TW202239748A - A kind of aromatic compound, pharmaceutical composition thereof, preparation method therefor and use thereof - Google Patents

Abstract

The present disclosure an aromatic compound, preparation method therefor and use thereof. It specifically disclosed a compound of formula I, its pharmaceutically acceptable salt, stereoisomer, tautomer or isotopic compound. The compound has higher P2X4 antagonistic activity, better security and pharmacokinetic properties.

Description

Aromatic compound, its preparation method and application

The present invention relates to an aromatic compound, its preparation method and application.

ATP receptors are classified into two major families, P2Y- and P2X-purinergic receptors, based on molecular structure, transduction mechanism, and pharmacological properties. P2X-purinergic receptors are a family of ATP-gated cation channels of which several subtypes have been subdivided, including: six homomeric receptors, P2X1; P2X2; P2X3; P2X4; P2X5; and P2X7; and three heteromeric Receptors P2X2/3, P2X4/6, P2X1/5. The P2X4 receptor is currently the only subtype of the P2X family whose crystal structure has been solved, and its resolution is as high as 2.8 Å, and studies have found that P2X4 is the P2X subtype with the strongest permeability to Ca ²⁺ .

Cough is the main symptom of respiratory diseases, and 70% to 80% of patients in respiratory clinics have cough symptoms. With the increasing prevalence of COPD, IPF, etc., and cough as the main symptom of most respiratory diseases, the demand is also increasing. As the body's defensive nerve reflex, coughing helps to clear respiratory secretions and harmful factors, but frequent and severe coughing will seriously affect the work, life and social activities of patients.

At present, the indications of drugs in research related to P2X4 targets are mostly neuropathic pain or inflammatory reactions, and there is no information on drug research related to cough indications. And there are no drugs on the market that inhibit the P2X4 pathway to treat many diseases, including chronic cough. Therefore, the development of new compounds that can inhibit the activity of P2X4 has positive significance for the treatment of diseases.

The present invention claims the prior application filed with the State Intellectual Property Office of China on January 27, 2021, with the patent application number 202110113303.4, entitled "An Aromatic Compound, Its Preparation Method and Application" and filed with China on June 08, 2021. Submitted by the State Intellectual Property Office, the patent application number is 202110638504.6, the priority of the previous application entitled "A kind of aromatic compound, its preparation method and application" and the patent application submitted to the State Intellectual Property Office of China on January 18, 2022 No. 202210055268.X, the priority of the earlier application titled "An Aromatic Compound, Its Preparation Method and Application". The entire contents of the three prior applications are hereby incorporated by reference.

The invention provides an aromatic compound, its preparation method and application. The compound has higher P2X4 antagonistic activity, better safety and pharmacokinetic properties.

The present invention provides a compound as shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotope compound, its crystal form, its nitrogen oxide, its solvate or a solvate of a pharmaceutically acceptable salt thereof;

； ^Wherein , R2 is selected from

;

R ^2-1 is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Ra: C ₁ ~C ₂₀ alkyl, C ₃ ~C ₂₀ cycloalkyl, 3-20 membered heterocycle base, C ₆ ~C ₂₀ aryl and 5-20 membered heteroaryl;

，無取代或任選被一個、兩個或更多個Ra1取代的下列基團：C ₁~C ₂₀烷基、C ₃~C ₂₀環烷基、C ₁~C ₂₀烷氧基、C ₁~C ₂₀烷硫基、-C(=O)-C ₁~C ₂₀烷基、-C(=O)-OC ₁~C ₂₀烷基、-O-C(=O)-C ₁~C ₂₀烷基、-SO ₂-C ₁~C ₂₀烷基、-S(=O)-C ₁~C ₂₀烷基、3-20元雜環基、C ₆~C ₂₀芳基、5-20元雜芳基以及NH ₂； Each Ra is the same or different, independently selected from halogen, OH, CN, NO ₂ , oxo (=O), COOH,

, the following groups that are unsubstituted or optionally substituted by one, two or more Ra1: C ₁ ~C ₂₀ alkyl, C ₃ ~C ₂₀ cycloalkyl, C ₁ ~C ₂₀ alkoxy, C ₁ ~C ₂₀ alkylthio, -C(=O)-C ₁ ~C ₂₀ alkyl, -C(=O)-OC ₁ ~C ₂₀ alkyl, -OC(=O)-C ₁ ~C ₂₀ alkane group, -SO ₂ -C ₁ ~C ₂₀ alkyl, -S(=O)-C ₁ ~C ₂₀ alkyl, 3-20 membered heterocyclic group, C ₆ ~C ₂₀ aryl group, 5-20 membered heterocyclic group Aryl and NH ₂ ;

Each Ra1 is the same or different, independently selected from halogen, OH, COOH, CN, NO2, oxo (=O) and the following groups which are unsubstituted or optionally substituted by one, _two or more Ra2 : C ₁ ~C ₂₀ alkyl, C ₃ ~C ₂₀ cycloalkyl, C ₁ ~C ₂₀ alkoxy and NH ₂ ;

Each Ra2 is the same or different, independently selected from halogen, OH, CN, NO ₂ , oxo (=O), C ₁ ~C ₂₀ alkyl and C ₁ ~C ₂₀ alkoxy;

R ^2-2 is selected from hydrogen, halogen, OH, CN, NO ₂ and the following groups that are unsubstituted or optionally substituted by one, two or more Rb: C ₁ ~C ₂₀ alkyl and C ₁ ~C ₂₀ alkoxy; each Rb is the same or different, independently selected from halogen, OH, CN and NO ₂ ;

R ^3-1 is selected from halogen, OH, CN, NO ₂ and the following groups that are unsubstituted or optionally substituted by one, two or more Rc: C ₁ ~C ₂₀ alkyl, C ₁ ~C ₂₀ alkane Oxygen and C ₃ ~C ₂₀ cycloalkyl; each Rc is the same or different, independently selected from halogen, OH, CN and NO ₂ ;

n is selected from 0, 1, 2, 3 or 4.

； ^In one embodiment of the invention, R is selected from

;

以及無取代或任選被一個、兩個或更多個Ra1取代的下列基團：C ₁~C ₁₂烷基、C ₃~C ₁₂環烷基、C ₁~C ₁₂烷氧基、C ₁~C ₁₂烷硫基、-C(=O)-C ₁~C ₁₂烷基、-C(=O)-OC ₁~C ₁₂烷基、-O-C(=O)-C ₁~C ₁₂烷基、-SO ₂-C ₁~C ₁₂烷基、-S(=O)-C ₁~C ₁₂烷基、3-12元雜環基、C ₆~C ₁₄芳基、5-14元雜芳基以及NH ₂； R ^2-1 is selected from the following groups that are unsubstituted or optionally substituted by one, two or more R: C ₁ ~C ₁₂ alkyl, C ₃ ~C ₁₂ cycloalkyl, 3-12 membered heterocycle group, C ₆ ~C ₁₄ aryl group and 5-14 membered heteroaryl group; each Ra is the same or different, independently selected from halogen, OH, CN, NO ₂ , oxo (=O),

And the following groups that are unsubstituted or optionally substituted by one, two or more Ra1: C ₁ ~C ₁₂ alkyl, C ₃ ~C ₁₂ cycloalkyl, C ₁ ~C ₁₂ alkoxy, C ₁ ~C ₁₂ alkylthio, -C(=O)-C ₁ ~C ₁₂ alkyl, -C(=O)-OC ₁ ~C ₁₂ alkyl, -OC(=O)-C ₁ ~C ₁₂ alkane group, -SO ₂ -C ₁ ~C ₁₂ alkyl group, -S(=O)-C ₁ ~C ₁₂ alkyl group, 3-12 membered heterocyclic group, C ₆ ~C ₁₄ aryl group, 5-14 membered heterocyclic group Aryl and NH ₂ ;

Each Ra1 is the same or different, independently selected from halogen, OH, COOH, CN, NO2, oxo (=O) and the following groups which are unsubstituted or optionally substituted by one, _two or more Ra2 : C ₁ ~C ₁₂ alkyl, C ₁ ~C ₁₂ alkoxy, C ₃ ~C ₁₂ cycloalkyl and NH ₂ ; each Ra2 is the same or different, independently selected from halogen, OH, CN, NO ₂ , oxo (=O), C ₁ ~C ₁₂ alkyl and C ₁ ~C ₁₂ alkoxy;

R ^2-2 is selected from hydrogen, halogen, OH, CN, NO ₂ and the following groups that are unsubstituted or optionally substituted by one, two or more Rb: C ₁ ~C ₁₂ alkyl and C ₁ ~C ₁₂ alkoxy; each Rb is the same or different, independently selected from halogen, OH, CN and NO ₂ ;

R ^3-1 is selected from halogen, OH, CN, NO ₂ and the following groups that are unsubstituted or optionally substituted by one, two or more Rc: C ₁ ~C ₁₂ alkyl, C ₁ ~C ₁₂ alkane Oxygen and C ₃ ~C ₁₂ cycloalkyl; each Rc is the same or different, independently selected from halogen, OH, CN and NO ₂ ;

n is selected from 0, 1, 2, 3 and 4.

或為

；其中，R ^2-1如上述所定義，R ^2-3選自鹵素、OH、CN、NO ₂以及無取代或任選被一個、兩個或更多個Rb取代的下列基團：C ₁~C ₂₀烷基以及C ₁~C ₂₀烷氧基；每個Rb相同或不同，彼此獨立地選自鹵素、OH、CN以及NO ₂； According to an embodiment of the invention, ^R is

or for

; wherein, R ^2-1 is as defined above, R ^2-3 is selected from halogen, OH, CN, NO ₂ and the following groups that are unsubstituted or optionally substituted by one, two or more Rb: C ₁ ~C ₂₀ alkyl and C ₁ ~C ₂₀ alkoxy; each Rb is the same or different, independently selected from halogen, OH, CN and NO ₂ ;

或

； According to an embodiment of the invention, ^R is

or

;

R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , C ₃ ~C ₁₀ cycloalkyl, "the number of heteroatoms is 1, 2 One or three, heteroatoms selected from one or more of N, O, S and S(=O) ₂ 3~10 membered heterocycloalkyl", "heterocycloalkyl" substituted by one or more R ^2-1c The number of atoms is 1, 2 or 3, and the heteroatom is selected from one or more of N, O, S and S(=O) _2. 3~10 membered heterocycloalkyl", C ₆ ~C ₁₀ aromatic group, C ₆ ~C ₁₀ aryl group substituted by one or more R ^2-1d , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5-10 membered heteroaryl" or substituted by one or more R ^2-1e "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5 ~10-membered heteroaryl";

R ^2-3 is halogen, OH, C ₁ ~C ₁₀ alkyl or C ₁ ~C ₁₀ alkoxy;

R ^2-1a is independently a C ₃ ~C ₆ cycloalkyl group or a 3~6 membered heteroatom with 1, 2 or 3 heteroatoms selected from one or more of N, O and S "Cycloalkyl";

、

、C ₃~C ₁₀環烷基或雜原子選自N、O、S和S(=O) ₂中的一種或多種的3~10元雜環烷基； R ^2-1c , R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkyl substituted by one or more R ^2-1c-1 , C ₁ ~C ₆ alkoxyl group, -C(=O)R ^2-1c-2 , -S(=O) ₂ R ^2-1c-3 ,

,

, C ₃ ~C ₁₀ cycloalkyl or heteroatoms are selected from one or more of N, O, S and S(=O) ₂ 3~10 membered heterocycloalkyl;

R ^2-1c-1 , R ^2-1c-2 and R ^2-1c-3 are independently halogen, OH, COOH, CN, NO ₂ , oxo (=O) or unsubstituted or optionally replaced by one or two The following groups substituted by one or more Ra2: C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy and NH ₂ ;

Each Ra2 is the same or different, independently selected from halogen, OH, CN, NO ₂ , oxo (=O), C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy and C ₃ ~C ₆ Cycloalkyl;

n is 0, 1, 2 or 3;

R ^3-1 is independently halogen, hydroxyl, cyano, C ₁ ~C ₆ alkyl, halogen substituted C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy or C ₃ ~C ₁₀ cycloalkyl .

； ^In one embodiment of the invention, R is

;

R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , C ₃ ~C ₁₀ cycloalkyl, "the number of heteroatoms is 1, 2 One or three, heteroatoms selected from one or more of N, O, S and S(=O) ₂ 3~10 membered heterocycloalkyl", "heterocycloalkyl" substituted by one or more R ^2-1c The number of atoms is 1, 2 or 3, and the heteroatom is selected from one or more of N, O, S and S(=O) _2. 3~10 membered heterocycloalkyl", C ₆ ~C ₁₀ aromatic group, C ₆ ~C ₁₀ aryl group substituted by one or more R ^2-1d , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5-6 membered heteroaryl" or substituted by one or more R ^2-1e "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5 ~6-membered heteroaryl";

R ^2-1a is independently a C ₃ ~C ₆ cycloalkyl group or a 3~6 membered heteroatom with 1, 2 or 3 heteroatoms selected from one or more of N, O and S "Cycloalkyl";

； R ^2-1c , R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkyl substituted by one or more R ^2-1c-1 , C ₁ ~C ₆ alkoxy, -C(=O)R ^2-1c-2 , -S(=O) ₂ R ^2-1c-3 or

;

R ^2-1c-1 is independently NH ₂ ;

R ^2-1c-2 and R ^2-1c-3 are independently NH ₂ or C ₁ ~C ₆ alkyl;

n is 0, 1, 2 or 3;

R ^3-1 is independently halogen, hydroxyl, cyano, C ₁ ~C ₆ alkyl, halogen substituted C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy or C ₃ ~C ₆ cycloalkyl .

； In a certain scheme, in the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound, some groups are defined as follows, not The defined group is the same as described in any previous scheme (hereinafter referred to as "in a certain scheme" ⁾ , and R2 is

;

R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from One or more of N, O, S and S(=O) ₂ 3-10 membered heterocycloalkyl", substituted by one or more R ^2-1c "the number of heteroatoms is 1, 2 or 3, heteroatoms selected from one or more of N, O, S and S(=O) ₂ 3~10 membered heterocycloalkyl", C ₆ ~C ₁₀ aryl, surrounded by one or more R ^{2 -1d} substituted C ₆ ~C ₁₀ aryl, "the number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from one or more of N, O, and S 5-6 membered heteroaryl" or "A 5-6 membered heteroaryl group with 1, 2 or 3 heteroatoms selected from one or more of N, O and S" substituted by one or more R ^2-1e ;

R ^2-2 is selected from hydrogen, halogen, OH, C ₁ ~C ₆ alkyl and C ₁ ~C ₆ alkoxy;

R ^2-1a is independently a C ₃ ~C ₆ cycloalkyl group or a 3~6 membered heteroatom with 1, 2 or 3 heteroatoms selected from one or more of N, O and S "Cycloalkyl";

、

、C ₃~C ₆環烷基或雜原子選自N、O、S和S(=O) ₂中的一種或多種的3~6元雜環烷基； R ^2-1c , R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkyl substituted by one or more R ^2-1c-1 , C ₁ ~C ₆ alkoxyl group, -C(=O)R ^2-1c-2 , -S(=O) ₂ R ^2-1c-3 ,

,

, C ₃ ~C ₆ cycloalkyl or heteroatoms selected from one or more of N, O, S and S(=O) ₂ 3~6 membered heterocycloalkyl;

R ^2-1c-1 is independently halogen, NH ₂ or C ₃ ~C ₆ cycloalkyl;

R ^2-1c-2 and R ^2-1c-3 are independently NH ₂ or C ₁ ~C ₆ alkyl;

n is 0, 1, 2 or 3;

R ^3-1 is independently halogen, hydroxyl, cyano, C ₁ ~C ₆ alkyl, halogen substituted C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy or C ₃ ~C ₆ cycloalkyl .

； ^In a scheme R2 is

;

R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from One or more of N, O, S and S(=O) ₂ 3-10 membered heterocycloalkyl", substituted by one or more R ^2-1c "the number of heteroatoms is 1, 2 or 3, heteroatoms selected from one or more of N, O, S and S(=O) ₂ 3~10 membered heterocycloalkyl", C ₆ ~C ₁₀ aryl, surrounded by one or more R ^{2 -1d} substituted C ₆ ~C ₁₀ aryl, "the number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from one or more of N, O, and S 5-6 membered heteroaryl" or "A 5-6 membered heteroaryl group with 1, 2 or 3 heteroatoms selected from one or more of N, O and S" substituted by one or more R ^2-1e ;

R ^2-1a is independently a C ₃ ~C ₆ cycloalkyl group or a 3~6 membered heteroatom with 1, 2 or 3 heteroatoms selected from one or more of N, O and S "Cycloalkyl";

； R ^2-1c , R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkyl substituted by one or more R ^2-1c-1 , C ₁ ~C ₆ alkoxy, -C(=O)R ^2-1c-2 , -S(=O) ₂ R ^2-1c-3 or

;

R ^2-1c-1 is independently NH ₂ ;

R ^2-1c-2 and R ^2-1c-3 are independently NH ₂ or C ₁ ~C ₆ alkyl;

n is 0, 1, 2 or 3;

R ^3-1 is independently halogen, hydroxyl, cyano, C ₁ ~C ₆ alkyl, halogen substituted C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy or C ₃ ~C ₆ cycloalkyl .

In a certain scheme, when R ^2-1 is a C ₁ ~C ₁₀ alkyl, or a C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , the C ₁ ~C ₁₀ alkane The base can be C ₁ ~C ₆ alkyl, and can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.

、

、

、

、

、

、

、

、

、

、

或

。 In a certain scheme, when R ^2-1 is "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, S and S(=O) ₂ 3~ 10-membered heterocycloalkyl" or "the number of heteroatoms substituted by one or more R ^2-1c is 1, 2 or 3, and the heteroatoms are selected from N, O, S and S(=O) ₂ When one or more 3-10 membered heterocycloalkyl groups are used, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N, O, S and S(=O) ₂ One or more 3-10-membered heterocycloalkyl groups" can be "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O, S and S(=O) ₂ ~8-membered heterocycloalkyl", for example: oxetane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, 2-azabicyclo[2.2.1]heptane, 3-nitrogen Heterobicyclo[3.1.1]heptanyl, 3-azabicyclo[2.2.2]octanyl or tetrahydrothiophene-1,1-dioxide such as:

,

,

,

,

,

,

,

,

,

,

or

.

In a certain scheme, when R ^2-1 is a C ₆ ~C ₁₀ aryl group or a C ₆ ~C ₁₀ aryl group substituted by one or more R ^2-1d , said C ₆ ~C ₁₀ aryl group Can be phenyl.

、

、

、

、

、

、

或

。 In a certain scheme, when R ^2-1 is "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, a 5-6 membered heteroaryl group" or When "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, a 5-6-membered heteroaryl group" substituted by one or more R ^2-1e , The said "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S is a 5-6 membered heteroaryl group" may be "the number of heteroatoms is 1 or 2, the heteroatoms are selected from one or more of N, O and S, 5-6 membered heteroaryls", or "the number of heteroatoms is 1 or 2, and the heteroatoms are 5-6 membered heteroaryls of N Heteroaryl", for example: pyrazolyl, imidazolyl or pyridyl, and for example:

,

,

,

,

,

,

or

.

In a certain scheme, when R ^2-1a is independently a C ₃ ~C ₆ cycloalkyl group, the C ₃ ~C ₆ cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl or cyclo Hexyl, for example: cyclopropyl, cyclobutyl or cyclopentyl.

或

。 In a certain scheme, when R ^2-1a is independently "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, a 3-6 membered heterocycloalkane In the case of group”, the said “3-6 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from one or more of N, O and S” can be “heteroatom The number is 1 or 2, the heteroatom is selected from one or more of N, O and S 3~6 membered heterocycloalkyl", it can also be "the number of heteroatoms is 1 or 2, the heteroatom is 3~6-membered heterocycloalkyl group of O", for example: oxetanyl or tetrahydrofuryl, and for example:

or

.

In a certain scheme, when R ^2-1c , R ^2-1d and R ^{2-1e are} independently halogen, the halogen can be fluorine, chlorine, bromine or iodine, for example: fluorine or chlorine.

In a certain scheme, when R ^2-1c , R ^2-1d and R ^{2-1e are} independently C ₁ ~C ₆ alkyl, or C ₁ ~C substituted by one or more R ^2-1c-1 ₆ alkyl, the C ₁ ~C ₆ alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example: methyl .

In a certain scheme, when R ^2-1c , R ^2-1d and R ^{2-1e are} independently C ₃ ~C ₁₀ cycloalkyl, said C ₃ ~C ₁₀ cycloalkyl is cyclopropyl, Cyclobutyl, cyclopentyl.

In a certain scheme, when R ^2-1c , R ^2-1d and R ^{2-1e are} independently C ₁ ~C ₆ alkoxy, the C ₁ ~C ₆ alkoxy can be methoxy , ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, eg methoxy.

In a certain scheme, when R ^2-1c-1 is C ₃ -C ₆ alkyl, the C ₃ -C ₁₀ cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl.

In a certain scheme, when R ^2-1c-2 and R ^2-1c-3 are independently C ₁ ~C ₆ alkyl, the C ₁ ~C ₆ alkyl can be methyl, ethyl, Propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.

In a certain scheme, when R ^2-2 is a C ₁ ~C ₆ alkyl group, the C ₁ ~C ₆ alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, Isobutyl, sec-butyl or tert-butyl, e.g. methyl.

In a certain scheme, when R ^3-1 is independently halogen or C ₁ ~C ₆ alkyl substituted by halogen, the halogen can be fluorine, chlorine, bromine or iodine, for example: fluorine or chlorine.

In a certain scheme, when R ^3-1 is independently C ₁ ~C ₆ alkyl or C _{1 ~C 6 alkyl substituted by halogen, the C 1 ~C 6 alkyl can} be methyl, Ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In a certain scheme, when R ^3-1 is independently C ₁ ~C ₆ alkoxy, the C ₁ ~C ₆ alkoxy can be methoxy, ethoxy, propoxy, iso Propoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

In a certain scheme, when R ^3-1 is independently a C ₃ ~C ₆ cycloalkyl group, the C ₃ ~C ₆ cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl or cyclo Hexyl.

、

、

、

或

。 In a certain scheme, when R ^2-1 is C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , said C ₁ ~C substituted by one or more R ^2-1a ₁₀ alkyl can be

,

,

,

or

.

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。 In a certain scheme, when R ^2-1 is a C ₆ ~C ₁₀ aryl group substituted by one or more R ^2-1d , said C ₆ ~C substituted by one or more R ^2-1d ₁₀ aryl can be

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

.

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。 In a certain scheme, when R ^2-1 is substituted by one or more R ^2-1e "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one of N, O and S or When a variety of 5-6 membered heteroaryl groups are used, the number of heteroatoms substituted by one or more R ^2-1e is 1, 2 or 3, and the heteroatoms are selected from N, O and S One or more 5-6 membered heteroaryls" can be

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or

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或

。 ^In a certain scheme, R2 can be

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,,

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or

.

In a certain aspect, R ^3-1 can be fluoro or chloro.

In a certain scheme, R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , C ₃ ~C ₁₀ cycloalkyl, "heteroatom The number is 1, 2 or 3, and the heteroatom is selected from one or more of N, O, S and S(=O) ₂ 3~10 membered heterocycloalkyl", C ₆ ~C ₁₀ aryl , a C ₆ ~C ₁₀ aryl group substituted by one or more R ^2-1d , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5 ~6-membered heteroaryl" or substituted by one or more R ^2-1e "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5~ 6-membered heteroaryl".

In a certain scheme, R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , "the number of heteroatoms is 1, 2 or 3 The heteroatoms are selected from one or more of N, O, S and S(=O) ₂ , 3~10 membered heterocycloalkyl", C ₆ ~C ₁₀ aryl, replaced by one or more R ^{2- 1d} substituted C ₆ ~C ₁₀ aryl, "the number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from one or more of N, O, and S, and the heteroatoms are 5-6 membered heteroaryl groups" or are "a 5-6 membered heteroaryl group with 1, 2 or 3 heteroatoms selected from one or more of N, O and S" substituted by one or more R ^2-1e .

In a certain scheme, R ^2-1 is C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , C ₆ ~C ₁₀ aryl substituted by one R ^2-1d , "the number of heteroatoms 1, 2 or 3, heteroatoms are selected from one or more of N, O and S 5~6 membered heteroaryl" or "the number of heteroatoms is substituted by one or more R ^2-1e 1, 2 or 3 heteroatoms selected from one or more of N, O and S, 5-6 membered heteroaryl."

In a certain scheme, R ^2-1 is a C ₆ ~C ₁₀ aryl group substituted by one or more R ^2-1d , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N, One or more of O and S 5-6 membered heteroaryl" or "the number of heteroatoms substituted by one or more R ^2-1e is 1, 2 or 3, and the heteroatoms are selected from N, O and one or more of 5-6 membered heteroaryls in S".

In a certain scheme, R ^2-2 is hydrogen, halogen, hydroxyl, C ₁ ~C ₁₀ alkyl or C ₁ ~C ₁₀ alkoxy.

In a certain scheme, R ^2-1a is independently "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S. A 3-6 membered heterocycloalkyl group ".

、

或C ₃~C ₆環烷基。 In a certain scheme, R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkane substituted by one or more R ^2-1c-1 group, C ₁ ~C ₆ alkoxy group, -C(=O)R ^2-1c-2 , -S(=O) ₂ R ^2-1c-3 ,

,

Or C ₃ ~C ₆ cycloalkyl.

、

或C ₃~C ₆環烷基。 In a certain scheme, R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, -C(=O)R ^{2-1c -2} 、-S(=O) ₂ R ^2-1c-3 、

,

Or C ₃ ~C ₆ cycloalkyl.

In a certain scheme, R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, -C(=O)R ^2-1c-2 or -S(=O) ₂ R ^2-1c-3 .

In a certain scheme, R ^2-1c-1 is independently halogen, NH ₂ or C ₃ ~C ₆ cycloalkyl;

In a certain embodiment, R ^2-1c-2 and R ^2-1c-3 are independently C ₁ -C ₆ alkyl.

In a certain scheme, R ^2-2 is hydrogen, C ₁ ~C ₁₀ alkyl or C ₁ ~C ₁₀ alkoxy.

In a certain aspect, R ^3-1 is independently halogen.

； ^In a certain scheme, R2 is

;

R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , C ₃ ~C ₁₀ cycloalkyl, "the number of heteroatoms is 1, 2 One or three, heteroatoms selected from one or more of N, O, S and S(=O) ₂ 3~10 membered heterocycloalkyl", C ₆ ~C ₁₀ aryl, by one or more R ^2-1d substituted C ₆ ~C ₁₀ aryl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S. 5~6 membered heteroaryl ” or “a 5-6-membered heteroaryl group with 1, 2 or 3 heteroatoms selected from one or more of N, O and S” substituted by one or more R ^2-1e ;

R ^2-2 is hydrogen, C ₁ ~C ₆ alkyl or C ₁ ~C ₆ alkoxy;

R ^2-1a is independently a C ₃ ~C ₆ cycloalkyl group or a 3~6 membered heteroatom with 1, 2 or 3 heteroatoms selected from one or more of N, O and S "Cycloalkyl";

、

或C ₃~C ₆環烷基； R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkyl substituted by one or more R ^2-1c-1 , C ₁ ~C ₆ alkoxy, -C(=O)R ^2-1c-2 , -S(=O) ₂ R ^2-1c-3 ,

,

or C ₃ ~C ₆ cycloalkyl;

R ^2-1c-1 is independently halogen, NH ₂ or C ₃ ~C ₆ cycloalkyl;

R ^2-1c-2 and R ^2-1c-3 are independently NH ₂ or C ₁ ~C ₆ alkyl;

n is 0, 1, 2 or 3;

R ^3-1 is independently halogen.

； ^In a certain scheme, R2 is

;

R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from One or more of N, O, S and S(=O) ₂ 3~10 membered heterocycloalkyl", C ₆ ~C ₁₀ aryl, C ₆ ~ substituted by one or more R ^2-1d C ₁₀ aryl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are 5-6 membered heteroaryls selected from one or more of N, O and S" or replaced by one or more R ^{2 -1e} substituted "5-6 membered heteroaryl with 1, 2 or 3 heteroatoms selected from one or more of N, O and S";

R ^2-2 is hydrogen or C ₁ ~C ₆ alkyl;

R ^2-1a is independently a C ₃ ~C ₆ cycloalkyl group or a 3~6 membered heteroatom with 1, 2 or 3 heteroatoms selected from one or more of N, O and S "Cycloalkyl";

、

或C ₃~C ₆環烷基； R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkyl substituted by one or more R ^2-1c-1 , C ₁ ~C ₆ alkoxy, -C(=O)R ^2-1c-2 , -S(=O) ₂ R ^2-1c-3 ,

,

or C ₃ ~C ₆ cycloalkyl;

R ^2-1c-1 is independently halogen, NH ₂ or cyclopropyl;

R ^2-1c-2 and R ^2-1c-3 are independently NH ₂ or C ₁ ~C ₆ alkyl;

n is 0, 1, 2 or 3;

R ^3-1 is independently halogen.

； ^In a certain scheme, R2 is

;

R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from One or more of N, O, S and S(=O) ₂ 3~10 membered heterocycloalkyl", C ₆ ~C ₁₀ aryl, C ₆ ~ substituted by one or more R ^2-1d C ₁₀ aryl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are 5-6 membered heteroaryls selected from one or more of N, O and S" or replaced by one or more R ^{2 -1e} substituted "5-6 membered heteroaryl with 1, 2 or 3 heteroatoms selected from one or more of N, O and S";

R ^2-2 is hydrogen or C ₁ ~C ₆ alkyl;

R ^2-1a is independently a C ₃ ~C ₆ cycloalkyl group or a 3~6 membered heteroatom with 1, 2 or 3 heteroatoms selected from one or more of N, O and S "Cycloalkyl";

、

或C ₃~C ₆環烷基； R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, -C(=O)R ^2-1c-2 , -S( =O) ₂ R ^2-1c-3 、

,

or C ₃ ~C ₆ cycloalkyl;

R ^2-1c-2 and R ^2-1c-3 are independently NH ₂ or C ₁ ~C ₆ alkyl;

n is 0, 1, 2 or 3;

R ^3-1 is independently halogen.

； ^In a certain scheme, R2 is

;

R ^2-1 is C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , C ₆ ~C ₁₀ aryl substituted by one R ^2-1d , "the number of heteroatoms is 1, 2 Or 3, heteroatoms are selected from one or more of N, O and S 5~6 membered heteroaryl" or "the number of heteroatoms is 1, 2 or substituted by one or more R ^2-1e 3, heteroatoms are selected from one or more of N, O and S 5-6 membered heteroaryl";

R ^2-2 is hydrogen or C ₁ ~C ₃ alkyl;

R ^2-1a is independently "a 3-6 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms selected from one or more of N, O and S";

、

或環丙烷； R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, -C(=O)R ^2-1c-2 , -S( =O) ₂ R ^2-1c-3 、

,

or cyclopropane;

R ^2-1c-2 and R ^2-1c-3 are independently C ₁ ~C ₆ alkyl;

n is 0, 1, 2 or 3;

R ^3-1 is independently halogen.

； ^In a certain scheme, R2 is

;

R ^2-1 is a C ₆ ~C ₁₀ aryl group substituted by one or more R ^2-1d , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one of N, O and S or a variety of 5-6 membered heteroaryls" or "the number of heteroatoms substituted by one or more R ^2-1e is 1, 2 or 3, and the heteroatoms are selected from one of N, O and S or A variety of 5-6 membered heteroaryls”;

R ^2-2 is hydrogen or methyl;

R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, -C(=O)R ^2-1c-2 or -S(=O) ₂ R ^{2-1c- 3} ;

R ^2-1c-2 and R ^2-1c-3 are independently C ₁ ~C ₆ alkyl;

n is 0, 1, 2 or 3;

R ^3-1 is independently halogen.

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以及

。 In a certain scheme, the compound shown in formula I can be any of the following structures:

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as well as

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According to an embodiment of the present invention, the compound represented by formula I may be any of the following compounds: Compound 1: N-(4-((3-acetylphenoxy)methyl)-3-sulfamo Acylphenyl)-2-(2-chlorophenyl)acetamide, N-(4-((3-acetylphenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide; Compound 2: 2-(2-Chlorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N -(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 3: 2-(2-chlorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy base)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide; Compound 4: N-(4-((4-chlorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide, N- (4-((4-chlorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide; Compound 5: 2-(2-chlorophenyl)-N-(4-((2,4- Dichlorophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-((2,4-dichlorophenoxy)methyl)-3-sulfamoylphenyl )acetamide; Compound 6: 2-(2-chlorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2- (2-chlorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 7: 2-(2-chlorophenyl)-N-(4-((2,4- Difluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-((2,4-difluorophenoxy)methyl)-3-sulfamoylphenyl )acetamide; Compound 8: 2-(2-chlorophenyl)-N-(4-(((4,5-dichloro-1-methyl-1H-pyrazol-3-yl)oxy)methyl )- 3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-(4-(((4,5-dichloro-1-methyl-1H-pyrazol-3-yl)oxy)methyl)- 3-sulfamoylphenyl)acetamide; Compound 9: 2-(2-chlorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl Base) acetamide, 2-(2-chlorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 10: 2-(2-chloro Phenyl)-N-(4-((3-cyano-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N- (4-((3-cyano-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 11: N-(4-((3-chloro-4-fluorophenoxy)methyl)-3-amine Sulfonylphenyl)-2-(2-chlorophenyl)acetamide, N-(4-((3-chloro-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl) acetamide; Compound 12: 2-(2-Chlorophenyl)-N-(4-((3-(methylsulfonyl)phenoxy)methyl)-3-sulfamoylphenyl)acetyl Amine, 2-(2-chlorophenyl)-N-(4-((3-(methylsulfonyl)phenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 13: 2-(2-chlorophenyl)-N-(4 -(((1,1-Dioxytetrahydrothiophen-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4 -(((1,1-dioxidotetrahydrothiophen-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 14: 2-(2-chlorophenyl)-N-(3-sulfamoylphenyl-4- ((((tetrahydrofuran-3-yl)oxy)methyl)phenyl)acetamide, 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydrofuran-3-yl)oxy )methyl)phenyl)acetamide; Compound 15: N -(4-((3-Acetyl-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide, N-(4 -((3-acetyl-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide; Compound 16: 2-(2-chlorophenyl)-N-(3-sulfamoylphenyl) -4-((p-tolyloxy)methyl)phenyl)acetamide, 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-((p-tolyloxy)methyl)phenyl)acetamide; compound 17: 2-(2-Chlorophenyl)-N-(4-((4-fluoro-3-methylphenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2- (2-chlorophenyl)-N-(4-((4-fluoro-3-methylphenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 18: 2-(2-chlorophenyl)-N-(4-(( 4-fluoro-3-methoxyphenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-((4-fluoro-3 -methoxyphenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 19: 2-(2-chlorophenyl)-N-(4-((4-fluoro-3-(2-oxopyrrolidin-1-yl) Phenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-((4-fluoro-3-(2-oxopyrrolidin-1-yl )phenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 20: 2-(2-chloro-6-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-amine Sulfonylphenyl)acetamide, 2-(2-chloro-6-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 21: 2-(2- Chloro-4-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chloro-4-fluorophenyl )-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 22: 2-(2-chloro -5-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chloro-5-fluorophenyl) -N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 23: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-pyridine Azol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-pyrazol- 4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 24: 2-(2-chlorophenyl)-N-(4-(((3-fluoro-1-methyl-1H-pyrazole- 5-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-(((3-fluoro-1-methyl-1H- pyrazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 25: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-5-yl )oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-5-yl)oxy )methyl)-3-sulfamoylphenyl)acetamide; Compound 26: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-2-yl)oxy)methyl) -3-Sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-2-yl)oxy)methyl)-3-sulfamoylphenyl )acetamide; Compound 27: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-4-yl)oxy)methyl)-3-sulfamoyl phenyl) acetamide, 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 28: 2 -(2-chlorophenyl)-N-(4-((cyclopropylmethoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N- (4-((cyclopropylmethox y)methyl)-3-sulfamoylphenyl)acetamide; Compound 29: 2-(2-chlorophenyl)-N-(4-((cyclobutylmethoxy)methyl)-3-sulfamoylphenyl)ethyl Amide, 2-(2-chlorophenyl)-N-(4-((cyclobutylmethoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 30: 2-(2-chlorophenyl)-N-(4-((cyclophenyl) Amylmethoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-((cyclopentylmethoxy)methyl)-3-sulfamoylphenyl)acetamide; compound 31: 2-(2-chlorophenyl)-N-(4-(cyclobutoxymethyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-( 4-(cyclobutoxymethyl)-3-sulfamoylphenyl)acetamide; Compound 32: 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-((((tetrahydro-2H-pyran-4 -yl)oxy)methyl)phenyl)acetamide, 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl) phenyl)acetamide; Compound 33: 2-(2-Chlorophenyl)-N-(4-((oxetan-3-ylmethoxy)methyl)-3-sulfamoylphenyl) Acetamide, 2-(2-chlorophenyl)-N-(4-((oxetan-3-ylmethoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 34: 2-(2-chlorophenyl)-N-( 3-sulfamoyl-4-(((tetrahydrofuran-3-yl)methoxy)methyl)phenyl)acetamide, 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-( ((tetrahydrofuran-3-yl)methoxy)methyl)phenyl)acetamide; Compound 35: 2-(2-chlorophenyl)-N-(4-((oxetan-3-yloxy)methyl )-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-((oxetan-3-yloxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 36: N- (4-((Azetidine -3-yloxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide, N-(4-((azetidin-3-yloxy)methyl)- 3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide; Compound 37: 2-(2-chlorophenyl)-N-(4-((pyrrolidin-3-yloxy)methyl)-3-amine sulfonylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-((pyrrolidin-3-yloxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 38: 2-(2-chlorophenyl Base) -N-(4-((piperidin-4-yloxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-( (piperidin-4-yloxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 39: 2-(2-chlorophenyl)-N-(4-((piperidin-3-yloxy)methyl)-3 -sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-((piperidin-3-yloxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 40: 2-(2- Chlorophenyl)-N-(3-sulfamoyl-4-(((((tetrahydro-2H-pyran-3-yl)oxy)methyl)phenyl)acetamide, 2-(2 -chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)phenyl)acetamide; Compound 41: N-(4-(((2-azabicyclo [2.2.1] Heptane-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide, N-(4-((( 2-azabicyclo[2.2.1]heptan-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide; Compound 42: N-(4-(((3-azabicyclo[ 3.1.1] heptane-6-yl) oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl) acetamide, N-(4-(((3 -azabicyclo[3.1.1]heptan-6-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide; Compound 43: N-(4 -(((2-Azabicyclo[2.2.2]oct-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide , N-(4-(((2-azabicyclo[2.2.2]octan-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide; Compound 44: 2-(2- Chlorophenyl)-N-(4-((3-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4- ((3-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 45: N-(4-((3-(aminomethyl)phenoxy)methyl)-3-sulfamoylphenyl) -2-(2-Chlorophenyl)acetamide, N-(4-((3-(aminomethyl)phenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide; Compound 46: 2- (2-Chloro-6-fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2 -(2-chloro-6-fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 47: 2-(2-chloro-5- Fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chloro-5 -fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 48: 2-(2-chloro-4-fluorophenyl)-N- (4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chloro-4-fluorophenyl)-N-( 4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 49: 2-(2-chloro-6-fluorophenyl)-N-(4-((4- cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chloro-6-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl) -3-sulfamoylphenyl)acetamide; Compound 50: 2-(2-chloro-5-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl base) acetamide, 2-(2-chloro-5-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 51: 2-(2-chloro-4- Fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chloro-4-fluorophenyl)-N -(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 52: 2-(2-chloro-3-fluorophenyl)-N-(4-((4-cyanophenoxy )methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chloro-3-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 53: 2-(2-Chloro-6-fluorophenyl)-N-(4-((((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl ) Acetamide, 2-(2-chloro-6-fluorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 54: 2-( 2-Chloro-5-fluorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2- (2-chloro-5-fluorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 55: 2-(2-chloro-4-fluoro Phenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chloro-4- fluorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 56: 2-(2-chlorophenyl)-N-(4-(( (1-Methyl-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl) -N-(4-(((1-methyl-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 57: 2-(2-chlorophenyl)-N-(4- (((1-cyclopropyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4 -(((1-cyclopropyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 58: 2-(2-chlorophenyl)-N-(4-((3-( S-methylsulfonylimido)phenoxy)methyl)-3-aminosulfonylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-((3-( S-methylsulfonimidoyl)phenoxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 59: 2-(2-chlorophenyl)-N-(4-(1-((6-fluoropyridin-3-yl)oxy) Ethyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-(1-((6-fluoropyridin-3-yl)oxy)ethyl)-3- sulfamoylphenyl)acetamide; Compound 60: N-(4-(((4-chloro-1H-pyrazol-3-yl)oxy)methyl)-3sulfamoylphenyl)-2-(2-chloro Phenyl)acetamide, N-(4-(((4-chloro-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide; Compound 61: 2 -(2-Chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl ) Acetamide, 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 62: 2 -(2-chloro-4-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl ) Acetamide, 2-(2-chloro-4-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamo ylphenyl)acetamide; Compound 63: 2-(2-Chlorophenyl)-N-(4-(((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)methyl) -3-aminosulfonylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-(((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)methyl)-3 -sulfamoylphenyl)acetamide; Compound 64: 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl) -3-aminosulfonylphenyl)acetamide, 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl) -3-sulfamoylphenyl)acetamide; Compound 65: 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4-yl) Oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol- 4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 66: 2-(2-chlorophenyl)-N-(4-(((1-(1,1-difluoropropyl)-1H -pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-(((1-(1,1 -difluoropropyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 67: 2-(2-chloro-4-fluorophenyl)-N-(4-(((1- (Difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chloro-4-fluorophenyl)-N- (4-(((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 68: N-(4-(((4-chloro-1-(difluoromethyl) Fluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chloro-4-fluorophenyl)acetamide, N- (4-((((4-chloro-1-(difluoromethyl)- 1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chloro-4-fluorophenyl)acetamide; Compound 69: N-(4-(((4-chloro-1-(di Fluoromethyl)-1H-pyrazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chloro-4-fluorophenyl)acetamide, N- (4-((((4-chloro-1-(difluoromethyl)-1H-pyrazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chloro-4-fluorophenyl)acetamide; Compound 70: N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-( 2-Chloro-5-fluorophenyl)acetamide, N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)- 2-(2-chloro-5-fluorophenyl)acetamide; Compound 72: 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazole-3- base)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 73: 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazole-5- base)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-5- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; Compound 74: 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyridine Azol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-(difluoromethyl )-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide; and compound 75: 2-(2-chloro- 4-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)ethyl Amide, 2-(2-chloro-4-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide.

The present invention provides a method for preparing the above-mentioned compound shown in formula I, which is method one or method two,

。 Method 1 includes the following steps: in a solvent, in the presence of an acid, react the compound shown in formula II with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) to generate the compound shown in formula IV , and then reacting the compound of formula IV with ammonia water to obtain the compound shown in formula I;

.

。 The second method comprises the following steps: reacting the compound shown in formula III and hydrazine hydrate in an organic solvent to obtain the compound shown in formula I;

.

Wherein, R ^3-1 , n, and R ² in formulas I, II, III, and IV are the same or different, and independently have the above-mentioned definitions.

In a certain scheme, in Method 1, the compound represented by formula IV does not need to be separated, and the reaction solution in the previous step is directly reacted with ammonia water. That is to react the compound shown in formula II with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), and then react the reaction solution with ammonia water to obtain the compound shown in formula I compound.

In a certain solution, in Method 1, the solvent may be a conventional solvent in the art, or a nitrile solvent, or a mixed solvent of a nitrile solvent and water, such as a mixed solvent of acetonitrile and water.

In a certain solution, in Method 1, the acid may be a conventional acid in the art, an organic acid, or an organic carboxylic acid, such as acetic acid.

In a certain scheme, in Method 1, the molar ratio of the DCDMH to the compound represented by formula II may be 1:1-5:1, such as 2:1 or 3:1.

In a certain scheme, in method one, the molar ratio of the acid and the compound shown in formula II can be 3:1 to 30:1, such as 5:1, 6:1, 8:1, 13:1, 17:1 or 25:1.

In a certain scheme, in method one, the molar concentration of the compound shown in formula II in the solvent can be 0.01~0.3 mol/L, such as 0.05 mol/L, 0.09 mol/L, 0.1 mol /L, 0.15 mol/L, 0.18 mol/L.

In a certain scheme, in Method 1, the temperature during the reaction with the DCDMH may be 10-40°C.

In a certain scheme, in Method 1, the reaction time with the DCDMH may be 5-120 minutes, such as 10 minutes, 15 minutes, or 60 minutes.

In a certain scheme, in method one, the molar volume ratio of the compound shown in formula II to the ammonia water can be 0.01~0.5 mol/L, such as 0.015 mol/L, 0.02 mol/L, 0.08 mol /L, 0.034 mol/L, 0.2 mol/L, 0.33 mol/L or 0.39 mol/L.

In a certain solution, in Method 1, the temperature when reacting with the ammonia water may be 10-40°C.

In a certain solution, in Method 1, the reaction time with the ammonia water may be 5 to 60 minutes, such as 10 minutes or 30 minutes.

In a certain solution, in Method 1, after reacting with the ammonia water, the subsequent treatment may include the following steps: removing the solvent in the reaction solution, and separating and purifying. The method for removing the solvent in the reaction solution can be a conventional method in the art, such as concentrating under reduced pressure to dryness. The separation and purification method can be a conventional method in the art, such as purification by preparative HPLC.

In a certain solution, in the second method, the organic solvent can be a conventional organic solvent in the art, and can also be an alcohol solvent and/or an ether solvent, such as methanol and/or tetrahydrofuran.

In a certain scheme, in the second method, the molar ratio of the hydrazine hydrate to the compound represented by formula III can be 2:1~8:1, for example 5:1.

In a certain scheme, in the second method, the molar concentration of the compound represented by formula III in the organic solvent may be 0.01-0.3 mol/L, such as 0.06 mol/L.

In a certain scheme, in the second method, the temperature of the reaction may be 10-40°C.

In a certain solution, in the second method, the reaction time may be 0.5-3 hours, such as 1 hour.

In a certain scheme, in the second method, the post-treatment of the reaction may include the following steps: removing the solvent in the reaction solution, and separating and purifying. The method for removing the solvent in the reaction solution can be a conventional method in the art, such as concentrating under reduced pressure to dryness. The separation and purification method can be a conventional method in the art, such as purification by preparative HPLC.

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以及

。 The present invention also provides an intermediate compound as shown in formula II, III or IV, which can be used to prepare the compound shown in formula I:

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as well as

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Wherein, the definitions of R ² , R ^3-1 and n are the same as those described in the previous scheme.

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The present invention provides a pharmaceutical composition, which comprises substance A and at least one pharmaceutical excipient;

The substance A is the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, its Solvates or solvates of pharmaceutically acceptable salts thereof.

In the pharmaceutical composition, the dose of the substance A may be a therapeutically effective amount.

The present invention also provides an application of substance A in the preparation of P2X4 receptor antagonists or medicines;

The substance A is the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, its Solvates or solvates of pharmaceutically acceptable salts thereof.

In a certain aspect, the P2X4 receptor antagonist is used in vitro.

In a certain aspect, the medicament can be used to treat or prevent urinary tract diseases, respiratory diseases, pain-related diseases, autoimmune diseases, inflammatory reactions, sleep disorders, mental diseases, arthritis, Neurodegenerative disease, traumatic brain injury, thrombosis, gastrointestinal disease, sexual dysfunction, cardiovascular system disease, endometriosis, musculoskeletal and connective tissue developmental disorders, cancer, or ophthalmic disease. Said urinary tract disease is for example urinary incontinence, overactive bladder, dysuria or cystitis. The respiratory disease is eg a respiratory disorder, including respiratory failure, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm or cough (eg chronic cough). The pain-related diseases are, for example, inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache, chronic pain or pruritus. The neurodegenerative diseases are for example Alzheimer's disease, Parkinson's disease, epilepsy or cerebral apoplexy. The cardiovascular diseases include myocardial infarction, atherosclerosis, heart failure, hypertension or blood diseases. The digestive tract diseases include colon syndrome, inflammatory bowel disease or gastrointestinal dysfunction. The autoimmune disease is eg arthritis (eg rheumatoid arthritis). The ophthalmic disease is such as dry eye syndrome, dry eye, ophthalmic nerve pain, ocular trauma or postoperative ocular pain.

In a certain aspect, the medicament can be used to prevent or treat diseases in animals (such as humans) that are at least partially mediated by P2X4.

The diseases mediated at least in part by P2X4, such as urinary tract diseases, respiratory diseases, pain-related diseases, autoimmune diseases, inflammatory reactions, sleep disorders, mental diseases, arthritis, neurodegenerative diseases, traumatic brain injury , thrombosis, gastrointestinal disease, sexual dysfunction, cardiovascular system disease, endometriosis, musculoskeletal and connective tissue developmental disorders, cancer, or eye disease. Said urinary tract disease is for example urinary incontinence, overactive bladder, dysuria or cystitis. The respiratory disease is eg a respiratory disorder, including respiratory failure, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm or cough (eg chronic cough). The pain-related diseases are, for example, inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache, chronic pain or pruritus. The neurodegenerative diseases are for example Alzheimer's disease, Parkinson's disease, epilepsy or cerebral apoplexy. The cardiovascular diseases include myocardial infarction, atherosclerosis, heart failure, hypertension or blood diseases. The digestive tract diseases include colon syndrome, inflammatory bowel disease or gastrointestinal dysfunction. The autoimmune disease is eg arthritis (eg rheumatoid arthritis). The ophthalmic disease is, for example, dry eye syndrome, dry eye, ophthalmic nerve pain, ocular trauma or postoperative ocular pain.

The present invention also provides a method of treating or preventing a disease, comprising administering a therapeutically effective amount of Substance A to a patient (e.g., a human being);

The disease is urinary tract disease, respiratory system disease, pain-related disease, autoimmune disease, inflammatory response, sleep disorder, mental disease, arthritis, neurodegenerative disease, traumatic brain injury, thrombosis, digestive tract disease , sexual dysfunction, diseases of the cardiovascular system, endometriosis, disorders of musculoskeletal and connective tissue development, cancer or eye diseases;

The substance A is the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, its Solvates or solvates of pharmaceutically acceptable salts thereof.

In a certain aspect, the urinary tract disorder is eg urinary incontinence, overactive bladder, dysuria or cystitis.

In a certain aspect, the respiratory disease, such as a respiratory disorder, includes respiratory failure, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or cough (eg, chronic cough).

In a certain aspect, the pain-related diseases such as inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache, chronic pain or itching.

In a certain embodiment, said neurodegenerative disease is such as Alzheimer's disease, Parkinson's disease, epilepsy or cerebral apoplexy.

In a certain aspect, the cardiovascular disease is such as myocardial infarction, atherosclerosis, heart failure, hypertension or blood disease.

In a certain aspect, the gastrointestinal disease is eg colon syndrome, inflammatory bowel disease or gastrointestinal disorder. The autoimmune disease is eg arthritis (eg rheumatoid arthritis).

In a certain aspect, the ophthalmic disease is, for example, dry eye syndrome, dry eye, ocular nerve pain, ocular trauma, or postoperative ocular pain.

The present invention also provides a method of treating or preventing a disease mediated at least in part by P2X4, comprising administering to a patient (eg, a human) a therapeutically effective amount of Substance A ;

The substance A is the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, its Solvates or solvates of pharmaceutically acceptable salts thereof.

In a certain aspect, the disease can be urinary tract disease, respiratory disease, pain-related disease, autoimmune disease, inflammatory response, sleep disorder, mental disease, arthritis, neurodegenerative disease, traumatic brain injury , thrombosis, gastrointestinal disease, sexual dysfunction, cardiovascular system disease, endometriosis, musculoskeletal and connective tissue developmental disorders, or cancer.

In a certain aspect, the urinary tract disorder is eg urinary incontinence, overactive bladder, dysuria or cystitis.

In a certain aspect, the respiratory disease, such as a respiratory disorder, includes respiratory failure, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or cough (eg, chronic cough).

In a certain aspect, the pain-related diseases such as inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache, chronic pain or itching.

In a certain embodiment, said neurodegenerative disease is such as Alzheimer's disease, Parkinson's disease, epilepsy or cerebral apoplexy.

In a certain aspect, the cardiovascular disease is such as myocardial infarction, atherosclerosis, heart failure, hypertension or blood disease.

In a certain aspect, the gastrointestinal disease is eg colon syndrome, inflammatory bowel disease or gastrointestinal disorder. The autoimmune disease is eg arthritis (eg rheumatoid arthritis).

In a certain aspect, the ophthalmic disease is, for example, dry eye syndrome, dry eye, ocular nerve pain, ocular trauma, or postoperative ocular pain.

Beneficial effect

The aromatic compound of the present invention has higher P2X4 antagonistic activity, better safety and better pharmacokinetic properties.

Definition and Explanation of Terms

All patents and publications referred to herein are hereby incorporated by reference in their entirety.

General principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito:1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York: 2007 , the entire contents of which are incorporated herein by reference.

Unless otherwise stated, the terms used in the present invention have the following definitions, and the definitions of terms not involved in the following are as commonly understood by those skilled in the art to which the present invention belongs.

Unless otherwise stated, the numerical ranges recorded in the specification and claims are equivalent to at least recording each specific integer value therein. For example, the numerical range "1~20" is equivalent to recording each integer value in the numerical range "1~10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, and the numerical range Each integer value in "11~20" is 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20. It should be understood that among one, two or more used herein when describing substituents, "more" shall refer to an integer ≥ 3, for example: 3, 4, 5, 6, 7, 8, 9 or 10. The term "plurality" refers to an integer ≥ 2, for example: 2, 3, 4 or 5, etc.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, the base addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent. A salt. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium and diethanolamine salts. When the compounds of the present invention contain relatively basic functional groups, acid addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. A salt. The pharmaceutically acceptable acid includes inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid and the like. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (ie 4, 4'-methylene-bis( 3-Hydroxy-2-naphthoic acid)) and amino acids (such as glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

The term "solvate" refers to a compound of the present invention in combination with a stoichiometric or non-stoichiometric solvent. The solvent molecules in a solvate may exist in an ordered or non-ordered arrangement. The solvents include, but are not limited to: water, methanol, and ethanol.

"Pharmaceutically acceptable salt" and "solvate" in the term "solvate of a pharmaceutically acceptable salt" refer to the compound of the present invention in combination with a relatively non-toxic, pharmaceutically acceptable acid or A base prepared by combining stoichiometric or non-stoichiometric solvents.

The term "stereoisomer" refers to isomers caused by the same sequence of interconnection of atoms or atomic groups in a molecule, but different spatial arrangements, such as cis-trans isomers, mirror-image isomers or atropisomers, etc. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be It is obtained by chiral resolution by forming a bond (chemical combination, etc.) or salt formation (physical combination, etc.) with other chiral compounds.

The term "tautomer" refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions. For example, acetone and 1-propen-2-ol can be interconverted by the rapid movement of hydrogen atoms on the oxygen and on the α-carbon.

The term "isotopic compound" refers to a compound in which one or more atoms are replaced by one or more atoms having a specified atomic mass or mass number. Examples of isotopes that may be incorporated into compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ¹⁸ F, ³⁵ S and ³⁶ Cl). The isotopic compounds of the invention can generally be prepared according to the methods described herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The term "crystal form" means that the ions or molecules in it are arranged strictly periodically in three-dimensional space according to a certain way, and have the regularity of periodic recurrence at a certain distance; due to the difference in the above periodic arrangement, there may be multiple crystal forms , that is, polymorphism.

The term "nitrogen oxide" means that when the compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form N-oxide. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids such as peroxycarboxylic acids to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), wherein an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as dichloromethane reaction.

When any variable (such as R ^2-1a ) appears multiple times in the definition of a compound, the definition at each position of the variable has nothing to do with the definitions at other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted by 1, 2 or 3 R ^2-1a groups, that is, the group may be substituted by up to 3 R ^2-1a groups, the definition of R ^2-1a in this position The definitions of R ^2-1a and the rest are independent of each other. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

」是指相應的基團通過該位點與化合物中的其它片段、基團進行連接。 The present invention describes the "

" means that the corresponding group is connected to other fragments and groups in the compound through this site.

In various sections of the invention linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group are to be understood as linking groups. For example, the C ₁ -C ₆ alkyl in the group "halo-C ₁ -C ₆ alkyl" should be understood as C ₁ -C ₆ alkylene.

The abbreviations of any protecting groups, amino acids and other compounds used in the present invention, unless otherwise stated, are based on their commonly used and recognized abbreviations, or refer to the IUPAC-IUB Commission on Biochemical Nomen clature (see Biochem. 1972, 11:942~944).

The term "oxo" means that a carbon atom, a nitrogen atom or a sulfur atom in a substituent is replaced by an oxygen group formed by oxidation (=O).

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "C ₁ -C ₂₀ alkyl" should be understood as a linear or branched saturated hydrocarbon group with 1 to 20 carbon atoms. For example, "C ₁ -C ₆ alkyl" means straight and branched chain alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. Wherein, the alkyl group may be optionally substituted by one or more substituents described in the present invention. In some embodiments, the alkyl group contains 1-12 carbon atoms or 13-20 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; in still other embodiments , the alkyl group contains 1 to 4 carbon atoms. Examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl Base, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2 -Dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers.

The term "C ₁ ~C ₂₀ alkoxy" refers to the group -OC ₁ ~C ₂₀ alkyl, such as C ₁ ~C ₁₂ alkoxy or C ₁₃ ~C ₂₀ alkoxy, preferably C ₁ ~C ₆ alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like base.

The term "C ₃ ~C ₂₀ cycloalkyl" should be understood as meaning a saturated monocyclic, bicyclic hydrocarbon ring or tricyclic hydrocarbon ring, which has 3 to 20 carbon atoms, preferably "C ₃ ~C ₁₂ cycloalkyl", And its bicyclic and tricyclic hydrocarbon rings contain bridged or spirocyclic hydrocarbon rings. The term "C ₃ ~C ₁₂ cycloalkyl" should be understood as meaning a saturated monocyclic, bicyclic hydrocarbon ring or tricyclic hydrocarbon ring, which has 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, and its bicyclic and tricyclic hydrocarbon rings contain bridged or spirocyclic hydrocarbon rings. The C _3-10 cycloalkyl group can be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic Hydrocarbon groups such as decahydronaphthalene rings.

The term "3-20 membered heterocyclic group" should be understood as meaning a saturated monocyclic, bicyclic hydrocarbon ring or tricyclic hydrocarbon ring, which contains 1 to 5, preferably 1 to 3, independently selected from N, O, S and S (=O) ₂ is a non-aromatic cyclic group with a total number of ring atoms of 3-20 (such as 3, 4, 5, 6, 7, 8, 9 or 10, etc.), and Its bicyclic and tricyclic hydrocarbon rings contain bridged or spirocyclic hydrocarbon rings, preferably "3-10 membered heterocyclic group". The term "3-10 membered heterocyclic group" means a saturated monocyclic, bicyclic hydrocarbon ring or tricyclic hydrocarbon ring, which contains 1-5, preferably 1 to 3, independently selected from N, O, S and S (= O) ₂ heteroatoms, such as 1, 2, 3 heteroatoms independently selected from N, O, S and S(=O) ₂ , and its bicyclic and tricyclic hydrocarbon rings contain bridged rings or spirocyclic hydrocarbon rings. More preferably "3-8 membered saturated monocyclic or bicyclic ring system containing 1, 2 or 3 ring heteroatoms independently selected from N, O, S and S(=O) ₂ " or containing 1, 2 A 3-6 membered saturated monocyclic ring having one or three ring heteroatoms independently selected from N, O and S. According to the invention, the heterocyclic group is non-aromatic. When the 3-20 membered heterocyclic group is connected with other groups to form the compound of the present invention, it can be that the carbon atom on the 3-20 membered heterocyclic group is connected with other groups, or it can be a 3-20 membered heterocyclic group The ring heteroatoms are connected to other groups. In particular, the heterocyclic group may include but not limited to: 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl Or a trithianyl group; or a 7-membered ring, such as a diazepanyl group. Optionally, the heterocyclyl group may be benzo-fused. The heterocyclic group can be bicyclic, such as but not limited to 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrole And[1,2-a]pyrazin-2(1H)-yl ring. A ring containing a nitrogen atom may be partially unsaturated, i.e. it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadi azinyl as well as 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, alternatively it may be benzo-fused such as but not limited to dihydroisoquinolinyl.

The term "C ₆ -C ₂₀ aryl" should be understood to mean an aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring with 6-20 carbon atoms, preferably "C ₆ -C ₁₄ aryl". The term "C ₆ ~C ₁₄ aryl" should be understood as preferably representing an aromatic or partially aromatic monocyclic, bicyclic or tricyclic group having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Cyclohydrocarbon rings (“C ₆ ~C ₁₄ aryl”), especially rings with 6 carbon atoms (“C ₆ aryl”), such as phenyl or biphenyl, or rings with 9 carbon atoms ("C ₉ aryl") such as indanyl or indenyl, or a ring having 10 carbon atoms ("C ₁₀ aryl") such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or is a ring having 13 carbon atoms (“C ₁₃ aryl”), such as fluorenyl, or a ring having 14 carbon atoms (“C ₁₄ aryl”), such as anthracenyl. When the C ₆ -C ₂₀ aryl is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution site, for example, it may be an ortho, para or meta substitution.

The term "5-20 membered heteroaryl" should be understood to include aromatic or partially aromatic monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 members independently selected from Heteroatoms of N, O and S, such as "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5, 6, 9 or 10 carbon atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S. And, additionally in each case may be benzo-fused. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, Diazolyl, thia-4H-pyrazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo Triazolyl, indazolyl, indolyl and isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, etc., and their benzo derivatives, such as quinoline base, quinazolinyl and isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxa Linyl, naphthyridinyl, pteridinyl, oxazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl, etc. Examples of heteroaryl include, but are not limited to, furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl , triazolyl, tetrazolyl, thiazolyl, isothiazolyl and thiadiazolyl, etc. When the 5-20 membered heteroaryl group is connected with other groups to form the compound of the present invention, it can be that the carbon atom on the 5-20 membered heteroaryl ring is connected with other groups, or it can be 5-20 membered heteroaryl group. Heteroatoms on the aryl ring are attached to other groups. When the 5-20 membered heteroaryl is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution site, for example, the hydrogen connected to the carbon atom on the heteroaryl ring may be replaced, or the hydrogen connected to the heteroatom on the heteroaryl ring may be replaced.

Unless stated otherwise, a heterocyclyl, heteroaryl or heteroarylene group includes all possible isomeric forms thereof, eg positional isomers thereof. Thus, for some illustrative non-limiting examples, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12 One, two or more positions in the - position (if present) are substituted or bonded to other groups, including pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, Pyridin-3-yl, pyridin-4-yl and pyridin-4-yl; thienyl or thienylene includes thiophen-2-yl, thiophen-2-yl, thiophen-3-yl and thiophen-3 -yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl.

The term "pharmaceutical excipients" refers to the excipients and additives used in the production of drugs and the preparation of prescriptions, and refers to all substances contained in pharmaceutical preparations except active ingredients. See Pharmacopoeia of the People's Republic of China (2015 Edition) Four Volumes or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

The term "treatment" refers to therapeutic therapy. In relation to a specific condition, treatment means: (1) amelioration of one or more biological manifestations of a disease or condition, (2) interference with (a) one or more points in a biological cascade leading to or causing a condition or (b) a condition (3) ameliorating one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing down the disorder or the effects of the disorder One or more biological manifestations develop.

The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

The term "therapeutically effective amount" refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by those skilled in the art.

The term "patient" refers to any animal that is about to or has received the administration of the compound or composition according to the embodiments of the present invention, preferably a mammal, and most preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being most preferred.

The biological activity of the compounds of the invention can be assessed by using any conventionally known method. Suitable detection methods are well known in the art. For example, the P2X4 inhibitory activity, pharmacokinetic activity and/or hepatic microsomal stability of the compounds of the present invention can be tested by appropriate conventional methods. The detection method provided in the present invention is presented as an example only and does not limit the present invention. Compounds of the invention are active in at least one assay provided herein.

Unless otherwise specified, "room temperature" in the present invention refers to 10-40°C. "min" means minutes. "h" refers to hours.

On the basis of conforming to common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.

Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available, or can be prepared by known methods, the experimental methods that do not indicate specific conditions in the following examples, according to conventional methods and conditions, or according to the product instructions choose.

The abbreviations of the Examples of the present invention are as follows: ACN: Acetonitrile AIBN: Azobisisobutyronitrile (2,2'-Azobis(2-methylpropionitrile)) Boc ₂ O: Di-tert-butyl dicarbonate ( Di-tert-butyl dicarbonate) B ₂ pin ₂ : Bis(pinacolato)diboron CAN: Ceric ammonium nitrate DIAD: Diisopropyl azodiformate Dioxane : 1,4-Dioxane DCM: Methylene chloride DIEA: N,N-Diisopropylethylamine (N,N-Diisopropylethylamine) DCDMH: 1,3-Dichloro-5,5- Dimethylhydantoin (1,3-Dichloro-5,5-dimethylhydantoin) DME: Ethylene glycol dimethyl ether (1,2-dimethoxy-ethan) DMF: N,N-dimethylformamide (N, N-Dimethylformamide) DMF-DMA: N,N-Dimethylformamide dimethyl acetal (N,N-Dimethylformamide dimethyl acetal) DMSO: Dimethyl sulfoxide (Dimethyl sulfoxide) EA: Ethyl acetate (ethyl acetate) FA: Formic acid (Formic acid) HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate, (2-( 7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) NBS: N-bromosuccinimide (N-Bromosuccinimide) NCS: N- Chlorobutanediamide PPh ₃ : Triphenylphosphine (triphenylphosphine) Pd ₂ (dba) ₃ : Tris(dibenzylideneacetone) dipalladium (Tris(dibenzylideneacetone)dipalladium) Pd(dppf)Cl ₂ : 1, 1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PMBNH ₂ : 4-Methoxybenzylamine THF: Tetrahydrofuran (Tetrahydrofuran) Tween80: Tween 80 T ₃ P: Propyl Propyl phosphate tricyclic anhydride solution TEA: Triethylamine TFA: Trifluoroacetic acid t-BuOK: Potassium tert-butoxide t-Bu ₃ P: Trifluoroacetic acid Tert-butylphosphine (Tri-tert-butylphosphine) Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene PE/EA: Petroleum ether/ethyl acetate LAH: Lithium aluminum hydride (Lithium Aluminum Hydride).

Comparative example 1

。 Compound D1: Preparation of 2-(2-chlorophenyl)-N-{4-[(4-cyanobenzyl)oxy]-3-sulfamoylphenyl}acetamide

.

。 synthetic route:

.

Step (1) Preparation of intermediate D1-IN-01

Dissolve the weighed intermediate D1-SM-01 (2.0 g, 9.012 mmol) in 150 mL THF, add intermediate D1-SM-02 (1.0 g, 7.51 mmol) and PPh ₃ (4.0 g, 15.02 mmol ), cooled to 0 ℃ after adding, added DIAD (4.5 g, 22.53 mmol) dropwise, and naturally cooled down to room temperature for 3 hours after adding, added water to the reaction solution, extracted with EA, washed the organic phase with saturated brine, and added sodium sulfate After drying, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE/EA=4/1) to obtain 2.0 g of intermediate D1-IN-01 as a white solid.

Step (2) Preparation of intermediate D1-IN-02

Dissolve the weighed intermediate D1-IN-01 (2.0 g, 6.003 mmol) in 80 mL of ethanol and 20 mL of water, add iron powder (1.7 g, 30.017 mmol) and ammonium chloride (1.6 g, 30.017 mmol) , reacted at 80 °C for 2 hours after the addition was completed, and the product was formed. The reaction solution was cooled to room temperature, quenched with saturated sodium bicarbonate solution and adjusted to pH 8.0~10.0, extracted with EA, and the organic phase was washed with saturated brine, sodium sulfate After drying, the reaction solution was concentrated under reduced pressure to obtain 1.7 g of the intermediate D1-IN-02 product as a pale yellow solid. LC-MS: [M+H] ⁺ =305.

Step (3) Preparation of intermediate D1-IN-03

Dissolve the weighed intermediate D1-IN-02 (1.7 g, 5.608 mmol) in 80 mL DCM, add 2-chlorophenylacetic acid (intermediate 1-3) (1.15 g, 6.729 mmol), T ₃ P (7.1 g, 11.216 mmol) and TEA (1.7 g, 16.824 mmol), after the addition was completed and reacted at room temperature for 1 h, the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography (PE/EA=3/1 ) was purified to obtain 2.4 g of the intermediate D1-IN-03 product as a pale yellow solid.

Step (4) Preparation of intermediate D1-IN-04

The weighed intermediate D1-IN-03 (1.2 g, 2.633 mmol) was dissolved in 1,4-dioxane (40 mL), and intermediate 1-9 (benzylthiol) (655 mg, 5.266 mmol), Pd ₂ (dba) ₃ (240 mg, 0.263 mmol), Xantphos (153 mg, 0.263 mmol) and DIEA (982 mg, 7.899 mmol), after addition, react overnight under nitrogen protection at 100 ℃ , the reaction solution was lowered to room temperature and added water, extracted with EA, the organic phase was washed with saturated brine, dried over sodium sulfate, and the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography (PE/EA = 3/ 1 ~ 1/1) to obtain 900 mg of intermediate D1-IN-04 as a pale yellow solid. LC-MS: [M+H] ⁺ =499.10.

Step (5) Preparation of compound D1

Intermediate D1-IN-04 (900 mg, 1.803 mmol), dissolved in CH ₃ CN (40 mL), AcOH (5 mL) and H ₂ O (5 mL), was added to Intermediate 1-11 (DCDMH) (711 mg, 3.607 mmol), react at room temperature for 10 minutes, add the reaction solution into ammonia (10 mL) under stirring, and then stir at room temperature for 10 minutes, add water to the reaction solution, extract with EA, combine organic phase, washed with saturated brine and dried over anhydrous sodium sulfate, the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified by Prep-HPLC to obtain 365.3 mg of compound D1 as a white solid. LC-MS: [M+H] ⁺ =456.10.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 8.07 (d, J = 2.6 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.70 (dd, J = 8.5, 4.6 Hz, 3H), 7.42 (ddd, J = 11.2, 5.8, 3.7 Hz, 2H), 7.35 – 7.26 (m, 2H), 7.22 – 7.08 (m, 3H), 5.42 (s, 2H), 3.80 (s, 2H).

Comparative example 2

。 Compound D2: Preparation of 2-(2-chlorophenyl)-N-(4-((4-fluorobenzyl)oxy)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of intermediate D2-IN-01

Dissolve the weighed intermediate D1-SM-01 (1.04 g, 4.757 mmol) in 75 mL THF, add intermediate D2-SM-01 (500 mg, 3.964 mmol) and PPh ₃ (2.08 g, 7.928 mmol ), cooled to 0 ℃ after adding, added dropwise DIAD (2.4 g, 11.892 mmol), reacted at room temperature for 3 hours after adding, added water to the reaction solution, extracted with EA, washed the organic phase with saturated brine, and dried with sodium sulfate , the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE/EA=20:1) to obtain 1.1 g of intermediate D2-IN-01 as a light yellow solid.

Step (2) Preparation of intermediate D2-IN-02

Dissolve the weighed intermediate D2-IN-01 (1.1 g, 3.373 mmol) in 40 mL of ethanol and 10 mL of water, add iron powder (945 mg, 16.865 mmol) and ammonium chloride (902 mg, 16.865 mmol) , reacted at 80 °C for 2 hours, a product was formed, the reaction solution was cooled to room temperature, quenched with saturated sodium bicarbonate solution and adjusted to pH 8.0~10.0, extracted with EA, washed with saturated brine, dried over sodium sulfate, Concentration under reduced pressure gave 1.0 g of the intermediate D2-IN-02 product as a pale yellow solid.

Step (3) Preparation of intermediate D2-IN-03

Dissolve the weighed intermediate D2-IN-02 (1.0 g, 3.377 mmol) in 40 mL of DCM, add 2-chlorophenylacetic acid (692 g, 4.052 mmol), T ₃ P (4.3 g, 6.754 mmol) and TEA (1.03 g, 10.131 mmol), after the addition was completed and reacted at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE/EA=4/1~3/1) to obtain Intermediate D2-IN-03 product 900 mg as light yellow solid.

Step (4) Preparation of intermediate D2-IN-04

The weighed intermediate D2-IN-03 (900 mg, 2.202 mmol) was dissolved in 1,4-dioxane (30 mL), and intermediate 1-9 (benzylthiol) (547 mg, 4.404 mmol), Pd ₂ (dba) ₃ (201 mg, 0.221 mmol), Xantphos (128 mg, 0.221 mmol) and DIEA (854 mg, 6.606 mmol), add nitrogen protection and react overnight at 100 ℃, the reaction The solution was lowered to room temperature and added with water, extracted with EA, the organic phase was washed with saturated brine, dried over sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography (PE/EA = 4/1 ~ 1/1 ) purification to obtain 700 mg of the intermediate D2-IN-04 product as a pale yellow solid.

Step (5) Preparation of compound D2

Intermediate D2-IN-04 (700 mg, 1.422 mmol), dissolved in CH ₃ CN (40 mL), AcOH (5 mL) and H ₂ O (5 mL), was added to Intermediate 1-11 (DCDMH) (561 mg, 2.845 mmol), react at room temperature for 10 minutes, add the reaction solution into ammonia water (10 mL) under stirring, and then stir at room temperature for 10 minutes, add water to the reaction solution, extract with EA, and combine the organic phases , washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by Prep-HPLC to obtain 256.6 mg of compound D2 as a white solid. LC-MS: [M+H] ⁺ =449.00.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.30 (s, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.70 (dd, J = 9.0, 2.7 Hz, 1H), 7.60 – 7.52 ( m, 2H), 7.47 – 7.36 (m, 2H), 7.35 – 7.27 (m, 2H), 7.24 – 7.13 (m, 3H), 7.09 (s, 2H), 5.30 (s, 2H), 3.80 (s, 2H).

Example 1

。 Compound 1: Preparation of N-(4-((3-acetylphenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 1-2

Intermediate 1-1 (10 g, 0.038 mol), iron powder (11 g, 0.196 mol) and NH ₄ Cl (20 g, 0.38 mol) were dissolved in ethanol/water (100 mL/20 mL) and heated to The reaction was stirred at 70°C for 2 hours. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase with EA twice, combine the EA phase, and concentrate the reaction solution under reduced pressure to obtain a crude product, which is subjected to silica gel column chromatography (PE /EA=10:1-5:1) to obtain intermediate 1-2. LC-MS: [M+H] ⁺ =230.

Step (2) Preparation of Intermediates 1-4

Intermediate 1-2 (9 g, 0.039 mol), Intermediate 1-3 (2-chlorophenylacetic acid) (8 g, 0.0468 mol), TEA (12 g, 0.117 mol) and T ₃ P (25 g, 0.078 mol) was dissolved in DCM (90 mL), stirred at room temperature for 0.5 hours. Add water and DCM to the reaction solution, stir well and separate the DCM phase, extract the water phase twice with DCM, combine the DCM phases, dry, and concentrate under reduced pressure to obtain the product. LC-MS: [M+H] ⁺ =382.

Step (3) Preparation of Intermediates 1-5

Intermediate 1-4 (14 g, 0.037 mol) was dissolved in THF (100 mL) and the temperature was lowered to 0 °C. LiAlH ₄ (4.22 g, 0.111 mol) was stirred at room temperature for 10 minutes. After treatment, add 1 ml of water and 3 mL of 2 M NaOH aqueous solution to the reaction solution, add a large amount of EA, then filter, and concentrate the filtrate under reduced pressure to obtain the product. LC-MS: [M+H] ⁺ =354.

Step (4) Preparation of Intermediates 1-6

Intermediate 1-5 (10 g, 0.028 mol) was dissolved in DCM (100 mL) and cooled to 0 °C, SOCl ₂ (6.61 g, 0.056 mol) was added thereto, warmed to room temperature, and stirred for 1 hour . After treatment, the reaction solution was concentrated under reduced pressure to obtain intermediate 1-6 (8.1 g). LC-MS: [M+H] ⁺ =372.

Step (5) Preparation of Intermediates 1-8

Intermediate 1-6 (500 mg, 1.34 mmol), Intermediate 1-7 (182 mg, 1.34 mmol) and K ₂ CO ₃ (370 mg, 2.68 mmol) were dissolved in DMF (5 mL), room temperature Stir for 1 hour. Add water (50 mL) to the reaction solution and extract it twice with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product, the crude product The intermediate 1-8 (385 mg, yield 60.9%) was purified by silica gel column chromatography ((PE/EA = 4/1 ~ 1/1)). LC-MS: [M+H] ⁺ =472.

Step (6) Preparation of Intermediates 1-10

Intermediate 1-8 (385 mg, 0.82 mmol), Intermediate 1-9 (303 mg, 2.45 mmol), Pd ₂ (dba) ₃ (116 mg, 0.164 mmol), Xantphos (94 mg, 0.164 mmol) and DIEA (316 mg, 2.449 mmol) was dissolved in 1,4-dioxane (5 mL), reacted at 115 °C for 16 hours, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 1-10 (340 mg, yield 80.4%). LC-MS: [M+H] ⁺ =516.

Step (7) Preparation of compound 1

Intermediate 1-10 (340 mg, 0.6 mmol) and Intermediate 1-11 (DCDMH) (238 mg, 1.2 mmol) were dissolved in CH ₃ CN (4 mL), AcOH (0.2 mL) and H ₂ O (0.1 mL), reacted at room temperature for 1 hour to obtain intermediate 1-12, TLC showed that the reaction was complete, the reaction solution was not separated, the above reaction solution was directly added dropwise to ammonia water (10 mL) under stirring, and then the room The mixture was stirred warmly for 0.5 hours, and TLC showed that the reaction was complete. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and compound 1 (2.5 mg) was obtained after lyophilization. LC-MS: [M+H] ⁺ =473.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.56 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.5, 2.2 Hz, 1H), 7.66 – 7.52 ( m, 5H), 7.48 – 7.38 (m, 3H), 7.34 – 7.24 (m, 3H), 5.47 (s, 2H), 3.84 (s, 2H), 2.54 (s, 3H).

Intermediate 1-12 LC-MS: [M+H] ⁺ =492.

In the following examples, the acyl chloride intermediates similar to intermediates 1-12 were not separated, and directly reacted with ammonia.

Example 2

。 Compound 2: Preparation of 2-(2-chlorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 2-2

Dissolve Intermediate 1-6 (600 mg, 1.69 mmol), Intermediate 2-1 (228 mg, 2.03 mmol) and K ₂ CO ₃ (467 mg, 3.384 mmol) in DMF (15 mL), at 60 °C Stir for 1 hour. After adding water (50 mL) to the reaction solution, extract it twice with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine in turn, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to perform PE column chromatography on silica gel. /EA=10/1) was purified to obtain intermediate 2-2 (360 mg, as pale yellow solid).

Step (3) Preparation of Intermediates 2-4

Intermediate 2-2 (360 mg, 0.802 mmol), Intermediate 1-9 (benzylthiol) (150 mg, 1.203 mmol), Pd ₂ (dba) ₃ (74 mg, 0.08 mmol), Xantphos (47 mg , 0.08 mmol) and DIEA (312 mg, 2.407 mmol) were dissolved in 1,4-dioxane (10 mL), reacted overnight at 100 °C under nitrogen protection, added water to the reaction solution, extracted with EA, and the organic phase Wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the reaction solution under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (PE/EA = 10/1 ~ 5/1) to obtain intermediate 2-4 (340 mg, as a yellow solid).

Step (4) Preparation of Compound 2

Intermediate 2-4 (340 mg, 0.691 mmol) and intermediate 1-11 (DCDMH) (409 mg, 2.073 mmol) were dissolved in CH ₃ CN (8 mL), AcOH (1 mL) and H ₂ O (1 mL), reacted at room temperature for 0.5 hours. Add the reaction solution dropwise to ammonia water (2 mL) under stirring, and stir at room temperature for 10 minutes, add water to the reaction solution, extract with EA, combine the organic phases, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and reduce Concentrate under reduced pressure to obtain a crude product, which is purified by Prep-HPLC to obtain compound 2 (29 mg, as a white solid). LC-MS: [M+H] ⁺ =449.05.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.58 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.81 (dd, J = 8.5, 2.2 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.58 (s, 2H), 7.46 – 7.41 (m, 2H), 7.33 – 7.29 (m, 2H), 7.16 – 7.11 (m, 2H), 7.05 – 7.01 (m, 2H) , 5.40 (s, 2H), 3.86 (s, 2H).

Example 2-1

。 Compound 2-1: Preparation of 2-(2-chlorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediates 2-8

Intermediate 2-7 (8 g, 33.9 mmol) was added into aqueous ammonia (100 mL) and THF (20 mL), and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain Intermediate 2-8 (11.0 g, white solid).

Step (2) Preparation of Intermediates 2-9

Intermediate 2-8 (11 g, 50.9 mmol) and DMF-DMA (30.3 g, 254 mmol) were dissolved in DMF (150 mL), and reacted at room temperature for 1 hour. After dilution with H ₂ O (200 mL). Extract twice with EA (100 mL). The EA phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2-9 (10.0 g, red solid). LC-MS: [M+H] ⁺ =272.05.

¹ H NMR (400 MHz, DMSO- d ₆ ) 8.09 (s, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.61 (dd, J = 8.0 , 2.4 Hz, 1H), 5.28 (s, 2H), 3.12 (s, 3H), 2.92 (s, 3H), 2.35 (s, 3H).

Step (3) Preparation of Intermediates 2-10

Intermediate 2-9 (9 g, 33.2 mmol), iron powder (18.5 g, 332 mmol) and NH ₄ Cl (26.6 g, 498 mmol) were dissolved in EtOH (120 mL) and water (24 mL), 60 ℃ for 1 hour, the ethanol in the reaction solution was spin-dried, filtered, water (200 mL) was added to the filtrate, extracted twice with EA (80 mL), the organic phase was washed twice with saturated brine, and dried over anhydrous sodium sulfate. , filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2-10 (6.20 g, purity 98.9%, yellow solid). LC-MS: [M+H] ⁺ =242.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (s, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.61 (dd, J = 8.0, 2.4 Hz, 1H), 5.28 (s, 2H), 3.12 (s, 3H), 2.92 (s, 3H), 2.35 (s, 3H).

Step (4) Preparation of intermediate 2-11

Intermediate 2-10 (5.5 g, 22.8 mmol), Boc ₂ O (7.45 g, 34.2 mmol) and DIEA (5.89 g, 45.6 mmol) were dissolved in DMF (51.5 mL), and reacted at 60°C for 12 hours. The reaction was cooled to room temperature, diluted with H ₂ O (100 mL) and extracted three times with EA (30 mL). The EA phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE/EA = 10/1-2/1) to obtain intermediate Compound 2-11 (3.60 g, purity 86.7%, white solid). LC-MS: [M+H] ⁺ =342.1.

¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.12 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 8.4, 2.0 Hz, 1H), 7.19 ( d, J = 8.4 Hz, 1H), 3.15 (s, 3H), 3.03 (t, J = 2.0 Hz, 3H), 2.56 (s, 3H), 1.50 (s, 9H).

Step (5) Preparation of Intermediates 2-12

Intermediate 2-11 (1.30 g, 3.81 mmol), AIBN (0.187 g, 1.14 mmol) and NBS (0.881 g, 4.95 mmol) were added to CCl ₄ (51.5 mL), reacted at 75 °C for 2 hours, and detected the reaction by LCMS complete. The reaction was cooled to room temperature, and the reaction solution was added dropwise to a solution containing intermediate 2-1 (4-fluorophenol) (0.133 g, 1.19 mmol), K ₂ CO ₃ (0.411 g, 2.97 mmol) and DMF (6 mL) in the system. The reaction was carried out at room temperature for 2 hours, and LCMS showed that the reaction was complete. Add H ₂ O (100 mL) to the reaction solution to dilute, then add DCM (30 mL) to extract twice, combine the organic phase, wash the organic phase twice with saturated brine, dry over anhydrous sodium sulfate, filter, and the filtrate The crude product was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (PE/EA = 10/1-5/1) to obtain intermediate 2-12 (150 mg, 80% purity, yellow solid). LC-MS: [M+H] ⁺ =452.1.

¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) 8.13 (d, J = 7.2 Hz, 2H), 7.54 (d, J = 2.4 Hz, 2H), 7.02 – 6.94 (m, 4H), 5.47 (s , 2H), 3.09 (s, 3H), 2.99 (s, 3H), 1.52 (s, 9H).

Step (6) Preparation of Intermediates 2-13

Intermediate 2-12 (150 mg, 332 μmol) was added to HCl·EA (4 M, 2 mL), reacted at room temperature for 2 hours, LCMS detection was completed, and the reaction solution was concentrated under reduced pressure to obtain intermediate 2-13 (90.0 mg, 85.5% purity, red solid). LC-MS: [M+H] ⁺ =352.1.

Step (7) Preparation of Intermediates 2-14

Intermediate 1-3 (2-chlorophenylacetic acid) (48.1 mg, 281 μmol), HATU (146 mg, 384 μmol) and DIEA (99.3 mg, 768 μmol) were added to DMF (2.5 mL) and reacted at room temperature After 0.5 h, Intermediate 2-13 (90.0 mg, 256 μmol) was added to the reaction. React at room temperature for 12 hours. Add H ₂ O (10 mL) to the reaction solution to dilute, then add EA (5 mL) to extract twice, wash the organic phase twice with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude The product, crude product was purified by preparative thin-layer chromatography (PE/EA = 1/1) to afford intermediate 2-14 (30.0 mg, 85.0% purity, yellow solid). LC-MS: [M+H] ⁺ =504.1.

¹ H NMR (400 MHz, CD ₃ OD- d ₄ ) 8.05 (s, 1H), 7.92 (dd, J = 8.4, 2.0 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.60 (d , J = 8.4 Hz, 1H), 7.47 – 7.38 (m, 3H), 7.32 – 7.29 (m, 2H), 6.95 – 6.86 (m, 4H), 5.53 (s, 2H), 3.87 (s, 2H), 3.04 (s, 3H), 2.96 (s, 3H).

Step (8) Preparation of Compound 2

Intermediate 2-14 (30.0 mg, 59.5 μmol) and hydrazine hydrate (15.0 mg, 298 μmol) were added to MeOH (0.5 mL) and THF (0.5 mL) solvent, reacted at 27 °C for 1 hour, and the reaction solution was reduced to The crude product was concentrated under reduced pressure to obtain a crude product, which was separated by prep-HPLC using FA.H ₂ O/ACN system, and the preparation solution was lyophilized to obtain compound 2 (11.4 mg, 99.8% purity, white powder). LC-MS: [M+H] ⁺ =449.05.

¹ H NMR (400 MHz, DMSO- d ₆ ) 10.59 (s, 1H), 8.46 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H ), 7.60 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.44 – 7.38 (m, 2H), 7.29 (dd, J = 5.6, 3.2 Hz, 2H), 7.11 (dd, J = 12.0, 5.6 Hz, 2H), 7.03 – 6.98 (m, 2H), 5.38 (s, 2H), 3.84 (s, 2H).

Example 3

。 Compound 3: 2-(2-Chlorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 3-2

Intermediate 1-5 (500 mg, 1.41 mmol) was dissolved in THF (4 mL), and intermediate 3-1 (162 mg, 1.41 mmol) and t-BuOK (317.9 mg, 2.82 mmol) were added at room temperature Stir for 1 hour. The reaction was stopped, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=10:1~1:1) to obtain intermediate 3-2 (145 mg, yield 33.4%, shallow yellow solid). LC-MS: [M+H] ⁺ =489.

Step (2) Preparation of Intermediate 3-3

Intermediate 3-2 (87 mg, 0.193 mmol), Intermediate 1-9 (benzylthiol) (71.6 mg, 0.578 mmol), Pd ₂ (dba) ₃ (27.4 mg, 0.0386 mmol), Xantphos (22 mg , 0.0386 mmol) and DIEA (74.5 mg, 0.578 mol) were dissolved in 1,4-dioxane (5 mL), and reacted at 115 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 3-3 (50 mg, yield 52.9%, yellow solid). LC-MS: [M+H] ⁺ =492.

Step (3) Preparation of compound 3

Intermediate 3-3 (50 mg, 0.102 mmol) and intermediate 1-11 (DCDMH) (40 mg, 0.204 mmol) were dissolved in CH ₃ CN (2 mL), AcOH (0.1 mL) and H ₂ O (0.1 mL), react at room temperature for 1 hour. The reaction solution was added dropwise to ammonia water (5 mL) under stirring, and then stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and compound 3 (12.4 mg, purity 99.745%, white solid) was obtained after lyophilization. LC-MS: [M+H] ⁺ =450.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.55 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 3.1 Hz, 1H), 7.79 (dd, J = 8.5, 2.0 Hz, 1H), 7.72 (ddd, J = 9.0, 8.1, 3.1 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.45 – 7.38 (m, 2H ), 7.33 – 7.25 (m, 2H), 7.01 (dd, J = 9.1, 3.6 Hz, 1H), 5.64 (s, 2H), 3.84 (s, 2H).

Example 4

。 Compound 4: N-(4-((4-chlorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 4-2

Intermediate 1-6 (500 mg, 1.34 mmol), Intermediate 4-1 (170 mg, 1.3 mmol) and K ₂ CO ₃ (358 mg, 2.6 mmol) were dissolved in DMF (10 mL), at 60 °C Stir for 1 hour. Add water (50 mL) to the reaction solution, extract it twice with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Purified by silica gel column chromatography to obtain intermediate 4-2 (280 mg, yield 46.3%, yellow solid). LC-MS: [M+H] ⁺ =465.

Step (2) Preparation of Intermediate 4-3

Intermediate 4-2 (280 mg, 0.6 mmol), Intermediate 1-9 (benzylthiol) (148.8 mg, 1.2 mmol), Pd ₂ (dba) ₃ (85.3 mg, 0.12 mmol), Xantphos (70 mg , 0.12 mmol) and DIEA (232.2 mg, 1.8 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 115 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 4-3 (230 mg, yield 75.7%, yellow solid). LC-MS: [M+H] ⁺ =508.

Step (3) Preparation of Compound 4

Intermediate 4-3 (230 mg, 0.45 mmol) and Intermediate 1-11 (DCDMH) (196 mg, 0.9 mmol) were dissolved in CH ₃ CN (4 mL), AcOH (0.2 mL) and H ₂ O (0.2 mL), react at room temperature for 1 hour. The reaction solution was added dropwise to ammonia water (10 mL) under stirring, and stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and compound 4 (24.8 mg, purity 95.2%, white solid) was obtained after lyophilization. LC-MS: [M+H] ⁺ =465.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.56 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.79 (dd, J = 8.4, 2.2 Hz, 1H), 7.64 – 7.51 ( m, 3H), 7.46 – 7.36 (m, 2H), 7.36 – 7.18 (m, 4H), 7.09 – 6.97 (m, 2H), 5.40 (s, 2H), 3.84 (s, 2H).

Example 5

。 Compound 5: 2-(2-chlorophenyl)-N-(4-((2,4-dichlorophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Compound 5

Intermediate 4-3 (230 mg, 0.45 mmol) and intermediate 1-11 (DCDMH) (196 mg, 0.9 mmol) were dissolved in CH ₃ CN (4 mL), AcOH (0.2 mL) and H ₂ O (0.2 mL), react at room temperature for 1 hour. The reaction solution was added dropwise to ammonia water (10 mL) under stirring, and stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and compound 5 (50 mg, purity 99.7%, white solid) was obtained after lyophilization. LC-MS: [M+H] ⁺ =499.

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.59 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 7.81 (dd, J = 8.4, 2.2 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 2.6 Hz, 1H), 7.58 (s, 2H), 7.46 – 7.35 (m, 3H), 7.33 – 7.25 (m, 2H), 7.17 (d, J = 9.0 Hz, 1H), 5.49 (s, 2H), 3.85 (s, 2H).

Example 6

。 Compound 6: Preparation of 2-(2-chlorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 6-2

Intermediate 1-6 (600 mg, 1.62 mmol), Intermediate 6-1 (280 mg, 1.95 mmol) and K ₂ CO ₃ (447 mg, 3.24 mmol) were dissolved in DMF (10 mL) and heated to 60 °C and stirred React for 3 hours. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA three times, combine the EA phase, concentrate the EA phase under reduced pressure to obtain the product, the reaction is successful, and the intermediate 6-2 is obtained. LC-MS: [M+H] ⁺ =455/457.

Step (2) Preparation of Intermediate 6-3

Intermediate 6-2 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (10 mL), under nitrogen protection, and stirred at 110 ℃ overnight. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase with EA twice, combine the EA phase, and concentrate under reduced pressure to obtain a crude product, which is subjected to silica gel column chromatography (PE/ EA=10:1-6:1) Separation and purification, and concentration under reduced pressure to pass through the column liquid to obtain intermediate 6-3. LC-MS: [M+H] ⁺ =499/501.

Step (3) Preparation of compound 6

Intermediate 6-3 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4 mL/0.4 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol) was added to it. The reaction was stirred at room temperature for 15 minutes. Then, the reaction solution was added dropwise into stirred aqueous ammonia (20 mg, 1.20 mmol), and stirred at room temperature for 10 minutes. After treatment, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by prep-HPLC using H ₂ O/ACN system, and the preparation was lyophilized to obtain compound 6. LC-MS: [M+H] ⁺ =456/458.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.57 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.82 – 7.76 (m, 3H), 7.59 (d, J = 6.7 Hz, 3H), 7.44 – 7.38 (m, 2H), 7.32 – 7.25 (m, 2H), 7.19 – 7.14 (m, 2H), 5.49 (s, 2H), 3.84 (s, 2H).

Example 7

。 Compound 7: Preparation of 2-(2-chlorophenyl)-N-(4-((2,4-difluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 7-2

Dissolve Intermediate 1-6 (600 mg, 1.62 mmol), Intermediate 7-1 (223 mg, 1.60 mmol) and K ₂ CO ₃ (440 mg, 3.20 mmol) in DMF (10 mL), at 60 °C Stir for 1 hour. Add water (50 mL) to the reaction solution, then extract it twice with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then perform silica gel column chromatography ( PE/EA=4/1) to obtain intermediate 7-2. LC-MS: [M+H] ⁺ =465.

Step (3) Preparation of Intermediate 7-3

Intermediate 7-2 (520 mg, 1.1 mmol), Intermediate 1-9 (benzylthiol) (276 mg, 2.2 mmol), Pd ₂ (dba) ₃ (156.4 mg, 0.22 mmol), Xantphos (115.6 mg , 0.22 mmol) and DIEA (424 mg, 3.3 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 115 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 7-3. LC-MS: [M+H] ⁺ =510.

Step (4) Preparation of Compound 7

Intermediate 7-3 (384 mg, 0.75 mmol) and Intermediate 1-11 (DCDMH) (297 mg, 1.5 mmol) were dissolved in CH ₃ CN (4 mL), AcOH (0.2 mL) and H ₂ O (0.2 mL), react at room temperature for 1 hour. The reaction solution was added dropwise to ammonia water (10 mL) under stirring, and stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and compound 7 was obtained after lyophilization. LC-MS: [M+H] ⁺ =467.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.57 (s, 1H), 8.27 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.55 (s, 2H), 7.46 – 7.38 (m, 2H), 7.37 – 7.26 (m, 3H), 7.18 (td, J = 9.4, 5.5 Hz, 1H), 7.01 (t, J = 8.8 Hz, 1H), 5.45 (s, 2H), 3.85 (s, 2H).

Example 8

。 Compound 8: 2-(2-chlorophenyl)-N-(4-(((4,5-dichloro-1-methyl-1H-pyrazol-3-yl)oxy)methyl)-3 - Preparation of sulfamoylphenyl) acetamide

.

。 synthetic route:

.

Step 1: Preparation of Intermediate 8-2

Dissolve the weighed intermediate 1-6 (500 mg, 1.34 mmol) in THF (20 mL), add intermediate 8-1 (160 mg, 1.608 mmol) and Ag ₂ CO ₃ (740 mg, 2.68 mmol ), and reflux at 70 °C overnight. LCMS monitoring showed that there was product formation, the reaction solution was added with water and extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine in turn, dried over anhydrous sodium sulfate, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was passed through a silica gel tube column layer The intermediate 8-2 was purified by analysis (PE/EA=5/1~2/1). LC-MS: [M+H] ⁺ =434.

Step 2: Preparation of Intermediate 8-3

Dissolve the weighed intermediate 8-2 (310 mg, 0.713 mmol) in 1,4-dioxane (10 mL), add intermediate 1-9 (benzylthiol) (178 mg, 1.423 mmol ), Pd ₂ (dba) ₃ (66 mg, 0.071 mmol), Xantphos (42 mg, 0.071 mmol) and DIEA (277 mg, 2.139 mmol), react overnight at 100 °C under nitrogen protection, add water to the reaction solution, and use EA was extracted, the organic phase was washed with saturated brine, dried over sodium sulfate, and the reaction liquid was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE/EA = 2/1) to obtain intermediate 8-3. LC-MS: [M+Na] ⁺ =500.15.

Step 3: Preparation of Compound 8

Intermediate 8-3 (60 mg, 0.125 mmol) was dissolved in CH ₃ CN (2 mL), AcOH (0.25 mL) and H ₂ O (0.25 mL), and Intermediate 1-11 (DCDMH) (50 mg , 0.251 mmol), react at room temperature for 5 minutes, add the reaction solution dropwise to ammonia water (0.5 mL) under stirring, add water to the reaction solution, extract with EA, combine the organic phases, wash with saturated brine, anhydrous sulfuric acid After sodium drying, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by Prep-HPLC to obtain compound 8. LC-MS: [M+H] ⁺ =503.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.66 (s, 1H), 8.31 (d, J = 2.1 Hz, 1H), 7.88 (dd, J = 8.4, 2.2 Hz, 1H), 7.64 – 7.55 ( m, 3H), 7.44 (ddd, J = 9.5, 5.1, 2.3 Hz, 2H), 7.35 – 7.29 (m, 2H), 5.66 (s, 2H), 3.88 (s, 2H), 3.25 (s, 3H) .

Example 9

。 Compound 9: Preparation of 2-(2-chlorophenyl)-N-(4-((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 9-2

Intermediate 1-6 (600 mg, 1.62 mmol), Intermediate 9-1 (280 mg, 1.95 mmol) and K ₂ CO ₃ (447 mg, 3.24 mmol) were dissolved in DMF (10 mL) and heated to 60 °C The reaction was stirred for 3 hours. After treatment, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA for 3 times, combine the EA phases, and concentrate the EA phases under reduced pressure to obtain the intermediate 9-2. LC-MS: [M+H] ⁺ =449.

Step (2) Preparation of Intermediate 9-3

Intermediate 9-2 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (10 mL), under nitrogen protection, and stirred at 110 ℃ overnight. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase twice with EA, combine the EA phase, and concentrate the reaction solution under reduced pressure to obtain a crude product, which is subjected to silica gel column chromatography (PE /EA=10:1-6:1) Separation and purification, and concentration under reduced pressure to obtain a crude product, which was subjected to preparative silica gel column chromatography to obtain intermediate 9-3. LC-MS: [M+H] ⁺ =493.

Step (3) Preparation of Intermediate 9-4

Intermediate 9-3 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4 mL/0.4 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol) was added to it. The reaction was stirred at room temperature for 15 minutes. The reaction solution was added dropwise into stirred aqueous ammonia (20 mg, 1.20 mmol), and stirred at room temperature for 10 minutes. After treatment, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by prep-HPLC, and the preparation was lyophilized to obtain compound 9. LC-MS: [M+H] ⁺ =450.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.57 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.95 (dd, J = 3.0, 1.8 Hz, 1H), 7.82 (dd, J = 8.5, 2.2 Hz, 1H), 7.68 – 7.60 (m, 2H), 7.58 (s, 2H), 7.47 – 7.36 (m, 2H), 7.35 – 7.25 (m, 2H), 7.14 (dd, J = 8.9, 3.4 Hz, 1H), 5.45 (s, 2H), 3.84 (s, 2H).

Example 10

。 Compound 10: Preparation of 2-(2-chlorophenyl)-N-(4-((3-cyano-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 10-2

Dissolve Intermediate 1-6 (600 mg, 1.62 mmol), Intermediate 10-1 (220 mg, 1.6 mmol) and K ₂ CO ₃ (440 mg, 3.2 mmol) in DMF (10 mL), at 60 °C Stir for 1 hour. Add water (50 mL) to the reaction solution, extract it twice with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Silica gel column chromatography yielded intermediate 10-2. LC-MS: [M+H] ⁺ =473.

Step (2) Preparation of Intermediate 10-3

Intermediate 10-2 (450 mg, 0.95 mmol), Intermediate 1-9 (benzylthiol) (235 mg, 1.9 mmol), Pd ₂ (dba) ₃ (90 mg, 0.1 mmol), Xantphos (60 mg , 0.1 mmol) and DIEA (367 mg, 2.85 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 115 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 10-3. LC-MS: [M+H] ⁺ =517.

Step (4) Preparation of Compound 10

Intermediate 10-3 (200 mg, 0.38 mmol) and Intermediate 1-11 (DCDMH) (190 mg, 0.96 mmol) were dissolved in CH ₃ CN (4 mL), AcOH (0.2 mL) and H ₂ O (0.2 mL), react at room temperature for 1 hour, add the reaction solution dropwise into ammonia water (10 mL) under stirring, and then stir at room temperature for 0.5 hour. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and compound 10 was obtained after lyophilization. LC-MS: [M+H] ⁺ =474.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.58 (s, 1H), 8.26 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.67 – 7.52 (m, 4H), 7.45 ( dt, J = 14.2, 8.4 Hz, 4H), 7.33 – 7.25 (m, 2H), 5.42 (s, 2H), 3.85 (s, 2H).

Example 11

。 Compound 11: Preparation of N-(4-((3-chloro-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 11-2

Intermediate 1-6 (600 mg, 1.62 mmol), Intermediate 11-1 (280 mg, 1.95 mmol) and K ₂ CO ₃ (447 mg, 3.24 mmol) were dissolved in DMF and heated to 60°C and stirred for 3 hours. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA three times, combine the EA phases, and concentrate the EA phases under reduced pressure to obtain the intermediate 11-2. LC-MS: [M+H] ⁺ =482.

Step (2) Preparation of Intermediate 11-3

Intermediate 11-2 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (10 mL), under nitrogen protection, and stirred at 110 °C overnight. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase with EA twice, combine the EA phases, concentrate under reduced pressure to obtain the crude product, the crude product is prepared by silica gel column chromatography (PE/ EA=10:1-6:1) separation and purification to obtain the column solution, and the column solution was concentrated under reduced pressure to obtain intermediate 11-3 (yellow solid product 290 mg). LC-MS: [M+H] ⁺ =526.

Step (3) Preparation of Compound 11

Intermediate 11-3 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4 mL/0.4 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol) was added to it. The reaction was stirred at room temperature for 15 minutes. The reaction solution was added dropwise into stirred aqueous ammonia (20 mg, 1.20 mmol), and stirred at room temperature for 10 minutes. After treatment, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative high-performance liquid chromatography, and the preparative solution was lyophilized to obtain compound 11. LC-MS: [M+H] ⁺ =483.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.56 (s, 1H), 8.25 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H) , 7.58 (s, 2H), 7.46 – 7.23 (m, 6H), 7.05 – 6.97 (m, 1H), 5.39 (s, 2H), 3.84 (s, 2H).

Example 12

。 Compound 12: Preparation of 2-(2-chlorophenyl)-N-(4-((3-(methylsulfonyl)phenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 12-2

Intermediate 1-6 (200 mg, 0.54 mmol), Intermediate 12-1 (100 mg, 0.58 mmol) and K ₂ CO ₃ (152 mg, 1.1 mmol) were dissolved in DMF (4 mL), room temperature Stir for 2 hours. Add water (20 mL) to the reaction solution, extract it twice with ethyl acetate (10 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then purify it by silica gel column chromatography Intermediate 12-2 was obtained. LC-MS: [M+H] ⁺ =508.

Step (2) Preparation of Intermediate 12-3

Intermediate 12-2 (180 mg, 0.35 mmol), Intermediate 1-9 (benzylthiol) (130 mg, 1.05 mmol), Pd ₂ (dba) ₃ (32 mg, 0.035 mmol), Xantphos (20 mg , 0.035 mmol) and DIEA (135 mg, 1.05 mmol) were dissolved in 1,4-dioxane (2 mL) and reacted at 115 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 12-3. LC-MS: [M+H] ⁺ =552.

Step (3) Preparation of Compound 12

Intermediate 12-3 (150 mg, 0.27 mmol) and Intermediate 1-11 (DCDMH) (108 mg, 0.54 mmol) were dissolved in CH ₃ CN (4 mL), AcOH (0.2 mL) and H ₂ O (0.1 mL), react at room temperature for 1 hour. The reaction solution was added dropwise to ammonia water (5 mL) under stirring, and stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and compound 12 was obtained after lyophilization. LC-MS: [M+H] ⁺ =509.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.58 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 8.4, 2.2 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 3.8 Hz, 2H), 7.56 – 7.53 (m, 1H), 7.53 – 7.49 (m, 1H), 7.46 – 7.38 (m, 2H), 7.35 (ddd , J = 8.2, 2.4, 1.0 Hz, 1H), 7.30 (ddd, J = 5.2, 4.2, 3.0 Hz, 2H), 5.49 (s, 2H), 3.85 (s, 2H), 3.21 (s, 3H).

Example 13

。 Compound 13: 2-(2-chlorophenyl)-N-(4-(((1,1-dioxotetrahydrothiophen-3-yl)oxy)methyl)-3-sulfamoylphenyl ) Preparation of acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =473.0

Example 14

。 Compound 14: 2-(2-Chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 14-2

Dissolve Intermediate 1-6 (400 mg, 1.07 mmol), Intermediate 14-1 (113.2 mg, 1.29 mmol) and K ₂ CO ₃ (295.3 mg, 2.14 mmol) in DMF (5 mL), at 60 °C Stir for 1 hour. Add water (50 mL) to the reaction solution, extract it twice with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then purify it by silica gel column chromatography Intermediate 14-2 was obtained. LC-MS: [M+H] ⁺ =423.

Step (2) Preparation of Intermediate 14-3

Intermediate 14-2 (70 mg, 0.115 mmol), Intermediate 1-9 (benzylthiol) (61.4 mg, 0.495 mmol), Pd ₂ (dba) ₃ (23.4 mg, 0.033 mmol), Xantphos (19 mg, 0.033 mmol) and DIEA (63.8 mg, 0.495 mmol) were dissolved in 1,4-dioxane (5 ml) and reacted at 115 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 14-3. LC-MS: [M+H] ⁺ =468.

Step (3) Preparation of Compound 14

Intermediate 14-3 (50 mg, 0.107 mmol) and Intermediate 1-11 (DCDMH) (42.1 mg, 0.214 mmol) were dissolved in CH ₃ CN (2 mL), AcOH (0.1 mL) and H ₂ O (0.1 mL), react at room temperature for 1 hour. The reaction solution was added dropwise to ammonia water (5 mL) under stirring, and stirred at room temperature for 0.5 hour. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and compound 14 was obtained after lyophilization of the preparation. LC-MS: [M+H] ⁺ =424.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.64 (s, 2H), 8.38 (s, 8H), 8.24 (s, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.69 – 7.29 ( m, 8H), 7.28 (s, 1H), 5.45 (s, 2H), 5.19 (s, 2H), 3.90 (s, 3H), 3.85 (s, 5H), 4.40 – 2.48 (m, 55H), 2.48 (s, 10H), 2.48 (s, 13H), 2.15 (dt, J = 14.4, 8.2 Hz, 2H), 1.97 (dd, J = 12.6, 6.2 Hz, 14H), , 3.80 – 3.69 (m, 5H) , 2.20 – 2.11 (m, 2H).

Example 15

。 Compound 15: Preparation of N-(4-((3-acetyl-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 15-2

Intermediate 1-6 (376 mg, 1.04 mmol), Intermediate 15-1 (160 mg, 1.04 mmol) and K ₂ CO ₃ (287 mg, 2.08 mmol) were dissolved in DMF (5 mL), at 60 °C Stir for 1 hour. Add water (50 mL) to the reaction solution, extract it twice with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then purify it by silica gel column chromatography Intermediate 15-2 was obtained. LC-MS: [M+H] ⁺ =490.

Step (2) Preparation of Intermediate 15-3

Intermediate 15-2 (87 mg, 0.18 mmol), Intermediate 1-9 (benzylthiol) (43.4 mg, 0.35 mmol), Pd ₂ (dba) ₃ (24.9 mg, 0.035 mmol), Xantphos (20.2 mg , 0.035 mmol) and DIEA (69.7 mg, 0.54 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 115 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 15-3. LC-MS: [M+H] ⁺ =534.

Step (3) Preparation of Intermediate 15

Intermediate 15-3 (80 mg, 0.15 mmol) and Intermediate 1-11 (59 mg, 0.3 mmol) were dissolved in CH ₃ CN (2 mL), AcOH (0.1 mL) and H ₂ O (0.1 mL), React at room temperature for 1 hour. The reaction solution was added dropwise to ammonia water (10 mL) under stirring, and stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and compound 15 was obtained after lyophilization of the preparation. LC-MS: [M+H] ⁺ =491.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.57 (s, 1H), 8.25 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 8.4, 2.2 Hz, 1H), 7.63 (d, J = 8.5 Hz, 3H), 7.57 (s, 1H), 7.47 – 7.39 (m, 1H), 7.38 – 7.35 (m, 0H), 7.33 – 7.24 (m, 2H), 5.42 (s, 2H), 3.84 (s, 2H), 2.55 (d, J = 4.3 Hz, 3H).

Example 16

。 Compound 16: Preparation of 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-((p-methylphenoxy)methyl)phenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 16-2

Dissolve Intermediate 1-6 (500 mg, 1.34 mmol), Intermediate 16-1 (140 mg, 1.34 mmol) and K ₂ CO ₃ (358 mg, 2.59 mmol) in DMF (10 mL), at 60 °C Stir for 1 hour. Add water (50 mL) to the reaction solution, extract it twice with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then purify it by silica gel column chromatography Intermediate 16-2 was obtained. LC-MS: [M+H] ⁺ =444.

Step (2) Preparation of Intermediate 16-3

Intermediate 16-2 (280 mg, 0.63 mmol), Intermediate 1-9 (benzylthiol) (150 mg, 1.26 mmol), Pd ₂ (dba) ₃ (120 mg, 0.18 mmol), Xantphos (105 mg , 0.18 mmol) and DIEA (240 mg, 1.88 mmol) were dissolved in 1,4-dioxane (4 mL) and reacted at 110 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 16-3. LC-MS: [M+H] ⁺ =488.

Step (4) Compound 16

Intermediate 16-3 (180 mg, 0.37 mmol) and Intermediate 1-11 (145 mg, 0.74 mmol) were dissolved in CH ₃ CN (4 mL), AcOH (0.2 ml) and H ₂ O (0.2 ml), React at room temperature for 1 hour. The reaction solution was added dropwise to ammonia water (10 mL) under stirring, and stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/CAN system, and compound 16 was obtained after lyophilization of the preparation. LC-MS: [M+H] ⁺ =445.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.54 (s, 1H), 8.25 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H) , 7.55 (s, 2H), 7.45 – 7.38 (m, 2H), 7.33 – 7.26 (m, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.38 (s, 2H), 3.84 (s, 2H), 2.21 (s, 3H).

Example 17

。 Compound 17: Preparation of 2-(2-chlorophenyl)-N-(4-((4-fluoro-3-methylphenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 17-2

Intermediate 17-1 (203 mg, 1.608 mmol) and K ₂ CO ₃ (369 mg, 2.68 mmol) were dissolved in DMF (20 mL), stirred at room temperature for 15 minutes, and intermediate 1-6 (500 mg, 1.34 mmol), and reacted at room temperature for 2 hours. Add water to the reaction solution and extract it twice with ethyl acetate, combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then go through silica gel column chromatography (PE/EA=10/1) Purification affords intermediate 17-2. LC-MS: [M+H] ⁺ =462.

Step (2) Preparation of Intermediate 17-3

Dissolve the weighed intermediate 17-2 (180 mg, 0.389 mmol) in 1,4-dioxane (5 mL), add intermediate 1-9 (benzylthiol) (73 mg, 0.583 mmol ), Pd ₂ (dba) ₃ (36 mg, 0.039 mmol), Xantphos (23 mg, 0.039 mmol) and DIEA (151 mg, 1.167 mmol), react overnight at 90 °C under nitrogen protection, add water to the reaction solution, and use EA extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE/EA = 10/1 ~ 5/1) to obtain intermediate Object 17-3. LC-MS: [M+H] ⁺ =506.

Step (3) Preparation of compound 17

Intermediate 17-3 (170 mg, 0.336 mmol) was dissolved in CH ₃ CN (4 mL), AcOH (0.5 mL) and H ₂ O (0.5 mL), and Intermediate 1-11 (DCDMH) (133 mg , 0.672 mmol), reacted at room temperature for 0.5 hours. Add the reaction solution dropwise to ammonia water (1 mL) under stirring and stir at room temperature for 10 minutes, add water to the reaction solution, extract with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure A crude product was obtained from the reaction solution, and the crude product was purified by Prep-HPLC to obtain compound 17. LC-MS: [M+H] ⁺ =463.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.59 (s, 1H), 8.29 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H) , 7.59 (d, J = 4.8 Hz, 2H), 7.47 – 7.28 (m, 5H), 7.22 – 6.98 (m, 2H), 5.47 (d, J = 8.3 Hz, 2H), 3.87 (s, 2H), 2.31 (d, J = 16.0 Hz, 1H), 2.21 (s, 2H).

Example 18

。 Compound 18: 2-(2-chlorophenyl)-N-(4-((4-fluoro-3-methoxyphenoxy)methyl)-3-sulfamoylphenyl)acetamide preparation

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 18-2

Intermediate 1-6 (600 mg, 1.62 mmol), Intermediate 18-1 (280 mg, 1.95 mmol) and K ₂ CO ₃ (447 mg, 3.24 mmol) were dissolved in DMF (10 mL) and heated to 60 °C The reaction was stirred for 3 hours. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA for 3 times, and combine the EA phases to obtain the intermediate 18-2. LC-MS: [M+H] ⁺ =478.

Step (2) Preparation of Intermediate 18-3

Intermediate 18-2 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (10 mL), under nitrogen protection, and stirred at 110 °C overnight. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase with EA twice, combine the EA phase, and concentrate the reaction solution under reduced pressure to obtain the crude product, which is subjected to silica gel column chromatography ( PE/EA=10:1-6:1) to purify and concentrate under reduced pressure to get the intermediate product 18-3. LC-MS: [M+H] ⁺ =522.

Step (3) Preparation of compound 18

Intermediate 18-3 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4 mL/0.4 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol) was added to it. The reaction was stirred at room temperature for 15 minutes. Then the reaction solution was added dropwise into stirred ammonia water (1 mL), and stirred at room temperature for 10 minutes. For post-processing, the reaction liquid was concentrated under reduced pressure, purified by prep-HPLC, and the preparation was lyophilized to obtain compound 18. LC-MS: [M+H] ⁺ =479.1.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.57 (s, 1H), 8.28 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 7.0 Hz, 3H) , 7.48 – 7.38 (m, 3H), 7.33 – 7.26 (m, 2H), 6.95 (d, J = 7.9 Hz, 1H), 5.51 (s, 2H), 3.84 (s, 2H), 3.77 (s, 3H ).

Example 19

。 Compound 19: 2-(2-chlorophenyl)-N-(4-((4-fluoro-3-(2-oxopyrrolidin-1-yl)phenoxy)methyl)-3-sulfamic acid Acyl phenyl) acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =532.1.

Example 20

。 Compound 20: Preparation of 2-(2-chloro-6-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 20-2

Intermediate 1-2 (500 mg, 2.18 mmol) was dissolved in DCM (5 mL), and Intermediate 20-1 (411.8 mg, 2.18 mmol), T ₃ P (2.08 g, 327 mmol) and Et ₃ N were added (662 mg, 6.54 mmol), after reacting at room temperature for 1 hour, the reaction solution was added with water (50 mL) and extracted twice with ethyl acetate (20 mL), the organic phases were combined, washed successively with saturated brine, and dried over anhydrous sodium sulfate , filtered, and the filtrate was concentrated under reduced pressure and passed through the column (PE:EA=5:1~2:1) to obtain the intermediate 20-2. LC-MS: [M+H] ⁺ =400.

Step (3) Preparation of Intermediate 20-3

Intermediate 20-2 (640 mg, 1.6 mmol) was dissolved in THF (6 ml), LiAlH ₄ (182 mg, 4.8 mmol) was added, and stirred at room temperature for 1 hour. Add H ₂ O (1 mL), NaOH solution (1 mL), filter with suction, and concentrate under reduced pressure to obtain intermediate 20-3. Not processed directly for the next step.

Step (4) Preparation of Intermediate 20-4

Intermediate 20-3 (610 mg, 1.64 mmol) was dissolved in DCM (5 mL), and SOCl ₂ (391 mg, 3.29 mmol) was added dropwise and stirred at room temperature for 1 hour. The reaction was stopped, and the reaction solution was concentrated and then purified by silica gel column chromatography (PE:EA=10:1~5:1) to obtain intermediate 20-4. LC-MS: [M+H] ⁺ =390.

Step (5) Preparation of Intermediate 20-5

Intermediate 20-4 (352 mg, 0.9 mmol), Intermediate 2-1 (121 mg, 1.08 mmol) and K ₂ CO ₃ (248.4 mg, 1.8 mmol) were dissolved in DMF (5 mL), room temperature Stir for 1 hour. Add water (50 mL) to the reaction solution, then extract it twice with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then perform silica gel column chromatography ( PE:EA=10:1~5:1) to obtain intermediate 20-5. LC-MS: [M+H] ⁺ =466.

Step (6) Preparation of Intermediate 20-6

Intermediate 20-5 (335 mg, 0.72 mmol), Intermediate 1-9 (benzylthiol) (267 mg, 2.15 mmol), Pd ₂ (dba) ₃ (102.4 mg, 0.144 mmol), Xantphos (83.2 mg , 0.144 mmol) and DIEA (277.4 mg, 2.15 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 115 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 20-6. LC-MS: [M+H] ⁺ =510.

Step (7) Preparation of Compound 20

Intermediate 20-6 (200 mg, 0.39 mmol) and Intermediate 1-11 (138.8 mg, 0.705 mmol) were dissolved in CH ₃ CN (4 mL), AcOH (0.2 mL) and H ₂ O (0.1 mL), React at room temperature for 5 minutes. The reaction solution was added dropwise to ammonia water (5 mL) under stirring, and stirred at room temperature for 0.5 hour. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and compound 20 was obtained after lyophilization. LC-MS: [M+H] ⁺ =467.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.64 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.77 (dd, J = 8.5, 2.2 Hz, 1H), 7.64 – 7.51 ( m, 3H), 7.40 – 7.30 (m, 2H), 7.23 (s, 1H), 7.12 (t, J = 8.8 Hz, 2H), 7.05 – 6.97 (m, 2H), 5.39 (s, 2H), 3.89 (d, J = 1.1 Hz, 2H).

Example 21

。 Compound 21: Preparation of 2-(2-chloro-4-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 21-2

The weighed intermediate 1-2 (2.0 g, 8.693 mmol) was dissolved in DCM (50 mL), and intermediate 21-1 (2-chloro-4-fluorophenylacetic acid) (2.0 g, 10.432 mmol) was added , T ₃ P (11 g, 17.386 mmol) and TEA (2.6 g, 26.079 mmol), reacted at room temperature for 1 hour, and concentrated the reaction solution under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography (PE/EA =4/1) Purification gave intermediate 21-2. LC-MS: [M+H] ⁺ =400.

Step (2) Preparation of Intermediate 21-3

Dissolve the weighed intermediate 21-2 (2.2 g, 5.491 mmol) in THF (50 mL), slowly add lithium aluminum hydride (627 mg, 16.474 mmol) under stirring, and react at room temperature for 10 minutes. TLC showed that a small amount of raw materials did not react completely, adding 1.0 eq lithium aluminum tetrahydrogen had no effect, adding 1 mL of water and 1 mL of 1.0M NaOH solution to the reaction solution, and adding 200 mL of ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product , the crude product was purified by silica gel column chromatography (PE/EA=3/1) to obtain intermediate 21-3. LC-MS: [M+H] ⁺ =372.

Step (3) Preparation of Intermediate 21-4

The weighed intermediate 21-3 (1.0 g, 2.684 mmol) was dissolved in DCM (40 mL), and SOCl ₂ (639 mg, 5.367 mmol) was added dropwise, and stirred at room temperature for 1 hour. The reaction was stopped, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE/EA=10/1) to obtain intermediate 21-4. LC-MS: [M+H] ⁺ =390.

Step (4) Preparation of Intermediate 21-5

Dissolve the weighed intermediate 21-4 (800 mg, 2.046 mmol) in DMF (20 mL), add intermediate 2-1 (4-fluorophenol) (276 mg, 2.455 mmol) and K ₂ CO ₃ (565 mg, 4.092 mmol), react at room temperature for 2 hours after addition. Add water (50 mL) to the reaction solution, extract it twice with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. The reaction solution is concentrated under reduced pressure to obtain a crude product, which is passed through a silica gel column Purification by chromatography (PE/EA=8/1) gave intermediate 21-5. LC-MS: [M+H] ⁺ =466.

Step (5) Preparation of Intermediate 21-6

Dissolve the weighed intermediate 21-5 (850 mg, 1.821 mmol) in 30 mL 1,4-dioxane, add intermediate 1-9 (benzylthiol) (453 mg, 3.643 mmol), Pd ₂ (dba) ₃ (166 mg, 0.182 mmol), Xantphos (105 mg, 0.182 mmol) and DIEA (709 mg, 5.463 mmol) were reacted overnight at 100 °C under nitrogen protection, and the reaction solution was added with water and used EA was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE/EA = 5/1) to obtain intermediate 21-6. LC-MS: [M+H] ⁺ =510.

Step (6) Preparation of Compound 21

The weighed intermediate 21-6 (400 mg, 0.784 mmol) was dissolved in CH ₃ CN (10 mL), and intermediate 1-11 (DCDMH) (232 mg, 1.176 mmol), AcOH (1 mL) and H ₂ O (1 mL), react at room temperature for 5 minutes, add the reaction solution to ammonia water (2 mL), add water to the reaction solution, extract with EA, combine the organic phases, wash with saturated brine, anhydrous sulfuric acid After sodium drying, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by Prep-HPLC to obtain compound 21. LC-MS: [M+H]+=467.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.56 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.5, 2.2 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.57 (s, 2H), 7.46 (ddd, J = 11.5, 8.7, 4.5 Hz, 2H), 7.21 (td, J = 8.5, 2.7 Hz, 1H), 7.18 – 7.09 (m , 2H), 7.06 – 6.99 (m, 2H), 5.40 (s, 2H), 3.85 (s, 2H).

Example 22

。 Compound 22: Preparation of 2-(2-chloro-5-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 22-2

Intermediate 1-2 (9 g, 0.039 mol), Intermediate 22-1 (2-chloro-5 fluorophenylacetic acid) (8 g, 0.0468 mol), TEA (12 g, 0.117 mol) and T ₃ P( 25 g, 0.078 mol) was dissolved in DCM (90 mL), stirred at room temperature for 0.5 hours. Add water and DCM to the reaction solution, stir well, separate the DCM phase, extract the water phase with DCM twice, combine the DCM phases, filter, and concentrate the filtrate under reduced pressure to obtain the intermediate 22-2. LC-MS: [M+H] ⁺ =400.

Step (2) Preparation of Intermediate 22-3

Intermediate 22-2 (14 g, 0.037 mol) was dissolved in THF (100 mL) and the temperature was lowered to 0 °C, LiAlH ₄ (4.22 g, 0.111 mol) was added thereto, and the reaction was stirred at room temperature for 10 minutes. For post-processing, 1 mL of water and 3 mL of 2M NaOH aqueous solution were added to the reaction solution, and a large amount of EA was added, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 22-3. LC-MS: [M+H] ⁺ =372.

Step (3) Preparation of Intermediate 22-4

Intermediate 22-3 (10 g, 0.028 mol) was dissolved in DCM (100 mL) and cooled to 0 °C, SOCl ₂ (6.61 g, 0.056 mol) was added thereto, raised to room temperature and stirred for 1 hour. For post-processing, the reaction solution was concentrated under reduced pressure to obtain the intermediate 22-4. LC-MS: [M+H] ⁺ =390.

Step (4) Preparation of Intermediate 22-5

Intermediate 22-4 (600 mg, 1.62 mmol), Intermediate 2-1 (280 mg, 1.95 mmol) and K ₂ CO ₃ (447 mg, 3.24 mmol) were dissolved in DMF (10 mL) and heated to 60 °C The reaction was stirred for 3 hours. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA three times, combine the EA phases, and concentrate the EA phases under reduced pressure to obtain the intermediate 22-5. LC-MS: [M+H] ⁺ =466.

Step (5) Preparation of Intermediate 22-6

Intermediate 22-5 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (10 mL), under nitrogen protection, then stirred at 110 ℃ overnight. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase with EA twice, combine the EA phase, concentrate the EA phase under reduced pressure to obtain the crude product, and the crude product is subjected to silica gel column chromatography (PE /EA=10:1-6:1) for purification, the column solution was concentrated under reduced pressure to obtain the intermediate 20-6. LC-MS: [M+H] ⁺ =510.

Step (6) Preparation of compound 22

Intermediate 20-6 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4mL/0.4mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol ) into it. The reaction was stirred at room temperature for 15 minutes. The reaction solution was added dropwise into stirred aqueous ammonia (20 mg, 1.20 mmol), and stirred at room temperature for 10 minutes. For post-treatment, the reaction liquid was concentrated under reduced pressure, purified by Prep-HPLC, and the preparation was lyophilized to obtain compound 22. LC-MS: [M+H] ⁺ =467.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.57 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.56 (s, 2H), 7.48 (dd, J = 8.8, 5.3 Hz, 1H), 7.33 (dd, J = 9.5, 3.1 Hz, 1H), 7.20 – 7.07 (m, 3H ), 7.04 – 6.96 (m, 2H), 5.39 (s, 2H), 3.86 (s, 2H).

Example 23

。 Compound 23: 2-(2-Chlorophenyl)-N-(4-((((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl base) preparation of acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 23-2

Dissolve the weighed intermediate 1-6 (500 mg, 1.34 mmol) in DMF (10 mL), add intermediate 23-1 (158 mg, 1.608 mmol) and K ₂ CO ₃ (370 mg, 2.68 mmol ), and reacted at room temperature for 2 hours. Add water to the reaction solution and extract it twice with ethyl acetate, combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure before going through silica gel column chromatography (PE/EA=3/1) Purification affords intermediate 23-2. LC-MS: [M+H] ⁺ =434.

Step (2) Preparation of Intermediate 23-3

Dissolve the weighed intermediate 23-2 (400 mg, 0.920 mmol) in 1,4-dioxane (20 mL), add intermediate 1-9 (benzylthiol) (229 mg, 1.840 mmol ), Pd ₂ (dba) ₃ (85 mg, 0.092 mmol), Xantphos (54 mg, 0.092 mmol) and DIEA (357 mg, 2.76 mmol), react overnight at 100 °C under nitrogen protection, add water to the reaction solution, and use EA extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE/EA = 3/1 ~ 1/1), Intermediate 23-3 was obtained. LC-MS: [M+H] ⁺ =478.

Step (3) Preparation of compound 23

Intermediate 23-3 (370 mg, 0.774 mmol) was dissolved in CH ₃ CN (16 mL), AcOH (2 mL) and H ₂ O (2 mL), and Intermediate 1-11 (DCDMH) (305 mg , 1.548 mmol), reacted at room temperature for 10 minutes, then added the reaction solution dropwise into aqueous ammonia (4 mL) under stirring, stirred at room temperature for 10 minutes, added water to the reaction solution, extracted with EA, combined the organic phases, and used After washing with saturated brine, drying over anhydrous sodium sulfate, concentration under reduced pressure and purification by Prep-HPLC to obtain compound 23. LC-MS: [M+H] ⁺ =435.15.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.57 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.82 (dd, J = 8.5, 2.2 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.50 (s, 2H), 7.47 – 7.38 (m, 3H), 7.35 – 7.28 (m, 2H), 7.22 (s, 1H), 5.26 (s, 2H), 3.86 (s , 2H), 3.72 (s, 3H).

Example 24

。 Compound 24: 2-(2-chlorophenyl)-N-(4-(((3-fluoro-1-methyl-1H-pyrazol-5-yl)oxy)methyl)-3-sulfamic acid Preparation of Acylphenyl) Acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =453.1.

Example 25

。 Compound 25: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)ethyl Preparation of amides

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =435.1.

Example 26

。 Compound 26: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-2-yl)oxy)methyl)-3-sulfamoylphenyl) Preparation of acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ = 435.1.

Example 27

。 Compound 27: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-4-yl)oxy)methyl)-3-sulfamoylphenyl) Preparation of acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =435.1.

Example 28

。 Compound 28: Preparation of 2-(2-chlorophenyl)-N-(4-((cyclopropylmethoxy)methyl)-3-sulfamoylphenyl)acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =409.1.

Example 29

。 Compound 29: Preparation of 2-(2-chlorophenyl)-N-(4-((cyclobutylmethoxy)methyl)-3-sulfamoylphenyl)acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =423.1.

Example 30

。 Compound 30: Preparation of 2-(2-chlorophenyl)-N-(4-((cyclopentylmethoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 30-2

Dissolve the weighed intermediate 1-6 (700 mg, 1.876 mmol) in 20 mL of DMF, add potassium carbonate (777 mg, 5.629 mmol) and intermediate 30-1 (376 mg, 3.753 mmol), and add React at room temperature for 2 hours, add water to the reaction solution, extract with EA, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate the reaction solution under reduced pressure, and then purify by silica gel column chromatography (PE/EA=10/1) Intermediate 30-2 was obtained. LC-MS: [M+H] ⁺ =436.

Step (2) Preparation of Intermediate 30-3

Dissolve the weighed intermediate 30-2 (170 mg, 0.389 mmol) in 1,4-dioxane (10 mL), add intermediate 1-9 (benzylthiol) (73 mg, 0.584 mmol ), Pd ₂ (dba) ₃ (36 mg, 0.039 mmol), Xantphos (23 mg, 0.039 mmol) and DIEA (152 mg, 1.17 mmol), react overnight at 100 °C under nitrogen protection, add water to the reaction solution, and use EA was extracted, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. The reaction solution was concentrated under reduced pressure and purified by Prep-TLC (PE/EA = 5/1) to obtain intermediate 30-3. LC-MS: [M+H] ⁺ =480.

Step (3) Preparation of Compound 30

Intermediate 30-3 (100 mg, 0.208 mmol) was dissolved in CH ₃ CN (2 mL), AcOH (0.25 mL) and H ₂ O (0.25 mL), and intermediate 1-11 (DCDMH) (83 mg , 0.417 mmol), reacted at room temperature for 1.0 hour, then added the reaction solution into ammonia water (2 mL), stirred at room temperature for 10 minutes, added water to the reaction solution, extracted with EA, combined the organic phases, and washed with saturated brine , dried over anhydrous sodium sulfate, the reaction solution was concentrated under reduced pressure and purified by Prep-HPLC to obtain compound 30. LC-MS: [M+H] ⁺ =437.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.60 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 8.4, 2.1 Hz, 1H), 7.54 – 7.39 ( m, 5H), 7.35 – 7.29 (m, 2H), 5.45 (s, 2H), 4.02 (d, J = 7.1 Hz, 2H), 3.87 (s, 2H), 2.18 (d, J = 7.5 Hz, 1H ), 1.70 (d, J = 8.0 Hz, 2H), 1.53 (ddd, J = 15.7, 13.1, 7.7 Hz, 4H), 1.27 – 1.22 (m, 2H).

Example 31

。 Compound 31: Preparation of 2-(2-chlorophenyl)-N-(4-(cyclobutoxymethyl)-3-sulfamoylphenyl)acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =409.1.

Example 32

。 Compound 32: 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl)ethyl Preparation of amides

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =439.1.

Example 33

。 Compound 33: 2-(2-Chlorophenyl)-N-(4-((oxetan-3-ylmethoxy)methyl)-3-sulfamoylphenyl)acetamide preparation

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =425.1.

Example 34

。 Compound 34: Preparation of 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-((((tetrahydrofuran-3-yl)methoxy)methyl)phenyl)acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =439.1.

Example 35

。 Compound 35: Preparation of 2-(2-chlorophenyl)-N-(4-((oxetan-3-yloxy)methyl)-3-sulfamoylphenyl)acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =411.1.

Example 36

。 Compound 36: Preparation of N-(4-((azetidin-3-yloxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =410.1.

Example 37:

。 Compound 37: Preparation of 2-(2-chlorophenyl)-N-(4-((pyrrolidin-3-oxyl)methyl)-3-sulfamoylphenyl)acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =508.1.

Example 38

。 Compound 38: Preparation of 2-(2-chlorophenyl)-N-(4-((piperidine-4-oxyl)methyl)-3-sulfamoylphenyl)acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =438.1.

Example 39

。 Compound 39: Preparation of 2-(2-chlorophenyl)-N-(4-((piperidine-3-oxyl)methyl)-3-sulfamoylphenyl)acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =438.1.

Example 40

。 Compound 40: 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)phenyl)acetyl Amine preparation

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =439.1.

Example 41

。 Compound 41: N-(4-(((2-azabicyclo[2.2.1]heptane-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2- Preparation of chlorophenyl) acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ = 450.1.

Example 42

。 Compound 42: N-(4-(((3-azabicyclo[3.1.1]heptane-6-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2- Preparation of chlorophenyl) acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ =450.1.

Example 43

。 Compound 43: N-(4-(((2-azabicyclo[2.2.2]octane-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2- Preparation of chlorophenyl) acetamide

.

Prepared with reference to Example 1. LC-MS: [M+H] ⁺ = 450.1.

Example 44

。 Compound 44: Preparation of 2-(2-chlorophenyl)-N-(4-((3-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 44-2

Intermediate 1-6 (600 mg, 1.62 mmol), Intermediate 44-1 (280 mg, 1.95 mmol) and K ₂ CO ₃ (447 mg, 3.24 mmol) were dissolved in DMF (10 mL) and heated to 60 °C , stirred for 3 hours. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA three times, combine the EA phases, and concentrate the EA phases under reduced pressure to obtain the intermediate 44-2. LC-MS: [M+H] ⁺ =455.

Step (2) Preparation of Intermediate 44-3

Intermediate 44-2 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (10 mL), under nitrogen protection, and stirred at 110 ℃ overnight. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase twice with EA, combine the EA phase, concentrate the reaction solution under reduced pressure, and then go through silica gel column chromatography (PE/EA=10: 1-6: 1) Purification, the column solution was concentrated under reduced pressure to obtain the intermediate 44-3. LC-MS: [M+H] ⁺ =499.

Step (3) Preparation of Compound 44

Intermediate 44-3 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4 mL/0.4 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol) was added to it. The reaction was stirred at room temperature for 15 minutes. After adding the reaction solution into ammonia water (10 mL) under stirring, the reaction was stirred at room temperature for 10 minutes. For post-processing, the reaction liquid was concentrated under reduced pressure, purified by Prep-HPLC, and the preparation was lyophilized to obtain compound 44. LC-MS: [M+H] ⁺ =456.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.57 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.82 (dd, J = 8.5, 2.2 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.59 (s, 2H), 7.50 (dd, J = 10.1, 5.9 Hz, 2H), 7.45 – 7.38 (m, 3H), 7.36 (dd, J = 8.1, 2.0 Hz, 1H ), 7.32 – 7.26 (m, 2H), 5.45 (s, 2H), 3.85 (s, 2H).

Example 45

。 Compound 45: Preparation of N-(4-((3-(aminomethyl)phenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 45-2

Intermediate 45-1 (300 mg, 2.43 mmol) was dissolved in THF (15 mL), Boc ₂ O (639 mg, 2.95 mmol) was added to the solution, and reacted under ice cooling. After 2 hours of reaction, the reaction solution was added with water (50 mL ) and extracted twice with ethyl acetate (20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 45-2, which was directly put into the next step without treatment . LC-MS: [M+H] ⁺ =224.1.

Step (2) Preparation of Intermediate 45-3

Intermediate 1-6 (525 mg, 1.41 mmol), Intermediate 45-2 (315 mg, 1.41 mmol) and K ₂ CO ₃ (390 mg, 2.83 mmol) were dissolved in DMF (5 mL), room temperature Stir for 1 hour. Add water (50 mL) to the reaction solution, then extract it twice with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then perform silica gel column chromatography ( PE/EA = 5/1 ~ 3/1) to obtain intermediate 45-3. LC-MS: [M+H] ⁺ =559.

Step (3) Preparation of Intermediate 45-4

Intermediate 45-3 (325 mg, 0.58 mmol), Intermediate 1-9 (benzylthiol) (216.3 mg, 1.74 mmol), Pd ₂ (dba) ₃ (82.5 mg, 0.116 mmol), Xantphos (67 mg , 0.116 mmol) and DIEA (225 mg, 1.74 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 115 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 45-4. LC-MS: [M+H] ⁺ =603.

Step (4) Preparation of Intermediate 45-5

Intermediate 45-4 (68 mg, 0.1134 mmol) and Intermediate 1-11 (DCDMH) (22.4 mg, 0.1134 mmol) were dissolved in CH ₃ CN (4 mL), AcOH (0.2 mL) and H ₂ O (0.1 mL), react at room temperature for 1 hour, add the reaction solution dropwise into ammonia water (10 mL) under stirring, and stir at room temperature for 0.5 hour. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 45-5. LC-MS: [M+H] ⁺ =560.

Step (6) Preparation of Compound 45

Dissolve intermediate 45-5 (50 mg, 0.088 mmol) in DCM (2 mL), add HCl (1 mL), react for 2 hours, dilute the reaction solution with water (10 mL), then add DCM (10 mL) Extract three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by prep-HPLC using H ₂ O/ACN system, and compound 45 was obtained after lyophilization of the preparation. LC-MS: [M+1]=460.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.60 (s, 1H), 8.25 (s, 3H), 7.81 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H) , 7.41 (t, J = 8.7 Hz, 2H), 7.29 (dd, J = 8.1, 3.9 Hz, 4H), 7.22 (d, J = 7.4 Hz, 2H), 7.13 (s, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 5.42 (s, 2H), 4.22 (d, J = 5.9 Hz, 2H), 3.84 (s, 2H).

Example 46

。 Compound 46: 2-(2-Chloro-6-fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)ethyl Preparation of amides

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 46-1

Intermediate 20-4 (2.15 g, 5.55 mmol), Intermediate 9-1 (627 mg, 5.55 mmol) and K ₂ CO ₃ (1.53 g, 11.1 mmol) were dissolved in DMF (20 mL), room temperature Stir for 1 hour. Add water (50 mL) to the reaction solution, then extract it twice with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then perform silica gel column chromatography ( PE/EA = 5/1 ~ 3/1) to obtain intermediate 46-1. LC-MS: [M+1]=467.

Step (2) Preparation of Intermediate 46-2

Intermediate 46-1 (1.33 g, 2.85 mmol), Intermediate 1-9 (benzylthiol) (1.05 g, 8.5 mmol), Pd ₂ (dba) ₃ (405 mg, 0.57 mmol), Xantphos (329 mg , 0.57 mmol) and DIEA (1.1 g, 8.5 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 115 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 46-2. LC-MS: [M+1]=511.

Step (3) Preparation of Compound 46

Intermediate 46-2 (345 mg, 0.67 mmol) and Intermediate 1-11 (DCDMH) (133 mg, 0.67 mmol) were dissolved in CH ₃ CN (5 mL), AcOH (0.2 mL) and H ₂ O (0.1 mL), react at room temperature for 5 minutes, add the reaction solution dropwise to ammonia water (5 mL) under stirring, and stir at room temperature for 0.5 hour. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and the preparation was lyophilized to obtain compound 46. LC-MS: [M+1]=468.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.65 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.95 (dd, J = 2.9, 1.8 Hz, 1H), 7.78 (dd, J = 8.5, 2.2 Hz, 1H), 7.68 – 7.60 (m, 2H), 7.56 (s, 2H), 7.40 – 7.30 (m, 2H), 7.26 – 7.19 (m, 1H), 7.13 (dd, J = 8.9, 3.4 Hz, 1H), 5.45 (s, 2H), 3.89 (d, J = 1.3 Hz, 2H).

Example 47

。 Compound 47: 2-(2-Chloro-5-fluorophenyl)-N-(4-((((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl ) Preparation of acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 47-1

Intermediate 22-4 (600 mg, 1.62 mmol), Intermediate 9-1 (280 mg, 1.95 mmol) and K ₂ CO ₃ (447 mg, 3.24 mmol) were dissolved in DMF (10 mL) and heated to 60 °C and stirred React for 3 hours. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA three times, combine the EA phases, and concentrate the EA phases under reduced pressure to obtain the intermediate 47-1. LC-MS: [M+H] ⁺ =469.

Step (2) Preparation of Intermediate 47-2

Intermediate 47-1 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL), under nitrogen protection, and then stirred at 110 ℃ overnight. After treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase with EA twice, combine the EA phase, concentrate the EA phase under reduced pressure, and then go through silica gel column chromatography (PE/EA=10: 1-6: 1) purification, the column solution was concentrated under reduced pressure to obtain the intermediate 47-2. LC-MS: [M+H] ⁺ =511.

Step (3) Preparation of Compound 47

Intermediate 47-2 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4 mL/0.4 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol) was added to it. The reaction was stirred at room temperature for 15 minutes. The reaction solution was added into stirred aqueous ammonia (20 mg, 1.20 mmol), and stirred at room temperature for 10 minutes. For post-processing, the reaction liquid was concentrated under reduced pressure, purified by Prep-HPLC, and the preparation was lyophilized to obtain compound 47. LC-MS: [M+H] ⁺ =468.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.59 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 7.95 (dd, J = 3.0, 1.8 Hz, 1H), 7.80 (dd, J = 8.5, 2.2 Hz, 1H), 7.67 – 7.60 (m, 2H), 7.57 (s, 2H), 7.47 (dd, J = 8.8, 5.3 Hz, 1H), 7.32 (dd, J = 9.5, 3.1 Hz , 1H), 7.20 – 7.09 (m, 2H), 5.45 (s, 2H), 3.85 (s, 2H).

Example 48

。 Compound 48: 2-(2-Chloro-4-fluorophenyl)-N-(4-((((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl ) Preparation of acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 48-1

Intermediate 21-4 (600 mg, 1.62 mmol), Intermediate 9-1 (280 mg, 1.95 mmol) and K ₂ CO ₃ (447 mg, 3.24 mmol) were dissolved in DMF (10 mL) and heated to 60 °C and stirred React for 3 hours. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA for 3 times, combine the EA phase, concentrate the EA phase under reduced pressure to obtain the product, the reaction is successful, and the intermediate 48-1 is obtained . LC-MS: [M+H] ⁺ =468.

Step (2) Preparation of Intermediate 48-2

Intermediate 48-1 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL), under nitrogen protection, and then stirred at 110 ℃ overnight. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase twice with EA, combine the EA phase, concentrate the reaction solution under reduced pressure, and then go through silica gel column chromatography (PE/EA=10: 1-6: 1) purification, the column solution was concentrated under reduced pressure to obtain the intermediate 48-2. LC-MS: [M+H] ⁺ =511.

Step (3) Preparation of Compound 48

Intermediate 48-2 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4 mL/0.4 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol) was added to it. The reaction was stirred at room temperature for 15 minutes. The reaction solution was added into stirred aqueous ammonia (20 mg, 1.20 mmol), and stirred at room temperature for 10 minutes. For post-processing, the reaction solution was concentrated under reduced pressure, purified by Prep-HPLC, and the preparation was lyophilized to obtain compound 48. LC-MS: [M+H] ⁺ =468.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.56 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 7.97 – 7.91 (m, 1H), 7.80 (dd, J = 8.5, 2.2 Hz, 1H), 7.67 – 7.59 (m, 2H), 7.57 (s, 2H), 7.43 (ddd, J = 11.5, 8.7, 4.5 Hz, 2H), 7.22 – 7.10 (m, 2H), 5.44 (s, 2H), 3.83 (s, 2H).

Example 49

。 Compound 49: Preparation of 2-(2-chloro-6-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 49-2

Intermediate 1-2 (2.43 g, 10.6 mmol) was dissolved in DCM (20 mL), and Intermediate 20-1 (2 g, 10.6 mmol), T ₃ P (10.1 g, 15.9 mmol) and Et ₃ N were added (4.8 g, 47.7 mmol), after reacting at room temperature for 1 hour, the reaction solution was added with water (50 mL) and extracted twice with ethyl acetate (20 mL), the organic phases were combined, washed successively with saturated brine, and dried over anhydrous sodium sulfate , filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA=5:1~2:1) to obtain intermediate 49-2. LC-MS: [M+H] ⁺ =400.

Step (2) Preparation of Intermediate 49-3

Intermediate 49-2 (4 g, 10 mmol) was dissolved in THF (10 mL), LiAlH ₄ (5.7 g, 15 mmol) was added, and stirred at room temperature for 1 hour. After adding H ₂ O (1 mL) and NaOH solution (2 mL), it was filtered with suction, and the filtrate was concentrated under reduced pressure to obtain 3.4 g of crude intermediate 49-3. Not processed directly for the next step.

Step (3) Preparation of Intermediate 49-4

Intermediate 49-3 (3.4 g, 9.2 mmol) was dissolved in DCM (10 mL), and SOCl ₂ (2.2 g, 18.2 mmol) was added dropwise and stirred at room temperature for 1 hour. The reaction was stopped, and the reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (PE:EA=10:1~5:1) to obtain intermediate 49-4. LC-MS: [M+H] ⁺ =400.

Step (4) Preparation of Intermediate 49-5

Intermediate 49-4 (300 mg, 0.76 mmol), Intermediate 6-1 (91.3 mg, 0.76 mmol) and K ₂ CO ₃ (211.7 g, 1.53 mmol) were dissolved in DMF (2 mL), room temperature Stir for 1 hour. Add water (50 mL) to the reaction solution, then extract it twice with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and the filtrate is concentrated under reduced pressure and then subjected to silica gel column chromatography ( PE/EA=5/1~3/1) to obtain intermediate 49-5. LC-MS: [M+H] ⁺ =473.

Step (5) Preparation of Intermediate 49-6

Intermediate 49-5 (255 mg, 0.54 mmol), Intermediate 1-9 (benzylthiol) (200.5 mg, 1.62 mmol), Pd ₂ (dba) ₃ (76.7 mg, 0.108 mmol), Xantphos (62.4 mg , 0.108 mmol) and DIEA (209 mg, 1.62 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 115 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 49-6. LC-MS: [M+H] ⁺ =517.

Step (6) Preparation of Compound 49

Intermediate 49-6 (254 mg, 0.49 mmol) and Intermediate 1-11 (DCDMH) (97 mg, 0.49 mmol) were dissolved in CH ₃ CN (5 mL), AcOH (0.2 mL) and H ₂ O (0.1 mL), react at room temperature for 5 minutes. The reaction solution was added dropwise to ammonia water (5 ml) under stirring, and stirred at room temperature for 0.5 hour. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and compound 49 was obtained after lyophilization of the preparation. LC-MS: [M+H] ⁺ =474.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.66 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 8.9 Hz, 3H), 7.58 (s, 3H) , 7.41 – 7.30 (m, 2H), 7.27 – 7.20 (m, 1H), 7.16 (d, J = 8.9 Hz, 2H), 5.49 (s, 2H), 3.89 (s, 2H).

Example 50

。 Compound 50: Preparation of 2-(2-chloro-5-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 50-1

Intermediate 22-4 (600 mg, 1.62 mmol), Intermediate 6-1 (280 mg, 1.95 mmol) and K ₂ CO ₃ (447 mg, 3.24 mmol) were dissolved in DMF (10 mL) and heated to 60 °C The reaction was stirred for 3 hours. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA for 3 times, combine the EA phases, and concentrate the EA phases under reduced pressure to obtain the intermediate 50-1. LC-MS: [M+H] ⁺ =473.

Step (2) Preparation of Intermediate 50-2

Intermediate 50-1 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL), under nitrogen protection, and stirred at 110 ℃ overnight. After treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase with EA twice, combine the EA phase, concentrate the EA phase under reduced pressure, and then go through silica gel column chromatography (PE/EA=10: 1-6: 1) purification, the column solution was concentrated under reduced pressure to obtain the intermediate 50-2. LC-MS: [M+H] ⁺ =517.

Step (3) Preparation of Compound 50

Intermediate 50-2 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4 mL/0.4 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol) was added to it. The reaction was stirred at room temperature for 15 minutes. The reaction solution was added into stirred aqueous ammonia (20 mg, 1.20 mmol), and stirred at room temperature for 10 minutes. After treatment, the reaction solution was concentrated under reduced pressure and then purified by Prep-HPLC, and the preparation solution was freeze-dried to obtain the product. The reaction was successful to obtain compound 50. LC-MS: [M+H] ⁺ =474.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.58 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.82 – 7.73 (m, 3H), 7.60 (s, 1H), 7.58 ( d, J = 2.5 Hz, 2H), 7.47 (dd, J = 8.8, 5.3 Hz, 1H), 7.32 (dd, J = 9.5, 3.1 Hz, 1H), 7.17 (td, J = 9.0, 2.8 Hz, 3H ), 5.48 (s, 2H), 3.85 (s, 2H).

Example 51

。 Compound 51: Preparation of 2-(2-chloro-4-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 51-1

Intermediate 21-4 (600 mg, 1.62 mmol), Intermediate 6-1 (280 mg, 1.95 mmol) and K ₂ CO ₃ (447 mg, 3.24 mmol) were dissolved in DMF (10 mL) and heated to 60 °C The reaction was stirred for 3 hours. For post-processing, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA for 3 times, combine the EA phases, and concentrate the EA phases under reduced pressure to obtain the intermediate 51-1. LC-MS: [M+H] ⁺ =473.

Step (2) Preparation of Intermediate 51-2

Intermediate 51-1 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL), under nitrogen protection, and then stirred at 110 ℃ overnight. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase with EA twice, combine the EA phase, concentrate and chromatographic column for separation and purification (PE/EA=10:1-6:1 ), the column solution was concentrated under reduced pressure to obtain the intermediate 51-2. LC-MS: [M+H] ⁺ =517.

Step (3) Preparation of compound 51

Intermediate 51-2 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4 mL/0.4 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) was added to it. The reaction was stirred at room temperature for 15 minutes. The reaction solution was added into stirred aqueous ammonia (20 mg, 1.20 mmol), and stirred at room temperature for 10 minutes. For post-treatment, the reaction liquid was concentrated under reduced pressure, purified by Prep-HPLC, and the preparation was lyophilized to obtain compound 51. LC-MS: [M+H] ⁺ =474.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.59 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 7.80 (ddt, J = 7.0, 4.7, 2.5 Hz, 3H), 7.65 – 7.55 (m, 3H), 7.46 (ddd, J = 11.5, 8.7, 4.5 Hz, 2H), 7.25 – 7.15 (m, 3H), 5.51 (s, 2H), 3.85 (s, 2H).

Example 52

。 Compound 52: Preparation of 2-(2-chloro-3-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 52-2

Intermediate 1-2 (9 g, 0.039 mol), intermediate 52-1 (2-chloro-3-fluorophenylacetic acid) (8 g, 0.0468 mol), TEA (12 g, 0.117 mol) and T ₃ P (25 g, 0.078 mol) was dissolved in DCM (90 mL), stirred at room temperature for 0.5 hours. Add water and DCM to the reaction solution, stir well and separate the DCM phase, extract the water phase twice with DCM, combine the DCM phases, and concentrate the reaction solution under reduced pressure to obtain intermediate 52-2. LC-MS: [M+H] ⁺ =400.

Step (2) Preparation of Intermediate 52-3

Intermediate 52-2 (14 g, 0.037 mol) was dissolved in THF (100 mL), and the temperature was lowered to 0 °C, and LiAlH ₄ (4.22 g, 0.111 mol) was stirred at room temperature for 10 minutes. For post-processing, 1 mL of water and 3 mL of 2M NaOH aqueous solution were added to the reaction liquid, and a large amount of EA was added, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 52-3. LC-MS: [M+H] ⁺ =372.

Step (3) Preparation of Intermediate 52-4

Intermediate 52-3 (10 g, 0.028 mol) was dissolved in DCM (100 mL) and cooled to 0 °C, SOCl ₂ (6.61 g, 0.056 mol) was added thereto, raised to room temperature and stirred for 1 hour. For post-processing, the reaction solution was concentrated under reduced pressure to obtain intermediate 52-4. LC-MS: [M+H] ⁺ =390.

Step (4) Preparation of Intermediate 52-5

Dissolve Intermediate 52-4 (600 mg, 1.62 mmol), Intermediate 6-1 (280 mg, 1.95 mmol) and K ₂ CO ₃ (447 mg, 3.24 mmol) in DMF (10 mL) and heat to 60 °C The reaction was stirred for 3 hours. For post-processing, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA three times, combine the EA phases, and concentrate the EA phases under reduced pressure to obtain the intermediate 52-5. LC-MS: [M+H] ⁺ =473.

Step (5) Preparation of Intermediate 52-6

Intermediate 52-5 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL), under nitrogen protection, and stirred at 110 ℃ overnight. After treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase with EA twice, combine the EA phase, concentrate the EA phase under reduced pressure, and then go through silica gel column chromatography (PE/EA=10: 1-6: 1) purification, the column solution was concentrated under reduced pressure to obtain the intermediate 52-6. LC-MS: [M+H] ⁺ =517.

Step (6) Preparation of compound 52

Intermediate 52-6 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4 mL/0.4 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol) was added to it. The reaction was stirred at room temperature for 15 minutes. The reaction solution was added dropwise into stirred aqueous ammonia (20 mg, 1.20 mmol), and stirred at room temperature for 10 minutes. For post-processing, the reaction liquid was concentrated under reduced pressure, purified by Prep-HPLC, and the preparation was lyophilized to obtain compound 52. LC-MS: [M+H] ⁺ =474.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.61 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.78 (ddt, J = 7.1, 4.7, 2.5 Hz, 3H), 7.60 ( d, J = 8.1 Hz, 3H), 7.39 – 7.22 (m, 3H), 7.21 – 7.12 (m, 2H), 5.49 (s, 2H), 3.90 (s, 2H).

Example 53

。 Compound 53: 2-(2-Chloro-6-fluorophenyl)-N-(4-((((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl ) Preparation of acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 53-2

Dissolve intermediate 20-4 (500 mg, 1.278 mmol) in THF (5 mL), add intermediate 53-1 (162 mg, 1.41 mmol) and Ag ₂ CO ₃ (702.9 mg, 2.56 mmol), 70 °C Stirring was continued for 8 hours. The reaction was stopped, and the reaction solution was diluted with water (10 mL), and then extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=10:1~1:1) to obtain intermediate Object 53-2. LC-MS: [M+H] ⁺ =467.

Step (2) Preparation of Intermediate 53-3

Intermediate 53-2 (217 mg, 0.46 mmol), Intermediate 1-9 (benzylthiol) (173.6 mg, 1.4 mmol), Pd ₂ (dba) ₃ (65.4 mg, 0.092 mmol), Xantphos (53.2 mg , 0.092mmol) and DIEA (180.6 mg, 1.4 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 115 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 5/1 ~ 3/1) to obtain intermediate 53-3. LC-MS: [M+H] ⁺ =511.

Step (3) Preparation of compound 53

Intermediate 53-3 (175 mg, 0.34 mmol) and Intermediate 1-11 (DCDMH) (67 mg, 0.34 mmol) were dissolved in CH ₃ CN (4 mL), AcOH (0.1 mL) and H ₂ O (0.1 mL), react at room temperature for 1 hour. The reaction solution was added dropwise to ammonia water (5 mL) under stirring, and stirred at room temperature for 0.5 hour. The reaction solution was diluted with water (10 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC using H ₂ O/ACN system, and compound 53 was obtained after lyophilization of the preparation. LC-MS: [M+H] ⁺ =468.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.63 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.13 (d, J = 3.1 Hz, 1H), 7.78 – 7.67 (m, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.48 (s, 2H), 7.40 – 7.31 (m, 2H), 7.26 – 7.17 (m, 1H), 7.07 – 6.97 (m, 1H), 5.64 (s, 2H), 3.90 (d, J = 8.9 Hz, 2H).

Example 54

。 Compound 54: 2-(2-Chloro-5-fluorophenyl)-N-(4-(((5-fluoropyridin-2-yloxy)methyl)methyl)-3-sulfamoylbenzene base) preparation of acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 54-1

Intermediate 22-4 (600 mg, 1.62 mmol), Intermediate 53-1 (280 mg, 1.95 mmol) and Ag ₂ CO ₃ (447 mg, 3.24 mmol) were dissolved in THF (10 mL), heated to 60 °C The reaction was stirred for 3 hours. For post-processing, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA three times, combine the EA phases, and concentrate the EA phases under reduced pressure to obtain the intermediate 54-1. LC-MS: [M+H] ⁺ =469.

Step (2) Preparation of Intermediate 54-2

Intermediate 54-1 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL), under nitrogen protection, and stirred at 110 ℃ overnight. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase twice with EA, combine the EA phase, concentrate the reaction solution under reduced pressure, and then go through silica gel column chromatography (PE/EA=10: 1-6: 1) purification, and concentration under reduced pressure to obtain the intermediate 54-2. LC-MS: [M+H] ⁺ =511.

Step (3) Preparation of Compound 54

Intermediate 54-2 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4 mL/0.4 mL), and DCDMH (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol) were added thereto. The reaction was stirred at room temperature for 15 minutes. The reaction solution was added dropwise into stirred aqueous ammonia (20 mg, 1.20 mmol), and stirred at room temperature for 10 minutes. After treatment, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC using H ₂ O/ACN system, and the preparation was lyophilized to obtain compound 54. LC-MS: [M+H] ⁺ =468.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.57 (s, 1H), 8.23 (d, J = 2.2 Hz, 1H), 8.13 (d, J = 3.1 Hz, 1H), 7.80 – 7.69 (m, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 8.7, 5.3 Hz, 3H), 7.33 (dd, J = 9.5, 3.1 Hz, 1H), 7.17 (td, J = 8.5 , 3.1 Hz, 1H), 7.01 (dd, J = 9.1, 3.6 Hz, 1H), 5.64 (s, 2H), 3.86 (s, 2H).

Example 55

。 Compound 55: 2-(2-Chloro-4-fluorophenyl)-N-(4-((((5-fluoropyridin-2-yloxy)methyl)methyl)-3-sulfamoyl The preparation of phenyl) acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 55-1

Dissolve Intermediate 21-4 (600 mg, 1.62 mmol), Intermediate 53-1 (280 mg, 1.95 mmol) and Ag ₂ CO ₃ (447 mg, 3.24 mmol) in THF (10 mL) and heat to 60 °C The reaction was stirred for 3 hours. For post-processing, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA for 3 times, combine the EA phases, and concentrate the EA phases under reduced pressure to obtain the intermediate 55-1. LC-MS: [M+H] ⁺ =469.

Step (2) Preparation of Intermediate 55-2

Intermediate 55-1 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL), under nitrogen protection, and stirred at 110 ℃ overnight. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase twice with EA, combine the EA phase, concentrate the reaction solution under reduced pressure, and then go through silica gel column chromatography (PE/EA=10: 1-6: 1) Purify, concentrate under reduced pressure and pass through the column liquid to obtain the intermediate 55-2. LC-MS: [M+H] ⁺ =511.

Step (3) Preparation of Compound 55

Intermediate 55-2 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4 mL/0.4 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol) was added to it. The reaction was stirred at room temperature for 15 minutes. The reaction solution was added dropwise into stirred aqueous ammonia (20 mg, 1.20 mmol), and stirred at room temperature for 10 minutes. After treatment, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC using H ₂ O/ACN system, and the preparation was lyophilized to obtain compound 55. LC-MS: [M+H] ⁺ =468.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.46 (s, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 8.4, 2.1 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.44 (ddd, J = 11.6, 8.8, 4.5 Hz, 2H), 7.32 (s, 2H), 7.19 (td, J = 8.6, 2.7 Hz, 2H), 5.37 (t, J = 5.6 Hz, 1H), 4.81 (d, J = 5.5 Hz, 2H), 3.82 (s, 2H).

Example 56

。 Compound 56: 2-(2-Chlorophenyl)-N-(4-(((1-methyl-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl ) Preparation of acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 56-1

Intermediate 1-4 (5 g, 0.013 mol) was dissolved in 1,4-dioxane (50 mL) and intermediate 1-9 (benzylthiol) (4.8 g, 0.039 mol), DIEA (5 g, 0.039 mol), Pd ₂ (dba)3 (2.4 g, 0.0026 mol) and xantphos (1.35 g, 0.0026 mol), react overnight at 110 ℃ after N ₂ displacement. Add EA, extract the organic phase with water, combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, add PE:EA (10:1) 50mL, beat and filter to obtain the product 5 of intermediate 56-1 g, yield 90.9%.

Step (2) Preparation of Intermediate 56-2

Intermediate 56-1 (5 g, 0.012 mol) was dissolved in ACN (50 mL), AcOH (3.6 g, 0.06 mol) and H ₂ O (5 mL) were added, and NCS was added in batches under ice-bath conditions ( N-chlorobutanediimide) (3.2 g, 0.024 mol) and stirred at room temperature for 1 hour. The reaction solution was extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4 g of intermediate 56-2.

Step (3) Preparation of Intermediate 56-3

Intermediate 56-2 (4 g, 0.01 mol) was dissolved in acetonitrile (40 mL), and 4-methoxybenzylamine (2.9 g, 0.02 mmol) was added to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 3.8 g of intermediate 56-3.

Step (4) Preparation of Intermediate 56-4

Intermediate 56-3 (3.5 g, 7 mmol) was dissolved in THF (35 mL), and LAH (lithium aluminum hydride, 518 mg, 14 mmol) was added in portions under ice-cooling conditions, and reacted under ice-cooling for 30 minutes. It was quenched by adding 1 mL of NaOH (3M) aqueous solution, filtered, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA=5:1~1:1) to obtain 2.6 g of intermediate 56-4.

Step (5) Preparation of Intermediate 56-5

Intermediate 56-4 (1.34 g, 0.03 mol) was dissolved in DCM (5 mL), and SOCl ₂ (0.67 g. 0.06 mmol) was added at room temperature, and reacted at room temperature for 1 hour. Directly concentrated under reduced pressure to obtain 1.4 g of intermediate 56-5.

Step (6) Preparation of Intermediate 56-6

Intermediate 56-5 (1.4 g, 2.8 mmol) was dissolved in THF (15 mL), and intermediate 8-1 (1-methyl-1H-pyrazol-3-ol) (329 mg, 3.6 mmol) was added and Silver carbonate (1.54 g, 5.6 mmol) was reacted at 70 °C for 3 hours, filtered and extracted three times with EA (20*3 mL), dried and subjected to silica gel column chromatography (PE/EA=5:1~1:1 ) purification, concentrated under reduced pressure and passed the column solution to obtain 490 mg of intermediate 56-6, with a yield of 31.6%.

Step (7) Preparation of compound 56

Intermediate 56-6 (375 mg, 0.67 mmol) was dissolved in DCM (4 mL), added with TFA (2 mL), reacted overnight at room temperature, and directly concentrated under reduced pressure to obtain a yellow crude product.

The crude product was separated by prep-HPLC using H ₂ O/ACN system, and after lyophilization, 32.6 mg of compound 56 was obtained, with a purity of 99.298% and a yield of 11.2%. LC-MS: [M+H] ⁺ =435.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.54 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.5, 2.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.47 (s, 1H), 7.46 (s, 2H), 7.44 – 7.39 (m, 2H), 7.30 (ddd, J = 5.1, 4.1, 3.0 Hz, 2H), 5.68 (d , J = 2.3 Hz, 1H), 5.44 (s, 2H), 3.84 (s, 2H), 3.65 (s, 3H).

Example 57

。 Compound 57: 2-(2-Chlorophenyl)-N-(4-(((1-cyclopropyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl base) preparation of acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 57-2

Add intermediate 57-1 (900 mg, 4.8 mmol), B ₂ pin ₂ (pinacol diborate, 2.54 g, 9.8 mmol), potassium acetate (1.41 g, 14.4 mmol), Pd (dppf)Cl ₂ (731 mg, 1.0 mmol) and 1,4-dioxane (3 mL) were reacted overnight at 100°C under nitrogen protection. Treatment: add water (30 mL), extract the aqueous phase twice with ethyl acetate (30 mL), combine the organic phases, wash with saturated sodium chloride (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure and pass through a silica gel column Purification by chromatography (PE/EA=3/1) yielded 1.2 g of intermediate 57-2.

Step (2) Preparation of Intermediate 57-3

Add 1.2 g of the intermediate 57-2 obtained in step (1) to methanol (10 mL) and hydrogen peroxide (3 mL 30%), and react overnight at room temperature. Add water (30 mL), quench the reaction with sodium sulfite, concentrate under reduced pressure to remove methanol, and then extract the product with EA 30 mL*3. After drying and concentrating under reduced pressure, 900 mg of intermediate 57-3 was obtained, which was directly used for the next step.

Step (3) Preparation of Intermediate 57-4

Add intermediate 57-3 (900 mg, 4.8 mmol), intermediate 1-6 (1.19 g, 3.2 mmol), potassium carbonate (1.33 g, 9.6 mmol) and DMF (10 mL) in a 25 mL reaction vial, nitrogen protected and reacted overnight at room temperature. Add water (100 mL), extract the aqueous phase twice with ethyl acetate (40 mL), combine the organic phases, wash twice with saturated sodium chloride (100 mL), dry, concentrate under reduced pressure and purify by silica gel column chromatography (PE/EA=5/1~3/1), 230 mg of intermediate 57-4 was obtained.

Step (4) Preparation of Intermediate 57-5

Add Intermediate 57-4 (230 mg, 0.5 mmol), Intermediate 1-9 (Benzylthiol) (186 mg, 1.5 mmol), Pd ₂ (dba) ₃ (100 mg, 0.1 mmol) to a 25 mL reaction vial ), Xantphos (58 mg, 0.1 mmol), DIEA (194 mg, 1.5 mmol) and 1,4-dioxane (6 mL), under nitrogen protection, react overnight at 110°C. The reaction solution was filtered to obtain a crude product, which was concentrated under reduced pressure and then purified by silica gel column chromatography (PE/EA=5/1~3/1) to obtain 230 mg of intermediate 57-5.

Step (5) Preparation of Compound 57

Add intermediate 57-5 (230 mg, 0.46 mmol), 30 µL of acetic acid, 3 mL of acetonitrile and 10 µL of water in a 25 mL reaction vial, and add intermediate 1-11 (DCDMH) (184 mg , 0.92 mmol), after adding the sample for 10 minutes, LCMS showed about 40% product. Ammonia (5 mL) and water (20 mL) were added to the reaction system and stirred for 10 minutes, the aqueous phase was extracted twice with ethyl acetate (30 mL), the organic phases were combined and washed with saturated sodium chloride (50 mL) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by prep-HPLC using H ₂ O/ACN system, and the preparation solution was lyophilized to obtain 40 mg of compound 57. LC-MS: [M+H] ⁺ =461.05.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.54 (s, 1H), 8.22 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H ), 7.53 (s, 1H), 7.49 (s, 2H), 7.46 – 7.37 (m, 2H), 7.33 – 7.25 (m, 2H), 7.20 (s, 1H), 5.23 (s, 2H), 3.84 ( s, 2H), 3.64 – 3.51 (m, 1H), 0.97 – 0.90 (m, 2H), 0.90 – 0.84 (m, 2H).

Example 58

。 Compound 58: 2-(2-chlorophenyl)-N-(4-((3-(methylsulfonylimidoyl)phenoxy)methyl)-3-aminosulfonylphenyl)ethyl Preparation of amides

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 58-2

Dissolve the weighed intermediate 1-6 (1.0 g, 2.68 mmol) in DMF (15 mL), add intermediate 58-1 (414 mg, 2.949 mmol) and K ₂ CO ₃ (741 mg, 5.36 mmol ), and reacted at room temperature for 2 hours. Add water to the reaction solution, extract it twice with ethyl acetate, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. The reaction solution is concentrated under reduced pressure and subjected to silica gel column chromatography (PE/EA=10/1~5/ 1) Purified to obtain 900 mg of the product of intermediate 58-2.

Step (2) Preparation of Intermediate 58-3

Dissolve the weighed intermediate 58-2 (850 mg, 1.783 mmol) in 30 mL of methanol, add ammonium carbonate (686 mg, 7.132 mmol), add iodobenzene acetate (1.7 g, 5.348 mmol) while stirring, and add After the reaction at room temperature for 1 hour, the reaction solution was quenched with saturated sodium sulfite solution, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure and then subjected to silica gel column chromatography (PE/EA=2/ 1~1/2) to obtain 800 mg of intermediate 58-3. LC-MS: [M+H] ⁺ =509.

Step (3) Preparation of Intermediate 58-4

Dissolve the weighed intermediate 58-3 (600 mg, 1.181 mmol) in 1,4-dioxane (20 mL), add intermediate 1-9 (benzyl thiol) (294 mg, 2.363 mmol ), Pd ₂ (dba) ₃ (108 mg, 0.118 mmol), Xantphos (69 mg, 0.118 mmol) and DIEA (610 mg, 4.726 mol), react overnight at 100 °C under nitrogen protection, add water to the reaction solution, and use EA was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (DCM/MeOH = 100/1) to obtain 600 mg of intermediate 58-4. LC-MS: [M+H] ⁺ =551.

Step (4) Preparation of Compound 58

The weighed intermediate 58-4 (350 mg, 0.635 mmol) was dissolved in CH ₃ CN (8 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.762 mmol), AcOH (1 mL) and H ₂ O (1 mL), react at room temperature for 5 minutes, add the reaction solution into ammonia water (2 mL), add water to the reaction solution, extract with EA, combine the organic phases, wash with saturated brine, anhydrous sulfuric acid After sodium drying, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC using H ₂ O/ACN system to obtain 78.1 mg of compound 58. LC-MS: [M+H] ⁺ = 508.1.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.61 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 7.86 (dd, J = 8.5, 2.2 Hz, 1H), 7.69 – 7.59 (m, 6H), 7.47 – 7.41 (m, 3H), 7.32 (ddd, J = 5.1, 4.1, 3.0 Hz, 2H), 5.52 (s, 2H), 3.87 (s, 2H), 3.52 (s, 3H ).

Example 59

。 Compound 59: 2-(2-Chlorophenyl)-N-(4-(1-((6-fluoropyridin-3-yl)oxy)ethyl)-3-sulfamoylphenyl)acetyl Amine preparation

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 59-2

Intermediate 59-1 (3 g, 0.01 mol), tributyl(1-ethoxyethylene) tin (5.6 g, 0.015 mol), Pd ₂ (dba) ₃ (915 mg, 0.001 mol), CsF( 3 g, 0.02 mol) and t-Bu ₃ P (0.2 g, 0.001 mol) were dissolved in 1,4-dioxane (30 mL), nitrogen was replaced, the temperature was raised to 110 ℃ and stirred overnight. Post-treatment, add KF aqueous solution and EA to the reaction solution, separate the EA phase after fully stirring, extract the water phase with EA twice, combine the EA phase and concentrate under reduced pressure to obtain the crude product, the crude product is subjected to silica gel column chromatography ( PE/EA=3:1-1:1), and concentrated under reduced pressure to pass through the column liquid to obtain 600 mg of the product of intermediate 59-2. LC-MS: [M+H] ⁺ =328.

Step (2) Preparation of Intermediate 59-3

Intermediate 59-2 (600 mg, 1.83 mmol) was dissolved in 1 M HCl/1,4-dioxane (12 mL, 9.17 mmol), and stirred at room temperature for 0.5 hours. After post-processing, the reaction solution was concentrated under reduced pressure to obtain 510 mg of intermediate 59-3. LC-MS: [M+H] ⁺ =300.

Step (3) Preparation of Intermediate 59-4

Intermediate 59-3 (530 mg, 1.77 mmol), Fe ( 495 mg, 8.85 mmol) and NH ₄ Cl (938 mg, 17.7 mmol) were dissolved in EtOH/H ₂ O (6 mL/1.5 mL), heated to The reaction was stirred at 70°C for 2 hours. After treatment, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 500 mg of the product intermediate 59-4. LC-MS: [M+H] ⁺ =270.

Step (4) Preparation of Intermediate 59-5

Intermediate 59-4 (500 mg, 1.86 mmol), Intermediate 1-3 (2-chlorophenylacetic acid) (316 mg, 1.86 mmol), TEA (563 mg, 5.58 mmol) and T ₃ P (887 mg, 2.79 mmol) was dissolved in DCM (8.0 mL), and stirred at room temperature for 2 hours. Post-treatment, add water and DCM to the reaction solution, stir well and separate the DCM phase, extract the water phase twice with DCM, combine the DCM phase, and concentrate the reaction solution under reduced pressure and then go through silica gel column chromatography (PE/EA=3: 1-2:1) Purified to obtain 440 mg of intermediate 59-5. LC-MS: [M+H] ⁺ =422.

Step (5) Preparation of Intermediate 59-6

Intermediate 59-5 (100 mg, 0.24 mmol) was dissolved in MeOH (2.0 mL), NaBH ₄ (18 mg, 0.48 mmol) was added into the reaction under ice-cooling, and the reaction was stirred at room temperature for 0.5 hours. After treatment, the reaction solution was purified by PREP-TLC. After the scraper was soaked, the soaking solution was concentrated under reduced pressure to obtain 42 mg of the intermediate 59-6 product. LC-MS: [M+H] ⁺ =406.

Step (6) Preparation of Intermediate 59-7

Intermediate 59-6 (40 mg, 0.096 mmol) and SOCl ₂ (24 mg, 0.192 mmol) were dissolved in DCM, and stirred at room temperature for 2 hours. Post-processing, direct concentration under reduced pressure to obtain 30 mg of intermediate 59-7. LC-MS: [M+H] ⁺ =442.

Step (7) Preparation of Intermediate 59-8

Intermediate 59-7 (30 mg, 0.069 mmol), Intermediate 9-1 (2-fluoro-5-hydroxypyridine) (12 mg, 0.083 mmol) and K ₂ CO ₃ (20 mg, 0.138 mmol) were dissolved in DMF (1.0 mL), and warmed up to 40°C and stirred overnight. After treatment, wash the reaction solution with water, extract it twice with EA, combine the EA phases, and concentrate under reduced pressure to 2-3mL crude product, the crude product is purified by Prep-TLC, soaked with a scraper to obtain a soaking solution, and the soaking solution is concentrated under reduced pressure The product 26 mg of intermediate 59-8 was obtained. LC-MS: [M+H] ⁺ =519/521.

Step (8) Preparation of Compound 59

Intermediate 59-8 (30 mg, 0.058 mmol) was dissolved in methanol (0.5 mL), and hydrazine hydrate (15 mg, 0.29 mmol) was added thereto, and the reaction was stirred at room temperature for 0.5 hours. After treatment, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC using H ₂ O/ACN system, and the preparation was lyophilized to obtain 7 mg of compound 59. LC-MS: [M+H] ⁺ =464/466.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.54 (s, 1H), 8.41 (s, 1H), 8.22 (d, J = 2.2 Hz, 1H), 7.88 – 7.82 (m, 2H), 7.73 (dd, J = 8.5, 2.1 Hz, 2H), 7.54 (dt, J = 7.4, 2.9 Hz, 2H), 7.40 (ddd, J = 9.3, 4.8, 2.5 Hz, 2H), 7.31 – 7.25 (m, 2H ), 6.98 (dd, J = 8.9, 3.4 Hz, 1H), 6.11 – 6.06 (m, 1H), 3.81 (s, 2H), 1.59 (d, J = 6.2 Hz, 3H).

Example 60

。 Compound 60: N-(4-(((4-chloro-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl) Preparation of acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 60-1

Dissolve the weighed 1,2-dihydro-3H-pyrazol-3-one (1.0 g, 11.893 mmol) in DCM (20 mL), add Boc anhydride (2.9 g, 13.083 mmol) and TEA (three Ethylamine) (3.6 g, 35.679 mmol), and reacted at room temperature for 12 hours. The reaction solution was directly spin-dried, diluted with EA, adjusted to pH 5.6~6.0 with 0.1N hydrochloric acid, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain intermediate 60-1 2.0 g of the product is a yellow oily liquid.

Step (2) Preparation of Intermediate 60-2

Dissolve the weighed intermediate 1-6 (500 mg, 1.34 mmol) in THF (20 mL), add intermediate 60-1 (297 mg, 1.609 mmol) and Ag ₂ CO ₃ (740 mg, 2.68 mmol ), and reflux at 70 °C for 24 hours. LCMS monitoring showed that the product was formed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE/EA=10/1~5/1) to obtain the product 420 of intermediate 60-2 mg.

Step (3) Preparation of Intermediate 60-3

Dissolve the weighed intermediate 60-2 (370 mg, 0.879 mmol) in 1,4-dioxane (15 mL), add intermediate 1-9 (benzyl thiol) (219 mg, 1.759 mmol ), Pd ₂ (dba) ₃ (81 mg, 0.088 mmol), Xantphos (51 mg, 0.088 mmol) and DIEA (341 mg, 2.639 mmol), react overnight at 110 °C under nitrogen protection, add water to the reaction solution, and use EA was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (PE/EA = 5/1) to obtain 270 mg of intermediate 60-3.

Step (4) Preparation of Intermediate 60-4

Intermediate 60-3 (170 mg, 0.301 mmol) was dissolved in CH ₃ CN (2 mL), AcOH (0.25 mL) and H ₂ O (0.25 mL), and Intermediate 1-11 (DCDMH) (116 mg , 0.603 mmol), reacted at room temperature for 10 minutes, added the reaction solution dropwise to ammonia water (0.5 mL) under stirring, added water to the reaction solution, extracted with EA, combined the organic phases, washed with saturated brine, and anhydrous After drying over sodium sulfate, the reaction solution was concentrated under reduced pressure to obtain 200 mg of intermediate 60-4, which was directly used in the next reaction.

Step (5) Preparation of Compound 60

Dissolve the weighed intermediate 60-4 (200 mg, 0.361 mmol) in DME (2 mL), add sodium carbonate (46 mg, 0.432 mmol), and react at 100 °C for 0.5 hours. Add water to the reaction solution, extract with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the reaction solution under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC using H ₂ O/ACN system, and the preparation was lyophilized to obtain 41.1 mg of compound 60. LC-MS: [M+H] ⁺ =455.05 .

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.29 (s, 1H), 10.58 (s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 7.89 – 7.79 (m, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.54 – 7.38 (m, 4H), 7.35 – 7.27 (m, 2H), 5.58 (s, 2H), 3.86 (s, 2H).

Example 61

。 Compound 61: 2-(2-Chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfonamide Preparation of acylphenyl) acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 61-2

Dissolve Intermediate 1-6 (400 mg, 1.08 mmol), Intermediate 61-1 (217 mg, 1.62 mmol) and K ₂ CO ₃ (300 mg, 2.16 mmol) in DMF (5 mL), stir at room temperature Respond overnight. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase with EA (15 mL*2) twice, combine the EA phase, and concentrate the reaction solution under reduced pressure, then go through silica gel column chromatography ( PE/EA=5:1-3:1) and concentrated under reduced pressure to obtain 300 mg of intermediate 61-2. LC-MS: [M+H] ⁺ =470/472.

Step (2) Preparation of Intermediate 61-3

Intermediate 61-2 (300 mg, 0.64 mmol), Intermediate 1-9 (benzylthiol) (120 mg, 0.96 mmol), Pd ₂ (dba) ₃ (58 mg, 0.064 mmol), DIEA (250 mg , 1.92 mmol) and Xantphos (37 mg, 0.064 mmol) were dissolved in 1,4-dioxane (3 mL), under nitrogen protection, and stirred at 110 ℃ overnight. The raw material reacted completely. Post-treatment, add water (15 mL) and EA (15 mL) to the reaction solution, stir well and separate the EA phase, extract the water phase with EA (10 mL*2) twice, combine the EA phase, and concentrate the reaction solution under reduced pressure Afterwards, it was purified by silica gel column chromatography (PE/EA=10:1-0:1), and concentrated under reduced pressure to obtain 300 mg of intermediate 61-3. LC-MS: [M+H] ⁺ =514/516.

Step (3) Preparation of Compound 61

Intermediate 61-3 (200 mg, 0.40 mmol) was dissolved in acetonitrile/water (2 mL/0.2 mL), and intermediate 1-11 (DCDMH) (110 mg, 0.60 mmol) and AcOH (120 mg, 2.0 mmol) added to it. The reaction was stirred at room temperature for 15 minutes. The reaction solution was added dropwise into ammonia water (1 mL) under stirring, and the reaction was stirred at room temperature for 20 minutes. After treatment, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC using H ₂ O/ACN system, and the preparation was lyophilized to obtain 20 mg of white solid. LC-MS: [M+H] ⁺ =471/473.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.59 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 7.99 (s, 1H), 7.85 (dd, J = 8.4, 1.9 Hz , 1H), 7.70 (d, J = 5.9 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 5.1 Hz, 2H), 7.49 – 7.41 (m, 2H), 7.35 – 7.30 (m, 2H), 5.34 (s, 2H), 3.88 (s, 2H).

Example 62

。 Compound 62: 2-(2-Chloro-4-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfonamide Preparation of acylphenyl) acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 62-2

Intermediate 21-4 (600 mg, 1.62 mmol), Intermediate 23-1 (280 mg, 1.95 mmol) and K ₂ CO ₃ (447 mg, 3.24 mmol) were dissolved in DMF (10 mL), and heated to 60 °C The reaction was stirred for 3 hours. Post-treatment, add water and EA to the reaction solution, stir well and separate the EA phase, then extract the water phase with EA for 3 times, combine the EA phases, concentrate the EA phases under reduced pressure to obtain 460 mg of intermediate 62-2. LC-MS: [M+H] ⁺ =452/454.

Step (2) Preparation of Intermediate 62-3

Intermediate 62-2 (450 mg, 0.94 mmol), Intermediate 1-9 (benzylthiol) (233 mg, 1.88 mmol), Pd ₂ (dba) ₃ (45 mg, 0.047 mmol), DIEA (365 mg , 2.82 mmol) and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL), under nitrogen protection, and stirred at 110 ℃ overnight. After treatment, add water and EA to the reaction solution, stir well and separate the EA phase, extract the water phase with EA twice, combine the EA phase, concentrate under reduced pressure, and then go through silica gel column chromatography (PE/EA=10:1- 6:1) Separation and purification, and concentration under reduced pressure to pass through the column liquid to obtain 290 mg of yellow solid product. LC-MS: [M+H] ⁺ =496/498.

Step (3) Preparation of Intermediate 62-4

Intermediate 62-3 (200 mg, 0.38 mmol) was dissolved in acetonitrile/water (4 mL/0.4 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol) was added to it. The reaction was stirred at room temperature for 15 minutes. After treatment, the reaction solution was directly concentrated under reduced pressure to obtain 150 mg of intermediate 62-4. LC-MS: [M+H] ⁺ =472/474.

Step (4) Preparation of compound 62

Intermediate 62-4 (120 mg, 0.24 mmol) was added into aqueous ammonia (1 mL), and stirred at room temperature for 10 minutes. After treatment, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC using H ₂ O/ACN system, and the preparation was lyophilized to obtain 39 mg of compound 62. LC-MS: [M+H] ⁺ =453/455.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.53 (s, 1H), 8.22 (d, J = 2.2 Hz, 1H), 7.79 (dd, J = 8.5, 2.2 Hz, 1H), 7.59 (d , J = 8.4 Hz, 1H), 7.48 (s, 2H), 7.47 – 7.38 (m, 3H), 7.19 (td, J = 8.4, 2.7 Hz, 2H), 5.24 (s, 2H), 3.82 (d, J = 8.2 Hz, 2H), 3.70 (s, 3H).

Example 63

。 Compound 63: 2-(2-Chlorophenyl)-N-(4-(((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)methyl)-3-amine Preparation of sulfonylphenyl) acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 63-2

Intermediate 63-1 (1 g, 5.2 mmol) was dissolved in DMF (10 mL), and cyclopropylmethyl bromide (696 mg, 5.2 mmol) and potassium carbonate (1.42 g, 10.4 mmol) were added, at room temperature Add water to the reaction solution for 2 hours, extract twice with ethyl acetate, combine the organic phases, wash with saturated brine in turn, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure before going through silica gel column chromatography (PE/EA=5 /1~3/1) to obtain 1.1 g of intermediate 63-2. LC-MS: [M+H] ⁺ =249.20.

Step (2) Preparation of Intermediate 63-3

Dissolve intermediate 63-2 (1 g, 4 mmol) in MeOH (10 mL) and add hydrogen peroxide (2.28 g, 20 mmol), react at room temperature for 5 hours, add sodium sulfite solution to extract the reaction solution, add ethyl acetate to the reaction solution The ester was extracted twice, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then subjected to silica gel column chromatography (PE/EA=5/1~3/1) to obtain intermediate Product 63-3 478 mg. LC-MS: [M+H] ⁺ =139.

Step (3) Preparation of Intermediate 63-4

Dissolve Intermediate 1-6 (500 mg, 1.35 mmol) in DMF (5 mL), add Intermediate 63-3 (225 mg, 1.62 mmol) and potassium carbonate (375.3 mg, 2.7 mmol) and stir at room temperature 2 hours. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then go through silica gel column chromatography (PE/EA=5/1~ 3/1), to obtain 650 mg of intermediate 63-4. LC-MS: [M+H] ⁺ =474.

Step (4) Preparation of Intermediate 63-5

Intermediate 63-4 (660 mg, 1.4 mmol) synthesized in multiple batches was dissolved in 1,4-dioxane (8 mL), and intermediate 1-9 (benzylthiol) (518 mg, 4.2 mmol) was added ), Pd ₂ (dba) ₃ (256 mg, 0.28 mmol), Xantphos (145 mg, 0.28 mmol) and DIEA (520 mg, 1.2 mol), reacted at 110 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure and subjected to silica gel column chromatography (PE/EA=5/1~3/1) to obtain 460 mg of intermediate 63-5. LC-MS: [M+H] ⁺ =517.

Step (5) Preparation of Compound 63

Intermediate 63-5 (200 mg, 0.38 mmol) and intermediate 1-11 (DCDMH) (151 mg, 0.774 mmol) were dissolved in CH ₃ CN (1 mL), AcOH (116 mg) and H ₂ O (0.1 mL), react at room temperature for 5 minutes. The reaction solution was added dropwise to ammonia water (10 mL) under stirring, and stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (20 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H2O/ACN system, and 24.2 mg of compound 63 was obtained after lyophilization. LC-MS: [M+H] ⁺ =476.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.54 (s, 1H), 8.23 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.4, 2.2 Hz, 1H), 7.61 (d , J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.42 (ddd, J = 8.9, 5.2, 2.3 Hz, 3H), 7.33 – 7.26 (m, 2H), 7.21 (d, J = 0.6 Hz, 1H), 5.24 (s, 2H), 3.89 – 3.77 (m, 4H), 1.19 – 1.08 (m, 1H), 0.52 – 0.43 (m, 2H), 0.32 – 0.26 (m, 2H).

Example 64

Compound 64: 2-(2-Chloro-5-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfonamide Preparation of acylphenyl) acetamide

synthetic route:

Step (1) Preparation of Intermediate 64-1

Dissolve Intermediate 22-4 (400 mg, 1.03 mmol) in DMF (3 mL), add Intermediate 23-1 (100 mg, 1.03 mmol) and potassium carbonate (284 mg, 2.06 mmol) and stir at room temperature 2 hours. Add water to the reaction solution and extract it twice with ethyl acetate, combine the organic phases, wash them successively with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then go through silica gel column chromatography (PE/EA=5/1~3 /1) 400 mg of intermediate 64-1 was obtained, with a yield of 86.3%. LC-MS: [M+H] ⁺ =452.

Step (2) Preparation of Intermediate 64-2

Intermediate 64-1 (400 mg, 0.88 mmol) was dissolved in 1,4-dioxane (4 mL), and intermediate 1-9 (benzylthiol) (329 mg, 2.65 mmol), Pd ₂ (dba) ₃ (161 mg, 0.176 mmol), Xantphos (101.7 mg, 0.1 mmol) and DIEA (330 mg, 2.65 mmol) were reacted at 110 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure and subjected to silica gel column chromatography (PE/EA=5/1~3/1) to obtain 400 mg of intermediate 64-2, with a yield of 90.1%. LC-MS: [M+H] ⁺ =496.

Step (3) Preparation of Compound 64

Intermediate 64-2 (65 mg, 0.13 mmol) and intermediate 1-11 (DCDMH) (38.7 mg, 0.197 mmol) were dissolved in CH ₃ CN (1 mL), AcOH (39 mg) and H ₂ O (0.1 mL), react at room temperature for 5 minutes.

The reaction solution was added dropwise to ammonia water (10 mL) under stirring, and stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (20 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H2O/ACN system, and the product was obtained after lyophilization, which was the product of compound 64 (10 mg, yield 16.9%). LC-MS: [M+H] ⁺ =454.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.55 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.6, 1.9 Hz, 1H), 7.59 (d , J = 8.4 Hz, 1H), 7.52 – 7.40 (m, 4H), 7.32 (dd, J = 9.5, 3.0 Hz, 1H), 7.19 (d, J = 3.7 Hz, 1H), 7.16 (dd, J = 8.5, 3.1 Hz, 1H), 5.24 (s, 2H), 3.85 (s, 2H), 3.70 (s, 3H).

Example 65

。 Compound 65: 2-(2-Chloro-5-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)- Preparation of 3-aminosulfonylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 65-1

Dissolve Intermediate 61-1 (207 mg, 1.5 mmol) in DMF (3 mL), add Intermediate 22-4 (400 mg, 1.0 mmol) and potassium carbonate (282 mg, 2.04 mmol) and stir at room temperature 2 hours. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then go through silica gel column chromatography (PE/EA=5/1~ 3/1) 250 mg of intermediate 65-1 was obtained, with a yield of 50%. LC-MS: [M+H] ⁺ =488.

Step (2) Preparation of Intermediate 65-2

Intermediate 65-1 (250 mg, 0.5 mmol) was dissolved in 1,4-dioxane (5 mL), and intermediate 1-9 (benzylthiol) (190 mg, 1.5 mmol), Pd ₂ (dba) ₃ (93.9 mg, 0.1 mmol), Xantphos (59 mg, 0.1 mmol) and DIEA (191 mg, 1.5 mmol) were reacted at 110 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure and then subjected to silica gel column chromatography (PE/EA=5/1~3/1) to obtain 218 mg of intermediate 65-2 with a yield of 81.9%. LC-MS: [M+H] ⁺ =532.

Step (3) Preparation of Compound 65

Intermediate 65-2 (204 mg, 0.39 mmol) and Intermediate 1-11 (DCDMH) (150.6 mg, 0.76 mmol) were dissolved in CH ₃ CN (2 mL), AcOH (115 mg) and H ₂ O (0.1 mL), reacted at room temperature for 5 minutes (obtained intermediate 65-3). The above reaction solution was added dropwise to ammonia water (10 ml) under stirring, and stirred at room temperature for 0.5 hour. The reaction solution was diluted with water (20 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and after lyophilization, 26.2 mg of compound 65 was obtained, with a yield of 13.7%. LC-MS: [M+H] ⁺ =489.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.58 (s, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.81 (d, J = 6.3 Hz, 1H), 7.67 (d , J = 5.9 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.57 – 7.42 (m, 3H), 7.33 (dd, J = 9.3, 2.6 Hz, 1H), 7.22 – 7.12 (m, 1H), 5.31 (s, 2H), 3.86 (s, 2H).

Example 66

。 Compound 66: 2-(2-chlorophenyl)-N-(4-(((1-(1,1-difluoropropyl)-1H-pyrazol-4-yl)oxy)methyl)- Preparation of 3-aminosulfonylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 66-2

Intermediate 63-1 (500 mg, 2.57 mmol) was dissolved in DMF (5 mL), and intermediate 66-1 (bromodifluoropropene) (605 mg, 3.85 mmol) and K ₂ CO ₃ (709 mg, 5.14 mmol), N ₂ protected room temperature and reacted overnight. Stop the reaction, add water to the reaction solution, extract EA and combine the EA phases, concentrate the reaction solution under reduced pressure and purify it by silica gel column chromatography (PE/EA=5/1~3/1) to obtain 410 mg of intermediate 66-2 , yield 59.2%. LC-MS: [M+H] ⁺ =271.

Step (2) Preparation of Intermediate 66-3

Intermediate 66-2 (410 mg, 1.51 mmol) was dissolved in methanol (10 mL), and after adding palladium on carbon (100 mg), stirred at room temperature under hydrogen protection for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 410 mg of intermediate 66-3. LC-MS: [M+H] ⁺ =273.

Step (3) Preparation of Intermediate 66-4

Intermediate 66-3 (410 mg, 1.51 mmol) was dissolved in methanol (5 mL), hydrogen peroxide (5 mL, 30%) was added and stirred at room temperature for 2 hours. The reaction solution was quenched with saturated sodium sulfite at 0 °C and extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (PE /EA=5/1~3/1) to obtain the product, 180 mg of intermediate 66-4 was obtained, and the yield was 72.8%. LC-MS: [M+H] ⁺ =163.

Step (4) Preparation of Intermediate 66-5

Dissolve Intermediate 66-4 (180 mg, 1.1 mmol) in DMF (4 mL), add Intermediate 1-6 (410 mg, 1.1 mmol) and potassium carbonate (455 mg, 3.3 mmol) and stir at room temperature 2 hours. Add water to the reaction solution and extract it twice with ethyl acetate, combine the organic phases, wash them successively with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then go through silica gel column chromatography (PE/EA=5/1~3 /1) 360 mg of intermediate 66-5 was obtained, with a yield of 65.6%. LC-MS: [M+H] ⁺ =499.

Step (5) Preparation of Intermediate 66-6

Intermediate 66-5 (360 mg, 0.72 mmol) was dissolved in 1,4-dioxane (5 mL), and intermediate 1-9 (benzylthiol) (267 mg, 2.16 mmol), Pd ₂ (dba) ₃ (64 mg, 0.07 mmol), Xantphos (40 mg, 0.07 mmol) and DIEA (280 mg, 2.16 mmol) were reacted at 110 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure and subjected to silica gel column chromatography (PE/EA=5/1~3/1) to obtain the product, 300 mg of intermediate 66-6, with a yield of 76.9%. LC-MS: [M+H] ⁺ =542.

Step (6) Preparation of Compound 66

Intermediate 66-6 (300 mg, 0.55 mmol) and Intermediate 1-11 (DCDMH) (216 mg, 1.1 mmol) were dissolved in CH ₃ CN (3 mL), AcOH (165 mg, 2.75 mmol) and H ₂ O (0.1 mL), react at room temperature for 5 minutes. The reaction solution was added dropwise to ammonia water (10 mL) under stirring, and stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (20 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system, and after lyophilization, 83.4 mg of compound 66 was obtained, with a yield of 30.3%. LC-MS: [M+H] ⁺ =499.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.54 (s, 1H), 8.23 (d, J = 2.2 Hz, 1H), 7.81 (dd, J = 8.4, 2.2 Hz, 1H), 7.60 (d , J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.49 (s, 2H), 7.42 (ddd, J = 8.4, 5.4, 2.2 Hz, 2H), 7.34 – 7.24 (m, 3H), 6.20 ( t, J = 4.4 Hz, 1H), 6.06 (t, J = 4.4 Hz, 1H), 5.92 (t, J = 4.4 Hz, 1H), 5.25 (s, 2H), 4.13 (t, J = 7.2 Hz, 2H), 3.84 (s, 2H), 2.41 – 2.22 (m, 2H).

Example 67

。 Compound 67: 2-(2-chloro-4-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)- Preparation of 3-aminosulfonylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 67-1

Dissolve Intermediate 61-1 (200 mg, 1.5 mmol) in DMF (3 mL), add Intermediate 21-4 (400 mg, 1.0 mmol) and potassium carbonate (410 mg, 3.0 mmol) and stir at room temperature 2 hours. Add water to the reaction solution and extract it twice with ethyl acetate, combine the organic phases, wash them successively with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, then go through silica gel column chromatography (PE/EA=5/1~3 /1) 240 mg of intermediate 67-1 was obtained, with a yield of 50%. LC-MS: [M+H] ⁺ =488.

Step (2) Preparation of Intermediate 67-2

Intermediate 67-1 (240 mg, 0.5 mmol) was dissolved in 1,4-dioxane (5 mL), and intermediate 1-9 (benzylthiol) (124 mg, 1.0 mmol), Pd ₂ (dba) ₃ (46 mg, 0.05 mmol), Xantphos (30 mg, 0.05 mmol) and DIEA (200 mg, 1.5 mmol) were reacted at 110 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure and subjected to silica gel column chromatography (PE/EA=5/1~3/1) to obtain 210 mg of intermediate 67-2 with a yield of 78.9%. LC-MS: [M+H] ⁺ =532.

Step (3) Preparation of Compound 67

Intermediate 67-2 (210 mg, 0.39 mmol) and intermediate 1-11 (DCDMH) (156 mg, 0.78 mmol) were dissolved in CH ₃ CN (2 mL), AcOH (120 mg) and H ₂ O (0.1 mL), react at room temperature for 5 minutes. The reaction solution was added dropwise to ammonia water (10 ml) under stirring, and stirred at room temperature for 0.5 hour. The reaction solution was diluted with water (20 mL), and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H2O/ACN system, and after lyophilization, 13.1 mg of compound 67 was obtained, with a yield of 6.9%. LC-MS: [M+H]+=489.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.56 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 7.96 (s, 1H), 7.84 – 7.78 (m, 1H), 7.67 (d, J = 5.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 6.0 Hz, 2H), 7.44 (ddd, J = 11.4, 8.8, 4.4 Hz, 2H) , 7.19 (td, J = 8.6, 2.8 Hz, 1H), 5.31 (s, 2H), 3.83 (s, 2H).

Example 68

Compound 68: N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)- Preparation of 2-(2-chloro-4-fluorophenyl)acetamide

。 Compound 69: N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)- Preparation of 2-(2-chloro-4-fluorophenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 68-1

Dissolve the weighed intermediate 21-4 (500 mg, 1.286 mmol) in THF (20 mL), add intermediate 60-1 (355 mg, 1.928 mmol) and Ag ₂ CO ₃ (709 mg, 2.571 mmol ), and reflux at 70°C overnight. LCMS monitoring showed that there was product formation, the reaction solution was added with water and extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure and subjected to silica gel column chromatography (PE/EA =10/1) Purified to obtain 560 mg of the product of intermediate 68-1.

Step (2) Preparation of Intermediate 68-2

Dissolve the weighed intermediate 68-1 (560 mg, 1.039 mmol) in DME/H ₂ O (7.5 mL/7.5 mL), add Na ₂ CO ₃ (133 mg, 1.247 mmol), and react at 100 °C for 1 Hour. Add water to the reaction solution and extract it twice with ethyl acetate, combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, and purify by silica gel column chromatography (PE/EA=2/1) to obtain intermediate 68-2 Product 320 mg.

Step (3) Preparation of Intermediate 68-3 and Intermediate 69-1

Dissolve the weighed intermediate 68-2 (320 mg, 0.729 mmol) in acetonitrile (10 mL), add diethyl bromofluoromethyl phosphate (585 mg, 2.188 mmol) and KF (170 mg, 2.916 mmol ), react overnight at 70 °C, add water to the reaction solution and extract it twice with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify by Prep-TLC (PE/EA=2/1) to obtain the intermediate 90 mg of the product of 68-3, and 90 mg of its isomer intermediate 69-1.

Step (4) Preparation of Intermediate 68-4 and Intermediate 69-2

The weighed intermediate 68-3 (90 mg, 0.184 mmol) and intermediate 69-1 (90 mg, 0.184 mmol) were dissolved in 1,4-dioxane (2 mL) in two pots respectively, Add intermediate 1-9 (benzylthiol) (46 mg, 0.368 mmol), Pd ₂ (dba) ₃ (17 mg, 0.018 mmol), Xantphos (11 mg, 0.018 mmol) and DIEA (72 mg, 0.555 mmol ), added nitrogen protection and reacted overnight at 100 °C, added water to the reaction solution, extracted with EA, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, and purified by Prep-TLC (PE/EA = 2/1) to obtain Product, 80 mg of intermediate 68-4 was obtained, and 80 mg of its isomer intermediate 69-2 was obtained.

Step (5) Preparation of Compound 68 and Compound 69

Intermediate 68-4 (80 mg, 0.150 mmol) and intermediate 69-2 (80 mg, 0.150 mmol) were dissolved in CH ₃ CN (2 ml), AcOH (0.25 mL) and H ₂ O ( 0.25 mL), add intermediate 1-11 (DCDMH) (45 mg, 0.226 mmol) respectively, react at room temperature for 5 minutes, add the reaction solution dropwise into ammonia water (0.5 mL) under stirring, Add water, extract with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the reaction solution under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using H ₂ O/ACN system to obtain the product Compound 68 (10.2 mg) and Compound 69 (13.6 mg) as white solids.

Compound 68: LC-MS: M fragment = 355.05 .

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.62 (s, 1H), 8.47 (d, J = 10.7 Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 8.4, 2.2 Hz, 1H), 7.76 (s, 1H), 7.65 – 7.60 (m, 2H), 7.57 – 7.40 (m, 4H), 7.22 (td, J = 8.5, 2.7 Hz, 1H), 5.61 ( s, 2H), 3.86 (s, 2H).

Compound 69: LC-MS: M fragment = 355.05 .

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.65 (s, 1H), 8.30 (d, J = 2.2 Hz, 1H), 7.92 – 7.79 (m, 2H), 7.72 (s, 1H), 7.62 (dd, J = 19.7, 10.3 Hz, 4H), 7.47 (ddd, J = 11.5, 8.7, 4.4 Hz, 2H), 7.22 (td, J = 8.5, 2.7 Hz, 1H), 5.74 (s, 2H), 3.87 (s, 2H).

Example 69

。 Compound 70: N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)- Preparation of 2-(2-chloro-5-fluorophenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 70-1

Dissolve the weighed intermediate 22-4 (1.0 g, 2.571 mmol) in THF (20 mL), add intermediate 60-1 (710 mg, 3.857 mmol) and Ag ₂ CO ₃ (1.4 g, 5.142 mmol ), and reflux at 70°C overnight. The reaction solution was extracted twice with water and ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, purified by silica gel column chromatography (PE/EA=8/1) to obtain intermediate 70-1 Product 1.2 g.

Step (2) Preparation of Intermediate 70-2

Dissolve the weighed intermediate 70-1 (1.2 g, 2.227 mmol) in DME/H ₂ O (7.5 mL/7.5 mL), add Na ₂ CO ₃ (284 mg, 2.673 mmol), and react at 100 °C for 2 Hour. Add water to the reaction solution and extract it twice with ethyl acetate, combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, and purify by silica gel column chromatography (PE/EA=2/1) to obtain intermediate 70-2 Product 900 mg.

Step (3) Preparation of Intermediate 70-3 and Intermediate 71-1

Dissolve the weighed intermediate 70-2 (900 mg, 2.052 mmol) in acetonitrile (25 mL), add diethyl bromofluoromethyl phosphate (1.6 g, 6.155 mmol) and KF (477 mg, 8.206 mmol ), react overnight at 70°C. Add water to the reaction solution and extract it twice with ethyl acetate, combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, and purify by silica gel column chromatography (PE/EA=8/1~4/1) to obtain the product, 400 mg of intermediate 70-3 and 200 mg of its isomer intermediate 71-1 were obtained.

Step (4) Preparation of Intermediate 70-4 and Intermediate 71-2

Dissolve the weighed intermediate 70-3 (400 mg, 0.818 mmol) and intermediate 71-1 (200 mg, 0.409 mmol) in 1,4-dioxane (2 mL/1mL) in two pots In , add intermediate 1-9 (benzylthiol) (204 mg/102 mg, 1.637 mmol/0.818 mmol), Pd ₂ (dba) ₃ (76 mg/38 mg, 0.082 mmol/0.041 mmol), Xantphos ( 48 mg/24 mg, 0.082 mmol/0.041 mmol) and DIEA (318 mg/159 mg, 2.456 mmol/1.228 mmol), add nitrogen protection and react overnight at 100 ℃, add water to the reaction solution, extract with EA, organic Wash with saturated brine, dry over sodium sulfate, and purify by silica gel column chromatography (PE/EA = 6/1~3/1) to obtain the product, 400mg of intermediate 70-4 and its isomer intermediate 71- 2 products 200mg.

Step (5) Preparation of Compound 70 and Compound 71

Intermediate 70-4 (400 mg, 0.752 mmol) and intermediate 71-2 (200 mg, 0.376 mmol) were dissolved in CH ₃ CN (4 mL), AcOH (0.5 mL) and H ₂ O ( 0.5 mL), add intermediate 1-11 (DCDMH) (224 mg/112 mg, 1.128 mmol/0.564 mmol) respectively, react at room temperature for 5 minutes, and add the reaction solution dropwise into ammonia water (0.5 mL), add water to the reaction solution, extract with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate the reaction solution under reduced pressure to obtain the crude product. The crude product was separated and purified by prep-HPLC using H2O/ACN system to obtain 155.8 mg of compound 70 and 14.7 mg of compound 71.

Compound 70: LC-MS: [M+H] ⁺ =522.95.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.63 (s, 1H), 8.45 (s, 1H), 8.29 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 8.5, 2.1 Hz , 1H), 7.76 (s, 1H), 7.67 – 7.60 (m, 2H), 7.59 – 7.41 (m, 3H), 7.35 (dd, J = 9.5, 3.1 Hz, 1H), 7.19 (td, J = 8.5 , 3.1 Hz, 1H), 5.62 (s, 2H), 3.89 (s, 2H).

Compound 71: LC-MS: Ms Fragment=355.00 .

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.50 (s, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.80 (dd, J = 8.4, 2.0 Hz, 1H), 7.65 (d , J = 8.4 Hz, 1H), 7.50 (dd, J = 8.8, 5.3 Hz, 1H), 7.34 (dd, J = 8.6, 3.9 Hz, 3H), 7.19 (td, J = 8.5, 3.1 Hz, 1H) , 5.38 (t, J = 3.7 Hz, 1H), 4.84 (d, J = 5.6 Hz, 2H), 3.87 (s, 2H).

Example 70

Compound 72: 2-(2-Chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfonamide Preparation of acylphenyl) acetamide

。 Compound 73: 2-(2-Chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-5-yl)oxy)methyl)-3-sulfonamide Preparation of acylphenyl) acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 72-1

The weighed intermediate 60-3 (1.5 g, 2.659 mmol) was dissolved in DME (10 mL) and water (10 mL), sodium carbonate (339 mg, 3.191 mmol) was added, and reacted at 100 °C for 2 hours. New spots were formed, the reaction solution was added with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE/EA=5/1~2/1) to obtain intermediate 72 Product of -1 880 mg.

Step (2) Preparation of Intermediates 72-2 and 73-1

Dissolve the weighed intermediate 72-1 (880 mg, 1.897 mmol) in acetonitrile (25 mL), add diethyl bromofluoromethyl phosphate (1.5 g, 5.690 mmol) and KF (441 mg, 7.587 mmol ), and react overnight at 70°C. Add water to the reaction solution, extract with EA, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 1.1 g of the product of intermediate 72-2 and its isomer intermediate 73-1 without purification directly used in the next reaction.

Step (3) Preparation of Compound 72 and Compound 73

The mixture of intermediate 72-2 and its isomer intermediate 73-1 obtained in the previous step (1.1 g, 2.141 mmol) was dissolved in glacial acetic acid (30 mL) and water (10 mL), and NCS was added in batches (858 mg, 6.421 mmol), react at room temperature for 3 hours, add water to the reaction solution, extract with EA, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 1.1 g of crude product. Dissolve the crude product in 20 mL of THF, add it dropwise to 20 mL of stirred ammonia water, react at room temperature for 10 minutes, LCMS monitoring shows that the product is formed, add water to the reaction solution, extract with EA, wash the organic phase with saturated brine, anhydrous sodium sulfate After drying, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC using H ₂ O/ACN system to obtain 240 mg of compound 72 and 103.3 mg of its isomer compound 73.

Compound 72: LC-MS: [M+H] ⁺ =471.05 .

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.59 (s, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 2.8 Hz, 1H), 7.84 (dd, J = 8.5, 2.1 Hz, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.61 (d, J = 4.0 Hz, 1H), 7.51 (s, 2H), 7.47 – 7.40 (m, 2H) , 7.32 (dd, J = 9.3, 4.9 Hz, 2H), 6.12 (d, J = 2.8 Hz, 1H), 5.55 (s, 2H), 3.87 (s, 2H).

Compound 73: LC-MS: [M+H] ⁺ =471.05 .

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.62 (s, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 8.5, 2.2 Hz, 1H), 7.68 (d , J = 2.7 Hz, 1H), 7.65 (s, 1H), 7.63 (s, 2H), 7.57 (d, J = 1.7 Hz, 1H), 7.54 (s, 1H), 7.44 (ddd, J = 6.6, 5.8, 3.7 Hz, 2H), 7.34 – 7.29 (m, 2H), 5.87 (d, J = 1.8 Hz, 1H), 5.55 (s, 2H), 3.87 (s, 2H).

Example 71

。 Compound 74: 2-(2-Chloro-5-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)- Preparation of 3-aminosulfonylphenyl)acetamide

.

。 synthetic route:

.

Step (1) Preparation of Intermediate 74-1

Add intermediate 22-2 (4.807 g, 12 mmol), intermediate 1-9 (benzylthiol) (4.471 g, 36 mmol), Pd ₂ (dba) ₃ (2.197 g, 2.4 mmol) in a 250 mL reaction flask ), DIEA (4.652 g, 36 mmol), Xantphos (1.388 g, 2.4 mmol) and 1,4-dioxane (95 mL), nitrogen protection. React overnight at 110°C. Treatment: The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography, eluent (PE/EA=5:1), to obtain 4.2 g of the product of intermediate 74-1.

Step (2) Preparation of Intermediate 74-2

Intermediate 74-1 (4.2 g, 9.46 mmol), NCS (3.59 g, 28.38 mmol), AcOH (1.556 g, 2.84 mmol) and ACN/H ₂ O (84 mL/0.84 mL) were added to a 250 mL reaction vial. After reacting at room temperature for 30 minutes, PMBNH ₂ (1.946 g, 14.192 mmol) was added, and the reaction was continued at room temperature for 30 minutes. Treatment: The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography, eluent (PE/EA=6:1), to obtain 3.8 g of the product of intermediate 74-2.

Step (3) Preparation of Intermediate 74-3

Intermediate 74-2 (3.8 g, 7.294 mmol) and THF 76 mL were added to a 100 mL reaction flask, lithium aluminum hydride (553 mg, 14.588 mmol) was added in batches, and the reaction was carried out at room temperature for 2 hours. Treatment: Quench the reaction solution with 3.8 ml of water, make it weakly acidic, extract twice with ethyl acetate, combine the organic phases, dry, and concentrate under reduced pressure to obtain 2.3 g of the product of intermediate 74-3.

Step (4) Preparation of Intermediate 74-4

Intermediate 74-3 (2.135 g, 4.331 mmol) and 20 mL of DCM were added to a 100 mL reaction flask, and SOCl ₂ (1.031 g, 8.662 mmol) was added dropwise, and reacted overnight at room temperature. Treatment: The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography, eluent (PE/EA=6:1), to obtain 2.4 g of the product of intermediate 74-4.

Step (5) Preparation of Intermediate 74-5

Add intermediate 74-4 (2.328 g, 4.55 mmol), THF 23 mL, intermediate 60-1 (1.006 g, 5.463 mmol) and Ag ₂ CO ₃ (2.51 g, 9.105 mmol) in a 50 mL reaction bottle, 70 Celsius reaction overnight. Treatment: The reaction solution was extracted twice with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and then purified by silica gel column chromatography, eluent (PE/EA=8:1), to obtain 2.3 g of intermediate 74-5 .

Step (6) Preparation of Intermediate 74-6

Add intermediate 74-5 (2.3 g, 3.49 mmol), DME/H ₂ O (15 mL/15 mL) and Na ₂ CO ₃ (517 mg, 4.885 mmol) into a 50 mL reaction vial, react at 100°C for 6 hours . Treatment: The reaction solution was extracted twice with ethyl acetate, the organic phases were combined, dried and concentrated to obtain 2.0 g of the product of intermediate 74-6.

Step (7) Preparation of Intermediate 74-7

Add intermediate 74-6 (1.0 g, 1.7 mmol), MeCN 20 mL, diethyl bromofluoromethyl phosphate (1.4 g, 5.1 mmol) and KF (415 mg, 7.1 mmol) to a 50 mL reaction bottle, 70 Celsius reaction overnight. Treatment: The reaction solution was extracted twice with ethyl acetate, the organic phases were combined, concentrated under reduced pressure and then purified by silica gel column chromatography, eluent (PE/EA=5:1), to obtain the product 567 of the intermediate 74-7 mg.

Step (8) Preparation of Compound 74

Intermediate 74-7 (188 mg, 0.31 mmol), MeCN/H ₂ O (0.8 mL/0.8 mL) and CAN (509 mg, 0.9 mmol) were added to a 25 mL reaction vial, and reacted overnight at room temperature. Treatment: The reaction solution was extracted twice with ethyl acetate, the organic phases were combined, dried and concentrated to obtain 27 mg of compound 74. LC-MS: [M+H] ⁺ =355.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.64 (s, 1H), 8.29 (d, J = 1.9 Hz, 1H), 7.84 (dd, J = 8.2, 2.0 Hz, 1H), 7.73 – 7.61 ( m, 4H), 7.58 (d, J = 1.1 Hz, 1H), 7.54 (s, 1H), 7.50 (dd, J = 8.8, 5.3 Hz, 1H), 7.35 (dd, J = 9.4, 3.0 Hz, 1H ), 7.20 (td, J = 8.5, 3.0 Hz, 1H), 5.87 (d, J = 1.5 Hz, 1H), 5.56 (s, 2H), 3.89 (s, 2H).

Example 72

。 Compound 75: 2-(2-Chloro-4-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)- Preparation of 3-aminosulfonylphenyl)acetamide

.

。 synthetic route:

.

experiment procedure

Step (1) Preparation of Intermediate 75-1

Add intermediate 21-2 (4.01g, 10 mmol), intermediate 1-9 (benzyl thiol) (3.72 g, 30 mmol), Pd ₂ (dba) ₃ (1.831 g, 2 mmol) in a 250 mL reaction vial ), DIEA (3.87 g, 30 mmol), Xantphos (1.15 g, 2 mmol) and 1,4-dioxane (10 mL), nitrogen protection. React overnight at 110°C. Treatment: The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography, eluent (PE/EA=5:1), to obtain 4.3 g of the product of intermediate 75-1.

Step (2) Preparation of Intermediate 75-2

Add intermediate 75-1 (2.3 g, 5.181 mmol), NCS (1.97 g, 15.543 mmol), AcOH (1.556 g, 25.905 mmol) and ACN/H ₂ O (46 mL/0.46 mL) in a 250 mL reaction vial . After reacting at room temperature for 30 minutes, PMBNH ₂ (1.066 g, 7.772 mmol) was added, and the reaction was continued at room temperature for 30 minutes. Treatment: The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography, eluent (PE/EA=6:1), to obtain 1.65 g of the product of intermediate 75-2.

Step (3) Preparation of Intermediate 75-3

Intermediate 75-2 (1.45 g, 2.78 mmol) and THF (29 mL) were added to a 100 mL reaction flask, lithium aluminum hydride (159 mg, 4.17 mmol) was added in batches, and the reaction was carried out at room temperature for 2 hours. Treatment: Quench the reaction solution with 1.45 ml of water, make it weakly acidic, extract twice with ethyl acetate, combine the organic phases, dry and concentrate to obtain 1.25 g of the product of intermediate 75-3.

Step (4) Preparation of Intermediate 75-4

Intermediate 75-3 (1.15 g, 2.33 mmol) and DCM (12 mL) were added to a 100 mL reaction vial, and SOCl ₂ (556 mg, 4.66 mmol) was added dropwise, and reacted overnight at room temperature. Treatment: The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography, eluent (PE/EA=6:1), to obtain 1.17 g of the product of intermediate 75-4.

Step (5) Preparation of Intermediate 75-5

Add intermediate 75-4 (1.17 g, 2.29 mmol), THF (12 mL), intermediate 60-1 (506 mg, 2.75 mmol) and Ag ₂ CO ₃ (1.26 g, 4.57 mmol) in a 50 mL reaction vial , react overnight at 70°C. Treatment: The reaction solution was extracted twice with ethyl acetate, the organic phases were combined, concentrated under reduced pressure and then purified by silica gel column chromatography, eluent (PE/EA=8:1), to obtain the product 800 of intermediate 75-5 mg.

Step (6) Preparation of Intermediate 75-6

Add intermediate 75-5 (395 mg, 0.6 mmol), DME/H ₂ O (4 mL/ 4 mL) and Na ₂ CO ₃ (77 mg, 0.72 mmol) into a 50 mL reaction vial, and react at 100°C for 6 hours. Treatment: The reaction solution was extracted twice with ethyl acetate, the organic phases were combined, dried and concentrated to obtain 315 mg of the product of intermediate 75-6.

Step (7) Preparation of Intermediate 75-7

Add intermediate 75-6 (336 mg, 0.6 mmol), 5 mL of MeCN, diethyl bromofluoromethyl phosphate (480 mg, 1.8 mmol) and KF (139 mg, 2.4 mmol) into a 50 mL reaction vial at 70 °C React overnight. Treatment: The reaction solution was extracted twice with ethyl acetate, the organic phases were combined, concentrated under reduced pressure and then purified by silica gel column chromatography, eluent (PE/EA=5:1), to obtain the product 130 of the intermediate 75-7 mg.

Step (8) Preparation of Compound 75

Add intermediate 75-7 (250 mg, 0.41 mmol), MeCN/H ₂ O (1.3 mL/1.3 mL) and CAN (ceric ammonium nitrate, 675 mg, 1.23 mmol) to a 25 mL reaction vial, and react overnight at room temperature . Treatment: The reaction solution was extracted twice with ethyl acetate, the organic phases were combined, dried and concentrated, and the crude product was separated by prep-HPLC using H ₂ O/ACN system. The product of compound 75 was 38 mg. LC-MS: [M+H] ⁺ =355.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.62 (s, 1H), 8.29 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 8.3, 2.2 Hz, 1H), 7.66 (dd, J = 14.2, 5.6 Hz, 4H), 7.58 (d, J = 1.7 Hz, 1H), 7.54 (s, 1H), 7.47 (ddd, J = 11.5, 8.7, 4.5 Hz, 2H), 7.22 (td, J = 8.5, 2.7 Hz, 1H), 5.87 (d, J = 1.8 Hz, 1H), 5.56 (s, 2H), 3.86 (s, 2H).

biological test

Example A: Evaluation of in vitro biological activity

FLIPR (fluorescence imaging plate reader) method was used to determine the antagonistic properties of the compounds of the present invention, which were expressed by hP2X4 (human purinergic P2X receptor subunits) expressed in HEK293 cells (human kidney epithelial cell line, ATCC) type 4, accession number NM_001256796.2) is an inhibitor of the increase in intracellular calcium induced by activation.

HEK293 cells stably expressing hP2X4 were placed in a cell culture incubator at 37 °C with a humidity of 5% to contain 10% FBS (fetal bovine serum, Biosera, FB-1058/500), 1% penicillin-streptomycin (Gibco, 15140-122), and 1 mg/mL G418 (CABIOCHE, 345810) in DMEM high glucose medium for culture. Eighteen to 24 hours before the FLIPR experiment, cells were seeded into 384 wells at a density of 400,000 cells/ml (10,000 cells/well) and incubated overnight in a cell culture incubator. On the day of the experiment, the medium was discarded, and the cells were incubated in FLIPR buffer (each 30 mL buffer contained 0.3 mL probenecid (Thermo, P36400), 0.6 mL 1M HEPES (Invitrogen, 15630080) and 29.1 mL HBSS (Invitrogen, 14065056) 20 μL of 0.5×Calcium 6 fluorescent dye (Molecular Devices, R8190) was added to each well, and the dye loading was incubated at 37 °C for 1.5 hours. Then 10 μL of the test compound (dissolved in DMSO at a concentration of 10 mM and serially diluted with buffer) or vehicle was added to the wells and allowed to pre-incubate at 37 °C for 30 minutes. The cell plate was then placed in the FLIPR for baseline fluorescence measurements (excitation at 485 nm, emission at 525 to 535 nm). Then add agonist (BZ-ATP (Sigma, B6396) at a final concentration of 5 μM) or vehicle (ultrapure water) at 10 μL/well, and measure fluorescence at 1 second intervals for 2 minutes , and finally analyze the output fluorescence counts.

The _IC50s obtained using the method described above are shown in Table 1.

Table 1. _IC50 Obtained for the Compounds in the Examples on the P2X4 Receptor Compound number IC ₅₀ /nM Compound number IC ₅₀ /nM Compound number IC ₅₀ /nM 1 24.3 27 B 56 67.6 2 27.10 30 C 57 51.2 3 25.1 33 C 59 B 4 124 34 C 60 12.8 6 9.8 35 C 61 17.7 7 88.4 39 C 62 13.7 9 7.6 40 C 63 B 10 18.3 42 C 64 17.3 12 13.0 43 C 65 3 16 70.5 46 5.9 66 B 18 C 47 3.8 67 5.8 19 C 48 4.6 68 71.9 20 31.8 49 32.8 69 27.0 twenty one 54.2 50 59.9 70 112.9 twenty two 32.4 51 189.9 72 30.5 twenty three 16.5 52 166.5 73 35.9 twenty four B 53 12.2 74 17.9 25 B 54 18.6 75 13.5 26 C 55 B Among them, A: IC ₅₀ ≤10 nM, B: 10<IC ₅₀ ≤50 nM, C: 50<IC ₅₀ ≤200 nM.

It can be seen from the data in Table 1 that the compounds of the present invention have good P2X4 inhibitory activity, and we particularly prefer compounds with IC ₅₀ ≤ 200 nM, more preferably compounds with IC ₅₀ ≤ 50 nM.

Example B: In Vitro Cytotoxicity Test

The in vitro cytotoxicity test of the compounds of the present invention was determined by the CCK-8 method in HepG2 cells. HepG2 cells in the logarithmic phase (Beina Bio) were collected, the concentration of the cell suspension was adjusted, and 50,000 cells/well were plated in a 96-well cell culture plate, and the cells were incubated overnight in a 5% cell culture incubator at 37 °C. After the confluence of the cells in the plate reached 80 to 90%, the medium was changed and various concentration gradients of the test compound or vehicle (DMSO) were added, and incubated at 5%, 37°C for 48 hours in a cell culture incubator. After the treatment, the culture medium in the plate was discarded, washed twice with PBS, 100 μL of CCK-8 working solution (Beyontian Biotechnology) was added to each well, and incubated at 37 °C in the dark for 1.5 hours, and the OD at _{450 nm} was detected on a microplate reader. The absorbance value of each well was analyzed to calculate the CC ₅₀ of each compound.

The _CC50s obtained using the method described above are shown in Table 2.

Table 2. CC ₅₀ Obtained for Some Compounds compound HepG2 CC ₅₀ (μM) compound HepG2 CC ₅₀ (μM) 1 >100 54 >100 2 >100 55 54.3 3 53.6 57 >100 6 >100 60 >100 9 94.92 61 >100 10 >100 62 >100 20 41.62 63 51.72 twenty one >100 64 >100 twenty two >100 65 >100 twenty three >100 66 >100 44 >100 67 >100 46 54.8 72 >100 47 55.5 73 51.23 48 67.9 74 99.78 49 >100 75 54.42

It can be seen from the data in Table 2 that most of the compounds of the present invention have good safety, and the range of CC ₅₀ is > 40 μM, which meets the requirements of general compounds on cytotoxicity in vitro. We prefer compounds with CC ₅₀ > 40 μM, more preferably Compounds with _CC50 > 100 μM.

Embodiment C: in vitro metabolic stability test

The in vitro metabolic stability of the compounds of the present invention was determined by the in vitro incubation method of liver microsomes of various species. In the liver microsome reaction system (1 mg/mL liver microsomal protein, 25 U/mL glucose-6-phosphate dehydrogenase, 1 mM NADP, 6 mM D-6-phosphate glucose, 5 mM MgCl ₂ ) The test compound was incubated in a 37°C water bath to start the reaction, and 100 μL of the reaction solution was added at each time point to 400 μL of 0°C pre-cooled internal standard working solution (containing 200 ng/mL dexamethasone, Acetonitrile solution of phenolic acid, tolbutamide, labetalol) centrifuge tube, stop the reaction, centrifuge at 10000 rpm for 10 minutes at 4 °C, take the supernatant and enter it into LC-MS for analysis and detection, and obtain the test compound in In vitro metabolic half-lives of various species in liver microsomes.

T _1/2 obtained using the method described above is shown in Table 3.

Table 3. T _1/2 Obtained for Selected Compounds Compound number Human liver microsome T _1/2 (min) Rat liver microsome T _1/2 (min) Guinea pig liver microsomes T _1/2 (min) D1 396.3 6.9 / D2 275.77 6.3 / 1 132.2 21.3 / 2 593.3 83.8 84.5 3 231.5 62.2 27.5 6 377.5 102.7 175.0 7 828.0 41.7 / 9 375.4 75.6 69.0 10 92.4 41.4 / 12 189.8 41.6 / 20 185.0 28.1 / twenty one 2587.3 97.4 62.7 twenty two 271.7 59.0 / twenty three 183.9 34.4 / 46 210.1 33.2 26.1 47 331.1 59.5 / 48 336.2 61.4 76.9 49 11.5 26.2 26.0 54 295.67 42.9 / 55 80.8 10.9 / 57 82.39 29.95 / 59 356.32 44.52 / 60 456 123.36 93.77 61 327.23 66.44 88.04 62 446.33 87.66 64.79 63 56.05 21.48 / 64 168.47 58.27 / 65 376.2 153.32 60.0 66 92.01 34.96 / 67 406.84 151.33 94.13 68 629.19 64.23 30.72 69 444.16 88.59 / 72 303.1 25.81 / 73 255.22 50.03 / Note: NA means basically no metabolism; "/" means not tested.

It can be seen from the data in Table 3 that the compound of the present invention has good metabolic stability in humans, rats and guinea pigs.

Example D: Pharmacokinetic (PK) analysis in rats

Some compounds in the present invention's preferred above-mentioned examples and reference compound D1, D2 are carried out rat pharmacokinetic experiment, and relevant experiment situation is as follows:

Rats: SD rats, SPF grade, 6 males, body weight range from 180 to 200 g (source & certificate number: provided by Haipu Biotech);

Administration method: PO/IV

Dosage: PO/IV: 1 mg/kg

Preparation: Dissolve in DMSO in PO group, add 4% Tween80, and dissolve by ultrasonic wave for 10 minutes;

Group IV ethanol and PEG400, ultrasonic wave for 5 minutes, add the required volume of pure water, ultrasonic wave for 5 minutes to dissolve.

Take 2 parts each of the upper, middle and lower layers for the suspension, and 2 parts for the middle layer for the clarified solution, accurately pipette 100 μL into a 1.5 mLEP tube for each part, take a sample before administration, store the sample in a -80 ℃ refrigerator, and keep it with the plasma sample Send samples together for bioanalysis testing.

Sampling points: The blood sampling time points of PO group were 0.167, 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 hours;

The time points of blood collection in group IV were 0.033, 0.167, 0.5, 1, 2, 4, 6, 8, 10 and 24 hours.

Animals in the PO group were fasted overnight before administration, and returned food 4 hours after administration, and animals in the IV group were not fasted throughout the process;

Sample handling:

1. After the administration of the two groups of rats, collect blood from the jugular vein of the rats according to the sampling time point, and collect about 0.2 to 0.3 mL of blood at each time point in an anticoagulant EP tube (containing 4 μL EDTA-K2, 375 mg/mL), slowly invert up and down 3 times, and store in an ice box (no more than 30 minutes),

2. Centrifuge at 3500 × g for 10 minutes at 4 °C, transfer the supernatant to a labeled EP tube, and store the sample at -80 °C.

3. Using Tolbutamide as the internal standard compound (IS), the sample was subjected to protein precipitation and extraction. The sample extract was analyzed by LC-MS/MS system, which used Sciex Exion LC AD high performance liquid chromatography system and XBridge BEH C18 (2.1×50 mm, 2.5 μm) chromatographic column for gradient elution, AB Sciex Qtrap 4500 mass spectrometer for analysis. Mass spectrometry was used to monitor Tolbutamide in the positive ion mode of electrospray ionization (ESI), and the mass-to-charge ratios (m/z) of its parent ion→product ion were 433→263.2 and 271.1→155, respectively.

data analysis:

The data will be analyzed using WinNonlin (version 5.2.1 Pharsight, Mountain View, CA) through a non-compartmental model to obtain PK parameters (select C _max , T _max , AUC _last , T _1/2 , F, etc. according to different routes of administration) parameter). The results are shown in Table 4.

Table 4 Pharmacokinetic parameters of some compounds in animals compound Route of administration Dosage (mg/kg) C _max (ng/mL) T _max (hr) T _1/2 (hr) AUC _last (ng/mL*hr) F (%) D1 PO 1 29.7±6.67 1.00±0.00 1.67±0.05 80.4±12.5 12.7 IV 1 722±34.3 / 0.70±0.07 632±106 / D2 PO 1 60.3±13.2 1.00±0.00 1.22±0.54 132±22.9 20.6 IV 1 566±9.70 / 0.86±0.12 639±69.5 / 1 PO 1 33.4±9.74 0.50±0.00 1.28±0.27 62.2±11.9 4.39 IV 1 2113±111 / 0.83±0.14 1417±38.4 / 2 PO 1 130±5.93 1.00±0.00 1.79±0.23 451±19.8 66 IV 1 266±21.2 / 3.27±0.61 686±52.7 / 3 PO 1 191±31.8 0.83±0.17 1.21±0.07 493±92.0 70.3 IV 1 622±13.0 / 1.26±0.10 701±71.7 / 6 PO 1 95.3±2.74 2.00±0.00 1.3±0.11 305±10.5 46.1 IV 1 354±53.2 / 1.74±0.13 661±8.36 / 7 PO 1 192±45.0 1.33±0.33 1.69±0.11 636±118 56.8 IV 1 442±54.4 / 2.60±0.43 1119±126 / 9 PO 1 118±12.1 1.00±0.00 1.68±0.21 414±26.1 38.4 IV 1 634±67.8 / 2.19±0.25 1077±195 / 10 PO 1 53.5±15.4 1.17±0.44 1.20±0.38 126±53.8 17 IV 1 1024±190 / 1.80±0.08 747±54.9 / 20 PO 1 60.6±15.7 1.33±0.33 1.75±0.00 175±38.8 33.7 IV 1 689±64.9 / 1.45±0.13 519±4.54 / twenty two PO 1 147±27.1 1.33±0.33 2.25±0.21 699±102 85.9 IV 1 572±9.07 / 3.55±0.09 814±113 / twenty three PO 1 14.5±33.9 1.33±0.33 1.34±0.09 461±167 60.6 IV 1 896±27.4 / 0.77±0.01 761±18.9 / 46 PO 1 47.1±6.0 2.00±0.00 2.07±0.21 204±19.9 37.5 IV 1 652±59.1 / 1.08±0.10 543±36.9 / 47 PO 1 199±50.1 1.67±0.33 2.86±0.40 978±260 54.6 IV 1 983±20.1 / 2.17±0.06 1791±133 / 48 PO 1 210±35.2 1.67±0.33 3.03±0.15 1186±246 98.0 IV 1 627±27.2 / 2.37±0.19 1211±136 / 49 PO 1 77.4±6.87 1.33±0.33 1.35±0.03 253±21.9 35.9 IV 1 703±6.01 / 1.29±0.19 704±41.8 / 54 PO 1 203±12.4 1.00±0.00 2.21±0.25 743±70.8 78.3 IV 1 485±71.9 / 2.13±0.32 949±28.2 / 57 PO 1 177±25.58 1.67±0.33 1.13±0.16 652±76.7 49.2 IV 1 1034±26.6 0.03±0.00 1.06±0.08 1325±120 / 61 PO 1 254±17.8 1.67±0.33 2.23±0.18 1113±114 79.5 IV 1 941±123 0.03±0.00 1.53±0.09 1400±252 / 62 PO 1 160±25.3 1.67±0.33 2.18±0.21 688±136 79.5 IV 1 1288±218 0.03±0.00 2.66±0.13 1745±218 / 65 PO 1 215±34.7 1.67±0.33 2.72±0.20 1062±131 101.0 IV 1 389±91.1 0.03±0.00 4.85±0.13 1053±217 / 67 PO 1 246±16.6 2.00±0.00 3.20±0.44 1355±122 64.0 IV 1 778±2.03 0.03±0.00 5.20±0.34 2104±150 / 69 PO 1 76.3±1.4 1.67±0.33 1.70±N/A 364±16 51.0 IV 1 810±111 0.03±0.00 1.84±0.13 714±69 / 72 PO 1 186±15.6 1.33±0.33 1.52±0.15 581±61.4 71.6 IV 1 1036±93.9 0.03±0.00 1.54±0.05 1449±79.2 / 73 PO 1 88.1±12.6 4.00±0.00 4.01±0.86 499±83.5 44.8 IV 1 612±28 0.03±0.00 2.25±0.30 1115±75.9 / Note: C _max means peak concentration, T _max means peak time, T _1/2 means elimination half-life, AUC _last means area under the plasma concentration-time curve from time 0 to the last quantifiable time point, F means bioavailability degree, "/" means not measured.

Conclusion: From the above table, it can be seen that the pharmacokinetic properties of the compounds of the present invention are better, among which, most of the compounds have higher bioavailability, and some compounds also have better performance in terms of C _max and T _1/2 .

The embodiments of the present invention have been described above. However, the present invention is not limited to the above-mentioned embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (15)

A compound as shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, its solvate or its pharmaceutical acceptable salt solvates;

^Wherein , R2 is selected from

; R ^2-1 is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Ra: C ₁ ~C ₂₀ alkyl, C ₃ ~C ₂₀ cycloalkyl, 3-20 membered hetero Cyclic group, C ₆ ~C ₂₀ aryl group and 5-20 membered heteroaryl group; each Ra is the same or different, independently selected from halogen, OH, CN, NO ₂ , oxo (=O), COOH,

And the following groups that are unsubstituted or optionally substituted by one, two or more Ra1: C ₁ ~C ₂₀ alkyl, C ₃ ~C ₂₀ cycloalkyl, C ₁ ~C ₂₀ alkoxy, C ₁ ~C ₂₀ alkylthio, -C(=O)-C ₁ ~C ₂₀ alkyl, -C(=O)-OC ₁ ~C ₂₀ alkyl, -OC(=O)-C ₁ ~C ₂₀ alkane group, -SO ₂ -C ₁ ~C ₂₀ alkyl, -S(=O)-C ₁ ~C ₂₀ alkyl, 3-20 membered heterocyclic group, C ₆ ~C ₂₀ aryl group, 5-20 membered heterocyclic group Aryl and NH ₂ ; each Ra1 is the same or different, independently selected from halogen, OH, COOH, CN, NO ₂ , oxo (=O) and unsubstituted or optionally replaced by one, two or more The following groups substituted by Ra2: C ₁ ~C ₂₀ alkyl, C ₃ ~C ₂₀ cycloalkyl, C ₁ ~C ₂₀ alkoxy and NH ₂ ; each Ra2 is the same or different, independently selected from halogen, OH, CN, NO ₂ , oxo (=O), C ₁ ~C ₂₀ alkyl and C ₁ ~C ₂₀ alkoxy; R ^2-2 is selected from hydrogen, halogen, OH, CN, NO ₂ and unsubstituted Or the following groups optionally substituted by one, two or more Rb: C ₁ ~C ₂₀ alkyl and C ₁ ~C ₂₀ alkoxy; each Rb is the same or different, independently selected from halogen, OH, CN and NO ₂ ; R ^3-1 is selected from halogen, OH, CN, NO ₂ and the following groups that are unsubstituted or optionally substituted by one, two or more Rc: C ₁ ~C ₂₀ alkyl , C ₁ ~C ₂₀ alkoxy and C ₃ ~C ₂₀ cycloalkyl; each Rc is the same or different, independently selected from halogen, OH, CN and NO ₂ ; n is selected from 0, 1, 2, 3 and ⁴ ; Preferably, R is

or for

; wherein, R ^2-1 is as defined above, R ^2-3 is selected from halogen, OH, CN, NO ₂ and the following groups that are unsubstituted or optionally substituted by one, two or more Rb: C ₁ ~C ₂₀ alkyl and C ₁ ~C ₂₀ alkoxy; each Rb is the same or different, independently selected from halogen, OH, CN and NO ₂ ; and preferably, R ² is

or for

; R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , C ₃ ~C ₁₀ cycloalkyl, "the number of heteroatoms is 1, 2 or 3, heteroatoms selected from one or more of N, O, S and S(=O) ₂ 3~10 membered heterocycloalkyl", substituted by one or more R ^2-1c " The number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, S and S(=O) _2. 3~10 membered heterocycloalkyl", C ₆ ~C ₁₀ Aryl, C ₆ ~C ₁₀ aryl substituted by one or more R ^2-1d , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5-10 membered heteroaryl" or "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S" substituted by one or more R ^2-1e 5~10 membered heteroaryl"; R ^2-3 is halogen, OH, C ₁ ~C ₁₀ alkyl or C ₁ ~C ₁₀ alkoxy; R ^2-1a is independently C ₃ ~C ₆ cycloalkyl Or "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S. A 3-6-membered heterocycloalkyl group"; R ^2-1c , R ^2-1d and R ^2-1e is independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkyl substituted by one or more R ^2-1c-1 , C ₁ ~C ₆ alkoxy, -C(=O)R ^2-1c-2 , -S(=O) ₂ R ^2-1c-3 ,

,

, C ₃ ~C ₁₀ cycloalkyl or heteroatoms selected from one or more of N, O and S and S(=O) ₂ 3~10 membered heterocycloalkyl; R ^2-1c-1 , R ^{2 -1c-2} and R ^2-1c-3 are independently halogen, OH, COOH, CN, NO ₂ , oxo (=O) or unsubstituted or optionally substituted by one, two or more Ra2 The following groups: C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy or NH ₂ ; each Ra2 is the same or different, independently selected from halogen, OH, CN, NO ₂ , oxo (=O ), C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy and C ₃ ~C ₆ cycloalkyl; n is 0, 1, 2 or 3; R ^3-1 is independently halogen, hydroxyl, cyanide group, C ₁ ~C ₆ alkyl, halogen substituted C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy or C ₃ ~C ₁₀ cycloalkyl. The compound shown in formula I as described in Claim 1, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, its solvent compound or a solvate of a pharmaceutically acceptable salt thereof, wherein R ² is

; R ^2-1 is H, C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , "the number of heteroatoms is 1, 2 or 3, hetero Atoms selected from one or more of N, O, S and S(=O) ₂ are 3 to 10 membered heterocycloalkyl", substituted by one or more R ^2-1c "the number of heteroatoms is 1, 2 or 3, heteroatoms selected from one or more of N, O, S and S(=O) ₂ 3~10 membered heterocycloalkyl", C ₆ ~C ₁₀ aryl, surrounded by one or more A C ₆ ~C ₁₀ aryl group substituted by R ^2-1d , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S. 5~6 membered heteroaryl group" or substituted by one or more R ^2-1e "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5~6 membered heteroaryl groups "; R ^2-2 is selected from hydrogen, halogen, OH, C ₁ ~ C ₆ alkyl and C ₁ ~ C ₆ alkoxy; R ^2-1a is independently C ₃ ~ C ₆ cycloalkyl or "heteroatom The number is 1, 2 or 3, and the heteroatom is selected from one or more of N, O and S. 3~6 membered heterocycloalkyl”; R ^2-1c , R ^2-1d and R ^2-1e independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkyl substituted by one or more R ^2-1c-1 , C ₁ ~C ₆ alkoxy, -C(= O)R ^2-1c-2 , -S(=O) ₂ R ^2-1c-3 ,

,

, C ₃ ~C ₆ cycloalkyl or heteroatoms selected from one or more of N, O, S and S(=O) ₂ 3~6 membered heterocycloalkyl; R ^2-1c-1 is independently Halogen, NH ₂ or C ₃ ~C ₆ cycloalkyl; R ^2-1c-2 and R ^2-1c-3 are independently NH ₂ or C ₁ ~C ₆ alkyl; n is 0, 1, 2 or 3 ; R ^3-1 is independently halogen, hydroxyl, cyano, C ₁ ~C ₆ alkyl, halogen substituted C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy or C ₃ ~C ₆ cycloalkane group; preferably, R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , "the number of heteroatoms is 1, 2 or 3 , the heteroatom is selected from one or more of N, O, S and S(=O) ₂ 3~10 membered heterocycloalkyl", C ₆ ~C ₁₀ aryl, replaced by one or more R ^2-1d Substituted C ₆ ~C ₁₀ aryl, "the number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from one or more of N, O, and S, and the heteroatoms are 5-6 membered heteroaryl groups" or replaced by one or multiple R ^2-1e substituted "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5~6 membered heteroaryl"; and/or , R ^2-1a is independently "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 3~6 membered heterocycloalkyl"; and/or , R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkyl substituted by one or more R ^2-1c-1 , C ₁ ~ C ₆ alkoxy, -C(=O)R ^2-1c-2 , -S(=O) ₂ R ^2-1c-3 or

; Preferably R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, -C(=O)R ^2-1c-2 , - S(=O) ₂ R ^2-1c-3 or

; More preferably R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, -C(=O)R ^2-1c-2 or -S(=O) ₂ R ^{2 -1c-3} ; and/or, R ^2-1c-2 and R ^2-1c-3 are independently C ₁ ~C ₆ alkyl; and/or, R ^3-1 is independently halogen. The compound shown in formula I as described in Claim 1, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, its solvent compound or a solvate of a pharmaceutically acceptable salt thereof, wherein the compound shown in formula I is any of the following schemes: Scheme 1: R ² is

; R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , C ₃ ~C ₁₀ cycloalkyl, "the number of heteroatoms is 1, 2 or 3, heteroatoms selected from one or more of N, O, S and S(=O) ₂ 3~10 membered heterocycloalkyl", C ₆ ~C ₁₀ aryl, surrounded by one or more A C ₆ ~C ₁₀ aryl group substituted by R ^2-1d , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S. 5~6 membered heteroaryl group" or substituted by one or more R ^2-1e "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5~6 membered heteroaryl groups "; R ^2-2 is hydrogen, C ₁ ~ C ₆ alkyl or C ₁ ~ C ₆ alkoxy; R ^2-1a is independently C ₃ ~ C ₆ cycloalkyl or "the number of heteroatoms is 1, 2 or 3 heteroatoms selected from one or more of N, O and S 3-6 membered heterocycloalkyl”; R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkyl substituted by one or more R ^2-1c-1 , C ₁ ~C ₆ alkoxy, -C(=O)R ^2-1c-2 ,- S(=O) ₂ R ^2-1c-3 、

,

Or C ₃ ~C ₆ cycloalkyl; R ^2-1c-1 is independently halogen, NH ₂ or C ₃ ~C ₆ cycloalkyl; R ^2-1c-2 and R ^2-1c-3 are independently NH ₂ or C ₁ ~C ₆ alkyl; n is 0, 1, 2 or 3; R ^3-1 is independently halogen; or, scheme 2: R ² is

; R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from A 3-10 membered heterocycloalkyl group selected from one or more of N, O, S and S(=O) ₂ ", C ₆ -C ₁₀ aryl, C ₆ substituted by one or more R ^2-1d ~C ₁₀ aryl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5~6 membered heteroaryl" or replaced by one or more R ^2-1e substituted "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5~6 membered heteroaryl"; R ^2-2 is hydrogen or C ₁ ~C ₆ alkyl; R ^2-1a is independently C ₃ ~C ₆ cycloalkyl or "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one of N, O and S or multiple 3-6 membered heterocycloalkyl groups”; R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ -C ₆ alkyl, substituted by one or more R ^2-1c-1 C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, -C(=O)R ^2-1c-2 , -S(=O) ₂ R ^2-1c-3 or

,

Or C ₃ ~C ₆ cycloalkyl; R ^2-1c-1 is independently halogen, NH ₂ or cyclopropyl; R ^2-1c-2 and R ^2-1c-3 are independently NH ₂ or C ₁ ~ C ₆ alkyl; n is 0, 1, 2 or 3; R ^3-1 is independently halogen; or, Scheme 3: R ² is

; R ^2-1 is C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from A 3-10 membered heterocycloalkyl group selected from one or more of N, O, S and S(=O) ₂ ", C ₆ -C ₁₀ aryl, C ₆ substituted by one or more R ^2-1d ~C ₁₀ aryl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5~6 membered heteroaryl" or replaced by one or more R ^2-1e substituted "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5~6 membered heteroaryl"; R ^2-2 is hydrogen or C ₁ ~C ₆ alkyl; R ^2-1a is independently C ₃ ~C ₆ cycloalkyl or "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one of N, O and S or multiple 3~6 membered heterocycloalkyl groups"; R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, replaced by one, C ₁ ~C ₆ alkyl substituted by two or more R ^2-1c-1 , -C(=O)R ^2-1c-2 , -S(=O) ₂ R ^2-1c-3 ,

,

,

Or C ₃ ~C ₆ cycloalkyl; R ^2-1c-2 and R ^2-1c-3 are independently NH ₂ or C ₁ ~C ₆ alkyl; R ^2-1c-1 are independently halogen, NH ₂ or cyclopropyl; n is 0, 1, 2 or 3; R ^3-1 is independently halogen; or, Scheme 4: R ² is

; R ^2-1 is C ₁ ~C ₁₀ alkyl substituted by one or more R ^2-1a , C ₆ ~C ₁₀ aryl substituted by one R ^2-1d , "the number of heteroatoms is 1, 2 1 or 3, heteroatoms selected from one or more of N, O and S 5-6 membered heteroaryl" or "the number of heteroatoms is 1 or 2" substituted by one or more R ^2-1e Or 3, heteroatoms are selected from one or more of N, O and S 5~6 membered heteroaryl"; R ^2-2 is hydrogen or C ₁ ~ C ₃ alkyl; R ^2-1a is independently "The number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S. A 3-6 membered heterocycloalkyl group"; R ^2-1d and R ^{2-1e are} independently is cyano, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkyl substituted by one, two or more R ^2-1c-1 , C ₁ ~C ₆ alkoxy, -C( =O)R ^2-1c-2 , -S(=O) ₂ R ^2-1c-3 ,

,

or cyclopropane; R ^2-1c-1 is independently halogen, NH ₂ or cyclopropyl; R ^2-1c-2 and R ^2-1c-3 are independently C ₁ ~C ₆ alkyl; n is 0, 1, 2 or 3; R ^3-1 is independently halogen; or, Scheme 5: R ² is

; R ^2-1 is a C ₆ ~C ₁₀ aryl group substituted by one or more R ^2-1d , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N, O and S One or more 5-6-membered heteroaryl groups" or "heteroatoms substituted by one or more R ^2-1e are 1, 2 or 3, and the heteroatoms are selected from one of N, O and S or a variety of 5~6 membered heteroaryls”; R ^2-2 is hydrogen or methyl; R ^2-1d and R ^{2-1e are} independently cyano, halogen, C ₁ ~ C ₆ alkyl, replaced by one, Two or more R ^2-1c-1 substituted C ₁ ~C ₆ alkyl or -C(=O)R ^2-1c-2 or -S(=O) ₂ R ^2-1c-3 ; R ^{2 -1c-1} is independently halogen, NH ₂ or cyclopropyl; R ^2-1c-2 and R ^2-1c-3 are independently C ₁ ~C ₆ alkyl; n is 0, 1, 2 or 3; R ^3-1 is independently halogen. The compound shown in formula I as described in Claim 1, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, its solvent compound or a solvate of a pharmaceutically acceptable salt thereof, wherein, when R ^2-1 is a C ₁ to C ₁₀ alkyl group or a C ₁ to C ₁₀ alkyl group substituted by one or more R ^2-1a , the C ₁ ~C ₁₀ alkyl group is a C ₁ ~C ₆ alkyl group; and/or, when R ^2-1 is "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N, O, One or more of S and S (=O) ₂ 3~10 membered heterocycloalkyl" or "heteroatoms 1, 2 or 3, heteroatoms substituted by one or more R ^2-1c , hetero When atoms are selected from one or more of N, O, S and S(=O) ₂ , a 3-10 membered heterocycloalkyl group”, the number of “heteroatoms is 1, 2 or 3, and the heteroatoms are selected from A 3-10 membered heterocycloalkyl group consisting of one or more of N, O, S and S(=O) ₂ " means "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O, S and One or more 3-8-membered heterocycloalkyl groups in S(=O) ₂ ; and/or, when R ^2-1 is C ₆ -C ₁₀ aryl or is substituted by one or more R ^2-1d When the C ₆ ~C ₁₀ aryl group, the C ₆ ~C ₁₀ aryl group is a phenyl group; and/or, when R ^2-1 is "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from One or more of N, O and S 5-6-membered heteroaryl" or substituted by one or more R ^2-1e "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O and S in one or more of 5~6 membered heteroaryl", the "number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5-6 membered heteroaryl" is "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S 5-6-membered heteroaryl"; and/or, when R When ^2-2 is a C ₁ ~C ₆ alkyl group, the C ₁ ~C ₆ alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and/or, when R ^2-1a is independently C ₃ ~C ₆ cycloalkyl, the C ₃ ~C ₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and /or, when R ^2-1a is independently "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 3~6 membered heterocycloalkyl" , the "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are 3-6 membered heterocycloalkyl groups selected from one or more of N, O and S" means "the number of heteroatoms is 1 or 2 One, the heteroatom is selected from one or more of N, O and S 3~6 membered heterocycloalkyl”; and/or, when R ^2-1c , R ^2-1d and R ^{2-1e are} independently halogen When, the halogen is fluorine, chlorine, bromine or iodine; and/or, when R ^2-1c , R ^2-1d and R ^{2-1e are} independently C ₁ When ~C ₆ alkyl or C ₁ ~C ₆ alkyl substituted by one or more R ^2-1c-1 , the C ₁ ~C ₆ alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and/or, when R ^2-1c , R ^2-1d and R ^{2-1e are} independently C ₁ ~C ₆ alkoxy, the C ₁ ~ C ₆ alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; and/or, when When R ^2-1c-2 and R ^2-1c-3 are independently C ₁ ~C ₆ alkyl, the C ₁ ~C ₆ alkyl is methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl; and/or, when R ^3-1 is independently halogen or C ₁ ~C ₆ alkyl substituted by halogen, the halogen is fluorine, chlorine, bromine or iodine and/or, when R ^3-1 is independently C ₁ ~C ₆ alkyl or C _{1 ~C 6 alkyl substituted by halogen, the C 1 ~C 6 alkyl is} methyl, ethyl, propyl Base, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and/or, when R ^3-1 is independently C ₁ ~C ₆ alkoxy, the C ₁ ~C ₆ Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; and/or when R ^3- When ¹ is independently a C ₃ -C ₆ cycloalkyl group, the C ₃ -C ₆ cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The compound shown in formula I as described in Claim 4, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, its solvent compound or a solvate of a pharmaceutically acceptable salt thereof, wherein, when R ^2-1 is a C ₁ to C ₁₀ alkyl group or a C ₁ to C ₁₀ alkyl group substituted by one or more R ^2-1a , the C ₁ ~C ₁₀ alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and/or, when R ^2-1 is " The number of heteroatoms is 1, ₂ or 3, and the heteroatoms are selected from one or more of N, O, S and S(=O) R ^2-1c substituted "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, S and S(=O) _2. A 3-10 membered heterocycloalkyl group ”, the “the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, S and S(=O) _2. A 3-10 membered heterocycloalkyl group” is Oxetane, Tetrahydrofuryl, Tetrahydropyranyl, Pyrrolidinyl, Piperidinyl, 2-Azabicyclo[2.2.1]heptane, 3-Azabicyclo[3.1.1]heptyl, 3-Azabicyclo[2.2.2]octyl or tetrahydrothiophene-1,1-dioxide, for example:

,

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,

,

,

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or

and/or, when R ^2-1 is a C ₆ ~C ₁₀ aryl group or a C _{6 ~C 10 aryl group substituted by one or more R 2-1d, the C 6 ~C 10} ^aryl _{group can} be benzene and/or, when R ^2-1 is "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5~6 membered heteroaryl" or When "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, a 5-6-membered heteroaryl group" substituted by one or more R ^2-1e , The "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S 5-6 membered heteroaryl" means "the number of heteroatoms is 1 or 2, 5~6-membered heteroaryl group whose heteroatom is N", for example: pyrazolyl, imidazolyl or pyridyl, and for example:

,

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or

and/or, when R ^2-1a is independently C ₃ ~C ₆ cycloalkyl, the C ₃ ~C ₆ cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl; and/or, When R ^2-1a is independently "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, a 3-6 membered heterocycloalkyl group", the " The number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S; A 3~6-membered heterocycloalkyl group whose atom is O", such as: oxetanyl or tetrahydrofuranyl, and another example:

or

and/or, when R ^2-1c , R ^2-1d and R ^{2-1e are} independently halogen, the halogen is fluorine or chlorine; and/or, when R ^2-1c , R ^2-1d and R ^{2 When -1e} is independently C ₁ ~C ₆ alkyl, or C 1 ~C ₆ alkyl substituted by one or more R ^2-1c-1 _{, the C 1 ~} C ₆ alkyl is methyl, ethyl , propyl; and/or, when R ^2-1c , R ^2-1d and R ^{2-1e are} independently C ₃ ~C ₁₀ cycloalkyl, the C ₃ ~C ₁₀ cycloalkyl is cyclopropyl, Cyclobutyl or cyclopentyl; And/or, when R ^2-1c , R ^2-1d and R ^{2-1e are} independently C ₁ ~C ₆ alkoxy, the C ₁ ~C ₆ alkoxy is Methoxy; and/or, when R ^2-1c-1 is C ₃ ~C ₆ alkyl, the C ₃ ~C ₁₀ cycloalkyl is cyclopropyl; and/or, when R ^2-1c-2 and R ^2-1c-3 are independently C ₁ ~C ₆ alkyl, the C ₁ ~C ₆ alkyl is methyl; and/or, when R ^2-2 is C ₁ ~C ₆ alkyl, The C ₁ ~C ₆ alkyl is methyl; and/or, when R ^3-1 is independently halogen or C ₁ ~C ₆ alkyl substituted by halogen, the halogen is fluorine or chlorine. The compound shown in formula I as described in claim 5, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotopic compound, wherein, when R ^2-1 is replaced by one or When multiple R ^2-1a substituted C ₁ ~C ₁₀ alkyl groups, the C ₁ ~C ₁₀ alkyl groups substituted by one or more R ^2-1a are

,

,

,

or

and/or, when R ^2-1 is a C ₆ ~C ₁₀ aryl group substituted by one or more R ^2-1d , the C ₆ ~C ₁₀ aryl group substituted by one or more R ^2-1d for

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or

and/or, when R ^2-1 is substituted by one or more R ^2-1e "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one of N, O and S or When a variety of 5-6 membered heteroaryl groups are used, the number of heteroatoms substituted by one or more R ^2-1e is 1, 2 or 3, and the heteroatoms are selected from one of N, O and S or a variety of 5-6 membered heteroaryls" as

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or

. The compound shown in formula I as described in Claim 6, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotope compound, its crystal form, its nitrogen oxide, its solvent compound or a solvate of a pharmaceutically acceptable salt thereof, wherein R ² is

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or

and/or, R ^3-1 is fluorine or chlorine. A compound shown in formula I as described in any one of claims 1 to 7, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, Its nitrogen oxide, its solvate or the solvate of its pharmaceutically acceptable salt, wherein, the compound shown in formula I is any of the following structures:

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or

. A method for preparing the compound shown in formula I as described in any one of claim items 1 to 8, which is method one or method two; method one comprises the following steps: in a solvent, in the presence of an acid, the The compound shown in formula II reacts with 1,3-dichloro-5,5-dimethylhydantoin to generate the compound shown in formula IV, and then reacts the compound shown in formula IV with ammonia water to obtain the compound shown in formula I compound;

The second method includes the following steps: reacting the compound shown in formula III with hydrazine hydrate in an organic solvent to obtain the compound shown in formula I;

wherein, R ^3-1 , n and R ² in formulas I, II, III and IV are the same or different, and independently have the definition as described in any one of claim items 1 to 8. A kind of intermediate compound as shown in formula II, formula III or formula IV,

,

or

; Wherein, the definitions of R ² , R ^3-1 and n are as described in any one of claims 1-8. A pharmaceutical composition comprising substance A and at least one pharmaceutical excipient; the substance A is the compound shown in formula I as described in any one of claims 1 to 8, its pharmaceutically acceptable salt, its Stereoisomers, tautomers thereof, isotopic compounds thereof, crystal forms thereof, nitrogen oxides thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof. A use of substance A in the preparation of P2X4 receptor antagonists or medicines; the substance A is the compound shown in formula I as described in any one of claim items 1 to 8, its pharmaceutically acceptable salt, its Stereoisomers, tautomers thereof, isotopic compounds thereof, crystal forms thereof, nitrogen oxides thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof. The application as described in claim 12, wherein the medicament is used to treat or prevent urinary tract diseases, respiratory diseases, pain-related diseases, autoimmune diseases, inflammatory reactions, sleep disturbances, mental diseases, arthritis, neurological diseases, etc. Degenerative disease, traumatic brain injury, thrombosis, gastrointestinal disease, sexual dysfunction, cardiovascular system disease, endometriosis, musculoskeletal and connective tissue developmental disorders, cancer, or eye disease. The application according to claim 12, wherein the drug is used to prevent or treat diseases in animals that are at least partially mediated by P2X4; The disease mediated at least in part by P2X4 can be urinary tract disease, respiratory disease, pain-related disease, autoimmune disease, inflammatory response, sleep disorder, psychiatric disease, arthritis, neurodegenerative disease, traumatic brain injury, Thrombosis, gastrointestinal disease, sexual dysfunction, cardiovascular system disease, endometriosis, musculoskeletal and connective tissue developmental disorders, cancer, or eye disease. The application according to claim 13 or 14, wherein the urinary tract disease is urinary incontinence, overactive bladder, dysuria or cystitis; And/or, the respiratory disease is a breathing disorder, such as: respiratory failure, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or cough (such as chronic cough); And/or, the pain-related disease is inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache, chronic pain or pruritus; And/or, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, epilepsy or stroke; And/or, the cardiovascular system disease is myocardial infarction, atherosclerosis, heart failure, hypertension or blood disease; And/or, the gastrointestinal disease is colon syndrome, inflammatory bowel disease or gastrointestinal disorder; And/or, the autoimmune disease is arthritis, such as rheumatoid arthritis; and And/or, the ophthalmic disease is dry eye syndrome, dry eye, ocular nerve pain, ocular trauma and postoperative ocular pain.