounds were formulated on the day of administration by dissolving them in 5% DMSO + 10% solutol + 85% saline, vortexing for 2min, and sonicating for 5min before formulating a dosing solution. Animals were fasted for 10-14 hours prior to oral administration and returned to food 4 hours after administration. After the SD rat is orally taken through the gavage and intravenously administered, pharmacokinetic samples are collected through jugular veins, and the collection time points are as follows: before administration, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after administration, 3 whole blood samples were collected at each time point, in an amount of about 0.2mL, and anticoagulated with heparin sodium. Immediately after the blood sample was collected, the blood was placed on ice and the plasma was centrifuged within 1 hour (centrifugation conditions: 6800 rpm, 6 minutes, 2-8 ℃). The collected plasma was stored in a-80 ℃ freezer before analysis.

TABLE 10 pharmacokinetic test results for some of the compounds of the invention

Examples	T1/2(po)h	Tmax(po)h	Cmax(po)ng/ml	AUC(po)ng/ml*h	Cl(iv)ml/hr/kg	F(po)％
							11	7.57	2.67	173	2166	698	15.1
19	3.32	3.33	1382	11301	370	41.2
							159	10.25	4.67	1045	16011	/	/
160	5.77	3.33	1192	12963	/	/
							165	5.20	6.00	599	7859	/	/
VX-150	1.71	1.33	1202	4663	697	31.8

From the data in table 10, it can be seen that: a plurality of compounds (such as examples 19, 159, 160 and 165) in the patent all show better rat in-vivo pharmacokinetics than VX-150 (second clinical stage), and the plasma exposure of examples 19, 159 and 160 reaches 2-4 times of VX-150, which indicates that the compounds in the patent may have better in-vivo drug effect.

From the research data of the patent drug property, the compound has obvious inhibition effect on Nav1.8 ion channel activity, and partial compound has obvious advantages compared with VX-150 in the second clinical stage in the aspects of cell activity, stability of liver microsome, heart safety, pharmacokinetics in rats and the like, can be used as a Nav1.8 inhibitor, and has wide application prospect in the fields of analgesia, atrial fibrillation, Bujia syndrome and the like.

Claims

1. A compound having the structure of formula IV or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, pharmaceutically acceptable hydrate, solvate, or salt thereof:

wherein R is₃、R₄Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxy, cyanoThe aryl group comprises an amino group, an ester group, an amide group, a sulfonyl group, a boric acid group, a borate group, a phosphoryl group, a substituted or unsubstituted alkenyl group and a substituted or unsubstituted alkynyl group, wherein the substituent is selected from halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 heteroalkyl, a cyano group, an ester group, an amide group, an aryl group, a heteroaryl group and a sulfonyl group;

q is selected from the following substituted or unsubstituted groups:

phenyl, 2-pyridonyl, pyridyl, pyrimidyl, imidazolyl, 2-pyrimidonyl, 2-pyridoimidazolyl, cyclohexyl, valerolactam, indazole, benzo [ d ] isoxazole, imidazo [1,2-a ] pyridine, imidazo [1,5-a ] pyridine, [1,2,4] triazolo [4,3-a ] pyridine, wherein the substituents are selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, guanidino, acyl guanidino, urea, aryl, heteroaryl, sulfonyl, sulfonamide, borate, phosphoryl, imine, or two adjacent substituents together form a C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl, carbodiimide ring, lactam ring, sulfonamide ring, lactam, and/or lactam, A boronic acid lactone ring;

R₅independently at each occurrence, is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, cyano, amino, ester, amide, alkenyl, alkynyl, wherein the substituents are selected from deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, hydroxy, cyano, amino;

n is an integer of 1 to 5.

2. The compound of claim 1, having a structure according to formula V or VI or VII or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, pharmaceutically acceptable hydrate, solvate, or salt thereof:

R₃、R₄each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxy, cyano, amino, ester, acyl, amide, sulfonyl, boronic acid, boronic ester, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R of formulas V and VI₃、R₄At least one of the substituent groups is one of substituted or unsubstituted naphthenic base, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl, wherein the substituent group is selected from halogen, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl, cyano, ester group, amido, aryl, heteroaryl and sulfonyl;

R₅independently at each occurrence, is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxyl, cyano, amino, ester, amide, alkenyl, alkynyl, wherein the substituents are selected from deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, hydroxyl, cyano, amino, sulfonamide;

R₆independently at each occurrence, is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxy, cyano, amino, ester, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acyl guanidino, substituted or unsubstituted guanidino, urea, aryl, heteroaryl, sulfonyl, boronic acid, boronic ester, substituted or unsubstituted phosphoryl, alkenyl, alkynyl, substituted or unsubstituted imine, or two adjacent R₆Together form a substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3E10-membered heterocycloalkyl, a succinimide ring, a lactam ring, a boronic acid lactone ring, aryl and heteroaryl, wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 3-6-membered heterocycloalkyl, 3-6-membered heteroaryl, halogen, hydroxyl, cyano, amino, ester group, amide group, sulfonamide group, guanidino and acyl guanidino;

m and n are respectively independently selected from integers of 1-5.

3. A compound of claim 2, wherein R is₆Independently at each occurrence, is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxy, cyano, amino, ester, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acyl guanidino, substituted or unsubstituted guanidino, urea, aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted imine, sulfonyl, boronic acid, boronic ester, substituted or unsubstituted phosphoryl, or two adjacent R₆The compound is a lactam ring, a sulfonamide ring and a boric acid lactone ring, wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heteroaryl, halogen, hydroxyl, cyano, amino, ester group, amide group, sulfonamide group and guanidino;

m is an integer of 1-3, and n is 1 or 2.

4. A compound of claim 3, wherein R is₆Independently at each occurrence, is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted imine, hydroxyl, ester, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acyl guanidino, substituted or unsubstituted guanidino, urea, sulfonyl, borate, substituted or unsubstituted phosphoryl, or two adjacent R₆The compound is a lactam ring, a sulfonamide ring and a boric acid lactone ring, wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heteroaryl, halogen, hydroxyl, cyano, amino, ester group, amide group, sulfonamide group and guanidino;

m is an integer of 1-3, and n is 2.

5. A compound of claim 4, wherein R is₆Independently for each occurrence, is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, boronic acid, boronic ester, hydroxyl, ester, or from substituted or unsubstituted:

R₂₇、R₂₈、R₂₉、R₃₀each independently selected from hydrogen, alkyl, heteroalkyl, cyano, acyl, or R₂₇And R₂₉And the atoms to which they are attached form a 3-to 10-membered heterocycloalkyl, or R₂₈And R₃₀And the atoms to which they are attached form a 3-to 10-membered heterocycloalkyl, or R₂₇And R₂₈And the atoms to which they are attached form a 5-membered heteroaryl group, Y is selected from the group consisting of a bond, CH₂、C(O)、-CH₂NH-、-C(O)NH-、-CH＝N-、-S(O)₂-、-CH₂O-；R₃₆Is selected from-NH₂、-CH₂NH₂、

wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxyl,Cyano, amino, ester, amide and guanidino.

6. A compound of claim 5, wherein R is₆Independently for each occurrence, is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, boronic acid, boronic ester, hydroxyl, ester, or from substituted or unsubstituted:

or two adjacent R₆Together form substituted or unsubstituted

Wherein, the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxyl, cyano, amino, ester group, amido and guanidyl.

7. A compound of claim 6, wherein R is₆Independently at each occurrence, is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, boronic acid, boronic ester, hydroxyl, ester, or from substituted or unsubstituted:

8. A compound according to claim 1 or 2, having a structure according to formula VIII or IX or X or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt thereof:

R₃、R₄each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxy, cyano, amino, ester, acyl, amide, sulfonyl, boronic acid, boronic ester, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R of formulas VIII and IX₃、R₄At least one of the substituent groups is one of substituted or unsubstituted naphthenic base, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl, wherein the substituent group is selected from halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 heteroalkyl, cyano, ester group, amido, aryl, heteroaryl and sulfonyl;

R₂₃、R₂₄each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxyl, cyano, amino, ester, amide, alkenyl, alkynyl, wherein the substituents are selected from deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, hydroxyl, cyano, amino, amide;

y is selected from a bond, CH₂、C(O)、-CH₂NH-、-C(O)NH-、-CH＝N-、-S(O)₂-、-CH₂O-；

R₂₅、R₂₆Each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxy, cyano, amino, ester, substituted or unsubstituted amide, substituted or unsubstituted acyl guanidino, ureido, aryl, heteroaryl, sulfonyl, boronic acid, boronic ester, substituted aryl, heteroaryl, sulfonyl, hydroxyl, substituted amido, substituted or unsubstituted acyl guanidino, hydroxyl, or hydroxylOr unsubstituted phosphoryl, alkenyl and alkynyl, wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxyl, cyano, amino, ester group, amido, guanidino and acyl guanidino;

R₂₇、R₂₈、R₂₉、R₃₀each independently selected from hydrogen, alkyl, heteroalkyl, cyano, acyl, or R₂₇And R₂₉And the atoms to which they are attached form a 3-to 10-membered heterocycloalkyl, or R₂₈And R₃₀And the atoms to which they are attached form a 3-to 10-membered heterocycloalkyl, or R₂₇And R₂₈And the atoms to which they are attached form a 5-membered heteroaryl group.

9. A compound of claim 8, wherein R is₂₇、R₂₈、R₂₉、R₃₀Each independently selected from hydrogen, alkyl, heteroalkyl, cyano, acyl, or R₂₇And R₂₉And the atoms to which they are attached form a 4-to 6-membered heterocycloalkyl, or R₂₈And R₃₀And the atoms to which they are attached form a 4-to 6-membered heterocycloalkyl, or R₂₇And R₂₈And the atoms to which they are attached form a 5-membered heteroaryl group.

10. The compound of claim 9, wherein R is₂₇、R₂₈、R₂₉、R₃₀Each independently selected from hydrogen, alkyl, heteroalkyl, cyano, acyl, or R₂₇And R₂₉And the atoms to which they are attached form a 4-to 6-membered heterocycloalkyl group.

11. The compound of claim 10, wherein R is₂₇、R₂₈、R₂₉、R₃₀Are respectively and independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, cyano, or R₂₇And R₂₉And the atoms to which they are attached form a 4-to 6-membered heterocycloalkyl group;

y is selected from a bond, c (o), -CH ═ N-.

12. The compound of claim 11,

selected from the following substituted or unsubstituted groups:

13. The compound of claim 1, having the structure of formula XI, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable hydrate, solvate, or salt thereof:

A₃、A₄、A₅、A₆each independently selected from C, CR₃₈、N、NR₃₉Or O, and A₃、A₄、A₅At least one of A6 is selected from N, NR₃₉Or O;

R₃₇、R₃₈、R₃₉independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxyl, cyano, amino, ester, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acyl guanidino, substituted or unsubstituted guanidino, ureido, aryl, heteroaryl, sulfonyl, boronic acid, boronic ester, substituted or unsubstituted phosphoryl, alkenyl, alkynyl, substituted or unsubstituted imino, wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heteroaryl, substituted or unsubstituted acyl guanidino, substituted or unsubstituted guanidino, ureido, aryl, heteroaryl, sulfonyl, boronic acid, boronic ester, substituted or unsubstituted phosphoryl, alkenyl, alkynyl, substituted or unsubstituted imino, or substituted imino,Halogen, hydroxyl, cyano, amino, ester group, amido, sulfamide, guanidino, acyl guanidino;

R₃、R₄each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxyl, cyano, amino, ester, acyl, amide, sulfonyl, boronic acid, borate, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, wherein the substituent is selected from halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 heteroalkyl, cyano, ester, amide, aryl, heteroaryl, sulfonyl;

R₂₃、R₂₄each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxyl, cyano, amino, ester, amide, alkenyl, alkynyl, wherein the substituents are selected from deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, hydroxyl, cyano, amino, amide.

14. The compound of claim 13,

selected from the group consisting of:

preference is given to

15. The compound of claim 14, wherein the compound is a pharmaceutically acceptable salt thereofIn that R₃₇Selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, ester, acyl, carboxyl, amide, sulfonyl, sulfonamide, boronic acid, boronic ester, phosphoryl, wherein the substituent is selected from the group consisting of halogen, hydroxyl, amino, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cyano, ester, acyl, carboxyl, amide, aryl, heteroaryl, sulfonyl, sulfonamide;

further, R₃₇Selected from hydrogen, halogen, hydroxyl, cyano, amino, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, ester, acyl, carboxyl, amide, wherein the substituent is selected from halogen, hydroxyl, amino, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cyano, ester, acyl, carboxyl, amide, sulfonyl, sulfonamide;

16. A compound according to any one of claims 8 to 15,

R₃、R₄each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, ester, acyl, amide, sulfonyl, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R of formulas VIII and IX₃、R₄At least one of the substituent groups is one of substituted or unsubstituted naphthenic base, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl, wherein the substituent group is selected from halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 heteroalkyl, cyano, ester group, amido, aryl, heteroaryl and sulfonyl.

17. The compound of claim 16,

R₃、R₄each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, acyl, amido, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R of formulas VIII and IX₃、R₄At least one of the substituent groups is one of substituted or unsubstituted naphthenic base, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl, wherein the substituent group is selected from halogen, hydroxyl, amino, C1-C6 alkyl and C1-C6 heteroalkyl.

18. The compound of claim 17,

R₃、R₄each independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted N-containing heterocycloalkyl, acyl, amido, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R of formulas VIII and IX₃、R₄At least one of the substituent groups is one of substituted or unsubstituted C3-C6 naphthenic base, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl, wherein the substituent group is selected from halogen, hydroxyl, amino, C1-C6 alkyl substituted or unsubstituted by halogen and C1-C6 heteroalkyl.

19. The compound according to claim 18,

R₃、R₄each independently selected from hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted cyclopropyl, cyclopentyl, substituted or unsubstituted alkoxy, substituted or unsubstituted N-containing heterocycloalkyl, acyl, amido, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R of formulas VIII and IX₃、R₄Each having at least one of substituted or unsubstituted cyclopropyl, cyclopentyl, substituted or unsubstituted alkenyl, substituted or unsubstitutedOne of the alkynyl radicals of (1), R₃、R₄Not H at the same time.

20. The compound of claim 19,

R₃、R₄each independently selected from hydrogen, halogen, trifluoromethyl, pentafluoroethyl, substituted or unsubstituted cyclopropyl, cyclopentyl, substituted or unsubstituted heteroalkyl, acetyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, trifluoromethyl, cyclopentyl, substituted or unsubstituted heteroalkyl, acetyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyclopentyl, or substituted or unsubstituted heteroalkyl, acetyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyclopentyl, or substituted or unsubstituted alkynyl,

And R of formulae VIII and IX₃、R₄At least one of the R, R and R is one of substituted or unsubstituted cyclopropyl, cyclopentyl, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl₃、R₄Not H at the same time;

the substituted or unsubstituted cyclopropyl is:

R₃₁independently at each occurrence, is selected from hydrogen, halogen, hydroxyl, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, wherein the substituents are selected from alkyl and halogen; a is an integer of 0-5;

the substituted or unsubstituted alkenyl is:

the substituted or unsubstituted alkynyl is:

21. The compound of claim 20,

R₃₁independently at each occurrence, is selected from hydrogen, halogen, hydroxyl, amino, C1-C3 alkyl substituted or unsubstituted by 0-3 halogens, and C1-C3 alkoxy substituted or unsubstituted by 0-3 halogens; a is an integer of 0 to 3;

22. A compound according to any one of claims 8 to 21,

R₂₃、R₂₄each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxyl, cyano, amino, ester group, amido, alkenyl, alkynyl, wherein the substituents are selected from deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, hydroxyl, cyano, amino, amido;

R₂₅、R₂₆each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxyl, cyano, amino, ester group and boric acid group, wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxyl, cyano, amino, ester group, amido and sulfonyl.

23. The compound of claim 22,

R₂₃、R₂₄independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, wherein the substituents are selected from deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, hydroxyl, amido;

R₂₅、R₂₆each independently selected from hydrogen, halogen, substituted or unsubstitutedAlkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxyl, boronic acid groups, wherein the substituents are selected from the group consisting of C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxyl, amino;

the heteroatom in the heteroalkyl or heterocycloalkyl group is one or more of O, N, S.

24. The compound of claim 23,

R₂₃、R₂₄are respectively and independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, wherein the substituent is selected from deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl and acylamino; further, when the substituent is deuterium or halogen, the number of deuterium or halogen substitution is 0-3;

R₂₅、R₂₆are respectively and independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl and hydroxyl, wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxyl and amino.

25. The compound of claim 24,

R₂₃selected from halogen, methyl, trifluoromethyl, substituted or unsubstituted alkoxy; further, R₂₃Selected from the group consisting of F, Cl, Br, methyl, trifluoromethyl, methoxy, trifluoromethoxy, preferably F, Cl, Br, trifluoromethoxy, more preferably F, trifluoromethoxy;

R₂₄selected from halogen, substituted or unsubstituted C1-C3 alkyl, CD₃Substituted or unsubstituted C1-C3 alkoxy;

further, R₂₄Selected from F, Cl, Br, methyl, CD₃Trifluoromethyl, methoxy, trifluoromethoxy,

Preferably F, Cl, Br,Methyl, CD₃A methoxy group,

More preferably F, methyl, CD₃A methoxy group,

R₂₅Selected from halogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy and hydroxyl; further, R₂₅Selected from F, Cl, Br, methyl, methoxy, hydroxy, preferably F, Cl, Br, more preferably F;

R₂₆selected from hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, further R₂₆Selected from hydrogen, F, Cl, Br, C1-C3 alkyl, preferably hydrogen.

26. The compound of claim 1, wherein the compound structure is selected from one of the following:

27. a pharmaceutical composition, wherein the active ingredient of the pharmaceutical composition is selected from the compounds of any one of claims 1 to 26, or one or more of stereoisomers, solvates, hydrates, pharmaceutically acceptable salts and co-crystals thereof.

28. Use of a compound of any one of claims 1 to 26, or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof, in the preparation of a sodium ion channel modulator; further, the sodium channel modulator is a Nav1.8 inhibitor.

29. Use of a compound of any one of claims 1 to 26, or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment of a disease that causes overexpression of Nav1.8.

30. Use of the compound of any one of claims 1-26, or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof, for the preparation of a medicament for the treatment of a disease caused by overexpression of Nav1.8.

31. Use of a compound of any one of claims 1 to 26, or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof, in the manufacture of a medicament for use in the treatment of any one or more of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, multiple sclerosis, charcot-marie-tooth syndrome, incontinence and cardiac arrhythmia.

32. The use according to claim 31 wherein the neuropathic pain is selected from one or more of post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, mouth burn syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve crush injury, spinal canal stenosis, carpal tunnel syndrome, radiculopathy, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, transcription virus therapy induced neuralgia, spinal cord injury post-pain, primary small-fiber neuropathy, primary sensory neuropathy, trigeminal autonomic headache;

the primary pain is selected from fibromyalgia.