CN114437062B

CN114437062B - Compound capable of being used as sodium channel regulator and application thereof

Info

Publication number: CN114437062B
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: 2024-05-17
Anticipated expiration: 2041-04-29
Also published as: CN114437062A

Abstract

The invention discloses a compound which can be used as a sodium channel regulator and application thereof, has obvious inhibition and blocking effects on voltage-gated sodium channel subtype Nav1.8 ion channel activity, can be used as a Nav1.8 specific inhibitor, can be used for preparing medicines for treating diseases such as intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, multiple sclerosis, marsdenia-Marsdenia, incontinence, arrhythmia and the like mediated by Nav1.8, 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 serving as a voltage-gated sodium ion channel subtype Nav1.8 specific inhibitor and application thereof.

Background

With the advent of the global aging society, the scope of the effects of chronic pain diseases has gradually expanded, with more than one-third of people worldwide suffering from chronic pain; in addition, cancer will eventually become a chronic disease, and cancer pain will be associated with patients for a long period of time, and it has been reported that more than half of cancer patients in China have not received cancer pain treatment. Pain is a mechanism of animal or human self-protection, however, many persistent pains exceed the usefulness, and the pain is a great pain brought to the physical or physical and mental health of patients, and the pain treatment is an important factor for improving the life quality of patients with symptoms, so the market prospect is very great.

In 2005, the global analgesic market amounted to over $800 billion and the prescription drug was sold in approximately $200 billion. According to statistical estimates from the national institutes of health (National Institutes of Health, NIH), up to 2500 tens of thousands of people in the united states struggle for pain every day, with 2300 tens of thousands of adults suffering from severe pain. However, abuse of opioid analgesic has had a dramatic impact on society, estimated by WHO that 6.9 tens of thousands of people die annually from opioid overdose, 1500 tens of thousands of people rely on opioid (i.e., opioid addiction), and the importance of developing new safe and effective analgesic drugs 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 of central and peripheral neurons, and increased excitability or responsiveness to stimulus of neurons is an important mechanism for development of various pains. Thus, the role of voltage-gated sodium ion channels in pain conduction pathways, particularly in peripheral sensory neurons, has been a hotspot in pain research.

The human sodium ion channels are 9, namely Nav1.1-Nav1.9, nav1.5, nav1.8 and Nav1.9 are tetrodotoxin (tetrodotoxin, TTX) insensitive sodium channels, wherein Nav1.8 is an important ion channel involved in chronic pain, atrial fibrillation and Buddha syndrome, and is a high-selectivity acting target point for pain treatment. Nav1.8 is mainly expressed in small diameter pain sensory neurons, involved in sensory neuron action potentials and rhythmic discharge. Nav1.8 is regulated by inflammatory mediators while up-regulating expression in sciatic nerve injury models, and Nav1.8 gene knockout and silencing studies indicate that it is involved in the regulation of neuropathic and inflammatory pain. Since Nav1.8 is primarily localized to painful neurons, selective Nav1.8 blockers are unlikely to induce the adverse effects common with non-selective Nav blockers. Thus, studies of specific inhibitor screening for the Nav1.8 pain target have become a hotspot in the pain field, but known Nav inhibitors mainly suffer from the disadvantage of poor therapeutic window, possibly due to their lack of subtype selectivity.

Among the currently known Nav1.8 inhibitors are PF-01247324, A803467, PF-06305591, VX150, and the like. Among them, the first three compounds all have poor selectivity, poor drug data, and low bioavailability, and the like, and thus the problems end up in preclinical stages. VX-150 is currently in clinical stage II, reaching major clinical endpoints in clinical studies including post-operative acute pain, osteoarthritis chronic pain, neuropathic pain, and the like. The VX-150 has good tolerance and no serious adverse reaction. The FDA has granted breakthrough therapy for VX-150 to treat moderate to severe pain. However, the clinical dose of VX-150 was large, 1500 mg first, followed by 750 mg every 12 hours, and the activity was still further improved. At the same time, there are also major problems with dissolution absorption of the compound, which, although partially addressed by the prodrug approach, remain undesirable.

Therefore, developing a higher affinity, high specificity, better pharmacokinetic Nav1.8 inhibitor has great social and economic value.

Disclosure of Invention

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

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

a compound of the invention having a structure of formula I or a tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt thereof:

Wherein:

A ₁、A₂ is independently selected from CR ₇ or N, or an atom to which A ₁、A₂ is connected forms a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted 3-C10 heterocyclic alkyl group, a substituted or unsubstituted C3-C10 aryl group, a substituted or unsubstituted 3-C10 heteroaryl group;

R ₇ is independently at each occurrence selected from 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, boronate, 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 substituents are selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, guanidino, acylguanidino, ureido, aryl, heteroaryl, sulfonyl, boric acid, borate, phosphoryl, imino;

W is selected from a bond, CR ₈R₉、O、NR₁₀, carbonyl, C (O) NR ₁₁、C(S)NR₁₂、S(O)、S(O)NR₁₃、 S(O)₂、S(O)₂NR₁₄, and the connecting end of W and Q is not limited; r ₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄ is independently selected from hydrogen or C1-C6 alkyl;

R ₁、R₂ is independently selected from hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted cycloalkyl, substituted OR unsubstituted heteroalkyl, substituted OR unsubstituted heterocycloalkyl, OR ₁₅、NR₁₆R₁₇、C(O)R₁₈、SR₁₉, hydroxy, cyano, amino, ester, amide, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, sulfonyl, OR R ₁、R₂ and the atoms to which they are attached form a substituted OR unsubstituted C3-C10 cycloalkyl, substituted OR unsubstituted 3-to 10-membered heterocycloalkyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl;

R ₁₅、R₁₆、R₁₇、R₁₈、R₁₉ is selected from hydrogen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted heteroalkyl or heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, amido, sulfonyl, wherein the substituents are selected from halo, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amido, aryl, heteroaryl, sulfonyl, boronic acid, boronate, phosphoryl, alkenyl, alkynyl;

The substituents in A ₁、A₂、R₇、R₁、R₂ are each independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, aryl, heteroaryl, sulfonyl;

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

Further, W is selected from a bond, C (O) NR ₁₁、C(S)NR₁₂、S(O)NR₁₃、S(O)₂NR₁₄.

Further, R ₁ is selected from hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted cycloalkyl, substituted OR unsubstituted heteroalkyl, substituted OR unsubstituted heterocycloalkyl, OR ₁₅、NR₁₆R₁₇、C(O)R₁₈、SR₁₉, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl, OR R ₁、R₂ and the atoms to which they are attached constitute substituted OR unsubstituted C3-C6 cycloalkyl, substituted OR unsubstituted 3-6 membered heterocycloalkyl, wherein the substituted substituent is selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino;

R ₂ is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, wherein the substituents are each independently selected from halogen, alkyl, heteroalkyl, hydroxy, cyano, amino;

r ₁₅、R₁₆、R₁₇、R₁₈、R₁₉ is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein each substituent is independently selected from halo, alkyl, cycloalkyl, heteroalkyl, heteroalicycloalkyl, aryl, heteroaryl, hydroxy, cyano, amino, ester, amide, alkenyl, alkynyl.

Further, R ₁ is selected from OR ₁₅、NR₁₆R₁₇、C(O)R₁₈、SR₁₉, OR R ₁、R₂ and the atoms connected with the R ₁、R₂ form substituted 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 and amino;

R ₂ is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, wherein the substituents are selected from halogen, alkyl, heteroalkyl, hydroxy, cyano, amino;

R ₁₅、R₁₆、R₁₇、R₁₈、R₁₉ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the substituents are selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, cyano, amino, ester, amide, alkenyl, alkynyl.

Further, the compounds of the present invention are in the form of a pharmaceutically acceptable hydrate, solvate or salt having a structure represented by formula II or III or an isomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof:

wherein R ₃、R₄ is 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, amido, sulfonyl, boric acid, borate, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, wherein the substituents are selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 heteroalkyl, cyano, ester, amido, aryl, heteroaryl, sulfonyl;

Q is selected from substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the substituents are selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amide, guanidine, acylguanidine, ureido, aryl, heteroaryl, sulfonyl, boric acid ester, phosphoryl, imino;

x is selected from O, S, NR ₂₀, carbonyl, CR ₂₁R₂₂;

R ₂₀、R₂₁、R₂₂ is independently selected from hydrogen, hydroxyl and C1-C6 alkyl;

A _r is selected from substituted or unsubstituted aryl, substituted or unsubstituted N-containing heteroaryl, wherein the substituents are selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, cyano, amino, ester, amide, alkenyl, alkynyl.

Further, Q is selected from substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted N-containing heteroaryl, wherein the substituents are selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxy, cyano, amino, ester, amido, guanidino, acylguanidino, ureido, aryl, heteroaryl, sulfonyl, boric acid, borate, phosphoryl, imino, or two adjacent substituents together form a C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl, lactam ring, boronate ring;

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

Phenyl, 2-pyridonyl, pyridyl, pyrimidinyl, imidazolyl, 2-pyrimidinyl, 2-pyridoimidazolyl, cyclohexyl, valerolactam-yl.

Further, X is selected from O, S, CR ₂₁R₂₂, carbonyl; r ₂₁、R₂₂ is independently selected from hydrogen, hydroxyl and C1-C6 alkyl;

Ar is selected from substituted or unsubstituted phenyl, wherein the substituents are selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, cyano, amino, ester, amide, alkenyl, alkynyl;

further, X is selected from O, S.

Further, the compounds of the present invention have a structure represented by formula IV or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, pharmaceutically acceptable hydrate, solvate, or salt thereof:

wherein R ₃、R₄ is 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, boric acid, borate, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, wherein the substituents are selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 heteroalkyl, cyano, ester, amide, aryl, heteroaryl, sulfonyl.

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

Phenyl, 2-pyridonyl, pyridinyl, pyrimidinyl, imidazolyl, 2-pyrimidinonyl, 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, amido, guanidino, acylguanidino, ureido, aryl, heteroaryl, sulfonyl, sulfonamide, boric acid, borate, phosphoryl, imino, or two adjacent substituents together comprise a C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl, heteroaryl, maleimide ring, lactam ring, boronate ring.

R ₅ is 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, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, hydroxy, cyano, amino, ester, amide, alkenyl, alkynyl, wherein the substituents are selected from the group consisting of deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, halo, hydroxy, cyano, amino;

n is an integer from 1 to 5.

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

A ₃、A₄、A₅、A₆ is independently selected from C, CR ₃₈、N、NR₃₉ or O, and at least one of A ₃、A₄、A₅、A₆ is selected from N, NR ₃₉ or O.

R ₃₇、R₃₈、R₃₉ is 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 amido, substituted or unsubstituted sulfonamido, substituted or unsubstituted acylguanidino, substituted or unsubstituted guanidino, ureido, aryl, heteroaryl, sulfonyl, boric acid, borate, substituted or unsubstituted phosphoryl, alkenyl, alkynyl, substituted or unsubstituted imino, wherein the substituents are selected from C1-C6 alkyl, C1-C6 heteroalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heteroaryl, halogen, hydroxy, cyano, amino, ester, amido, sulfonamido, guanidino, acylguanidino.

Further, the method comprises the steps of,Selected from the following groups:

preference/>

Further, R ₃₇ is selected from 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, boronate, phosphoryl, wherein the substituents are selected from halogen, hydroxy, amino, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cyano, ester, acyl, carboxy, amide, aryl, heteroaryl, sulfonyl, sulfonamide.

Further, R ₃₇ is selected from 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, wherein the substituents are selected from halogen, hydroxy, amino, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cyano, ester, acyl, carboxy, amide, sulfonyl, sulfonamide.

Still further, R ₃₇ is selected from hydrogen, hydroxy, amino, carboxy, amido, preferably amino, amido.

R ₃、R₄ is 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, amido, sulfonyl, boric acid, borate, phosphoryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R ₃、R₄ of formula V or VI is at least one of substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R ₃、R₄ of formulas VIII and IX is at least one of substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, wherein the substituents are selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 heteroalkyl, cyano, ester, amido, aryl, heteroaryl, sulfonyl;

the phrase "R ₃、R₄ of formula V or VI has at least one of substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl" means that: at least one of R ₃、R₄ in formula V is one of substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and at least one of R ₃、R₄ in formula VI is also one of substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; the rest of the similar situation is the same.

Further, R ₃、R₄ is 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 ₃、R₄ of formula V or VI is at least one of substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R ₃、R₄ of formulas VIII and IX is at least one of substituted or unsubstituted cycloalkyl, alkenyl, alkynyl, wherein the substituents are selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 heteroalkyl, cyano, ester, amide, aryl, heteroaryl, sulfonyl.

Further, R ₃、R₄ is 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 ₃、R₄ of formula V or VI is at least one of substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R ₃、R₄ of formulas VIII and IX is at least one of substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 heteroalkyl.

Further, R ₃、R₄ is independently selected from the group consisting of 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, R ₃、R₄ of formula V or VI is at least one of substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R ₃、R₄ of formulas VIII and IX is at least one of substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, amino, C1-C6 alkyl substituted or unsubstituted by halogen, C1-C6 heteroalkyl.

Further, R ₃、R₄ is independently selected from the group consisting of 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 ₃、R₄ of formula V or VI is at least one of substituted or unsubstituted cyclopropyl, cyclopentyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and R ₃、R₄ of formulas VIII and IX is at least one of substituted or unsubstituted cyclopropyl, cyclopentyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, R ₃、R₄ is not simultaneously H.

Further, R ₃、R₄ is independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, pentafluoroethyl, substituted or unsubstituted cyclopropyl, cyclopentyl, substituted or unsubstituted heteroalkyl, acetyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,And R ₃、R₄ of formulas VIII and IX are each at least one of substituted or unsubstituted cyclopropyl, cyclopentyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, R ₃、R₄ are not both H;

The substituted or unsubstituted cyclopropyl is:

r ₃₁ is selected 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 selected from integers of 0 to 5;

the substituted or unsubstituted alkenyl group is: The substituted or unsubstituted alkynyl group is: /(I)

R ₃₂、R₃₃、R₃₄、R₃₅ is independently selected from hydrogen, halogen and C1-C6 alkyl.

Further, R ₃₁ is selected from hydrogen, halogen, hydroxy, amino, C1-C3 alkyl substituted or unsubstituted with 0-3 halogens, C1-C3 alkoxy substituted or unsubstituted with 0-3 halogens; a is selected from integers of 0 to 3;

R ₃₂、R₃₃、R₃₄、R₃₅ is independently selected from hydrogen, halogen and C1-C3 alkyl.

Further, R ₅ is independently selected at each occurrence 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 heteroalkyl, halogen, hydroxy, cyano, amino, sulfonamide;

The term "R ₅ is independently selected at each occurrence" as used herein, means that when n, which defines the number of R ₅, is greater than 1, different R ₅ groups may be selected from the same or different groups. For example, n=2, one R ₅ may be selected from substituted or unsubstituted alkyl groups and the other R ₅ may be selected from halogen; or n=2, both R ₅ may be selected from substituted or unsubstituted alkyl; the rest of the similar situation is the same.

Further, R ₆ is independently selected from the group consisting of, for each occurrence, 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 amido, substituted or unsubstituted sulfonylamino, substituted or unsubstituted acylguanidino, substituted or unsubstituted guanidino, ureido, aryl, heteroaryl, sulfonyl, boronic acid, boronate, substituted or unsubstituted phosphoryl, alkenyl, alkynyl, substituted or unsubstituted imino, or two adjacent R ₆ together form a substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, a lactam ring, a sultam ring, a boronate ring, an aryl, a heteroaryl, wherein the substituents are selected from the group consisting of C1-C6 alkyl, C1-C6 heteroalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heteroaryl, halogen, hydroxy, cyano, amino, ester, amido, sulfonamide, guanidino;

m and n are each independently selected from integers of 1 to 5.

Further, R ₆ is 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 amido, substituted or unsubstituted sulfonamide, substituted or unsubstituted acylguanidino, substituted or unsubstituted guanidino, ureido, aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted imino, sulfonyl, boronic acid, boronate, substituted or unsubstituted phosphoryl, or two adjacent R ₆ together form a lactam ring, sultam ring, boronate ring, wherein the substituents are selected from C1-C6 alkyl, C1-C6 heteroalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heteroaryl, halogen, hydroxy, cyano, amino, ester, amido, sulfonamide, guanidino;

m is an integer from 1 to 3, and n is 1 or 2.

Further, R ₆ is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted imino, hydroxy, ester, substituted or unsubstituted amido, substituted or unsubstituted sulfonamide, substituted or unsubstituted acylguanidino, substituted or unsubstituted guanidino, ureido, sulfonyl, boronic acid, boronic ester, substituted or unsubstituted phosphoryl, or two adjacent R ₆ together form a maleimide ring, lactam ring, sultam ring, and borolactone ring, wherein the substituents are selected from C1-C6 alkyl, C1-C6 heteroalkyl, 3-6 membered heteroaryl, halogen, hydroxy, cyano, amino, ester, amido, sulfonamide, and guanidino;

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

Further, R ₆ is independently selected at each occurrence from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, boric acid group, boric acid ester group, hydroxyl, ester group, or a substituted or unsubstituted group selected from the group consisting of:

R ₂₇、R₂₈、R₂₉、R₃₀ is independently selected from hydrogen, alkyl, heteroalkyl, cyano, acyl, or R ₂₇ and R ₂₉ and the attached atoms form 3-10 membered heterocycloalkyl, or R ₂₈ and R ₃₀ and the attached atoms form 3-10 membered heterocycloalkyl, or R ₂₇ and R ₂₈ and the attached atoms form 5-membered heteroaryl, Y is selected from a bond, CH ₂、C(O)、 -CH₂NH-、-C(O)NH-、-CH＝N-、-S(O)₂-、-CH₂O-;R₃₆ is selected from-NH ₂、-CH₂NH₂, Or two adjacent R ₆ together form a substituted or unsubstituted group:

Wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxy, cyano, amino, ester, amide and guanidine.

The order of attachment of the two attachment sites to the benzene ring is not limited, e.gAfter substitution, it may be that of formationThe structure may be formedThe structure and the rest of similar conditions are the same.

In a specific embodiment of the present invention,May be selected from the group consisting of substituted or unsubstituted:

Further, R ₆ is independently selected at each occurrence from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, boric acid group, boric acid ester group, hydroxyl, ester group, or substituted or unsubstituted:

Or two adjacent R ₆ together form a substituted or unsubstituted Wherein the substituent is selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxyl, cyano, amino, ester, amide and guanidine.

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

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

Further, R ₂₇、R₂₈、R₂₉、R₃₀ is independently selected from hydrogen, alkyl, heteroalkyl, cyano, acyl, or R ₂₇ and R ₂₉ and their associated atoms form a 3-to 10-membered heterocycloalkyl, or R ₂₈ and R ₃₀ and their associated atoms form a 3-to 10-membered heterocycloalkyl, or R ₂₇ and R ₂₈ and their associated atoms form a 5-membered heteroaryl.

Further, R ₂₇、R₂₈、R₂₉、R₃₀ is independently selected from hydrogen, alkyl, heteroalkyl, cyano, acyl, or R ₂₇ and R ₂₉ and their associated atoms form a 4-6 membered heterocycloalkyl, or R ₂₈ and R ₃₀ and their associated atoms form a 4-6 membered heterocycloalkyl, or R ₂₇ and R ₂₈ and their associated atoms form a 5 membered heteroaryl.

Further, R ₂₇、R₂₈、R₂₉、R₃₀ is independently selected from hydrogen, alkyl, heteroalkyl, cyano, acyl, or R ₂₇ and R ₂₉ and the atoms to which they are attached form a 4-to 6-membered heterocycloalkyl.

Further, R ₂₇、R₂₈、R₂₉、R₃₀ is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, cyano, or R ₂₇ and R ₂₉ and the atoms to which they are attached constitute a 4-to 6-membered heterocycloalkyl.

Further, the method comprises the steps of, Selected from the group consisting of substituted and unsubstituted:

Further, R ₂₃、R₂₄ is 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, 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, amide.

Further, R ₂₃、R₂₄ is 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, 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, amide.

Further, R ₂₃、R₂₄ is 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 hetero atom in the hetero alkyl or the heterocyclic alkyl is one or more of O, N, S.

Further, R ₂₃、R₂₄ is independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, wherein the substituents are selected from deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, and amido; further, when the substituent is deuterium or halogen, the number of substitution of deuterium or halogen is 0 to 3.

Further, R ₂₃ is selected from halogen, methyl, trifluoromethyl, substituted or unsubstituted alkoxy; r ₂₄ is selected from halogen, substituted or unsubstituted C1-C3 alkyl, CD ₃, substituted or unsubstituted C1-C3 alkoxy; wherein the substituent is selected from C1-C3 alkyl, C1-C3 heteroalkyl, halogen, hydroxy and amino.

Further, R ₂₃ is selected from F, cl, br, methyl, trifluoromethyl, methoxy, trifluoromethoxy, preferably F, cl, br, trifluoromethoxy, more preferably F, trifluoromethoxy; r ₂₄ is selected from F, cl, br, methyl, CD ₃, trifluoromethyl, methoxy, trifluoromethoxy,Preferably F, cl, br, methyl, CD ₃, methoxy,More preferably F, methyl, CD ₃, methoxy,

Further, R ₂₅、R₂₆ is 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 acylguanidine, guanidino, ureido, aryl, heteroaryl, sulfonyl, boric acid, borate, substituted or unsubstituted phosphoryl, alkenyl, alkynyl, wherein the substituents are selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxy, cyano, amino, ester, amide, guanidino, acylguanidine;

further, R ₂₅、R₂₆ is 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, boric acid, wherein the substituents are selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxy, cyano, amino, ester, amide, sulfonyl;

Further, R ₂₅、R₂₆ is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, hydroxy, and boric acid groups, wherein the substituents are selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxy, and amino; the hetero atom in the hetero alkyl or the heterocyclic alkyl is one or more of O, N, S.

Further, R ₂₅、R₂₆ is independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl and hydroxy, wherein the substituents are selected from C1-C6 alkyl, C1-C6 heteroalkyl, halogen, hydroxy and amino.

Further, R ₂₅ is selected from halogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, hydroxy; r ₂₆ is selected from hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl; wherein the substituent is selected from C1-C3 alkyl, C1-C3 heteroalkyl, halogen, hydroxy and amino.

Further, R ₂₅ is selected from F, cl, br, methyl, methoxy, hydroxy, preferably F, cl, br, more preferably F; r ₂₆ is selected from hydrogen, F, cl, br, C-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 more than two of the compounds or stereoisomers, solvates, hydrates, pharmaceutically acceptable salts or eutectic crystals thereof.

The invention also provides application of the compound or stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or eutectic crystal thereof in preparing sodium ion channel regulator; further, the sodium ion channel modulator is a nav1.8 inhibitor.

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

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

The invention also provides the use of the above compound or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof in the manufacture of a medicament for 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, charpy-Ma-Chart three's syndrome, disability and arrhythmia.

Further, the neuropathic pain is selected from one or more of postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuropathy, trigeminal neuralgia, oral burn syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, morton neuroma, nerve crush injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, spinal cord injury post-pain, 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 or the stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or eutectic crystal thereof can contain pharmaceutically acceptable auxiliary materials.

The term "pharmaceutically acceptable" as used herein is meant to include any material which does not interfere with the effectiveness of the biological activity of the active ingredient and which is not toxic to the host to which it is administered.

The pharmaceutically acceptable auxiliary materials are the general names of all additional materials except the main drugs in the medicine, and the auxiliary materials have the following properties: (1) no toxic or side effect to human body; (2) The chemical property is stable, and is not easily influenced by temperature, pH, preservation time and the like; (3) No incompatibility with the main medicine, and no influence on the curative effect and quality inspection of the main medicine; (4) does not interact with the packaging material. Adjuvants in the present invention include, but are not limited to, fillers (diluents), lubricants (glidants or anti-adherents), dispersants, wetting agents, binders, conditioning agents, solubilizing agents, antioxidants, bacteriostats, emulsifiers, disintegrants, and the like. The binder comprises syrup, acacia, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose 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 aerosil, magnesium stearate, talcum powder, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol and the like; 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 dodecyl sulfate, water or alcohol, etc.; the antioxidant comprises sodium sulfite, sodium bisulphite, sodium metabisulfite, dibutyl benzoic acid and the like; the bacteriostat comprises 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol and the like; the regulator comprises hydrochloric acid, citric acid, potassium hydroxide (sodium), sodium citrate, buffer (including sodium dihydrogen phosphate and disodium hydrogen phosphate), etc.; the emulsifier comprises polysorbate-80, sorbitan without acid, pluronic F-68, lecithin, soybean lecithin, etc.; the solubilizer comprises Tween-80, bile, glycerol, etc. The term "pharmaceutically acceptable salt" refers to salts of the compounds of the invention with acids or bases that are suitable for use as medicaments. The acid base is a broad Lewis acid base. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid, and 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, and benzenesulfonic acid; 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 admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, 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 with 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 released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.

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

In addition to these inert diluents, the compositions can also include 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-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 excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the compounds of the present invention for topical administration 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 formulations. Wherein the injection is selected from liquid injection (water injection), sterile powder for injection (powder injection) or tablet for injection (refers to a stamped tablet or a machine pressed tablet prepared by a sterile operation method for medicines), and is dissolved by water for injection when in use for subcutaneous or intramuscular injection.

Wherein the powder for injection contains at least an excipient in addition to the above-mentioned compounds. The excipients described in the present invention, which are components intentionally added to a drug, should not have pharmacological properties in the amounts used, but may aid in processing, dissolution or dissolution of the drug, delivery by targeted route of administration, or stability.

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

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

The term "one-touch" in the present invention means that there is only one connecting key, 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 alkyl group or a branched alkyl group. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.

The C1-Cn used in the invention comprises C1-C2, C1-C3 … … C1-Cn, n is an integer more than one; the prefix as a substituent means minimum and maximum values of the number of carbon atoms in the substituent, for example, "C1-C6 alkyl" means a straight-chain or branched alkyl group having 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 or branched.

"Alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group may be straight 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 chemical structure having the formula-S (=o) ₂ R, including sulfonamide groups, 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 'wherein R, R' may be independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, amino, and the like;

"ester" means having the chemical structure of 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.

"Acylguanidino" means having the formulaWherein 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, for example, "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms in the ring backbone.

"Heterocycloalkyl" refers to cycloalkyl groups 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), aromatic groups (e.g., aryl or heteroaryl), non-aromatic groups (e.g., cycloalkyl or heterocycloalkyl). The "ring" in the present invention may be a single ring or multiple rings, and may be a parallel ring, a spiro ring or a bridged ring.

Typical heterocycloalkyl groups include, but are not limited to:

"aryl" means that the planar ring has a delocalized pi electron system and contains 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, with the elemental symbol typically D or ² H.

The alkyl, heteroalkyl, cyclic, heterocyclic, amino, ester, carbonyl, amide, sulfonyl, phosphoryl, boric acid, borate, guanidino, acylguanidino, aryl, heteroaryl, imide, and the like as described herein may be unsubstituted alkyl, heteroalkyl, cyclic, heterocyclic, amino, ester, carbonyl, amide, sulfonyl, phosphoryl, boric acid, borate, guanidino, acylguanidino, aryl, heteroaryl, imide, and may be substituted alkyl, heteroalkyl, cyclic, heterocyclic, amino, ester, carbonyl, amide, sulfonyl, phosphoryl, boric acid, borate, guanidino, acylguanidino, aryl, heteroaryl, imide.

In the above, unless already indicated, the "substitution" means that the mentioned groups may be substituted by one or more additional groups each and independently selected from alkyl, cycloalkyl, aryl, carboxyl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, alkylthio, aryloxy, o=, guanidino, cyano, nitro, acyl, halogen, haloalkyl, amino, and the like.

The beneficial effects of the invention are as follows: the invention provides a series of compounds with obvious inhibition effect on Nav1.8 ion channel activity, provides a new scheme for treating diseases taking Nav1.8 as a treatment target point, such as chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, multiple sclerosis, margaret-Tourette's 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 diagram of the voltage test of test example 1.

Detailed Description

The following description of the present invention will be made clearly and fully, and it is apparent that the embodiments described are some, but not all, of the embodiments of the present invention. All other embodiments, which can be made by one of ordinary skill in the art without undue burden on the person of ordinary skill in the art based on the embodiments of the present invention, are within the scope of the present invention.

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

DMF: n, N-dimethylformamide

THF: tetrahydrofuran (THF)

DIAD: diisopropyl azodicarboxylate

DIPEA: n, N-diisopropylethylamine

PE: petroleum ether

EA: acetic acid ethyl ester

DCM: dichloromethane (dichloromethane)

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

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

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

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

To the reaction flask was added methyl 2-fluoro-4- (trifluoromethyl) benzoate (1.11 g,5 mmol), 4-fluoro-2-methylphenol (0.63 g,5 mmol), potassium carbonate (1.38 g,10 mmol) and 10mL N-methylpyrrolidone, and the reaction mixture was heated to 120℃and stirred for 20 hours, and TLC showed complete reaction. The reaction system was cooled to room temperature, 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) to give 1.3g of the target product, yield: 79%.

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 (656 mg,2 mmol), sodium hydroxide (320 mg,8 mmol), 10mL water and 10mL methanol, and the reaction mixture was stirred at room temperature for 8 hours, TLC indicated complete reaction. The reaction system was poured into 50mL of water, pH was adjusted to 5 with 1M hydrochloric acid, extracted with ethyl acetate, the organic phase was dried and spin-dried to give 620mg of the target product, yield: 99%.

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

To the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (314 mg,1 mmol), 2-methoxy-5-nitropyridin-4-amine (167 mg,1 mmol), DIPEA (258 mg,2 mmol) and 5mL tetrahydrofuran, HATU (569 mg,1.5 mmol) 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, and the organic phase was dried and purified by silica gel column chromatography (PE/ea=3/1) to give 350mg of the objective product in the yield: 75%.

Step 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 (233 mg,0.5 mmol) was dissolved in 5mL of acetic acid and iron powder (112 mg,2 mmol) was added at room temperature and the mixture stirred at 70℃for 2 hours. The reaction was poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and purified by TLC chromatography (PE/ea=1/1) after spin-drying to give 150mg of the target product, yield: 75%.

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 (83 mg,0.2 mmol) is dissolved in 5mL of acetonitrile, potassium iodide (166 mg,1 mmol) and TMSCl (109 mg,1 mmol) 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, and the organic phase was dried and purified by TLC (DCM/meoh=20/1) after spin-drying to give 45mg of the target product as a white solid, yield: 56%.

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

To the reaction flask was added 2-fluoro-4- (trifluoromethyl) benzonitrile (0.95 g,5 mmol), 4-fluoro-2-methylphenol (0.63 g,5 mmol), potassium carbonate (1.38 g,10 mmol) and 10mL N-methylpyrrolidone, and the reaction mixture was heated to 100deg.C and stirred for 10 hours, TLC showed complete reaction. The reaction system was cooled to room temperature, 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) to give 1.2g of the target product, yield: 81%.

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

2- (4-Fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzonitrile (1.2 g,4.1 mmol) was dissolved in 15mL tetrahydrofuran, liHMDS (1M in THF,8.2mL,8.2mmol) was added dropwise at 0deg.C under nitrogen, after which the reaction mixture was stirred at room temperature for 12 hours and TLC showed complete reaction. The reaction system was poured into 50mL of water, extracted with ethyl acetate, and the organic phase was dried and spun-dried to give 1.2g of crude product, yield: 96%.

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

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

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

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

Step 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 (88 mg,0.2 mmol) was dissolved in 5mL of acetonitrile and potassium iodide (166 mg,1 mmol) and TMSCl (109 mg,1 mmol) 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, and the organic phase was dried and purified by TLC (DCM/meoh=20/1) after spin-drying to give 65mg of the target product as a white solid, yield: 76%.

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 methyl 2-cyano-5-fluoroisonicotinate

To the reaction flask was added methyl 2-bromo-5-fluoroisonicotinate (4.68 g,20 mmol), cuprous cyanide (8.96 g,100 mmol), and 50mL N-methylpyrrolidone, and the reaction mixture was heated to 120℃under nitrogen and stirred for 10 hours. The reaction system was cooled to room temperature, poured into 200mL of water, 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 3.10g of the target product, yield: 86%.

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

To the reaction flask was added methyl 2-cyano-5-fluoroisonicotinate (2.70 g,15 mmol), 4-fluoro-2-methylphenol (1.89 g,15 mmol), potassium carbonate (4.14 g,30 mmol) and 30mL N-methylpyrrolidone, and the reaction mixture was heated to 100deg.C and stirred for 10 hours, TLC showed complete reaction. The reaction system was cooled to room temperature, poured into 100mL of water, extracted with ethyl acetate, and 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%.

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

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

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 (2.32 g,8 mmol) in 30mL toluene was added 4mL trifluoroacetic anhydride and the reaction mixture was heated to 80℃and stirred for 6 hours. The reaction system was cooled to room temperature, poured into 100mL of water, pH was adjusted to 8 with sodium carbonate, extracted with ethyl acetate, the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=8/1), yielding 1.44g of the target product, yield: 49%.

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

To the reaction flask was added methyl 6- (4-fluoro-2-methylphenoxy) -3- (trifluoromethyl) imidazo [1,5-a ] pyridine-7-carboxylate (356 mg,2 mmol), sodium hydroxide (320 mg,8 mmol), 10mL water and 10mL methanol, and the reaction mixture stirred at room temperature for 8 hours, and TLC showed complete reaction. The reaction system was poured into 50mL of water, pH was adjusted to 5 with 1M hydrochloric acid, extracted with ethyl acetate, the organic phase was dried and spin-dried to give 690mg of the target product, yield: 97%.

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

To the reaction flask was added 6- (4-fluoro-2-methylphenoxy) -3- (trifluoromethyl) imidazo [1,5-a ] pyridine-7-carboxylic acid (354 mg,1 mmol), 2-methoxypyridin-4-amine (124 mg,1 mmol), DIPEA (258 mg,2 mmol) and 5mL of tetrahydrofuran, HATU (569 mg,1.5 mmol) 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, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=2/1) to give 270mg of the objective product, yield: 59%.

Step 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 (230 mg,0.5 mmol) is dissolved in 5mL of acetonitrile, potassium iodide (336 mg,2.0 mmol) and TMSCl (218 mg,2.0 mmol) are added at room temperature and the mixture is stirred overnight at 70 ℃. The reaction was poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and purified by TLC (DCM/meoh=20/1) after spin-drying to give 70mg of the target product as a white solid, yield: 30%.

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 the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (31 mg,0.1 mmol), 4-amino-2-piperidone (12 mg,0.1 mmol), DIPEA (26 mg,0.2 mmol) and 2mL tetrahydrofuran, HATU (76 mg,0.2 mmol) 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, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=1/1) to give 26mg of the objective product, yield: 63%.

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 the reaction flask was added 1- (2-fluoro-4- (trifluoromethyl) phenyl) ethan-1-one (2.06 g,10 mmol), 4-fluoro-2-methylphenol (1.26 g,10 mmol), potassium carbonate (2.76 g,20 mmol) and 20mL N-methylpyrrolidone, and the reaction mixture was heated to 120℃and stirred for 20 hours. The reaction system was cooled to room temperature, poured into 100mL 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) to give 2.20g of the objective product, yield: 71%.

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 (1.56 g,5 mmol) was dissolved in 15mL toluene, 2mL acetic acid and Br ₂ (0.80 g,5 mmol) were added sequentially, after addition the reaction mixture was stirred at room temperature for 3 hours, the reaction system was poured into 50mL water, sodium bicarbonate adjusted pH to 8, ethyl acetate extracted, the organic phase dried and spun dry and purified by silica gel column chromatography (PE/ea=20/1) to give 0.43g crude product, yield: 22%.

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

To the reaction flask was added 2-bromo-1- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) phenyl) ethan-1-one (399mg, 1 mmol), 2-methoxypyridine-4-carboxamidine (151 mg,1 mmol), sodium bicarbonate (168 mg,2 mmol), 5mL of water and 5mL of tetrahydrofuran, and the reaction mixture was heated to 60℃and stirred for 10 hours, and TLC showed complete reaction. After the reaction system is cooled to room temperature, the mixture is poured into 20mL of water, extracted by ethyl acetate, dried by organic phase and purified by silica gel column chromatography (PE/EA=2/1) to obtain 210mg of target product, and the yield is: 47%.

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 (89 mg,0.2 mmol) was dissolved in 5mL of acetonitrile and potassium iodide (166 mg,1.0 mmol) and TMSCl (109 mg,1.0 mmol) 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, and the organic phase was dried and purified by TLC (DCM/meoh=20/1) after spin-drying to give 62mg of the target product as a white solid, yield: 72%.

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-carboxamide

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

To the reaction flask was added 7-bromo-3-oxoisoindoline-4-carbonitrile (948 mg,4 mmol), 4-fluoro-1-iodo-2-methylbenzene (944 mg,4 mmol), cesium carbonate (2608 mg,8 mmol), N, N' -dimethylethylenediamine (44 mg,0.5 mmol), cuprous iodide (95 mg,0.5 mmol) and 10mL DMSO, and the reaction mixture was heated to 120℃under nitrogen and stirred for 10 hours. The reaction system was cooled to room temperature, 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=5/1) to give 740mg of the objective product, yield: 54%.

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

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

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

To the reaction flask was added 7-bromo-2- (4-fluoro-2-methylphenyl) -3-oxoisoindoline-4-carboxylic acid (264 mg,1 mmol), 2-methoxypyridin-4-amine (124 mg,1 mmol), DIPEA (258 mg,2 mmol) and 5mL of tetrahydrofuran, HATU (569 mg,1.5 mmol) 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, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=2/1) to give 255mg of the objective product, yield: 54%.

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 (235 mg,0.5 mmol) was dissolved in 5mL of acetonitrile, potassium iodide (336 mg,2.0 mmol) and TMSCl (218 mg,2.0 mmol) were added at room temperature and the mixture was stirred overnight at 70 ℃. The reaction was poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and purified by TLC (DCM/meoh=20/1) after spin-drying to give 130mg of the target product as a white solid, yield: 57%.

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 the reaction flask was added methyl 2-fluoro-4-nitrobenzoate (1.99 g,10 mmol), 4-fluoro-2-methylphenol (1.26 g,10 mmol), potassium carbonate (2.76 g,20 mmol) and 20mL N-methylpyrrolidone, and the reaction mixture was heated to 120℃and stirred for 20 hours. The reaction system was cooled to room temperature, poured into 100mL 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) to give 2.64g of the objective product, yield: 86%.

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

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

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

To a solution of methyl 4-amino-2- (4-fluoro-2-methylphenoxy) benzoate (823mg, 3 mmol) and potassium carbonate (284 mg,8 mmol) in 20mL of tetrahydrofuran at 0deg.C was added dropwise 4-bromobutyryl chloride (557 mg,3 mmol), and after the addition, the reaction mixture was stirred at room temperature for 1 hour, heated to 60deg.C and stirred overnight. The reaction system was cooled to room temperature, filtered, and the filtrate was purified by silica gel column chromatography (PE/ea=2/1) after spin-drying to give 350mg of the target product, yield: 37%.

Step 4: synthesis of 2- (4-fluoro-2-methylphenoxy) -4- (2-oxopyrrolidin-1-yl) benzoic acid

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

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

To the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -4- (2-oxopyrrolidin-1-yl) benzoic acid (165 mg,0.5 mmol), 2-methoxypyridin-4-amine (62 mg,0.5 mmol), DIPEA (129 mg,1 mmol) and 5mL tetrahydrofuran, HATU (379 mg,1 mmol) 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, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=1/1) to give 140mg of the objective product, yield: 64%.

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 (44 mg,0.1 mmol) was dissolved in 2mL of acetonitrile and potassium iodide (83 mg,0.5 mmol) and TMSCl (55 mg,0.5 mmol) 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, and the organic phase was dried and purified by TLC (DCM/meoh=20/1) after spin-drying to give 12mg of the target product as a white solid, yield: 29%.

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 (20.8 g,100 mmol) was dissolved in 100mL trifluoroacetic acid, 10mL of concentrated sulfuric acid and NBS (17.8 g,100 mmol) 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, the organic phase was backwashed 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 target product, yield: 79%.

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

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

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

To the reaction flask was added methyl 5-bromo-2-fluoro-4- (trifluoromethyl) benzoate (12.0 g,40 mmol), 4-fluoro-2-methylphenol (5.0 g,40 mmol), potassium carbonate (11.0 g,80 mmol) and 150mL N-methylpyrrolidone, and the reaction mixture was heated to 100deg.C and stirred for 20 hours. The reaction system was cooled to room temperature, poured into 500mL 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) to give 14.2g of the objective product, yield: 87%.

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

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

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

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

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

To the reaction flask was added 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (499 mg,1 mmol), cesium carbonate (652 mg,2 mmol), N' -dimethylethylenediamine (18 mg,0.2 mmol), cuprous iodide (38 mg,0.2 mmol) and 5mL DMSO, and the reaction mixture was heated to 120 ℃ under nitrogen and stirred for 10 hours. The reaction system was cooled to room temperature, poured into 20mL of water, extracted with ethyl acetate, and 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%.

Step 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 (48 mg,0.1 mmol) was dissolved in 2mL of acetonitrile, potassium iodide (83 mg,0.5 mmol) and TMSCl (55 mg,0.5 mmol) were added at room temperature and the mixture was stirred overnight at 70 ℃. The reaction was poured into 10mL of water, extracted with ethyl acetate, and the organic phase was dried and purified by TLC (DCM/meoh=10/1) after spin-drying to give 23mg of the target product as a white solid, yield: 49%.

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 the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (314 mg,1 mmol), 4-fluoro-3-iodoaniline (237 mg,1 mmol), DIPEA (258 mg,2 mmol) and 5mL tetrahydrofuran, HATU (569 mg,1.5 mmol) 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, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=1/1) to give 385mg of the objective product, yield: 72%.

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

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

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

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

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

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

To the reaction flask was added 5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (71 mg,0.2 mmol), 2-methoxypyridin-4-amine (25 mg,0.2 mmol), DIPEA (52 mg,0.4 mmol) and 2mL tetrahydrofuran, HATU (114 mg,0.3 mmol) 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, and the organic phase was dried and spun-dried and purified by TLC (PE/ea=1/1) to give 58mg of the target product, yield: 63%.

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 (46 mg,0.1 mmol) was dissolved in 2mL of acetonitrile, potassium iodide (83 mg,0.5 mmol) and TMSCl (55 mg,0.5 mmol) 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, and the organic phase was dried and purified by TLC (DCM/meoh=10/1) after spin-drying to give 30mg of the target product as a white solid, 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- (guanidinoformyl) -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) benzamide) benzoate

To the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (63 mg,0.2 mmol), methyl 5-amino-2-fluorobenzoate (34 mg,0.2 mmol), DIPEA (52 mg,0.4 mmol) and 2mL tetrahydrofuran, HATU (114 mg,0.3 mmol) 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, and the organic phase was dried and spun-dried 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) benzamide) benzoic acid

To the reaction flask was added methyl 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide) (47 mg,0.1 mmol), sodium hydroxide (16 mg,0.4 mmol), 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, pH was adjusted to 4 with 1M hydrochloric acid, extracted with ethyl acetate, the organic phase was dried and spin-dried to give 45mg of the target product, yield: 100%.

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

To the reaction flask was added 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide) benzoic acid (45 mg,0.1 mmol), CDI (16 mg,0.1 mmol) and 2mL tetrahydrofuran, and after stirring at room temperature for 1 hour, DIPEA (103 mg,0.8 mmol) and guanidine hydrochloride (48 mg,0.5 mmol) were added in sequence and the reaction mixture was stirred at 50℃overnight. The reaction system is directly subjected to reverse phase preparation and purification to obtain 12mg of target product as white solid with the 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 the reaction flask was added 4-bromo-2-fluorobenzoic acid (219 mg,1.0 mmol), 2-methoxypyridin-4-amine (124 mg,1.0 mmol), DIPEA (258 mg,2.0 mmol) and 5mL tetrahydrofuran, HATU (569 mg,1.5 mmol) were 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, and the organic phase was dried and purified by silica gel column chromatography (PE/ea=1/1) to give 280mg of the objective product, yield: 86%.

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

To the reaction flask was added 4-bromo-2-fluoro-N- (2-methoxypyridin-4-yl) benzamide (163 mg,0.5 mmol), dimethylphosphine oxide (78 mg,1 mmol), triethylamine (101 mg,1 mmol), xantphos (29 mg,0.05 mmol) and 5mL dioxane, after displacement of nitrogen, pd ₂(dba)₃ (27 mg,0.03 mmol) was added and the reaction mixture was heated to 110℃under nitrogen and stirred overnight. The reaction system was cooled to room temperature, poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=1/1) to give 100mg of the objective product, yield: 62%.

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

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

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 (43 mg,0.1 mmol) was dissolved in 2mL of acetonitrile, potassium iodide (83 mg,0.5 mmol) and TMSCl (55 mg,0.5 mmol) 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, and the organic phase was dried and purified by TLC (DCM/meoh=10/1) after spin-drying to give 30mg of the target product as a white solid, yield: 73%.

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- (guanidinoformyl) -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) benzamide) -2-fluorobenzoate

To the reaction flask was added 5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (71 mg,0.2 mmol), methyl 5-amino-2-fluorobenzoate (34 mg,0.2 mmol), DIPEA (52 mg,0.4 mmol) and 2mL tetrahydrofuran, HATU (114 mg,0.3 mmol) 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, and the organic phase was dried and spun-dried and purified by TLC (PE/ea=1/1) to give 70mg of the desired product in 69% yield.

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

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

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

To the reaction flask was added 5- (5-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide) -2-fluorobenzoic acid (39 mg,0.08 mmol), CDI (13 mg,0.08 mmol) and 2mL tetrahydrofuran, followed by DIPEA (78 mg,0.6 mmol) and guanidine hydrochloride (38 mg,0.4 mmol) after stirring at room temperature for 1 hour, and the reaction mixture was stirred overnight at 50 ℃. The reaction system is directly subjected to reverse phase preparation and purification to obtain a target product of 15 mg, which is white solid with the 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 the reaction flask was added 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (499 mg,1 mmol), cyclopent-1-ylboronic acid (224 mg,2 mmol), sodium carbonate (424 mg,4 mmol) and 10mL DMF, pd (dppf) Cl ₂ (37 mg,0.05 mmol) was added after the nitrogen substitution and the reaction mixture was heated to 90 ℃ under nitrogen protection and stirred overnight. The reaction system was cooled to room temperature, poured into 40mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=10/1) to give 360mg of the target product, yield: 74%.

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

To the reaction flask was added 5- (cyclopent-1-en-1-yl) -2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (243 mg,0.5 mmol), 10% Pd/C (20 mg) and 10mL methanol and the reaction mixture was stirred overnight at room temperature under a pressure of 0.2MPa H ₂ and TLC showed complete reaction. The reaction system is directly filtered, and the filtrate is dried by spin to obtain 230mg of target product with yield: 94%.

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 (49 mg,0.1 mmol) was dissolved in 2mL of acetonitrile, potassium iodide (83 mg,0.5 mmol) and TMSCl (55 mg,0.5 mmol) 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, and the organic phase was dried and purified by TLC (DCM/meoh=10/1) after spin-drying to give 24mg of the target product as a white solid, yield: 51%.

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) benzamide) phenyl) -4-methylpiperazine-1-carboxamide

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

To the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (63 mg,0.2 mmol), 4-fluoro-3-nitroaniline (31 mg,0.2 mmol), DIPEA (52 mg,0.4 mmol) and 2mL tetrahydrofuran, HATU (114 mg,0.3 mmol) 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, and the organic phase was dried and spun-dried and purified by TLC (PE/ea=1/1) to give 75mg of the desired product in 83% yield.

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

To the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-nitrophenyl) -4- (trifluoromethyl) benzamide (45 mg,0.1 mmol), 10% pd/C (5 mg) and 5mL methanol and the reaction mixture was stirred at room temperature under 1MPa H ₂ pressure overnight, TLC showed complete reaction. The reaction system is directly filtered, and the filtrate is dried by spin to obtain 42mg of target product with yield: 100%.

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

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

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, 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 the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (314 mg,1 mmol), 3-iodoaniline (319 mg,1 mmol), DIPEA (258 mg,2 mmol) and 5mL tetrahydrofuran, HATU (569 mg,1.5 mmol) 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, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=20/1) to give 430mg of the objective product, yield: 83%.

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

To the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -N- (3-iodophenyl) -4- (trifluoromethyl) benzamide (258 mg,0.5 mmol), diethyl methylphosphonite (136 mg,1 mmol), triethylamine (101 mg,1 mmol), xantphos (29 mg,0.05 mmol) and 5mL dioxane, pd ₂(dba)₃ (27 mg,0.03 mmol) was added after displacement of nitrogen and the reaction mixture was heated to 110℃under nitrogen and stirred for 6 hours. The reaction system was cooled to room temperature, poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=10/1) to give 172mg of the objective product, yield: 69%.

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

To the reaction flask was added ethyl (3- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide) phenyl ] (methyl) phosphinate (149 mg,0.3 mmol), sodium hydroxide (40 mg,1.0 mmol), 5mL of water and 5mL of methanol, and the reaction mixture was stirred at room temperature overnight.

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).

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 (47 mg,0.1 mmol) was dissolved in 1mL phosphorus oxychloride and the reaction mixture was stirred at 80℃for 1 hour. The reaction system was dried by spinning, and the obtained solid was directly used for the next reaction after carrying out twice with chloroform.

Step 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) benzamide) phenyl) (methyl) phosphinate

The solid obtained in the above step was added to 5mL of 7M methanolic ammonia, and the reaction mixture was stirred at room temperature overnight. The reaction was purified by reverse phase preparation directly after spin-drying to give example 17 (20 mg, white solid, yield 42%) and example 18 (14 mg, 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 (3.58 g,20 mmol) was dissolved in 50mL DMF and NBS (3.56 g,20 mmol) 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, and the organic phase was dried and purified by silica gel column chromatography (PE/ea=2/1) to give 4.80g of the objective product in the yield: 93%.

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

To the reaction flask was added 4-bromo-2-fluoro-5- (trifluoromethyl) aniline (2.58 g,10 mmol), cyclopropylboronic acid (3.44 g,40 mmol), sodium carbonate (5.30 g,50 mmol) and 30mL DMF, pd (dppf) Cl ₂ (220 mg,0.3 mmol) was added after nitrogen substitution and the reaction mixture was heated to 90℃under nitrogen with stirring. The reaction system was cooled to room temperature, poured into 200mL of water, extracted with ethyl acetate, 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 the target product, yield: 74%.

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

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

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

1-Iodo-4-cyclopropyl-2-fluoro-5- (trifluoromethyl) benzene (660 mg,2 mmol) and triethylamine (404 mg,4 mmol) were dissolved in DMF/H ₂ O (10 mL/1 mL), pd (dppf) Cl ₂ (73 mg,0.1 mmol) was added and 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. The reaction system was cooled to room temperature, 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 (DCM/meoh=10/1) to give 190mg of the target product, yield: 38%.

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

To the reaction flask was added 4-cyclopropyl-2-fluoro-5- (trifluoromethyl) benzoic acid (124 mg,0.5 mmol), 2-methoxypyridin-4-amine (62 mg,0.5 mmol), DIPEA (129 mg,1.0 mmol) and 3mL tetrahydrofuran, HATU (303 mg,0.8 mmol) 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, and the organic phase was dried and spun-dried and purified by TLC (PE/ea=1/1) to give 140mg of the desired product in yield: 49%.

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

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

Step 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 (23 mg,0.05 mmol) was dissolved in 1mL of acetonitrile, potassium iodide (33 mg,0.2 mmol) and TMSCl (22 mg,0.2 mmol) were added at room temperature and the mixture was stirred at 70℃overnight. The reaction was filtered directly, and the filtrate was purified by TLC (DCM/meoh=10/1) after spin-drying to give 8mg of the target product as a white solid, yield: 36%.

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

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 (22 mg,0.05 mmol) was dissolved in 1mL of acetonitrile, potassium iodide (33 mg,0.2 mmol) and TMSCl (22 mg,0.2 mmol) were added at room temperature, and the mixture was stirred at 70℃overnight. The reaction was filtered directly, and the filtrate was purified by TLC (DCM/meoh=10/1) after spin-drying to give 12mg of the target product as a white solid, yield: 54%.

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

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 (52 mg,0.1 mmol) was dissolved in 2mL of a 40% solution of HBr acetic acid and the mixture was stirred at 70℃overnight. The reaction was cooled to room temperature and poured into 10mL of water, pH was adjusted to 8 with sodium carbonate, extracted with ethyl acetate, the organic phase was dried and dried by spin-drying and purified by TLC (DCM/meoh=10/1) to give 10mg of the target product as a white solid, yield: 23%.

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 (483 mg,3 mmol) was added dropwise to a solution of 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) -5-vinylbenzamide (447 mg,1 mmol) in 10mL of dichloromethane at 0deg.C, NBS (178 mg,1 mmol) was added after 5 minutes, and the system was stirred at room temperature for 1 hour after the addition. The reaction mixture was poured into 20mL of water, extracted with dichloromethane, and the organic phase was backwashed with saturated brine, dried and dried by spin-drying. The resulting solid was dissolved in 10mL of tetrahydrofuran, and after adding potassium t-butoxide (224 mg,2 mmol), the reaction system was stirred at 50℃for 2 hours. The reaction solution was cooled to room temperature, poured into 30mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=1/1) to give 185mg of the objective product, yield: 40%.

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,1 mmol) was added dropwise to a solution of diiodomethane (268 mg,1 mmol) in 5mL of dry dichloromethane under nitrogen at 0deg.C, and after stirring the reaction system at 0deg.C for 0.5 hours, trifluoroacetic acid (114 mg,1 mmol) was slowly added dropwise, stirring was continued for 0.5 hours, and after further stirring a solution of 2- (4-fluoro-2-methylphenoxy) -5- (1-fluorovinyl) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (185 mg,0.4 mmol) in 2mL of dichloromethane was slowly added, and after the addition, the system was stirred overnight at room temperature. The reaction solution was poured into 20mL of water, pH was adjusted to 8 with sodium carbonate, dichloromethane was extracted, and 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%.

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 (48 mg,0.1 mmol) was dissolved in 2mL of acetonitrile, potassium iodide (83 mg,0.5 mmol) and TMSCl (55 mg,0.5 mmol) 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, and the organic phase was dried and purified by TLC (DCM/meoh=10/1) after spin-drying to give 30mg of the target product as a white solid, yield: 65%.

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 (4476 mg,1 mmol), trimethylsilyl 2- (fluorosulfonyl) difluoroacetate (500 mg,2 mmol) and sodium fluoride (8 mg,0.2 mmol) 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, and 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, yield: 52%.

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 (50 mg,0.1 mmol) was dissolved in 2mL of acetonitrile, potassium iodide (83 mg,0.5 mmol) and TMSCl (55 mg,0.5 mmol) were added at room temperature and the mixture was stirred overnight at 70 ℃. The reaction was poured into 10mL of water, extracted with ethyl acetate, and the organic phase was dried and purified by TLC (DCM/meoh=10/1) after spin-drying to give 25mg of the target product as a white solid, yield: 52%.

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

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 (11 mg,0.02 mmol) was dissolved in 2mL of acetonitrile, potassium iodide (17 mg,0.1 mmol) and TMSCl (11 mg,0.1 mmol) 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, and the organic phase was dried and purified by TLC (DCM/meoh=10/1) after spin-drying to give 3mg of the target product as a white solid, yield: 29%.

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

To the reaction flask was added methyl 2-hydroxy-5-nitrobenzoate (1.97 g,10 mmol), (2-bromoethyl) carbamic acid tert-butyl ester (2.24 g,10 mmol), potassium carbonate (2.76 g,20 mmol) and 20mL DMF, and the reaction mixture was heated to 80deg.C and stirred overnight. The reaction system was cooled to room temperature, poured into 100mL of water, extracted with ethyl acetate, and 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%.

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

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

Step 3: synthesis of methyl 2- (2- ((tert-butoxycarbonyl) amino) ethoxy) -5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide) benzoate

To the reaction flask was added methyl 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (6278 mg,2 mmol), 5-amino-2- (2- (((tert-butoxycarbonyl) amino) ethoxy) benzoate (620 mg,2 mmol), DIPEA (516 mg,4 mmol) and 10mL tetrahydrofuran, HATU (1137 mg,3 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight.

Step 4: synthesis of 2- (2- ((tert-butoxycarbonyl) amino) ethoxy) -5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide) benzoic acid

To the reaction flask was added methyl 2- (2- ((tert-butoxycarbonyl) amino) ethoxy) -5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide) benzoate (603 mg,1 mmol), sodium hydroxide (160 mg,4 mmol), 10mL water and 10mL methanol and the reaction mixture was stirred at room temperature overnight. The reaction was poured into 40mL of water, 1M diluted hydrochloric acid adjusted to pH 5, extracted with ethyl acetate, the organic phase dried and spin-dried and purified by silica gel column chromatography (DCM/meoh=10/1) to give 466mg of the target product in yield: 79%.

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

To the reaction flask was added 2- (2- ((tert-butoxycarbonyl) amino) ethoxy) -5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide) benzoic acid (298 mg,0.5 mmol), CDI (81 mg,0.5 mmol) and 5mL tetrahydrofuran, followed by DIPEA (258 mg,2.0 mmol) and guanidine hydrochloride (96 mg,1.0 mmol) after stirring at room temperature for 1 hour, and the reaction mixture was stirred overnight at 50 ℃. 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) benzamide) phenoxy) ethyl) carbamate (66 mg,0.1 mmol) was dissolved in 2mL trifluoroacetic acid and the reaction mixture was stirred at room temperature for 2 hours. After the reaction system is spin-dried, 2mL of methanol is added, the pH value is adjusted to 8 by using 1M sodium carbonate aqueous solution, and the mixture is directly subjected to reverse phase preparation and purification to obtain 20mg of target product which is white solid with the yield: 38%.

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) benzamide

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

To the reaction flask was added methyl 2-fluoro-3-methyl-5-nitrobenzoate (2.13 g,10 mmol), NBS (1.78 g,10 mmol), BPO (480 mg,2 mmol) and 30mL acetonitrile and the reaction mixture was stirred at 70℃overnight. The reaction system was cooled to room temperature, poured into 100mL of water, extracted with ethyl acetate, and 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%.

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

To the reaction flask was added methyl 3- (bromomethyl) -2-fluoro-5-nitrobenzoate (1.46 g,5 mmol), dimethylamine (450 mg,10 mmol), potassium carbonate (1.38 g,10 mmol) and 20mL DMF, and the reaction mixture was heated to 50deg.C and stirred overnight. The reaction system was cooled to room temperature, poured into 100mL of water, 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 870mg of the objective product, yield: 68%.

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

To the reaction flask was added 3- ((dimethylamino) methyl) -2-fluoro-5-nitrobenzoate (870 mg,3.4 mmol), 10% Pd/C (100 mg) and 20mL methanol and the reaction mixture was stirred overnight at room temperature under a pressure of 0.2MPa H ₂, TLC indicated that the reaction was complete. The reaction system is directly filtered, the filtrate is dried by spin to obtain 770mg of target product, and the yield is: 100%.

Step 4: synthesis of methyl 3- ((dimethylamino) methyl) -2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide) benzoate

To the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (6278 mg,2 mmol), methyl 5-amino-3- (((dimethylamino) methyl) -2-fluorobenzoate (452 mg,2 mmol), DIPEA (516 mg, 4 mmol) and 10mL tetrahydrofuran, HATU (1137 mg,3 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight.

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

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

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

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

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

To the reaction flask was added 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide) benzoic acid (226 mg,0.5 mmol), CDI (81 mg,0.5 mmol) and 5mL tetrahydrofuran, and after stirring at room temperature for 1 hour, DIPEA (258 mg,2.0 mmol) and imidazolidine-2-imine hydrochloride (122 mg, 1.0 mmol) were added sequentially and the reaction mixture was stirred at 50℃overnight. The reaction was directly purified by reverse phase preparation to give example 27 (15 mg, white solid, yield 6%) and example 28 (66 mg, 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 the reaction flask was added 1-fluoro-2-methyl-4-nitrobenzene (1.55 g,10 mmol), NBS (1.78 g,10 mmol), BPO (480 mg,2 mmol) and 30mL acetonitrile and the reaction mixture was stirred at 70℃overnight. The reaction system was cooled to room temperature, poured into 100mL of water, extracted with ethyl acetate, and 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%.

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

Guanidine hydrochloride (955 mg,10 mmol) was dissolved in 20mL DMF and potassium tert-butoxide (2.24 g,20 mmol) was added at room temperature, followed by stirring for 0.5 h by the addition of 2- (bromomethyl) -1-fluoro-4-nitrobenzene (1.17 g,5 mmol) and the reaction mixture heated to 50deg.C and stirred overnight. The reaction system was cooled to room temperature, poured into 100mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (DCM/meoh=10/1) to give 560mg of the target product, yield: 53%.

Step 3: synthesis of 1- (5-amino-2-fluorobenzyl) guanidine

1- (2-Fluoro-5-nitrobenzyl) guanidine (424 mg,2 mmol) was dissolved in 5mL of acetic acid, iron powder (560 mg,10 mmol) was added at room temperature, and the mixture was stirred at 70℃for 2 hours. The reaction system is filtered, and the filtrate is purified by reversed phase preparation after spin drying to obtain 230mg of target product with yield: 63%.

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

To the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (314 mg,1 mmol), 1- (5-amino-2-fluorobenzyl) guanidine (182 mg,1 mmol), DIPEA (258 mg,2 mmol) and 5mL tetrahydrofuran, HATU (570 mg,1.5 mmol) 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, and the organic phase was dried and purified by column chromatography on silica gel (DCM/meoh=10/1) to give 30mg of the target product as a white solid, yield: 6%.

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

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

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) formamidino) 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) benzamide) benzoyl) guanidino) butyl) carbamate

To the reaction flask was added 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide) benzoic acid (226 mg,0.5 mmol), CDI (81 mg,0.5 mmol) and 5mL tetrahydrofuran, and after stirring at room temperature for 1 hour, DIPEA (258 mg,2.0 mmol) and tert-butyl (4-guanidinobutyl) carbamate (230 mg,1.0 mmol) were added in sequence 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) formamidino) 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) benzamide) benzoyl) guanidino) butyl) carbamate (66 mg,0.1 mmol) was dissolved in 2mL trifluoroacetic acid and the reaction mixture was stirred at room temperature for 2 hours. After the reaction system is spin-dried, 2mL of methanol is added, the pH value is adjusted to 8 by using 1M sodium carbonate aqueous solution, and the mixture is directly subjected to reverse phase preparation and purification to obtain 30mg of target product which is white solid with the yield: 54%.

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 the reaction flask was added methyl 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (4.07 g,10 mmol), tributyl (1-ethoxyethylene) tin (3.61 g,10 mmol) and 50mL DMF, pd (PPh) ₂Cl₂ (351 mg,0.5 mmol) was added after nitrogen substitution and the reaction mixture was heated to 100deg.C under nitrogen and stirred overnight. The reaction system was cooled to room temperature, poured into 100mL of water, 10mL of concentrated hydrochloric acid was added, 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), to obtain 2.80g of the objective product, yield: 76%.

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

To the reaction flask was added methyl 5-acetyl-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (1.85 g,5 mmol), triethylamine (1.01 g,10 mmol) and 20mL of dichloromethane, and after cooling to 0deg.C, trimethylsilyl triflate (1.11 g,5 mmol) was added dropwise and the reaction mixture stirred at room temperature for 2 hours. The reaction system was poured into 100mL of water, extracted with methylene chloride, and after drying and spin-drying the organic phase, 2.25g of crude product was obtained and used directly in the next reaction.

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

Under the protection of nitrogen and at 0 ℃, diethyl zinc (1M n-hexane solution, 15mL,15 mmol) is dropwise added to 50mL of dry dichloromethane solution of diiodomethane (4.02 g,15 mmol), after the reaction system is stirred for 0.5 hours at 0 ℃,10 mL of dichloromethane solution of methyl 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilyl) oxy) vinyl) benzoate (2.21 g,5 mmol) is slowly dropwise added, after the addition, the system is stirred at room temperature overnight, the reaction solution is poured into 200mL of water, dichloromethane extraction is carried out, the organic phase is dried and dried by spin-drying, and then the target product is purified by silica gel column chromatography (PE/EA=10/1), and the yield is 46%.

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

To the reaction flask was added methyl 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilyl) oxy) cyclopropyl) benzoate (912 mg,2 mmol), lithium hydroxide monohydrate (168 mg, 4 mmol), 10mL of water and 10mL of methanol, and the reaction mixture was stirred at room temperature overnight.

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

To the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilyl) oxy) cyclopropyl) benzoic acid (4402 mg,1 mmol), methyl 5-amino-2-fluorobenzoate (169 mg,1 mmol), DIPEA (258 mg,2 mmol) and 8mL tetrahydrofuran, HATU (569 mg, 1.5 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight.

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

To the reaction flask was added methyl 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilyl) oxy) cyclopropyl) benzamide) (294 mg,0.5 mmol), lithium hydroxide monohydrate (42 mg,1 mmol), 5mL of water and 5mL of methanol, and the reaction mixture was stirred at room temperature overnight.

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

To the reaction flask was added 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) -5- (1- (((trimethylsilyl) oxy) cyclopropyl) benzamido) benzoic acid (116 mg,0.2 mmol), CDI (32 mg,0.2 mmol) and 3mL tetrahydrofuran, followed by stirring at room temperature for 1 hour, DIPEA (129 mg,1.0 mmol) and guanidine hydrochloride (48 mg,0.5 mmol) and the reaction mixture was stirred overnight at 50℃0.5mL of water and 0.5mL of acetic acid were added to the reaction system and stirring was continued for 0.5 hour, after which the reaction system was directly purified by reverse phase 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 the reaction flask was added 3-fluoro-4-nitrobenzotrifluoride (209 mg,1 mmol), 4-fluoro-2-methylphenol (126 mg,1 mmol), potassium carbonate (276 mg,2 mmol) and 5mL acetonitrile and the reaction mixture was heated to 60℃and stirred overnight. The reaction system was cooled to room temperature, poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and spun-dried and purified by TLC (PE/ea=10/1) to give 280mg of the target product, yield: 89%.

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

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

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

To the reaction flask was added 2-oxo-1, 2-dihydropyridine-4-carboxylic acid (14 mg,0.1 mmol), 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) aniline (29 mg,0.1 mmol), DIPEA (39 mg,0.3 mmol) and 2mL tetrahydrofuran, HATU (76 mg,0.2 mmol) 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, and the organic phase was dried and purified by TLC (DCM/meoh=20/1) after spin-drying to give 26mg of the desired 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-trifluoroprop-1-en-2-yl) benzamide

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

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

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 (11 mg,0.02 mmol) was dissolved in 2mL of acetonitrile, potassium iodide (17 mg,0.1 mmol) and TMSCl (11 mg,0.1 mmol) 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, and the organic phase was dried and purified by TLC (DCM/meoh=10/1) after spin-drying to give 6mg of the target product as a white solid, yield: 60%.

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 methyl 4-amino-5-bromo-2-fluorobenzoate

Methyl 4-amino-2-fluorobenzoate (1.69 g,10 mmol) was dissolved in 20mL of acetonitrile, NBS (1.78 g,10 mmol) was added at room temperature, and the mixture was stirred at room temperature overnight. After the reaction was spin-dried, purified by silica gel column chromatography (DCM/meoh=20/1) to give 1.90g of the target product, yield: 77%.

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

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

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

To the reaction flask were added methyl 5-bromo-2-fluoro-4-iodobenzoate (428 mg,2 mmol), sodium pentafluoropropionate (272 mg,2 mmol) and cuprous iodide (191 mg,1 mmol), after which 10mL of anhydrous NMP was added after nitrogen substitution, and the reaction mixture was heated to 150℃under nitrogen protection and stirred overnight. The reaction system was cooled to room temperature, 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) to give 330mg of the objective product, yield: 47%.

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

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

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

Using the corresponding substrate as a starting material, example 35 was obtained according to the same protocol as in example 10

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 (156 mg,1 mmol) and triethylamine (303 mg,3 mmol) were dissolved in 5mL of dry tetrahydrofuran, methyl chloroformate (190 mg,2 mmol) was added dropwise at 0℃and the system was stirred at room temperature for 1 hour after the addition. Suction filtration, the filtrate was dried and dissolved in 5mL dry tetrahydrofuran, and 2mL deuterated aqueous solution of NaBD ₄ (168 mg,4 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction system was poured into 20mL of water, pH was adjusted to 5 with 1M of dilute hydrochloric acid, 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 90mg of the target product, yield: 70%.

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

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

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

Using the corresponding substrate as a starting material, example 36 was obtained according to the same protocol as in example 10

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 the reaction flask was added 4-bromo-2-fluoro-5- (trifluoromethyl) aniline (258 mg,1 mmol), pinacol vinylborate (310 mg,2 mmol), sodium carbonate (318 mg,3 mmol) and 5mL DMF, pd (dppf) Cl ₂ (37 mg,0.05 mmol) was added after nitrogen substitution and the reaction mixture was heated to 100deg.C under nitrogen and stirred overnight. The reaction system was cooled to room temperature, poured into 20mL of water, extracted with ethyl acetate, and 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%.

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

2-Fluoro-5- (trifluoromethyl) -4-vinylaniline (164 mg,0.8 mmol) was dissolved in 3mL of acetonitrile, and isoamyl nitrite (93 mg,0.8 mmol) was added dropwise at 0℃and the system was stirred at room temperature for 1 hour after the addition. A1 mL aqueous solution of potassium iodide (336 mg,2 mmol) 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 an organic phase by using 1M dilute hydrochloric acid, 1M sodium carbonate aqueous solution and saturated saline water, drying and spin-drying to obtain 160mg of target product, and obtaining the yield: 63%.

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

1-Iodo-2-fluoro-5- (trifluoromethyl) -4-vinylbenzene (158 mg,0.5 mmol) and triethylamine (101 mg,1 mmol) were dissolved in DMF/H ₂ O (3 mL/0.3 mL), pd (dppf) Cl ₂ (37 mg,0.05 mmol) was added and 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, poured into 10mL of water, extracted with ethyl acetate, and the organic phase was dried and spun-dried and purified by TLC (PE/ea=10/1) to give 65mg of the target product, yield: 56%.

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

To the reaction flask was added 2-fluoro-5- (trifluoromethyl) -4-vinylbenzoic acid (47 mg,0.2 mmol), 2-methoxypyridin-4-amine (25 mg,0.2 mmol), DIPEA (52 mg,0.4 mmol) and 2mL tetrahydrofuran, HATU (114 mg,0.3 mmol) 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, and the organic phase was dried and spun-dried and purified by TLC (PE/ea=1/1) to give 50mg of the desired product in 74% yield.

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

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

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

Using the corresponding substrate as a starting material, example 37 was obtained according to the same protocol as in example 22

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 the reaction flask was added 4-bromo-2-fluoro-5- (trifluoromethyl) aniline (2.58 g,10 mmol), tributyl (1-ethoxyethylene) tin (3.61 g,10 mmol) and 50mL DMF, pd (PPh) ₂Cl₂ (351 mg,0.5 mmol) was added after nitrogen substitution and the reaction mixture was heated to 100deg.C under nitrogen and stirred overnight. The reaction system was cooled to room temperature, poured into 100mL of water, 10mL of concentrated hydrochloric acid was added, 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), to give 1.60g of the objective product, yield: 72%.

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

2-Fluoro-5- (trifluoromethyl) -4-vinylaniline (884 mg,4 mmol) was dissolved in 10mL of acetonitrile, and isoamyl nitrite (460 mg,4 mmol) was added dropwise at 0℃and the system was stirred at room temperature for 1 hour after the addition. A solution of potassium iodide (1328 mg,8 mmol) in 3mL of water was added and the reaction mixture was stirred at room temperature for 6 hours. Pouring the reaction system into 30mL of water, extracting by ethyl acetate, backwashing an organic phase by using 1M dilute hydrochloric acid, 1M sodium carbonate aqueous solution and saturated saline water, drying and spin-drying to obtain 576mg of target product, and obtaining the yield: 33%.

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

1-Iodo-2-fluoro-5- (trifluoromethyl) -4-vinylbenzene (332 mg,1 mmol) and triethylamine (202 mg,2 mmol) were dissolved in DMF/MeOH (5 mL/1 mL), pd (dppf) Cl ₂ (37 mg,0.05 mmol) was added and 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, poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=10/1) to give 200mg of the objective product, yield: 76%.

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

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

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

Starting from the corresponding substrate, example 38 was obtained according to the same procedure as in example 32

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 (46 mg,0.1 mmol) and potassium carbonate (28 mg,0.2 mmol) were dissolved in 2mL of acetonitrile, acetic anhydride (10 mg,0.1 mmol) was added at room temperature and the reaction mixture was stirred at room temperature overnight. Suction filtration, and the filtrate is purified by reversed phase preparation after spin drying, thus obtaining 17mg of target product with yield: 33%.

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 the reaction flask was added methyl 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (407 mg,1 mmol), pinacol vinylborate (310 mg,2 mmol), sodium carbonate (318 mg,3 mmol) and 5mL DMF, pd (dppf) Cl ₂ (37 mg,0.05 mmol) was added after nitrogen substitution and the reaction mixture was heated to 100deg.C under nitrogen and stirred overnight. The reaction system was cooled to room temperature, poured into 20mL 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) to give 210mg of the target product, yield: 59%.

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

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

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

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

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

To the reaction flask was added methyl 2- (4-fluoro-2-methylphenoxy) -5- (1-fluorocyclopropyl) -4- (trifluoromethyl) benzoate (39 mg,0.1 mmol), lithium hydroxide monohydrate (21 mg,0.5 mmol), 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 raw materials were removed by ether extraction, the pH of the aqueous phase was adjusted to 7 with 1M dilute hydrochloric acid, extracted with ethyl acetate, dried organic phase and spun-dried to give 35mg of the target product, yield: 94%.

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

Using the corresponding substrate as a starting material, example 40 was obtained according to the same protocol as in example 11

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- (guanidinoformyl) -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 (354 mg,1 mmol), trimethylsilyl 2- (fluorosulfonyl) difluoroacetate (500 mg,2 mmol) and sodium fluoride (8 mg,0.2 mmol) 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, and 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, yield: 78%.

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

To the reaction flask was added methyl 5- (2, 2-difluorocyclopropyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (202 mg,0.5 mmol), lithium hydroxide monohydrate (84 mg,2.0 mmol), 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 by using 1M dilute hydrochloric acid, extracting with ethyl acetate, organically drying and spin-drying to obtain 190mg of target product, and obtaining the yield: 97%.

Step 3: synthesis of N- (3- (guanidinoformyl) -4-fluorophenyl) -5- (2, 2-difluorocyclopropyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide

Using the corresponding substrate as a starting material, example 41 was obtained according to the same procedure as in example 11

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-formamidino-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 the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (314 mg,1.0 mmol), 5-amino-2-fluorobenzonitrile (136 mg,1.0 mmol), DIPEA (258 mg,2.0 mmol) and 10mL of tetrahydrofuran, HATU (570 mg,1.5 mmol) 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, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=2/1) to give 265mg of the objective product in 61% yield.

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

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

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 a solution of butynoic acid (84 mg,1 mmol), pd (PPh) ₂Cl₂ (70 mg,0.1 mmol) and dppb (83 mg,0.2 mmol) in 10mL DMSO was added methyl 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoate (407 mg,1 mmol) and DBU (0.44 mL,3 mmol). After nitrogen substitution, the reaction mixture was heated to 80 ℃ under nitrogen and stirred overnight. The reaction system was cooled to room temperature, poured into 20mL 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) to give 190mg of the objective product, yield: 52%.

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

To the reaction flask was added methyl 2- (4-fluoro-2-methylphenoxy) -5- (prop-1-yn-1-yl) -4- (trifluoromethyl) benzoate (183 mg,0.5 mmol), lithium hydroxide monohydrate (84 mg,2.0 mmol), 5mL water and 5mL 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 by using 1M dilute hydrochloric acid, extracting with ethyl acetate, organically drying and spin-drying to obtain 170mg of target product, and obtaining the yield: 97%.

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

Using the corresponding substrate as a starting material, example 43 was obtained according to the same procedure as in example 11

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

N- (3-amino-4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide (42 mg,0.1 mmol), triethylamine (20 mg,0.2 mmol), N-cyanocarbonylimine diphenyl ester (24 mg,0.1 mmol) and 2mL acetonitrile were added to the reaction flask, stirred at room temperature for 6 hours, then a methanol solution of methylamine (2M,0.5 mL,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 spin-dried and purified by TLC (DCM/meoh=10/1) to give 15mg of the target product as a white solid, yield: 30%.

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-formamidinylhydrazono) 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 the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (314 mg,1.0 mmol), 5-amino-2-fluorobenzaldehyde (139 mg,1.0 mmol), DIPEA (258 mg,2.0 mmol) and 10mL tetrahydrofuran, HATU (570 mg,1.5 mmol) 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, and the organic phase was dried and purified by silica gel column chromatography (PE/ea=2/1) to give 280mg of the objective product in 64% yield.

Step 2: synthesis of N- (3- ((2-formamidinylhydrazono) 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 (218 mg,0.5 mmol), aminoguanidine hydrochloride (55 mg,0.5 mmol), sodium acetate (41 mg,0.5 mmol) 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, and the organic phase was dried and purified by TLC (DCM/meoh=10/1) to give 160mg of the target product as a white solid, yield: 63%.

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 (9 mg,0.02 mmol) was dissolved in 2mL of acetonitrile, potassium iodide (17 mg,0.1 mmol) and TMSCl (11 mg,0.1 mmol) 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, and the organic phase was dried and purified by TLC (DCM/meoh=10/1) after spin-drying to give 6mg of the target product as a white solid, 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 a solution of butynoic acid (84 mg,1 mmol), pd (PPh) ₂Cl₂ (70 mg,0.1 mmol) and dppb (83 mg,0.2 mmol) in 10mL DMSO was added 4-bromo-2-fluoro-5- (trifluoromethyl) aniline (258 mg,1 mmol) and DBU (0.44 mL,3 mmol). After nitrogen substitution, the reaction mixture was heated to 80 ℃ under nitrogen and stirred overnight. The reaction system was cooled to room temperature, poured into 20mL 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) to give 85mg of the objective product, yield: 39%.

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

Using the corresponding substrate as a starting material, example 47 was obtained according to the same protocol as in example 37

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) benzamide) (47 mg,0.1 mmol) and hydrazine hydrate (0.2 mL) in 1mL of methanol was stirred at room temperature for 6 hours. Pouring the reaction system into 10mL of water, carrying out suction filtration, and obtaining 47mg of target product after the obtained solid is dried in a spinning way, wherein the yield is: 100%.

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 the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3- (hydrazinoformyl) phenyl) -4- (trifluoromethyl) benzamide (47 mg,0.1 mmol), S-methyl isothiourea sulfate (19 mg,0.1 mmol) and 2mL water, and the reaction mixture was heated to 100deg.C 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 cooling to room temperature, the reaction solution is directly prepared and purified by reverse phase to obtain 8mg of target product which is white solid with yield: 16%.

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 the reaction flask was added 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide) benzoic acid (45 mg,0.1 mmol), cyanamide (9 mg,0.2 mmol), DIPEA (26 mg,0.2 mmol) and 2mL tetrahydrofuran, HATU (76 mg,0.2 mmol) 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, and the organic phase was dried and spun-dried 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 (20 mg,0.04 mmol) 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, and the organic phase was dried and spun-dried and purified by TLC (DCM/meoh=10/1) to give 6mg of the target product, yield: 29%.

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: following a procedure similar to that set forth in the examples above, the following compounds were prepared starting from the corresponding reagents.

Example 96

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

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

N-butyllithium (1.6M, 1 mL) was added dropwise to a 3mL anhydrous tetrahydrofuran solution of 2, 6-tetramethylpiperidine (212 mg,1.5 mmol) at 0℃under nitrogen, the system was cooled to-70℃after stirring for 1 hour, and 1-chloro-4-fluoro-2- (trifluoromethyl) benzene (198mg, 1.0 mmol) was added dropwise and stirring was continued for 1 hour after the addition. The system was poured into excess dry ice, 10mL of water was added after stirring for 10min, the pH was adjusted to acidic with hydrochloric acid, extracted with ethyl acetate, the organic phase dried and spin-dried, purified by Prep-TLC (DCM/meoh=10/1), affording 155mg of a pale yellow solid, yield: 64%.

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

Using the corresponding substrates as starting materials, example 96 was obtained according to the same protocol as in examples 1 and 11

LC/MS:m/z＝527.1[M+H]⁺.

Example 97

2- (4-Fluoro-2-methylphenoxy) -N- (4-fluoro-3- (sulfamoyl carbamoyl) phenyl) -4- (trifluoromethyl) benzamide

2-Fluoro-5- (2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzamide) benzoic acid (50 mg, 0.11 mmol), triethylamine (56 mg,0.55 mmol) and sulfonamide (21 mg,0.22 mmol) were dissolved in 5mL of LDMF, HATU (57 mg,0.15 mmol) was added at room temperature and stirred for 3 hours. The reaction was poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and purified by Prep-TLC (PE/ea=1/1) after spin-drying to give 15mg of a white solid, yield: 29%.

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 (120 mg,0.28 mmol) was dissolved in 4mL acetic acid and 1mL water, and sodium isocyanate (36 mg,0.56 mmol) was added 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 give 90mg of a white solid, yield: 69%.

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- ((guanidinyloxy) 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

Step 3: synthesis of methyl 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide) benzoate

Step 3 intermediates were obtained according to the same protocol as in example 1 starting from the corresponding substrates.

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

To the reaction flask were added methyl 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide) (500 mg,1.08 mmol), anhydrous lithium chloride (4.2 mg,0.1 mmol) and 20mL of methanol, sodium borohydride (205 mg,5.4 mmol) was added in portions at room temperature, and the reaction system was stirred at room temperature for 3 hours. The reaction was quenched with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase dried and concentrated to dryness to give 430mg of a grey solid with a yield: 91%.

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

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

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

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

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

N- (3- ((((1, 3-dioxoisoindolin-2-yl) oxy) methyl) -4-fluorophenyl) -2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide (180 mg,0.31 mmol), 3mL of hydrazine hydrate and 10mL of ethanol were added to the reaction flask and the reaction mixture was stirred overnight at room temperature.

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

Using the corresponding substrate as a starting material, example 99 was obtained according to the same protocol as in example 30

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

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

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- (trifluoromethyl benzamide

Using the corresponding substrate as a starting material, example 102 was obtained according to the same protocol as in example 100

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

Using the corresponding substrate as a starting material, example 103 was obtained according to the same protocol as in example 30

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 (500 mg,2.26 mmol), guanidine hydrochloride (216 mg,4.52 mmol), sodium hydroxide (271mg, 6.78 mmol) dissolved in 5mL water and 20mL ethanol, and the reaction mixture stirred at room temperature for 2 hours and TLC showed completion of the reaction. The reaction system was concentrated, diluted with water, extracted with ethyl acetate, the organic phase was dried and concentrated to dryness, and purified by silica gel column chromatography to give about 280mg of yellow solid, yield: 51%.

Step 2: synthesis of 3-amino-N-carbamoyl-benzenesulfonamide

To a reaction flask were added N-carbamoylamino-3-nitrobenzenesulfonamide (280 mg,1.15 mmol) and 10 mL% ethanol, the reaction system was replaced with hydrogen, pd/C (56 mg,20% wt) was added at room temperature, the reaction mixture was stirred under a hydrogen atmosphere for 3 hours, the reaction system was directly filtered and dried by spin-drying to give 210mg of pale yellow solid, yield: 85%.

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

To the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (50 mg,0.16 mmol), 3-amino-N-carbamoyl-benzenesulfonamide (43 mg,0.2 mmol), DIPEA (62 mg,0.48 mmol) and 10mL tetrahydrofuran, HATU (76 mg,0.2 mmol) 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, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=1/1) to give 10mg of the objective product, yield: 12%. 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 the reaction flask was added 5-bromo-2- (4-fluoro-2-methylphenoxy) -4- (trifluoromethyl) benzoic acid (500 mg, 1.28 mmol), cuCN (229 mg,2.56 mmol), and 10mL NMP, and the reaction mixture was heated to 120 ℃ and stirred overnight, after cooling the reaction to room temperature 50mL water was added, extracted with ethyl acetate, the organic phase was dried and concentrated to dryness and purified by PE/EA (5/1) slurrying to give about 300mg yellow solid, yield: 69%.

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

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 (50 mg,0.12 mmol) was dissolved in 5mL of methylene chloride, chlorosulfonyl isocyanate (51 mg,0.36 mmol) 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, and the organic phase was dried and purified by Prep-TLC (DCM/meoh=15/1) after spin-drying to give 36mg of a white solid, yield: 60%.

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

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

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

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

Step 3: synthesis of (5- (5-amino-2-fluorophenyl) -1H-imidazol-2-yl) carbamic acid tert-butyl ester

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

Step 4: synthesis of tert-butyl (5- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide) phenyl) -1H-imidazol-2-yl) carbamate

To the reaction flask was added tert-butyl 2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoate (100 mg,0.32 mmol), (5- (5-amino-2-fluorophenyl) -1H-imidazol-2-yl) carbamate (120 mg,0.41 mmol), DIPEA (83 mg,0.64 mmol) and 15mL tetrahydrofuran, HATU (144 mg,0.38 mmol) was added at room temperature and the reaction mixture stirred at room temperature overnight. The reaction system was poured into 30mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=1/1) to give 120mg of the objective product, yield: 64 percent of

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

To the reaction flask was added tert-butyl (5- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide) phenyl) -1H-imidazol-2-yl) carbamate (120 mg,0.2 mmol) and 8mL 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-dried and purified by Prep-TLC (DCM/meoh=15/1) to give 60mg of a white solid, yield: 61%.

LC/MS:m/z＝489.1[M+H]⁺.

Examples 109 and 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 the reaction flask was added methyl 2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide) (300 mg,0.65 mmol), hydrazine hydrate (3 mL) and 10mL methanol, the reaction mixture was stirred overnight at room temperature, the reaction was directly filtered, the filter cake was washed 2 times with ethanol/water (3/1), and the resulting solid was dried by spin to give about 125mg of white solid in yield: 42%.

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

Using the corresponding substrate as a starting material, example 110 was obtained according to the same protocol as in example 30

LC/MS:m/z＝490.1[M+H]⁺.

Example 111

6-Amino-5- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide) phenyl) -N-methylpyridine-namide

Step 1: synthesis of 6-amino-5-bromo-N-methylpyridine methylamide

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

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

To a reaction flask was added 6-amino-5-bromo-N-methylpyridine methylamide (400 mg,1.75 mmol), (2-fluoro-5-nitrophenyl) boronic acid (389 mg,2.1 mmol), potassium carbonate (483 mg,3.5 mmol), pd (dppf) Cl ₂ (132 mg,0.18 mmol) and 3mL of water and 10mL of 1, 4-dioxane, the reaction mixture was stirred overnight at 90 ℃ under nitrogen, the reaction was directly dried by spin-drying and purified by silica gel column chromatography (DCM/meoh=20/1) to give 230mg of a pale yellow solid, yield: 45%.

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

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

Step 4: synthesis of 6-amino-5- (2-fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide) phenyl) -N-methylpyridine-namide

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

LC/MS:m/z＝557.2[M+H]⁺.

Example 112

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

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

(Boc) proline (26 mg,0.12 mmol), N- (3-amino-4-fluorophenyl) -2- (4-fluorophenoxy) -5- (trifluoromethyl) benzamide (50 mg,0.12 mmol), DIPEA (46 mg,0.36 mmol) were dissolved in 3mL of LDMF, HATU (57 mg,0.15 mmol) was added at room temperature and stirred overnight. The reaction system was poured into 20mL of water, extracted with ethyl acetate, backwashed twice with an organic phase saturated sodium chloride solution, dried and spin-dried to obtain 80mg of crude product which was directly used in the next reaction.

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

2- ((2-Fluoro-5- (2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide) phenyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester (80 mg, crude) was dissolved in 5mL ethyl acetate hydrochloride solution and stirred at room temperature for 2 hours. The reaction was concentrated to dryness, water was added to adjust pH to basic with sodium carbonate, extracted with ethyl acetate, the organic phase dried and spin-dried 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 (50 mg, 0.12 mmol), triethylamine (61 mg,0.6 mmol), p-nitrophenyl chloroformate (48 mg,0.24 mmol) were dissolved in 5mL tetrahydrofuran, stirred at room temperature for 2 hours, then glycinamide hydrochloride (26 mg,0.24 mmol) was added and the reaction heated to 50℃overnight with stirring. The reaction was poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and purified by Prep-TLC (DCM/meoh=20/1) after spin-drying to give 20mg of a white solid, yield: 32%.

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 (50 mg, 0.12 mmol), DIPEA (46 mg,0.36 mmol), 3, 4-dimethoxy-3-cyclobutene-1, 2-dione (51 mg,0.36 mmol) were dissolved in 5mL of methanol, the system was concentrated to dryness after stirring at room temperature for 2 hours, and 5mL of aminomethylol was added and stirred at room temperature overnight. The reaction was purified by Prep-TLC (DCM/meoh=20/1) after direct spin-drying to give 16mg of white solid, yield: 26%.

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 (50 mg, 0.12 mmol), potassium carbonate (50 mg,0.36 mmol), 2-bromoacetamide (50 mg,0.36 mmol) was dissolved in 5 mLDMF, the reaction was stirred at 90℃for 3 hours, quenched with water, extracted with ethyl acetate, and the organic phase was dried by drying. Purification by Prep-TLC (DCM/meoh=30/1) afforded 30mg of a white solid, yield: 52%.

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 the reaction flask was added 5-bromo-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (250 mg,0.5 mmol), tributyl (1-ethoxyvinyl) stannane (272 mg, 0.75 mmol), ditriphenylphosphine palladium dichloride (35 mg,0.05 mmol) and 5mL toluene, heated to 100 ℃ under nitrogen protection overnight, TLC showed complete reaction. 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 which is directly used 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 the reaction flask was added 5-acetyl-2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (300 mg,0.65 mmol), trimethylchlorosilane (424 mg,3.9 mmol), potassium iodide (216 mg,1.3 mmol) and 8mL acetonitrile and the reaction mixture was heated to 75 ℃ and stirred for 2 hours, TLC showed complete reaction. The reaction system was cooled to room temperature, poured into 20mL of water, extracted with ethyl acetate, the organic phase was backwashed once with sodium bisulphite 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- (trifluoromethyl benzamide

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

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- (trifluoromethyl benzamide

To the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -N- (2-methoxypyridin-4-yl) -5- (2-methylpropan-1-en-1-yl) -4- (trifluoromethyl) benzamide (60 mg,0.13 mmol), trimethylchlorosilane (85 mg, 0.78 mmol), potassium iodide (43 mg,0.26 mmol) and 4mL acetonitrile, and the reaction mixture was stirred at 75 ℃ for 2 hours, TLC showed complete reaction. The reaction was poured into 15mL of water, extracted with ethyl acetate, the organic phase was backwashed once with sodium bisulphite solution, dried and purified by preparative TLC (DCM-meoh=15/1) to give 22mg of pure product, yield: 37%.

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

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

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

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

Diethyl zinc (1M in n-hexane, 18mL,18 mmol) was added dropwise to a 60mL dry dichloromethane solution of diiodomethane (4.82 g,18 mmol) under nitrogen protection at 0deg.C, after stirring the reaction system at 0deg.C for 1 hour, a 10mL dichloromethane solution of tert-butyl ((1- (5-fluoro-2- ((4-methoxybenzyloxy) phenyl) vinyl) oxy) dimethylsilane (2.33 g,6 mmol) was slowly added dropwise, after the addition, the system was stirred overnight at room temperature.

Step 4: synthesis of 4-fluoro-2- (1-hydroxycyclopropyl) phenol

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

LC/MS:m/z＝169.1[M+H]⁺.

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

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

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

To the reaction flask was added 4-cyclopropyl-2- (4-fluoro-2- (1-hydroxycyclopropyl) phenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (50 mg,0.1 mmol), trimethylchlorosilane (108 mg,1 mmol), potassium iodide (83 mg,0.5 mmol), and 3mL acetonitrile, and the reaction mixture was heated to 75 ℃ and stirred for 3 hours, and TLC showed complete reaction. After the reaction was cooled to room temperature, it was poured into 20mL of water, extracted with ethyl acetate, the organic phase was dried and spin-dried to prepare TLC purification (DCM/meoh=15/1) to give 3mg of the target product, yield: 6%.

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 the reaction flask was added 4-cyclopropyl-2-fluoro-N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (1.78 g,5 mmol), 4-fluoro-2- ((4-methoxybenzyl) oxy) phenol (1.49 g,6 mmol), potassium carbonate (1.38 g,10 mmol) and 20mL N-methylpyrrolidone, and the reaction mixture was heated to 100 ℃ and stirred overnight. The reaction system is cooled to room temperature, poured into 100mL of water, extracted by ethyl acetate, backwashed for 2 times by an organic phase saturated sodium chloride solution, dried and spin-dried, and 3.2g of crude product is obtained without purification, and the yield is: 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 (3.2 g, crude product of the above step) was dissolved in 25mL dichloromethane, 5mL trifluoroacetic acid was added, the reaction mixture was stirred at room temperature for 30 minutes after the addition, 50mL water was added after the reaction system was concentrated to dryness, 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 crude product, yield: 70%.

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

To the reaction flask was added 24-cyclopropyl-2- (4-fluoro-2-hydroxyphenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (100 mg,0.22 mmol), 2-bromoethane-1-ol (83 mg,0.66 mmol), potassium carbonate (138 mg,1 mmol), and 2mL N-methylpyrrolidone, and the reaction mixture was heated to 100 ℃ and stirred for 3 hours, TLC showed complete reaction. The reaction system was cooled to room temperature, poured into 10mL of water, extracted with ethyl acetate, and 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: 63%.

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 (70 mg,0.14 mmol) was dissolved in 5mL of acetonitrile, potassium iodide (117 mg,0.7 mmol) and TMSCl (151 mg,1.4 mmol) were added at room temperature and the mixture was stirred overnight at 70 ℃. The reaction was poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and purified by TLC (DCM/meoh=15/1) after spin-drying to give 25mg of the target product as a white solid, yield: 37%.

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- (trifluoromethylphenyl) phenoxy) -5-fluorophenoxy) acetate

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

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

To the reaction flask was added ethyl 2- (2- (5-cyclopropyl-2- ((2-methoxypyridin-4-yl) carbamoyl) -4- (trifluoromethyl) phenoxy) -5-fluorophenoxy) acetate (200 mg,0.36 mmol), sodium hydroxide (43 mg, 1.08 mmol), 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 the organic phase and spin-drying to obtain 120mg of target product, and obtaining the yield: 63%.

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

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

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 the reaction flask was added 2- (2- (5-cyclopropyl-2- ((2-methoxypyridin-4-yl) carbamoyl) -4- (trifluoromethyl) phenoxy) -5-fluorophenoxy) acetic acid (60 mg,0.12 mmol), ammonium chloride (32 mg,0.6 mmol), N, N-diisopropylethylamine (155 mg,1.2 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (137 mg,0.36 mmol) 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, and the organic phase was dried and purified by preparative TLC (DCM/meoh=50/1) to give 45mg of the target product in yield: 75%.

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

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

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

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

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

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

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 the reaction flask was added 2-fluoro-N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (628 mg, 2 mmol), 4-fluoro-2-iodophenol (711 mg,3 mmol), potassium carbonate (8238 mg,6 mmol) and 10Ml N-methylpyrrolidone, and the reaction mixture was stirred at 100℃overnight. The reaction system 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=8/1) to give 780mg of the objective product in yield: 74%.

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

To the reaction flask was added 2- (4-fluoro-2-iodophenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (600 mg,1.13 mmol), ethyl propiolate (332 mg,3.39 mmol), triethylamine (685 mg,6.78 mmol), cuprous iodide (38 mg,0.2 mmol), ditolylphosphine palladium dichloride (70 mg,0.1 mmol) and 10mL of N, N-dimethylformamide, and the reaction mixture was heated to 80℃after displacement of nitrogen and stirred overnight. The reaction system was cooled to room temperature, 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=5/1) to give 380mg of the target product, yield: 67%.

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

Ethyl 3- (5-fluoro-2- (2- (((2-methoxypyridin-4-yl) carbamoyl) -5- (trifluoromethyl) phenoxy) phenyl) propynoate (380 mg,0.76 mmol), 10% palladium on carbon (76 mg,20% wt), and 15mL methanol were added to the reaction flask, and after hydrogen was replaced, the reaction mixture was stirred at 45 ℃ overnight.

Step 4: synthesis of (2- (2- (3-amino-3-oxypropyl) -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 (100 mg,0.2 mmol) was dissolved in 10mL ammonia methanol solution and the reaction mixture was stirred at 45 ℃ overnight.

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

To the reaction flask was added (2- (2- (3-amino-3-oxypropyl) -4-fluorophenoxy) -N- (2-methoxypyridin-4-yl) -4- (trifluoromethyl) benzamide (95 mg,0.2 mmol), trimethylchlorosilane (216 mg,2 mmol), potassium iodide (166 mg,1 mmol) and 5mL acetonitrile, and the reaction mixture was stirred at 70 ℃ for 2 hours, TLC showed complete reaction, the reaction was poured into 30mL water, extracted with ethyl acetate, and the organic phase was dried and dried by preparative TLC purification (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

Ethyl 3- (5-fluoro-2- (2- (((2-methoxypyridin-4-yl) carbamoyl) -5- (trifluoromethyl) phenoxy) phenyl) propionate (100 mg,0.2 mmol) and 5mL of methanol were added to the reaction flask, sodium borohydride (76 mg,2 mmol) was added to the reaction system in portions, and after completion of the TLC detection, the reaction was quenched with water and extracted with ethyl acetate to give 60mg of the desired product in 65% yield.

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

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

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 the reaction flask was added 2- (4-fluoro-2-hydroxyphenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (211 mg,0.5 mmol), 6- (((((tert-butyldiphenylsilyl) oxy) methyl) tetrahydro-2H-pyran-3-ol (370 mg,1 mmol), triphenylphosphine (393 mg,1.5 mmol) and 10mL tetrahydrofuran, and DIAD (505 mg,2.5 mmol) was added dropwise at room temperature, and the reaction mixture was stirred overnight at room temperature.

Step 2: 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

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

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 the reaction flask was added 2- (4-fluoro-2-hydroxyphenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (428 mg,1 mmol), 2-bromoethan-1-ol (250 mg,2 mmol), triphenylphosphine (524 mg,2 mmol) and 12mL tetrahydrofuran, DIAD (606 mg,3 mmol) was added dropwise at room temperature and the reaction mixture was stirred overnight at room temperature. The reaction was poured into 40mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by column chromatography (PE/ea=4/1) to give 340mg of the objective product in 64% yield.

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

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

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

To the reaction flask was added 2- (2- (2- (dimethylamino) ethoxy) -4-fluorophenoxy) -N- (2-methoxypyridin-4-yl) -5- (trifluoromethyl) benzamide (110 mg,0.22 mmol) and 4mL hydrobromic acid in 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, and the organic phase was dried and spun-dried and purified by TLC (DCM/meoh=10/1) to give 30mg of the target product, yield: 28%.

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: following a procedure similar to that set forth in the examples above, the following compounds were prepared starting from the corresponding reagents.

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 the reaction flask was added 2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (314 mg,1 mmol), 5-amino-2-fluorobenzonitrile (163 mg,1.2 mmol), DIPEA (258 mg,2 mmol) and 5ml of n, n-dimethylformamide, HATU (458 mg,1.2 mmol) 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, and the organic phase was dried and purified by column chromatography (PE/ea=2/1) to give 355mg of the objective product in 82% yield.

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

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

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

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

Step1: synthesis of tert-butyl (2-acetyl-4-nitrophenoxy) carbamate

To the reaction flask was added 1- (2-fluoro-5-nitrophenyl) ethan-1-one 1.0g,5.5 mmol), tert-butyl hydroxy carbamate (879 mg,6.6 mmol), potassium carbonate (911 mg,6.6 mmol) and 20mL acetonitrile, and stirred at room temperature for 3 hours. The reaction system was diluted with 30mL of ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=3/1) to give 1.35g of the objective 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 (292 mg,2 mmol), 15mL ethyl acetate hydrochloride solution, and the reaction mixture was stirred at room temperature for 1 hour, and TLC showed completion of the reaction. The reaction system is directly spin-dried, 30mL of water is added, ph is regulated by sodium carbonate to 9, the mixture is stirred for 30 minutes, ethyl acetate is extracted and dried, and then, 280mg of target product is obtained through silica gel flash column chromatography purification, and the yield is: 79%.

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

3-Methyl-5-nitrobenzo [ d ] isoxazole (280 mg,1.57 mmol) and 10mL of ethanol were added to the reaction flask, hydrogen was replaced and Pd/C (28 mg,10% wt) was added, the reaction system was stirred at room temperature for 3 hours, after TLC detection of the reaction was complete, direct filtration was performed, the filtrate was dried by spinning and ethyl acetate was added 2 to 3 times to give 220mg of the objective product, yield: 94%.

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

To the reaction flask was added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (50 mg, 0.14 mmol), 3-methylbenzo [ d ] isoxazol-5-amine (25 mg,0.17 mmol), DIPEA (54 mg,0.42 mmol) and 3 ln, n-dimethylformamide, HATU (65 mg,1.7 mmol) 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, and the organic phase was dried and spun-dried and purified by preparative TLC (PE/ea=2/1) to give 44mg of the desired product in 65% yield.

LC/MS:m/z＝485.2[M+H]⁺.

Example 157

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

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

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

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

To the reaction flask was added 5-nitrobenzo [ d ] isoxazole-3-carboxylic acid (130 mg, 0.63 mmol), ammonium chloride (170 mg,3.15 mmol), DIPEA (406 mg,3.15 mmol) and 8mL of N, N-dimethylformamide, HATU (479 mg,1.26 mmol) 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, and the organic phase was dried and purified by silica gel column chromatography (PE/ea=2/1) to give 60mg of the objective product in 26% yield (2 steps).

Step 3: synthesis of (5-aminobenzo [ d ] isoxazole-3-carboxamide

To the reaction flask were added 5-nitrobenzo [ d ] isoxazole-3-carboxamide (60 mg,0.29 mmol) and 5mL of ethanol, hydrogen was replaced and Pd/C (12 mg,20% wt) was added, the reaction system was stirred at room temperature for 3 hours, after completion of the reaction by TLC detection, it was directly filtered, the filtrate was dried by spinning and ethyl acetate was added 2 times to give 43mg of the objective product, yield: 84%.

Step 4: synthesis of 5- (4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide) benzo [ d ] isoxazole-3-carboxamide

To the reaction flask was added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (50 mg, 0.14 mmol), (5-aminobenzo [ d ] isoxazole-3-carboxamide (30 mg,0.17 mmol), DIPEA (54 mg, 0.42 mmol) and 3mL of n, n-dimethylformamide, HATU (65 mg,1.7 mmol) was added at room temperature and the reaction mixture stirred at room temperature overnight.

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

To the reaction flask was added 6-bromo-3-nitroimidazo [1,2-a ] pyridine (100 mg,0.41 mmol), benzophenone imine (89 mg,0.49 mmol), cesium carbonate (267 mg,0.82 mmol), xphos (19 mg,0.04 mmol), dissolved in 8mL toluene, pd ₂(dba)₃ (37 mg,0.04 mmol) under nitrogen at room temperature, and the reaction mixture stirred overnight at 100deg.C. The reaction system was poured into 30mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by silica gel column chromatography (PE/ea=2/1) to give 90mg of the objective product, yield: 66%.

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

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

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 (50 mg,0.14 mmol), 3-nitroimidazo [1,2-a ] pyridin-6-amine (30 mg,0.17 mmol), pyridine (0.5 mL) are dissolved in 15mL dry DCM and phosphorus oxychloride (107 mg,0.7 mmol) is added dropwise at 0deg.C and the system is stirred for 1 hour at room temperature after addition. After the TLC detection reaction is completed, the system is directly spin-dried and purified by silica gel column chromatography to obtain 55mg of target product, and the yield is: 76%.

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 (55 mg,0.11 mmol) is dissolved in 10mL ethanol, pd/C (11 mg,20% wt) and after displacement with hydrogen the reaction mixture is stirred at room temperature for 3 hours. The reaction was purified by silica prep TLC (DCM/meoh=15/1) after direct filtration and spin-drying to give 20mg of the target product, yield: 39%.

LC/MS:m/z＝485.2[M+H]⁺.

Table 3: the following compounds were prepared starting from the corresponding reagents in a manner analogous to the procedure set forth in the examples above

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

4-Cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (354 mg,1.0 mmol), 4-fluoro-3-iodoaniline (237 mg,1.0 mmol), DIPEA (258 mg,2 mmol) and 5mL of N, N-dimethylformamide were added to the reaction flask, HATU (458 mg,1.2 mmol) was added at room temperature and the reaction mixture stirred at room temperature overnight. The reaction was poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by column chromatography (PE/ea=5/1) to give 430mg of the desired product in 75% yield.

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

To the reaction flask was added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-iodophenyl) -5- (trifluoromethyl) benzamide (289 mg,0.50 mmol), ethyl acrylate (98 mg,1.00 mmol), triethylamine (101 mg,1.00 mmol), cuprous iodide (10 mg,0.05 mmol) and 5mL tetrahydrofuran, pd (PPh ₃)₂Cl₂ (21 mg,0.03 mmol) was added after nitrogen substitution, and nitrogen substitution was again performed.

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

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

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

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 the reaction flask was added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-iodophenyl) -5- (trifluoromethyl) benzamide (57 mg,0.10 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (20 mg,0.10 mmol), potassium carbonate (27 mg,0.20 mmol) and 2mL DMF, and after displacement of nitrogen Pd (dppf) Cl ₂, (7 mg,0.01 mmol) was added, again displacement of nitrogen. The reaction mixture was stirred overnight at 90 ℃ under nitrogen. The reaction was taken up in 10mL of water, extracted with ethyl acetate, and the organic phase dried and then spun-dried to give 12mg of the target product as a white solid after preparative TLC purification (DCM/meoh=20/1), yield: 24%.

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 the reaction flask was added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (4-fluoro-3-iodophenyl) -5- (trifluoromethyl) benzamide (57 mg,0.10 mmol), (1H-pyrrol-2-yl) boronic acid (22 mg,0.20 mmol), potassium carbonate (41 mg,0.30 mmol) and 2mL DMF, after which the nitrogen was replaced with Pd (dppf) Cl ₂, (7 mg,0.01 mmol) and the nitrogen was replaced again. The reaction mixture was stirred overnight at 90 ℃ under nitrogen. The reaction was taken up in 10mL of water, extracted with ethyl acetate, and the organic phase dried and then spun-dried to give 5mg of the target product as a white solid after preparative TLC purification (DCM/meoh=20/1), yield: 10%.

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 was added N- (3-aminobenzo [ d ] isoxazol-5-yl) -4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide (49 mg,0.10 mmol), 2-bromoethanol (12 mg,0.10 mmol), potassium carbonate (41 mg,0.30 mmol) and 2mL 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 then spun-dried and purified by preparative TLC (DCM/meoh=10/1) to give 15mg of the desired product as a white solid, yield: 28%.

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 (900 mg,5.84 mmol), (Boc) ₂ O (1267 mg,5.84 mmol), DIPEA (1507 mg,11.68 mmol) and 10mL tetrahydrofuran and the reaction mixture was stirred at room temperature overnight. The reaction system was poured into 50mL of water, extracted with ethyl acetate, and the organic phase was backwashed twice with saturated brine, dried and spin-dried to give 1500mg of the target product.

Step 2: synthesis of tert-butyl 2- (5-aminopyridin-2-yl) hydrazine-1-carboxylate

To the reaction flask was added tert-butyl 2- (5-nitropyridin-2-yl) hydrazine-1-carboxylate (1500 mg,5.91 mmol) and 20mL ethanol, pd/C (10%, 200 mg) was added and the reaction mixture was stirred at room temperature under a hydrogen atmosphere (0.1 MPa) overnight. Filtration and spin drying of the filtrate gave 1370mg of the desired product.

Step 3: synthesis of tert-butyl 2- (5- (4- (4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide) pyridin-2-yl) hydrazine-1-carboxylate

To the reaction flask was added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzoic acid (354 mg,1.0 mmol), tert-butyl 2- (5-aminopyridin-2-yl) hydrazine-1-carboxylate (224 mg,1.0 mmol), DIPEA (258 mg,2 mmol) and 5ml of n, n-dimethylformamide, HATU (457 mg,1.2 mmol) 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 organic phase and purified by column chromatography (DCM/meoh=20/1) to give 470mg of the desired product in 84% yield.

Step 4: synthesis of 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (6-hydrazinopyridin-3-yl) -5- (trifluoromethyl) benzamide

To the reaction flask was added tert-butyl 2- (5- (4- (4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -5- (trifluoromethyl) benzamide) pyridin-2-yl) carboxylate (470 mg,0.84 mmol) and 10mL hydrogen chloride in dioxane (4M), and the reaction mixture was stirred at room temperature for 4 hours.

Step 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 the reaction flask was added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (6-hydrazinopyridin-3-yl) -5- (trifluoromethyl) benzamide (46 mg,0.1 mmol), CDI (16 mg,0.1 mmol), TEA (20 mg,0.2 mmol) and 5mL tetrahydrofuran, and the reaction mixture was stirred at room temperature overnight. The reaction system was poured into 20mL of water, extracted with ethyl acetate, and the organic phase was dried and spin-dried and purified by Prep-HPLC to give 10mg of the desired product as a white solid in 20% yield.

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 the reaction flask was added 4-cyclopropyl-2- (4-fluoro-2-methylphenoxy) -N- (6-hydrazinopyridin-3-yl) -5- (trifluoromethyl) benzamide (46 mg,0.1 mmol), cyanogen bromide (10 mg,0.1 mmol), and 3mL ethanol, and the reaction mixture was stirred overnight at 90 ℃. The reaction system was directly purified by Prep-HPLC to give 6mg of the desired 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 in a similar manner to that described in examples 171 and 172 using the corresponding reagents as starting materials.

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 efficacy

Test example 1: inhibition activity assay of compounds on human Na _V 1.8.8 ion channels of HEK293 cells

1: Test compound formulations

Reagents were purchased from Sigma (St. Louis, MO) corporation, except for NaOH and KOH for acid-base titration. The final concentrations of the test compounds were all formulated on the same day and re-dissolved in extracellular fluid. Extracellular fluid (mM) was: naCl,137; KCl,4; caCl ₂,1.8;MgCl₂, 1; HEPES,10; glucose 10; pH 7.4 (NaOH titration). Intracellular fluid (mM) ASPARTIC ACID,140; mgCl2,2; EGTA 11; HEPES,10; pH 7.2 (CsOH titration). All test compound solutions contained 1. Mu.M TTX.

The storage concentration of the test compound was 3mM. Dissolved in dimethyl sulfoxide (DMSO). The day of testing was re-dissolved in extracellular fluid and configured to the desired concentration.

Test compound solvents

2: Test method

2.1: Cells

All experiments were performed at room temperature. Each cell was self-controlled.

2.1.1: Testing of Compounds

The compounds are all perfused by a perfusion system utilizing self gravity. At least one cell was tested for each concentration. After current stabilization (or 5 minutes), the blocking effect of the compound was calculated by comparing the current magnitude changes before and after compound use.

2.1.2: Test cells

HEK293 cells stably expressed by nav1.8 ion channels.

2.1.3: Experimental instrument

Patch clamp amplifier: PATCH CLAMP PC-505B (WARNER instruments)/MultiClamp 700 and 700A (Axon instrument)

A digital-to-analog converter: digidata 1440A (Axon CNS)/Digidata 1550A (Axon instruments)

Micro-controller: MP-225 (SUTTER instrument)

Inverted microscope: TL4 (Olympus)

Glass microelectrode drawing instrument: PC-10 (NARISHIGE)

Microelectrode glass capillary: B12024F (Wuhan micro-detection science instruments Co., ltd.)

2.2: Electrophysiology

Cells were transferred to perfusion cells and perfused with extracellular fluid. Intracellular fluid (mM) ASPARTIC ACID, 140; mgCl2,2; EGTA 11; HEPES,10; pH 7.2 (CsOH titration). The intracellular fluid was stored in small portions in-80 degree freezer and thawed on the day of the experiment. The electrode was drawn with PC-10 (Narishige, japan). The whole cell membrane patch clamp was recorded and noise was filtered with one fifth of the sampling frequency.

2.3: Test voltage equation (resting) and results

The cells were clamped at-80 mV and then depolarized to 10mV with a square wave for 10 ms to give Na _V 1.8.8 current (see figure 1). This procedure was repeated every 5 seconds. The maximum current induced by the square wave is detected, after which the test compound is perfused and after the reaction is stable, the intensity of the blockage is calculated.

Table 4: inhibition ratio measurement (inhibition ratio at 100 nm/%: 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 (subsequent table 4): inhibition ratio measurement (inhibition ratio at 100 nm/%: 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 (subsequent table 4): inhibition ratio measurement (inhibition ratio at 100 nm/%: 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: list of partial Compounds IC ₅₀

From the data in table 7, it can be seen that: examples 10, 13, 19, 20, etc. have significant activity advantages over VX-150 (clinical stage II), and some of the examples have comparable activity.

Test example 2: liver microsome stability experiment

1: Adding 10 mu L of a test sample or a control sample working solution and 80 mu L of a microsome working solution (the concentration of liver microsome protein is 0.5 mg/mL) to the T0, T5, T10, T20, T30, T60 and NCF60 sample hole sites, adding only the microsome working solution to the Blank60 hole sites, and then pre-incubating the samples Blank60, T5, T10, T20, T30 and T60 except for the T0 and NCF60 sample hole sites in a water bath at 37 ℃ for about 10 minutes;

2: the T0 sample is added with 300 mu L of stop solution (acetonitrile solution of 200ng/mL tolbutamide and 200ng/mL labetalol) and then added with 10ul of NADPH regeneration system working solution;

3: after the incubation plates Blank60, T5, T10, T20, T30 and T60 were pre-incubated, 10 μl of NADPH regeneration system working solution was added to each sample well to initiate the reaction, and 10ul of 100mm potassium phosphate buffer was added to NCF60 sample wells;

4: after incubation for a suitable period of 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 control sample wells of the Blank60, T5, T10, T20, T30, T60, and NCF60 plates, respectively, to terminate the reaction.

5: All sample plates were shaken and centrifuged at 4000rpm for 20 minutes, and 100. Mu.L of the supernatant of the test or control sample was diluted into 300. Mu.L of pure water for LC-MS/MS analysis, respectively

6: Data analysis, T1/2 and CL _int(mic) (μL/min/mg) values were calculated according to the first order elimination kinetics, which was given by the equation:

TABLE 8 results of liver microsome stability test of the inventive compounds

From the data in table 8, it can be seen that: examples 11, 19, 30, 82 and 154 have comparable or superior hepatic microsomal stability relative to VX-150 (clinical stage two), i.e., may translate into comparable or superior in vivo pharmacokinetics.

Test example 3: inhibition activity test of compound on HEK293 cell hERG ion channel

This experiment was used as a compound heart safety test.

1: Test instrument

Patch clamp instrument: PC-505B, MC-700A

Micro-manipulation instrument: MP-225

Drawing electrode instrument: PC-10 (Narishige, japan)

2: Pharmaceutical formulation

Compounds are commercially available from Sigma (St. Louis, MO) except for NaOH and KOH for acid-base titration. The final concentrations of the test compounds were all formulated on the same day and re-dissolved in extracellular fluid. Extracellular fluid (mM) is NaCl,137; KCl,4; caCl2,1.8; mgCl2,1; HEPES,10; glucose 10; pH 7.4 (NaOH titration). All test compound and control compound solutions contained 0.3% dmso. Intracellular fluid (mM) is: k ASPARTATE,130; mgCl2,5; EGTA 5; HEPES,10; tris-ATP 4; pH 7.2 (KOH titration).

3: Test method

And (3) cells: all experiments were performed at room temperature. Each cell was self-controlled.

Testing of the compounds: the compounds are all perfused by a perfusion system utilizing self gravity. At least two cells were tested per concentration. After current stabilization (or 5 minutes), the blocking effect of the compound was calculated by comparing the current magnitude changes before and after compound use.

Positive control: the concentration of the positive control CISAPRIDE is selected according to the sensitivity test of the positive control to cells, and the concentration with the blocking rate of about 90% is the optimal concentration of the positive control. As a result of the test CISAPRIDE, the blocking rate was about 90%, and thus, the positive control CISAPRIDE was set to 100nM. The method is the same as for the test compounds.

Electrophysiology: cells were transferred to perfusion cells and perfused with extracellular fluid. Intracellular fluid (mM) is: k ASPARTATE,130; mgCl2,5; EGTA 5; HEPES,10; tris-ATP 4; pH 7.2 (KOH titration). The intracellular fluid was stored in small portions in-80 degree fridge and thawed on the day of the experiment. The electrode was drawn with PC-10 (Narishige, japan). Whole cell patch clamp recordings, noise was filtered with one fifth of the sampling frequency.

Test procedure and results: the cells were clamped at-80 mV, then depolarized to 40mV with a square wave for 4 seconds, and then hyperpolarized to-40 mV with a square wave for 2 seconds to obtain hERG tail current. This procedure is repeated every 20 seconds. The hERG tail current is pure hERG current. The maximum tail current induced by the second square wave is detected, after which the test compound is perfused after it has stabilized, and after the reaction has stabilized, the intensity of the blockage is calculated.

TABLE 9 IC50 test results of compounds of the invention on hERG inhibition

Examples	19	30	131	VX-150
					IC50(uM)	21.74	9.74	23.48	6.98

Strong inhibition of hERG by compounds creates serious cardiac safety risks such as prolongation of cardiac QT interval. From the data in table 9, it can be seen that: the inhibition of hERG by some compounds of this patent is significantly weaker than VX-150 (clinical stage II) and therefore likely will show better cardiac safety.

Test example 4: compound rat in vivo pharmacokinetic test

SD rats, male (purchased from Shanghai Sipuler-BiKai laboratory animal Co., ltd.). The test compounds were administered to SD rats in a single dose by oral administration (10 mg/kg, 3 in each group) and intravenous administration (1 mg/kg, 3 in each group) respectively. Test compounds were formulated on the day of administration, dissolved with 5% dmso+10% solutol+85% saline, and vortexed for 2min, sonicated for 5min, and formulated into dosing solutions. Animals were fasted for 10-14 hours prior to oral administration and resumed feeding after 4 hours post administration. After oral administration and intravenous administration of SD rats by gastric lavage, pharmacokinetic samples are collected by jugular vein, and the collection time points are as follows: 3 whole blood samples were collected at each time point, at about 0.2mL, before, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after administration, and anticoagulated with heparin sodium. Immediately after blood sample collection, the plasma was centrifuged (centrifugation conditions: 6800 rpm, 6 minutes, 2-8 ℃) on ice for 1 hour. The collected plasma was stored in a-80℃refrigerator 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: the compounds of this patent (examples 19, 159, 160 and 165) all showed superior in vivo pharmacokinetics in rats compared to VX-150 (clinical second phase), and the plasma exposure of examples 19, 159, 160 was 2-4 times that of VX-150, suggesting that the compounds of this patent may have better in vivo efficacy.

As can be seen from the above pharmaceutical research data, the compound has obvious inhibition effect on Nav1.8 ion channel activity, and part of the compounds have obvious advantages in cell activity, liver microsome stability, heart safety, in vivo pharmacokinetics of rats and the like compared with clinical secondary VX-150, can be used as Nav1.8 inhibitor, and has wide application prospects in the fields of analgesia, atrial fibrillation, buddha syndrome and the like.

Claims

1. A compound characterized by having the structure shown below or a tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, a pharmaceutically acceptable salt thereof:

wherein,

R ₃、R₄ is selected from trifluoromethyl, substituted or unsubstituted cyclopropyl, and at least one of R ₃、R₄ is substituted or unsubstituted cyclopropyl; the substituted or unsubstituted cyclopropyl is: R ₃₁ is independently selected from hydrogen, halogen, hydroxy, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy; a is selected from integers of 0 to 5;

R ₂₃ is selected from halogen;

R ₂₄ is selected from substituted or unsubstituted C1-C3 alkyl, CD ₃;

r ₂₅ is selected from halogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy and hydroxy;

r ₂₆ is selected from hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl;

R ₂₇、R₂₈、R₂₉、R₃₀ is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, cyano, or R ₂₇, R ₂₉ and the connected atoms form 4-6 membered heterocycloalkyl;

y is selected from a bond, -C (O), -CH=N-;

wherein the substituent is selected from C1-C6 alkyl and halogen;

the hetero atom in the hetero alkyl and the heterocyclic alkyl is O, S, N.

2. A compound according to claim 1, wherein R ₃ is selected from trifluoromethyl and R ₄ is selected from cyclopropyl; or R ₃ is selected from cyclopropyl, and R ₄ is selected from trifluoromethyl.

3. The compound of claim 1, wherein R ₂₃ is selected from F, cl, br; r ₂₄ is selected from methyl, CD ₃.

4. The compound of claim 1, wherein R ₂₃ is selected from F; r ₂₄ is selected from methyl.

5. The compound of claim 1, wherein R ₂₅ is selected from halogen; r ₂₆ is selected from hydrogen.

6. The compound of claim 1, wherein R ₂₇、R₂₈、R₂₉、R₃₀ is each independently selected from hydrogen; y is selected from a bond or-C (O).

7. A compound characterized by having the structure shown below or a tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, a pharmaceutically acceptable salt thereof:

wherein,

Selected from the group consisting of

R ₃、R₄ is independently selected from hydrogen, halogen, trifluoromethyl, pentafluoroethyl, substituted or unsubstituted cyclopropyl, R ₃、R₄ is not H at the same time;

The substituted or unsubstituted cyclopropyl is:

R ₃₁ is independently selected from hydrogen, halogen, hydroxy, amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy; a is selected from integers of 0 to 5;

R ₂₃ is selected from halogen;

R ₂₄ is selected from substituted or unsubstituted C1-C3 alkyl, CD ₃;

r ₃₇ is selected from hydrogen, hydroxy, amino, carboxyl;

Wherein the substituent is selected from C1-C6 alkyl and halogen.

8. The compound of claim 7, wherein R ₃、R₄ is independently selected from hydrogen, trifluoromethyl, cyclopropyl, and R ₃、R₄ is not simultaneously H.

9. The compound of claim 7, wherein R ₃ is selected from trifluoromethyl or cyclopropyl; r ₄ is selected from H or trifluoromethyl.

10. The compound of claim 7, wherein R ₂₃ is selected from F, cl, br; r ₂₄ is selected from methyl, CD ₃.

11. The compound of claim 7, wherein R ₂₃ is selected from F; r ₂₄ is selected from methyl.

12. The compound of claim 7, wherein R ₃₇ is selected from amino.

13. A compound having the structure or a pharmaceutically acceptable salt thereof, as shown below:

14. a pharmaceutical composition comprising an active ingredient selected from a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a combination of two or more thereof.

15. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the preparation of a nav1.8 inhibitor.