MAS-related G protein receptor X4 modulators and uses thereof

Abstract

The invention provides a compound as shown in a formula I, and a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. The compound has a relatively good MAS-related G protein receptor X4 regulating effect.

Description

[0001] This invention claims the following:

[0002] Priority is claimed for the earlier application filed with the China National Intellectual Property Administration on April 30, 2024, with patent application number 202410547886.5 and title "MAS-related G protein receptor X4 regulator and its use".

[0003] Priority is claimed for the earlier application filed with the China National Intellectual Property Administration on June 20, 2024, with patent application number 202410804556.X and title "MAS-related G protein receptor X4 regulator and its use".

[0004] Priority is claimed for the earlier application filed with the China National Intellectual Property Administration on September 11, 2024, with patent application number 202411274031.6 and title "MAS-related G protein receptor X4 regulator and its use".

[0005] Priority is claimed for the earlier application filed with the China National Intellectual Property Administration on April 10, 2025, with patent application number 202510450102.1 and title "MAS-related G protein receptor X4 regulator and its use".

[0006] The full text of the aforementioned prior application is incorporated herein by reference. Technical Field

[0007] This invention belongs to the field of medicine, specifically, it relates to a MAS-associated G protein receptor X4 modulator and its uses. Background Technology

[0008] Based on the pruritus receptors, pruritus can be classified into histaminergic pruritus and nonhistaminergic pruritus. Histaminergic pruritus can be relieved with antihistamines, but these drugs are often ineffective for nonhistaminergic pruritus.

[0009] Studies have shown that Mas-related G protein-coupled receptor X4 (MRGPRX4), expressed by human sensory neurons, acts as an pruritus receptor and plays an important role in cholestatic pruritus and other types of pruritus. Using calcium ion imaging, it has been identified that many bile acids activate MRGPRX4 at pathophysiologically relevant levels. MRGPRX4 in cultured human DRGs... 4+Neurons respond to bile acids and play a key role in inducing chronic pruritus in patients with cholestatic pruritus. Cholestasis-related pruritus exhibits a diurnal rhythm, with the intensity of itching increasing in the quiet of the night. EP547, the world's first small-molecule MRGPRX4 antagonist, inhibits the production of pruritus at its source and is used to treat cholestatic pruritus and uremic pruritus. It has entered Phase II clinical trials, and existing clinical data show excellent therapeutic efficacy and good safety.

[0010] Currently, there are no marketed drugs that act as modulators of the MAS-associated G protein receptor X4. Therefore, developing new compounds that can modulate the activity of the MAS-associated G protein receptor X4 is of positive significance for the treatment of this disease. Summary of the Invention

[0011] The purpose of this invention is to provide a novel compound as a regulator of MAS-associated G protein receptor X4.

[0012] In a first aspect of the invention, compounds of Formula I, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs are provided:

[0013]

[0014] in,

[0015] A is a 6-10 membered aryl, a 3-11 membered heterocyclic alkyl, a 5-10 membered heteroaryl, or a saturated or partially unsaturated 9-12 membered fused and bicyclic heteroaryl; the heteroatoms in the heterocyclic alkyl, heteroaryl, and fused and bicyclic heteroaryl are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different;

[0016] R 1 The substituent on A is a halogen, hydroxyl, amino, cyano, carbonyl, oxo, carboxyl, or C group. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 1-1 Replacement C 1-6 Alkyl, optional R 1-1 Replacement -OC 1-6 Alkyl, optional R 1-1 Replacement C 3-8 cycloalkyl, optional R 1-1 Substituted 3- to 11-membered heterocyclic alkyl groups, optionally R 1-1 Substituted 5- to 10-membered heteroaryl groups, -C(O)-NH-S(O)2-R 1-1 -S(O)2-NH-C(O)-OR 1-1 The R 1-1 For H, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 1-1 The number of substitutions can be 0, 1, 2, 3, 4, or 5; when there are multiple substituents, the substituents may be the same or different;

[0017] R 2 H, halogen, cyano, carbonyl, oxo, carboxyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 2-1 Replacement C 1-6 Alkyl or optionally R 2-1 Replacement C 3-8 cycloalkyl; the R 2-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 2-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different;

[0018] Z represents -O-, -S-, -N(R) 3 -CH2-, -OC(R) 3 )2-、-O-CH(R 3 )-; The R 3 For H or C 1-6 alkyl;

[0019] Each R 4 Each of the following groups can be independently represented as SF5, SCF3, H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, or C. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 4-1 Replacement C 1-6 Alkyl or optionally R 4-1 Replacement C 3-8 Cycloalkyl, and wherein at least one R 4 For SF5 or SCF3, r is 1, 2, 3, 4 or 5; or when R 4 When it is a halogen, r is 4 or 5;

[0020] The R 4-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 4-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different;

[0021] m is selected from 0, 1, 2, 3, 4, 5, 6, or 7; n is selected from 0, 1, 2, or 3;

[0022] In some implementations, m and n are 0, 1, 2, or 3, respectively.

[0023] In a preferred embodiment of the present invention, A is a 6-8 membered aryl, a 3-8 membered heterocyclic alkyl, a 5-8 membered heteroaryl, or a saturated or partially unsaturated 9-10 membered fused and bicyclic heteroaryl; the heteroatoms in the heterocyclic alkyl, heteroaryl, and fused and bicyclic heteroaryl are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different; R 1 The substituent on A is a halogen, hydroxyl, amino, cyano, carbonyl, oxo, carboxyl, or C group. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 1-1 Replacement C 1-6 Alkyl, optional R 1-1 Replacement -OC 1-6 Alkyl, optional R 1-1 Replacement C 3-8 cycloalkyl, optional R 1-1 Substituted 3- to 11-membered heterocyclic alkyl groups, optionally R 1-1 Substituted 5- to 10-membered heteroaryl groups, -C(O)-NH-S(O)2-R 1-1 -S(O)2-NH-C(O)-OR 1-1 The R 1-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 1-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different; R 2 H, halogen, cyano, carbonyl, oxo, carboxyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 2-1 Replacement C 1-6 Alkyl or optionally R 2-1 Replacement C 3-8 cycloalkyl; the R 2-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 2-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different; Z is -O-, -S-, or -N(R).3 -CH2-, -OC(R) 3 )2-、-O-CH(R 3 )-; The R 3 For H or C 1-6 Alkyl groups; each R 4 Each of the following groups can be independently represented as SF5, SCF3, H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, or C. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 4-1 Replacement C 1-6 Alkyl or optionally R 4-1 Replacement C 3-8 Cycloalkyl, and wherein at least one R 4 It is SF5 or SCF3, and r is 1, 2, 3, 4 or 5; the R 4-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 4 -1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different; m and n are 0, 1, 2, or 3, respectively.

[0024] In a preferred embodiment of the present invention, A is a 6-8 membered aryl, a 3-8 membered heterocyclic alkyl, a 5-8 membered heteroaryl, or a saturated or partially unsaturated 9-10 membered fused and bicyclic heteroaryl; the heteroatoms in the heterocyclic alkyl, heteroaryl, and fused and bicyclic heteroaryl are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different; R 1 The substituent on A is a halogen, hydroxyl, amino, cyano, carbonyl, oxo, carboxyl, or C group. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 1-1 Replacement C 1-6 Alkyl, optional R 1-1 Replacement -OC 1-6 Alkyl, optional R 1-1 Replacement C 3-8 cycloalkyl, optional R 1-1 Substituted 3- to 11-membered heterocyclic alkyl groups, optionally R 1-1 Substituted 5- to 10-membered heteroaryl groups, -C(O)-NH-S(O)2-R 1-1 -S(O)2-NH-C(O)-OR 1-1 The R 1-1 For H, C 1-6 Alkyl, C 1-6Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 1-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different; R 2 H, halogen, cyano, carbonyl, oxo, carboxyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 2-1 Replacement C 1-6 Alkyl or optionally R 2-1 Replacement C 3-8 cycloalkyl; the R 2-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 2-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different; Z is -O-, -S-, or -N(R). 3 -CH2-, -OC(R) 3 )2-、-O-CH(R 3 )-; The R 3 For H or C 1-6 Alkyl; R 4 When it is halogen, r is 4 or 5; m and n are 0, 1, 2 or 3 respectively.

[0025] In some embodiments, A is selected from 5- to 6-membered nitrogen-containing heteroaryl groups, wherein the number of nitrogen atoms is 1, 2, or 3; in still other embodiments, A is a saturated or partially unsaturated 5- or 6-membered fused bicyclic heteroaryl group, or a saturated or partially unsaturated 6-membered fused bicyclic heteroaryl group.

[0026] In some embodiments, A is phenyl, pyrimidinyl, pyridinyl,

[0027] The R 1 For F, Cl, cyano, -CH3, -CHF2, -CH2CF3, -COOH, -OCHF2, -OCH3, -C(O)-NH-S(O)2-CH3, -S(O)2-NH-C(O)-O-CH3,

[0028] In some implementation schemes, Selected from Among them, Ra1, Ra2, Ra3, Ra4, and Ra5 are selected from H or R. 1 (R 1As defined above, Ra1, Ra2, Ra3, Ra4, and Ra5 are independent and may be the same or different; in some embodiments, Ra2 is selected from COOH, -C(O)-NH-S(O)2-R 1-1 -S(O)2-NH-C(O)-OR 1-1 , Ra1, Ra3, Ra4, and Ra5 may be the same or different, and each is independently selected from H, F, Cl, CN, or arbitrarily selected by R. 1-1 Replacement C 1-6 Alkyl or optionally R 1-1 Replacement -OC 1-6 alkyl;

[0029] In some implementation schemes, Selected from Among them, Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, and Rb7 are selected from H or R. 1 (R 1 As defined above, Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, and Rb7 are independent of each other and may be the same or different; in some embodiments, Rb4 is oxidized, i.e. Selected from Wherein, Rb1 is selected from any of the R... 1-1 Replacement C 1-6 Alkyl groups, Rb2, Rb3, Rb4, Rb5, Rb6, and Rb7, may be the same or different, and each is independently selected from H or halogen.

[0030] In some implementation schemes, Selected from Among them, Rc1, Rc2, Rc3, Rc4, and Rc5 are the same as R mentioned above. 4 As defined, Rc1, Rc2, Rc3, Rc4, and Rc5 are independent of each other and may be the same or different; in some embodiments, Rc3 is selected from SF5 or SCF3, and Rc1, Rc2, Rc4, and Rc5 may be the same or different, each independently selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 4-1 Replacement C 1-6 Alkyl or optionally R 4-1 Replacement C 3-8 Cycloalkyl; in some embodiments, Rc4 is selected from SF5 or SCF3, and Rc1, Rc2, Rc3, and Rc5 may be the same or different, each independently selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 2-6 alkynyl group, -OC 1-6Alkyl, optional R 4-1 Replacement C 1-6 Alkyl or optionally R 4-1 Replacement C 3-8 Cycloalkyl; in some embodiments, Rc1 is selected from SF5 or SCF3, and Rc2, Rc3, Rc4, and Rc5 may be the same or different, each independently selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 4-1 Replacement C 1-6 Alkyl or optionally R 4-1 Replacement C 3-8 Cycloalkyl; in some embodiments, Rc1, Rc2, Rc3, Rc4, and Rc5 may be the same or different, each independently selected from H or a halogen; in some embodiments, Selected from the following structure: In some implementation schemes, Selected from the following structure:

[0031] According to some embodiments of the present invention, in formula (I),

[0032] A is a 6-10 membered aryl, 3-11 membered heterocyclic alkyl, 5-10 membered heteroaryl, or a saturated or partially unsaturated 9-12 membered fused and bicyclic heteroaryl; the heteroatoms in the heteroaryl and fused and bicyclic heteroaryl are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different; R 1 The substituent on A is a halogen, hydroxyl, amino, cyano, carbonyl, oxo, carboxyl, or C group. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 1-1 Replacement C 1-6 Alkyl or optionally R 1-1 Replacement C 3-8 cycloalkyl; the R 1-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 1-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different;

[0033] R 2 H, halogen, cyano, carbonyl, oxo, carboxyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, optional R2-1 Replacement C 1-6 Alkyl or optionally R 2-1 Replacement C 3-8 cycloalkyl; the R 2-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 2-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different;

[0034] Z represents -O-, -S-, -N(R) 3 -CH2-, -OC(R) 3 )2-、-O-CH(R 3 )-; The R 3 For H or C 1-6 alkyl;

[0035] Each R 4 Each of the following groups can be independently represented as SF5, SCF3, H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, or C. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 4-1 Replacement C 1-6 Alkyl or optionally R 4-1 Replacement C 3-8 Cycloalkyl, and wherein at least one R 4 For SF5 or SCF3, r is 2, 3, 4 or 5; or when R 4 When it is a halogen, r is 4 or 5;

[0036] The R 4-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 4-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different;

[0037] m and n are 0, 1, 2 or 3 respectively.

[0038] According to some embodiments of the present invention, in formula (I), A is a 6-10 aryl, a 3-11 heterocyclic alkyl, a 5-10 heteroaryl, or a saturated or partially unsaturated 9-12 fused and bicyclic heteroaryl; the heteroatoms in the heteroaryl and fused and bicyclic heteroaryl are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different; R 1The substituent on A is a halogen, hydroxyl, amino, cyano, carbonyl, oxo, carboxyl, or C group. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 1-1 Replacement C 1-6 Alkyl or optionally R 1-1 Replacement C 3-8 cycloalkyl; the R 1-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 1-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different;

[0039] R 2 H, halogen, cyano, carbonyl, oxo, carboxyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 2-1 Replacement C 1-6 Alkyl or optionally R 2-1 Replacement C 3-8 cycloalkyl; the R 2-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 2-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different;

[0040] Z represents -O-, -S-, -N(R) 3 -CH2-, -OC(R) 3 )2-; The R 3 For H or C 1-6 alkyl;

[0041] There are at least 2 R's 4 And the R 4 Each of the following groups can be independently represented as SF5, SCF3, H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, or C. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 4-1 Replacement C 1-6 Alkyl or optionally R 4-1 Replacement C 3-8 Cycloalkyl, and wherein at least one R 4 It is SF5 or SCF3; the R 4-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-6 cycloalkyl, hydroxyl, or halogen; the R 4-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different;

[0042] m and n are 0, 1, 2 or 3 respectively;

[0043] r can be 2, 3, 4 or 5.

[0044] According to some embodiments of the present invention, in formula (I), A is a 6-8 aryl, a 3-8 heterocyclic alkyl, a 5-8 heteroaryl, or a saturated or partially unsaturated 9-10 fused and bicyclic heteroaryl; the heteroatoms in the heteroaryl and fused and bicyclic heteroaryl are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different; R 1 The substituent on A is a halogen, hydroxyl, amino, cyano, carbonyl, oxo, carboxyl, or C group. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 1-1 Replacement C 1-6 Alkyl or optionally R 1-1 Replacement C 3-8 cycloalkyl; the R 1-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 1-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different;

[0045] R 2 H, halogen, cyano, carbonyl, oxo, carboxyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 2-1 Replacement C 1-6 Alkyl or optionally R 2-1 Replacement C 3-8 cycloalkyl; the R 2-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 2-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different;

[0046] Z represents -O-, -S-, -N(R) 3 -CH2-, -OC(R) 3 )2-、-O-CH(R3 )-; The R 3 For H or C 1-6 alkyl;

[0047] Each R 4 Each of the following groups can be independently represented as SF5, SCF3, H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, or C. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 4-1 Replacement C 1-6 Alkyl or optionally R 4-1 Replacement C 3-8 Cycloalkyl, and wherein at least one R 4 It is SF5 or SCF3, and r is 2, 3, 4 or 5; the R 4-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 4-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different;

[0048] m and n are 0, 1, 2 or 3 respectively.

[0049] According to some embodiments of the present invention, in formula (I), A is a 6-8 aryl, a 3-8 heterocyclic alkyl, a 5-8 heteroaryl, or a saturated or partially unsaturated 9-10 fused and bicyclic heteroaryl; the heteroatoms in the heteroaryl and fused and bicyclic heteroaryl are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different; R 1 The substituent on A is a halogen, hydroxyl, amino, cyano, carbonyl, oxo, carboxyl, or C group. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 1-1 Replacement C 1-6 Alkyl or optionally R 1-1 Replacement C 3-8 cycloalkyl; the R 1-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 1-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different;

[0050] R 2 H, halogen, cyano, carbonyl, oxo, carboxyl, C 2-6 alkynyl group, -OC1-6 Alkyl, optional R 2-1 Replacement C 1-6 Alkyl or optionally R 2-1 Replacement C 3-8 cycloalkyl; the R 2-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 2-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different;

[0051] Z represents -O-, -S-, -N(R) 3 -CH2-, -OC(R) 3 )2-、-O-CH(R 3 )-; The R 3 For H or C 1-6 alkyl;

[0052] R 4 When it is a halogen, r is 4 or 5;

[0053] m and n are 0, 1, 2 or 3 respectively.

[0054] In this invention, the definitions of certain substituents in the compounds shown in Formula I are as follows, and the definitions of substituents not mentioned are as described in any of the above schemes.

[0055] In a preferred embodiment of the present invention, A is a 6-8 aryl group or a 5-8 heteroaryl group.

[0056] In a preferred embodiment of the present invention, A is a 5-6 member nitrogen-containing heteroaryl group, and the number of nitrogen atoms is 1, 2 or 3.

[0057] In a preferred embodiment of the present invention, A is phenyl, pyrazolyl, or pyridyl.

[0058] In a preferred embodiment of the present invention, A is a saturated or partially unsaturated 5-membered and 6-membered fused bicyclic heteroaryl group, or a saturated or partially unsaturated 6-membered and 6-membered fused bicyclic heteroaryl group.

[0059] In a preferred embodiment of the present invention, one ring in A is a 5- or 6-membered saturated heterocycle, and the other ring is an unsaturated aromatic ring or a heteroaryl ring; the heteroatom in the heteroaryl ring is selected from N, O and S, and the number of the heteroatom is 1, 2, 3 or 4; when the number of the heteroatom is multiple, the heteroatoms may be the same or different.

[0060] In a preferred embodiment of the present invention, both rings in A are unsaturated 5- or 6-membered aromatic rings or heteroaryl rings; the heteroatoms in the heteroaryl ring are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different.

[0061] In a preferred embodiment of the present invention, A is

[0062] In a preferred embodiment of the present invention, A is

[0063] In a preferred embodiment of the present invention, the R 1 For F, Cl, cyano, -CH3, -CHF2, -CH2CF3, -COOH, -OCHF2, -OCH3, -C(O)-NH-S(O)2-CH3, -S(O)2-NH-C(O)-O-CH3,

[0064] In a preferred embodiment of the present invention, the R 2 For H, cyano, oxo, -COOH, -CH3,

[0065] In a preferred embodiment of the present invention, Z is -O-, -S-, -NH-, -NCH3-, -CH2-, -O-CH2-, or -O-CH(CH3)-.

[0066] In a preferred embodiment of the present invention, there are at least two Rs. 4 And the R 4 Each can be independently SF5, SCF3, H, F, Cl, -CH3, -CH2CF3, -COOH or And at least one of them R 4 It is either SF5 or SCF3.

[0067] In a preferred embodiment of the present invention, there are at least 4 Rs. 4 And the R 4 They are F or Cl, respectively, independently.

[0068] In a preferred embodiment of the present invention, the compound represented by Formula I is selected from any of the following compounds:

[0069]

[0070]

[0071]

[0072] In a second aspect, the present invention provides a pharmaceutical composition comprising: a compound of formula I as described in the present invention, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug; and a pharmaceutically acceptable carrier.

[0073] In a third aspect, the present invention provides compounds of Formula I as described herein, and their tautomers.

[0074] Use of the construct, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the use of the pharmaceutical composition of the present invention, said use including: modulating MRGPRX4; and / or, preventing and / or treating MRGPRX4-related diseases; and / or, preparing a medicament, pharmaceutical composition or formulation for modulating anti-MRGPRX4, and / or preventing and / or treating MRGPRX4-related diseases.

[0075] Preferably, the MRGPRX4-related diseases include pruritus-related diseases.

[0076] Preferably, the pruritus-related diseases include: nonhistamine pruritus.

[0077] Preferably, the nonhistaminergic pruritus includes cholestatic pruritus and uremic pruritus.

[0078] In a fourth aspect of the invention, a method for regulating MRGPRX4, or for preventing and / or treating MRGPRX4-related diseases, is provided, comprising the steps of administering to a desired subject a compound of Formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof.

[0079] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

[0080] Terms and Definitions

[0081] Unless otherwise stated, the terms and definitions used in this application, including those set forth in the specification and claims, are as follows. Those skilled in the art will understand that, according to conventions used in the art, in the structural formula of this application, Used to describe chemical bonds, which are points where a portion or a substituent is connected to a core or skeletal structure.

[0082] Unless otherwise specified, the term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0083] Unless otherwise specified, the term "pharmaceutically acceptable salt" means a pharmaceutically acceptable non-toxic salt of an acid or base, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0084] Unless otherwise specified, the term "pharmaceutical composition" means a mixture of one or more compounds described in this text or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0085] Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of the present invention are prepared by modifying functional groups in the compound; such modification can be performed by conventional methods or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group within the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free hydroxyl and free amino groups, respectively.

[0086] Unless otherwise specified, the term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0087] Depending on the choice of raw materials and methods, the compounds of the present invention may exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation of light induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of said isomers are generally referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method. Many geometric isomers of alkenes, C=N double bonds, etc., can also exist in the compounds described herein, and all such stable isomers are considered in this invention. When the compounds described herein contain an alkene double bond, unless otherwise stated, such double bond includes E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in cis or trans (cis- or trans-) configuration.

[0088] When the bonds of the chiral carbon in the formulas of this invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise stated, wedge-shaped and dashed bonds represent the absolute configuration of a stereocenter.

[0089] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in either an optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of many methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure α-methylbenzylamine (e.g., S and R forms or diastereoisomeric forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be achieved by elution onto a chromatographic column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High-performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be used. The specific method, elution conditions, and column selection can be chosen by those skilled in the art based on the structure of the compound and experimental results. Furthermore, any enantiomer or diastereomeric form of the compound described in this invention can be obtained through stereoorganic synthesis using optically pure starting materials or reagents with known configurations.

[0090] Unless otherwise specified, the term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions in a molecule. The compounds of this invention can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer usually produce a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0091] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid.

[0092] Unless otherwise stated, the term "solvent" means that the compounds of the present invention or their salts comprise a stoichiometric or nonstoichiometric solvent bound by intermolecular noncovalent forces, and when the solvent is water, it is a hydrate.

[0093] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0094] Unless otherwise specified, the terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or condition.

[0095] Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are replaced. Ketone substitution does not occur on aromatic groups.

[0096] In this application, "optional" or "optionally" means that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or not substituted, and the description includes both substituted and unsubstituted aryl groups.

[0097] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6 and C5 alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0098] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0099] The term "halogenated" is used interchangeably with the term "halogenated" when used alone or as part of other substituents.

[0100] Unless otherwise specified, "halogenated alkyl" or "halogen-substituted alkyl" means a saturated aliphatic hydrocarbon group comprising a specific number of carbon atoms, branched and straight-chained and substituted with one or more halogens.

[0101] Unless otherwise specified, "C 2-6 "Alkenyl" is used to denote a hydrocarbon group, whether straight-chain or branched, consisting of 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms containing at least one carbon-carbon double bond, wherein the carbon-carbon double bond can be located at any position within the group. The C 2-6 Alkenes include C 2-4 C 2-3 C4, C3, and C2 alkenyl groups, etc.; they can be monovalent, divalent, or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.

[0102] Unless otherwise specified, "C 2-6 "Alkyne" is used to denote a hydrocarbon group, whether straight-chain or branched, consisting of 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms containing at least one carbon-carbon triple bond. The carbon-carbon triple bond can be located at any position within the group. The C... 2-6 Alkyne groups include C 2-4 C 2-3 C4, C3, and C2 alkynyl groups, etc. They can be monovalent, divalent, or polyvalent. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and penynyl.

[0103] Unless otherwise specified, the term "C" 1-6 Alkoxy (i.e., "-OC") 1-6 Alkyl groups ("alkyl") refer to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-6 Alkoxy groups include C1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

[0104] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0105] Unless otherwise specified, the term "C" 3-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. The C 3-8 Cycloalkyl groups include C 3-6 C 3-5 C 4-8 C 4-6 C 4-5 C 5-8 Or C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, etc.

[0106] Unless otherwise specified, the term "C" 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which can be monocyclic or bicyclic systems. 3-6 Cycloalkyl groups include C 3-5 C 4-5 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0107] Unless otherwise specified, C n-n+m Or C n -Cn+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0108] Unless otherwise specified, the term "aryl" refers to a monocyclic or polycyclic carbon ring having 6 to 20 carbon atoms, wherein at least one ring is an aromatic ring. When one of the rings is a non-aromatic ring, the group may be linked by an aromatic ring or by a non-aromatic ring, for example, further comprising 6-8-membered aryl, 6-10-membered aryl. Specifically, the term "6- to 10-membered aryl" refers to a monocyclic or polycyclic carbon ring having 6 to 10 carbon atoms, wherein at least one ring is an aromatic ring. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthracene, and acenaphthene.

[0109] Unless otherwise specified, the term "heterocyclic alkyl" refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are substituted with heteroatoms, such as, but not limited to, N, O, S, and P. The terms "mn-membered heterocyclic alkyl" or "Cm-Cn heterocyclic alkyl" should be understood to represent a saturated, unsaturated, or partially saturated ring having m to n atoms, wherein the heterocyclic atoms are selected from N, O, S, and P, preferably from N, O, or S. The term "3-11-membered heterocyclic alkyl" itself, or in combination with other terms, respectively represents a saturated cyclic group consisting of 3 to 11 ring atoms, and may be further selected from "3-8-membered" and "6-8-membered" heterocyclic alkyl groups. The term "6-8 membered heterocyclic alkyl" itself, or in combination with other terms, refers to a saturated cyclic group consisting of 6 to 8 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p, where p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. Furthermore, with respect to "6-8 membered heterocyclic alkyl," the heteroatom may occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. For example, 6-8 membered heterocyclic alkyl groups include, but are not limited to, 6-, 7-, and 8-membered groups. Examples of 6-8 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, and hexahydropyridazinyl.

[0110] Unless otherwise specified, the term "heteroaromatic ring" refers to a monocyclic or polycyclic (i.e., fused polycyclic) carbon ring in which at least one ring atom (e.g., 1, 2, 3, or 4 ring atoms) is independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon, wherein at least one ring is an aromatic ring. The heteroaromatic ring may have 5-14 (5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms, for example, 5-10 membered heteroaromatic rings or 9-12 membered heteroaromatic rings. The heteroaromatic ring may be monocyclic or bicyclic. When the heteroaromatic ring is bicyclic, it may be saturated or partially unsaturated, for example, selected from "9-12 membered fused bicyclic heteroaromatic groups" (including 9-, 10-, 11-, and 12-membered fused bicyclic heteroaromatic groups). Examples of heteroaryl groups include, but are not limited to: imidazolyl, acridinel, carbazolel, cyclolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thiophenel, benzothiophenel, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrroleyl, N-methylpyrroleyl, and tetrahydroquinoline. The term "heteroaromatic ring" may be used interchangeably with the terms "heteroaromatic ring," "heteroaryl," or "heteroaromatic ring group." The meaning of "fused" is the same as "fused together."

[0111] Unless otherwise specified, the term "oxo" refers to the replacement of the two hydrogen atoms on the methylene group with oxygen, that is, the methylene group is replaced by a carbonyl group, and is represented as =O.

[0112] Unless otherwise specified, the terms "halogen" or "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0113] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently" used in this invention should be interpreted broadly, meaning that the described individuals are independent of each other and can independently be the same or different specific groups. More specifically, the descriptive phrase "...independently" can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0114] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is permitted by the relevant government regulatory authority to be acceptable for human or animal use.

[0115] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0116] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0117] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has already received administration of the compound or composition according to embodiments of the invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.

[0118] The term "therapeutic effective amount" refers to the amount of a compound, when administered to a patient, sufficient to effectively treat the disease or condition described herein. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and may be adjusted as needed by those skilled in the art.

[0119] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention. Attached Figure Description

[0120] Appendix Figure 1 This indicates the results of the antipruritic test for compound 22;

[0121] Appendix Figure 2 This indicates the results of the antipruritic test of compound 24.

[0122] Figure 1 and Figure 2 Compared with the model group, * represents P<0.05, ** represents P<0.01, *** represents P<0.001, and **** represents P<0.0001. (Beneficial effects are indicated by: * indicating P<0.05, ** indicating P<0.01, *** indicating P<0.001, **** indicating P<0.0001.)

[0123] Through extensive and in-depth research, the inventors have unexpectedly developed a compound or a pharmaceutically acceptable salt thereof, along with its preparation method and uses. This invention provides a compound of Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs. The compound of Formula I exhibits significant regulatory activity against MRGPRX4 and can serve as a modulator of MAS-associated G protein receptor X4, possessing high safety and pharmaceutical properties. Detailed Implementation

[0124] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the following description is merely the most preferred embodiment of the present invention and should not be considered as a limitation on the scope of protection of the present invention. Based on a full understanding of the present invention, experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present invention, and such modifications should be considered to be included within the scope of protection of the present invention.

[0125] Abbreviations in the examples:

[0126] BPO: Benzoyl peroxide

[0127] LDA: Lithium diisopropylamino

[0128] NBS: N-bromosuccinimide

[0129] Preparation of DMF: N,N-dimethylformamide intermediate A1 2-chloro-4-(pentafluoro-λ6-thioalkyl)phenol (intermediate A1)

[0130] The synthetic route for intermediate A1 is as follows:

[0131]

[0132] At room temperature, 4-(pentafluoro-λ6-thioalkyl)phenol (200 mg, 0.910 mmol) was dissolved in anhydrous acetonitrile (3 mL), and then N-chlorosuccinimide (133 mg, 1.00 mmol) and trifluoromethanesulfonic acid (88.0 μL, 1.00 mmol) were added at 0 °C. After the addition was complete, the reaction mixture was reacted at 35 °C for 8 hours. After the reaction was complete, the reaction mixture was poured into water (20 mL) and then extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated brine (20 mL), dried, and concentrated to give compound 2-chloro-4-(pentafluoro-λ6-thioalkyl)phenol (231 mg, 100% yield).

[0133] LC / MS (ESI) (m / z): 252.5 (MH) + .

[0134] Preparation of intermediate A2 2-chloro-4-[(trifluoromethyl)thioalkyl]phenol (intermediate A2)

[0135] The synthetic route for intermediate A2 is as follows:

[0136]

[0137] At room temperature, 4-[(trifluoromethyl)thioalkyl]phenol (300 mg, 1.55 mmol) was dissolved in toluene (10 mL), followed by the addition of diisobutylamine (27.0 μL, 0.155 mmol) and sulfonyl chloride (125 μL, 1.55 mmol). The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the reaction mixture was slowly poured into water (10 mL), and then extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed successively with saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL), dried, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:1 to 5:1) to give 2-chloro-4-[(trifluoromethyl)thioalkyl]phenol (200 mg, yield 56.6%).

[0138] LC / MS (ESI) (m / z): 226.5 (MH) + .

[0139] Example 1 Preparation of 3-{[2-chloro-4-(pentafluoro-λ6-thioalkyl)phenoxy]methyl}-2-fluorobenzoic acid (compound 1)

[0140] The synthetic route for compound 1 is as follows:

[0141]

[0142] Step 1: Methyl 3-(bromomethyl)-2-fluorobenzoate

[0143]

[0144] At room temperature, methyl 2-fluoro-3-methylbenzoate (500 mg, 2.97 mmol) was dissolved in 1,2-dichloroethane (5 mL), followed by the addition of N-bromosuccinimide (635 mg, 3.57 mmol) and benzoyl peroxide (72.0 mg, 0.30 mmol). The reaction mixture was then reacted at 80 °C for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature and diluted with ethyl acetate (20 mL), then washed successively with saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL), dried, and concentrated by filtration. The crude product was purified by column chromatography (PE:EA = 100:1 to 10:1) to give methyl 3-(bromomethyl)-2-fluorobenzoate (500 mg, yield 68.2%).

[0145] 1 H NMR (400MHz, CDCl3) δ7.88(t,J=7.2Hz,1H),7.57(t,J=7.2Hz,1H),7.18(t,J=7.2Hz,1H),4.52(s,2H),3.93(s,3H).

[0146] Step 2: Methyl 3-{[2-chloro-4-(pentafluoro-λ6-thioalkyl)phenoxy]methyl}-2-fluorobenzoate

[0147]

[0148] At room temperature, 2-chloro-4-(pentafluoro-λ6-thioalkyl)phenol (231 mg, 0.910 mmol) was dissolved in acetonitrile (3 mL), followed by the addition of potassium carbonate (251 mg, 1.81 mmol) and methyl 3-(bromomethyl)-2-fluorobenzoate (268 mg, 1.09 mmol). The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (20 mL), washed with water and saturated brine, dried, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:1 to 5:1) to give methyl 3-{[2-chloro-4-(pentafluoro-λ6-thioalkyl)phenoxy]methyl}-2-fluorobenzoate (250 mg, yield 65.2%).

[0149] LC / MS (ESI) (m / z): 418.8 (MH) + ;

[0150] Step 3: 3-{[2-chloro-4-(pentafluoro-λ6-thioalkyl)phenoxy]methyl}-2-fluorobenzoic acid

[0151]

[0152] At room temperature, methyl 3-{[2-chloro-4-(pentafluoro-λ6-thioalkyl)phenoxy]methyl}-2-fluorobenzoate (100 mg, 0.240 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL), followed by the addition of lithium hydroxide monohydrate (50.0 mg, 1.19 mmol). The reaction was allowed to proceed at room temperature for 1 hour after the addition was complete. After the reaction was complete, the organic solvent was removed and the mixture was diluted with water (1.5 mL). The pH was adjusted to approximately 4 using 1 N HCl at 0 °C. After post-treatment, the mixture was purified by high performance liquid chromatography (column: YMC-Triart Prep C18 7 μm 30 mm × 40 cm; solvent: A = 0.1% FA, B = acetonitrile; gradient: 30–90% for 10 min) to obtain compound 3-{[2-chloro-4-(pentafluoro-λ6-thioalkyl)phenoxy]methyl}-2-fluorobenzoic acid (53.4 mg, yield 54.5%).

[0153] LC / MS (ESI) (m / z): 404.7 (MH) + ;

[0154] 1H NMR (400MHz, DMSO-d6) δ8.03(d,J=2.8Hz,1H),7.89(dd,J=9.2,2.8Hz,1H),7.81(t,J=7.2 Hz,1H),7.72(t,J=6.8Hz,1H),7.47(d,J=9.2Hz,1H),7.30(t,J=7.8Hz,1H),5.37(s,2H).

[0155] Example 2: Synthesis of 3-({2-chloro-4-[(trifluoromethyl)thioalkyl]phenoxy}methyl)-2-fluorobenzoic acid (compound 2)

[0156] The synthetic route for compound 2 is as follows:

[0157]

[0158] Step 1: Methyl 3-({2-chloro-4-[(trifluoromethyl)thioalkyl]phenoxy}methyl)-2-fluorobenzoate

[0159]

[0160] At room temperature, 2-chloro-4-[(trifluoromethyl)thioalkyl]phenol (200 mg, 0.870 mmol) was dissolved in anhydrous acetonitrile (3 mL), followed by the addition of potassium carbonate (157 mg, 1.14 mmol) and methyl 3-(bromomethyl)-2-fluorobenzoate (216 mg, 0.870 mmol). The reaction mixture was then reacted at 60 °C for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature and poured into water (20 mL). The solution was then extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (20 mL), dried, and concentrated. The crude product was subjected to column chromatography (PE:EA = 100:1–3:1) to obtain methyl 3-({2-chloro-4-[(trifluoromethyl)thioalkyl]phenoxy}methyl)-2-fluorobenzoate (250 mg, yield 73.1%). LC / MS (ESI) (m / z): 392.7 (MH) + .

[0161] Step 2: 3-({2-chloro-4-[(trifluoromethyl)thioalkyl]phenoxy}methyl)-2-fluorobenzoic acid

[0162]

[0163] Methyl 3-({2-chloro-4-[(trifluoromethyl)thioalkyl]phenoxy}methyl)-2-fluorobenzoate (150 mg, 0.380 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (1 mL), and water (1 mL) at room temperature, followed by the addition of lithium hydroxide monohydrate (80.0 mg, 1.90 mmol). The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the organic solvent was removed, and the mixture was diluted with water (1.5 mL). The pH was adjusted to approximately 4 using 1 N HCl at 0 °C. Post-treatment yielded compound 3-({2-chloro-4-[(trifluoromethyl)thioalkyl]phenoxy}methyl)-2-fluorobenzoic acid (98.6 mg, yield 68.0%).

[0164] LC / MS (ESI) (m / z): 378.6 (MH) + ;

[0165] 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),7.83(dd,J=12.4,4.4Hz,2H),7.77(t,J=6.8Hz,1H ),7.68(dd,J=8.8,2.0Hz,1H),7.44(d,J=8.8Hz,1H),7.32(t,J=7.6Hz,1H),5.34(s,2H).

[0166] Example 3: Synthesis of 2-fluoro-3-((3-(pentafluoride thio)phenoxy)methyl)benzoic acid (compound 20)

[0167] The synthetic route for compound 20 is as follows:

[0168]

[0169] Step 1: Methyl 2-fluoro-3-((3-(pentafluoride sulfo)phenoxy)methyl)benzoate

[0170]

[0171] At room temperature, potassium carbonate (207 mg, 1.5 mmol) and methyl 3-(bromomethyl)-2-fluorobenzoate (222 mg, 0.9 mmol) were added to a solution of 3-pentafluoride thiophenol (160 mg, 0.75 mmol) in N,N-dimethylformamide (5 mL). After stirring for 4 hours, the mixture was washed with saturated ammonium chloride solution (10 mL), extracted twice with ethyl acetate (20 mL), and the organic phases were separated and combined. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 90:10) to give methyl 2-fluoro-3-((3-(pentafluoride thio)phenoxy)methyl)benzoate (280 mg, yield 96.7%).

[0172] Step 2: 2-Fluoro-3-((3-(pentafluoride thio)phenoxy)methyl)benzoic acid

[0173]

[0174] 2-fluoro-3-((3-(pentafluoridesulfo)phenoxy)methyl)benzoate (400 mg, 1.05 mmol), THF / H₂O (10 mL, v:v = 1:1), and sodium hydroxide (290 mg, 7.25 mmol) were added sequentially to a 100 mL single-necked flask, and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then subjected to reverse-phase preparation (column: YMC-Triart Prep C18 (30 mm × 40 cm, 7 μm); mobile phase: A = 0.1% formic acid, B = acetonitrile; gradient: 10%-100%) to obtain 2-fluoro-3-((3-(pentafluoridesulfo)phenoxy)methyl)benzoic acid (290 mg, yield 75.2%).

[0175] 1 H NMR (400MHz, CDCl3) δ8.04(td,1H),7.76(td,1H),7.38(d,3H),7.31(t,1H),7.12-7.10(m,1H),5.20(s,2H),3.4(b,1H).

[0176] LC / MS (ESI) (m / z): 370.6 (MH) -

[0177] Example 4: 2-Fluoro-3-{[2-(pentafluoro-λ)} 6 Synthesis of β-thioalkyl)phenoxy]methyl}benzoic acid (compound 21)

[0178] The synthetic route for compound 21 is as follows:

[0179]

[0180] Step 1: 1-(benzyloxy)-2-(pentafluoro-λ) 6 -Thioalkyl)benzene

[0181]

[0182] At room temperature, 1-fluoro-2-(pentafluoro-λ) 6 1-Thioalkyl)benzene (100 mg, 0.490 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), followed by the addition of benzyl alcohol (161 mg, 1.48 mmol) and 60% sodium hydroxide (36.0 mg, 1.48 mmol). The reaction was then carried out at 80 °C for 1 hour. After the reaction was complete, the reaction solution was cooled to 0 °C and quenched by slow addition of water (5 mL). Extraction was then performed using ethyl acetate (3 × 5 mL). The combined organic phases were washed successively with saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL), dried, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:1 to 5:1) to obtain 1-(benzyloxy)-2-(pentafluoro-λ) 6 β-thioalkyl)benzene (70.0 mg, yield 49.3%).

[0183] 1 H NMR (400MHz, CDCl3) δ7.76(dd,J=8.4,1.2Hz,1H),7.45–7.36(m,5H),7.33(d,J=7.2Hz,1H),7.08(d,J=8.4Hz,1H),7.01(d,J=7.6Hz,1H),5.19(s,2H).

[0184] Step 2: 2-(pentafluoro-λ) 6 -Thioalkyl)phenol

[0185]

[0186] At room temperature, 1-(benzyloxy)-2-(pentafluoro-λ) 6 2-(thioalkyl)benzene (70.0 mg, 0.241 mmol) was dissolved in methanol (2 mL), and then 10% wet palladium on carbon (20 mg) was added. After the addition was complete, the mixture was purged three times with hydrogen and reacted at 25 °C for 12 hours. After the reaction was complete, the mixture was diluted with methanol (10 mL), filtered, and concentrated to give compound 2-(pentafluoro-λ). 6 β-thioalkyl)phenol (40.0 mg, yield 75.4%).

[0187] LC / MS (ESI) (m / z): 219 (MH) + ;

[0188] Step 3: 2-Fluoro-3-{[2-(pentafluoro-λ)}6 Methyl benzoate (-thioalkyl)phenoxy]methyl benzoate

[0189]

[0190] At room temperature, 2-(pentafluoro-λ) 6 2-( ... 6 Methyl benzoate (60.0 mg, yield 86.9%).

[0191] LC / MS (ESI) (m / z): 384.8 (MH) + .

[0192] Step 4: 2-Fluoro-3-{[2-(pentafluoro-λ)} 6 -thioalkyl)phenoxy]methyl}benzoic acid

[0193]

[0194] At room temperature, 2-fluoro-3-{[2-(pentafluoro-λ)} 6 Methyl benzoate (60.0 mg, 0.160 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL), followed by the addition of lithium hydroxide monohydrate (33.0 mg, 0.780 mmol). The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the organic solvent was removed using a rotary evaporator, and the mixture was diluted with water (1.5 mL). The pH was adjusted to approximately 4 using 1 N HCl at 0 °C. The solution was collected after filtration to yield compound 2-fluoro-3-{[2-(pentafluoro-λ] 6 [-thioalkyl)phenoxy]methyl}benzoic acid (23.2 mg, yield 38.9%).

[0195] LC / MS (ESI) (m / z): 370.8 (MH) + .

[0196] 1H NMR(400MHz,DMSO-d6)δ7.84–7.79(m,2H),7.75–7.70(m,1H),7.63–7.59(m,1H), 7.46(d,J=8.4Hz,1H),7.31(t,J=7.6Hz,1H),7.12(t,J=7.6Hz,1H),5.31(s,2H).

[0197] Example 5: Synthesis of 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluorobenzoic acid (compound 22)

[0198] The synthetic route for compound 22 is as follows:

[0199]

[0200] Step 1: 2,4-Dichloro-3,5-Difluorophenol

[0201]

[0202] Under ice bath cooling, concentrated hydrochloric acid (2 mL), 3,5-difluorophenol (1508 mg, 0.0116 mol), and N-chlorosuccinimide (3872 mg, 0.029 mol) were added sequentially to water (8 mL), and the reaction was carried out at 60 °C for 5 hours. The reaction was monitored by LCMS. After no starting material remained, the reaction solution was cooled to room temperature, and methyl tert-butyl ether (50 mL) was added to the reaction solution. The mixture was allowed to stand and separate into layers. The organic phase was collected, washed once with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give 2,4-dichloro-3,5-difluorophenol (2000 mg, yield 86.7%).

[0203] Step 2: Methyl 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluorobenzoate

[0204]

[0205] At room temperature, potassium carbonate (829 mg, 0.006 mol) and 2,4-dichloro-3,5-difluorophenol (398 g, 0.002 mol) were added sequentially to a solution of methyl 3-(bromomethyl)-2-fluorobenzoate (492 mg, 0.002 mol) in acetonitrile (9.8 mL). The reaction was carried out at 60 °C for 16 hours. The reaction was monitored by LCMS. After no starting material remained, the reaction solution was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain methyl 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluorobenzoate (620 mg, yield 85.2%).

[0206] Step 3: 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluorobenzoic acid

[0207]

[0208] Sodium hydroxide (339 mg, 0.0085 mol) was added to a solution of methyl 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluorobenzoate (620 mg, 0.0017 mol) in tetrahydrofuran (6.2 mL) and water (6.2 mL) under ice bath cooling, and the reaction was carried out at 25 °C for 3 hours. The reaction was monitored by LCMS. After no raw material remained, the reaction solution was cooled to room temperature. The reaction solution was concentrated to remove most of the tetrahydrofuran. Hydrochloric acid aqueous solution (2M) was added dropwise under ice bath cooling to adjust the pH of the system to 3-4. Ethyl acetate (40ml) was added and mixed evenly. After standing, the organic phase was collected. The organic phase was washed twice with water (10mL) and once with saturated brine (10mL). It was dried over anhydrous sodium sulfate and concentrated. The mixture was then separated by preparative high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10μm; solvent: A = water + formic acid (0.05%), B = acetonitrile; gradient: 52%-82%) to obtain 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluorobenzoic acid (362mg, yield 60.7%).

[0209] LC-MS, M / Z (ESI): 348.70 [M-1] -

[0210] 1 H NMR (400MHz, DMSO-d6) δ13.31(s,1H),7.88–7.84(m,1H),7.80–7.74(m,1H),7.51(dd,J=11.3,2.1Hz,1H),7.33(t,J=7.7Hz,1H),5.31(s,2H).

[0211] Example 6: Synthesis of 2-fluoro-3-[(2,4,6-trichloro-3,5-difluorophenoxy)methyl]benzoic acid (compound 23)

[0212] The synthetic route for compound 23 is as follows:

[0213]

[0214] Step 1: 2,4,6-Trichloro-3,5-Difluorophenol

[0215]

[0216] Under ice bath cooling, concentrated hydrochloric acid (2.4 mL), 2,4-dichloro-3,5-difluorophenol (1600 mg, 0.008 mol), and N-chlorosuccinimide (1602 mg, 0.012 mol) were added sequentially to water (9.6 mL), and the reaction was carried out at 60 °C for 16 hours. The reaction was monitored by LCMS. When 8% of the starting material remained, the reaction solution was cooled to room temperature, and methyl tert-butyl ether (50 mL) was added to the reaction solution. After standing and separating the layers, the organic phase was collected, washed once with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give 2,4,6-trichloro-3,5-difluorophenol (1400 mg, yield 74.5%).

[0217] Step 2: Methyl 2-fluoro-3-[(2,4,6-trichloro-3,5-difluorophenoxy)methyl]benzoate

[0218]

[0219] At room temperature, potassium carbonate (829 mg, 0.006 mol) and 2,4,6-trichloro-3,5-difluorophenol (398 g, 0.002 mol) were added sequentially to a solution of methyl 3-(bromomethyl)-2-fluorobenzoate (492 mg, 0.002 mol) in acetonitrile (9.8 mL). The reaction was carried out at 60 °C for 16 hours. The reaction was monitored by LCMS. After no starting material remained, the reaction solution was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain methyl 2-fluoro-3-[(2,4,6-trichloro-3,5-difluorophenoxy)methyl]benzoate (700 mg, yield 87.9%).

[0220] Step 3: 2-Fluoro-3-[(2,4,6-trichloro-3,5-difluorophenoxy)methyl]benzoic acid

[0221]

[0222] Sodium hydroxide (359 mg, 0.0090 mol) was added to a solution of methyl 2-fluoro-3-[(2,4,6-trichloro-3,5-difluorophenoxy)methyl]benzoate (700 mg, 0.0018 mol) in tetrahydrofuran (7 mL) and water (7 mL) under ice bath cooling, and the reaction was carried out at 25 °C for 3 hours. The reaction was monitored by LCMS. After no raw material remained, the reaction solution was cooled to room temperature, concentrated to remove most of the tetrahydrofuran, and then adjusted to pH 3-4 by adding 2 M hydrochloric acid solution dropwise under ice bath cooling. Ethyl acetate (40 mL) was added, mixed thoroughly, and allowed to stand. The organic phase was collected, washed twice with water (10 mL), once with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and separated by preparative high-performance liquid chromatography (column: Phenomenex luna C). 18 150*25mm*10μm; Solvent: A = water + formic acid (0.05%), B = acetonitrile; Gradient: 52%-82%) purified to obtain 2-fluoro-3-[(2,4,6-trichloro-3,5-difluorophenoxy)methyl]benzoic acid (471mg, yield 69.7%).

[0223] LC-MS, M / Z (ESI): 384.60 [M-1]- 1 H NMR (400MHz, DMSO-d6) δ13.34(s,1H),7.92–7.84(m,1H),7.81–7.73(m,1H),7.34–7.29(m,1H),5.18(d,J=5.3Hz,2H)

[0224] Example 7: Synthesis of 5-(3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorophenyl)-1H-tetrazole (compound 24)

[0225] The synthetic route for compound 24 is as follows:

[0226]

[0227] Step 1: Synthesis of 3-(bromomethyl)-2-fluorobenzonitrile

[0228]

[0229] N-bromosuccinimide (1.58 g, 8.9 mmol) and benzoyl peroxide (170 mg, 0.7 mmol) were added to a solution of 2-fluoro-3-methylbenzonitrile (1 g, 7.4 mmol) in 1,2-dichloroethane (10 mL), and the mixture was stirred at 80 °C for 18 h. The reaction solution was concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-5 / 1) to give 3-(bromomethyl)-2-fluorobenzonitrile (1.1 g, 69% yield).

[0230] Step 2: Synthesis of 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorobenzonitrile

[0231]

[0232] To a solution of 3-(bromomethyl)-2-fluorobenzonitrile (300 mg, 1.4 mmol) in acetonitrile (3 mL), 2,4-dichloro-3,5-difluorophenol (279 mg, 1.4 mmol) and potassium carbonate (581 mg, 4.2 mmol) were added, and the mixture was stirred at 60 °C for 18 h. Water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 - 2 / 1) to obtain 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorobenzonitrile (330 mg, yield 71%).

[0233] LC-MS, M / Z (ESI): 333.2 [M+H] + .

[0234] Step 3: Synthesis of 5-(3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorophenyl)-1H-tetrazazole

[0235]

[0236] To a xylene (1 mL) solution of 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorobenzonitrile (3) (300 mg, 0.9 mmol), tri-n-butyltin azide (1.8 g, 5.4 mmol) and ammonium chloride (5 mg, 0.09 mmol) were added, and the mixture was stirred at 140 °C for 10 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 mL x 3). The organic phase was washed with saturated brine (3 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to reverse-phase preparation (column: Phenomenex Synergi C).18 100*25mm*4um; Solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; Gradient: 5%-95%) to obtain 5-(3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorophenyl)-1H-tetrazole (87.3 mg, purity 97.05%, yield 28%).

[0237] 1 H NMR (400MHz, DMSO-d6) δ8.14–8.05(m,1H),7.87–7.78(m,1H),7.59–7.54(m,1H),7.50(t,J=7.7Hz,1H),5.41(s,2H).

[0238] LC-MS, M / Z(ESI): 374.8[M+H]+.

[0239] Example 8: Synthesis of 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluoro-N-(methanesulfonyl)benzamide (compound 26)

[0240] The synthetic route for compound 26 is as follows:

[0241]

[0242] Under ice bath cooling, N,N-diisopropylethylamine (426 mg, 0.0033 mol), HATU (608 mg, 0.0016 mol), and methanesulfonamide (123 mg, 0.0013 mol) were added sequentially to a solution of 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluorobenzoic acid (390 mg, 0.0011 mol) in dichloromethane (7.8 mL), and the reaction was carried out at 25 °C for 20 hours. The reaction was monitored by LCMS. After the product was detected, dichloromethane (30 ml) and water (20 ml) were added to the reaction solution. The mixture was allowed to stand and separate into layers. The organic phase was collected, washed twice with water (10 ml), once with saturated saline (10 ml), dried over anhydrous sodium sulfate, concentrated, and then separated by preparative high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10μm; solvent: A = water + formic acid (0.05%), B = acetonitrile; gradient: 52%-82%) to obtain 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluoro-N-(methanesulfonyl)benzamide (202 mg, yield 42.4%).

[0243] LC-MS, M / Z (ESI): 427.50 [M+1] +

[0244] 1H NMR(400MHz,dmso)δ12.35(s,1H),7.78–7.75(m,1H),7.70–7.64(m,1H),7. 52(dd,J=11.3,2.0Hz,1H),7.36(t,J=7.7Hz,1H),5.31(s,2H),3.35(s,3H).

[0245] Example 9: Synthesis of 3-(3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (compound 28) The synthetic route of compound 28 is as follows:

[0246]

[0247] Step 1: Synthesis of 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluoro-N'-hydroxyphenyl-1-formamidinamide

[0248]

[0249] Hydroxylamine (0.5 mL, 50% aqueous solution) was added to a 4 mL ethanol solution of 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorobenzonitrile (400 mg, 1.2 mmol), and the mixture was stirred at 83 °C for 2 h. The reaction solution was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0-20 / 1) to obtain 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluoro-N'-hydroxybenzene-1-carbamate (240 mg, yield 54.5%).

[0250] LC-MS, M / Z (ESI): 366.3 [M+H]+

[0251] Step 2: Synthesis of 3-(3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one

[0252]

[0253] Triethylamine (72 mg, 0.71 mmol) and ethyl chloroformate (71 mg, 0.66 mmol) were added to a solution of 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluoro-N'-hydroxybenzene-1-carbamate (2) (200 mg, 0.55 mmol) in dichloromethane (2 mL) at 0 °C, and the mixture was stirred at room temperature for 18 h. Water (10 mL) and saturated sodium bicarbonate solution (10 mL) were added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The yellow oil was dissolved in dimethyl sulfoxide (2 mL), and sodium hydroxide (26 mg, 0.66 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 3 h. Water (10 mL) was added to the reaction solution, and the pH was adjusted to 3-4 with 1N hydrochloric acid aqueous solution. Extraction was performed with ethyl acetate (5 mL * 3). The organic phase was washed with saturated brine (5 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to reverse-phase preparation (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%) to obtain 3-(3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (137.7 mg, purity 97.99%, yield 64%).

[0254] 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),7.92–7.77(m,2H),7.58(dd,J=11.3,2.1Hz,1H),7.49(t,J=7.7Hz,1H),5.39(s,2H).

[0255] LC-MS, M / Z (ESI): 388.6 [MH] - .

[0256] Example 10: Synthesis of 3-(1-(2,4-dichloro-3,5-difluorophenoxy)ethyl)-2-fluorobenzoic acid (compound 29)

[0257] The synthetic route for compound 29 is as follows:

[0258]

[0259] Step 1: Synthesis of methyl 3-(1-bromoethyl)-2-fluorobenzoate

[0260]

[0261] Hydrogen bromide (269 mg, 3.33 mmol, 33% acetic acid solution) was added to a solution of methyl 3-vinyl-2-fluorobenzoate (500 mg, 2.78 mmol) in acetic acid (2.5 mL) at 0 °C, and the reaction was allowed to proceed naturally to room temperature for 18 h. The pH of the reaction mixture was adjusted to 7–8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0–2 / 1) to obtain methyl 3-(1-bromoethyl)-2-fluorobenzoate (310 mg, yield 42.8%).

[0262] Step 2: Synthesis of methyl 3-(1-(2,4-dichloro-3,5-difluorophenoxy)ethyl)-2-fluorobenzoate

[0263]

[0264] To a solution of methyl 3-(1-bromoethyl)-2-fluorobenzoate (300 mg, 1.15 mmol) in N,N-dimethylformamide (3 mL), 2,4-dichloro-3,5-difluorophenol (297 mg, 1.5 mmol) and potassium carbonate (476 mg, 3.44 mmol) were added, and the mixture was stirred at 60 °C for 6 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-2 / 1) to give methyl 3-(1-(2,4-dichloro-3,5-difluorophenoxy)ethyl)-2-fluorobenzoate (220 mg, yield 50.5%).

[0265] LC-MS, M / Z (ESI): 380.2 [M+H]+

[0266] Step 3: Synthesis of 3-(1-(2,4-dichloro-3,5-difluorophenoxy)ethyl)-2-fluorobenzoic acid

[0267]

[0268] Sodium hydroxide (116 mg, 2.9 mmol) was added to a solution of methyl 3-(1-(2,4-dichloro-3,5-difluorophenoxy)ethyl)-2-fluorobenzoate (220 mg, 0.58 mmol) in tetrahydrofuran (2 mL) and water (2 mL), and the mixture was stirred at room temperature for 18 h. Water (10 mL) was added to the reaction mixture, and the pH was adjusted to 4–5 with 1 N hydrochloric acid solution, followed by extraction with ethyl acetate (3 mL x 3). The organic phase was washed with saturated brine (3 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to reverse-phase preparation (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%) to obtain 3-(1-(2,4-dichloro-3,5-difluorophenoxy)ethyl)-2-fluorobenzoic acid (9.6 mg, purity 95.84%, yield 4%).

[0269] 1 H NMR (400MHz, DMSO-d6) δ13.37(s,1H),7.81(td,J=7.6,1.8Hz,1H),7.73–7.63(m,1H),7.37–7.28(m,2H),6.04–5.93(m,1H),1.64(d,J=6.3Hz,3H).

[0270] LC-MS, M / Z (ESI): 362.6 [MH] - .

[0271] Example 11: Synthesis of 5-cyano-3-(2,4-dichloro-3,5-difluorophenoxy)methyl)-2-methoxybenzoic acid (compound 30)

[0272] The synthetic route for compound 30 is as follows:

[0273]

[0274] Step 1: Synthesis of methyl 5-bromo-2-fluoro-3-methylbenzoate

[0275]

[0276] Under nitrogen protection, 5-bromo-2-fluoro-3-methylbenzoic acid (600 mg, 2.57 mmol) was dissolved in N,N-dimethylformamide (8 mL), followed by the addition of iodomethane (730.91 mg, 5.15 mmol, 320.57 μL) and potassium carbonate (1.07 g, 7.72 mmol). The reaction mixture was stirred at 80 °C for 2 hours. LC-MS was used to monitor the reaction until complete. After the reaction was complete, the mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:tetrahydrofuran (V / V) = 10:1–5:1, gradient elution) to obtain methyl 5-bromo-2-fluoro-3-methylbenzoate (550 mg).

[0277] LC-MS, M / Z (ESI): 247.2 [M+H] + .

[0278] Step 2: Synthesis of methyl 5-cyano-2-fluoro-3-methylbenzoate

[0279]

[0280] Under nitrogen protection, methyl 5-bromo-2-fluoro-3-methylbenzoate (260 mg, 1.05 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of zinc cyanide (247.15 mg, 2.10 mmol) and tetraphenylphosphine palladium (243.22 mg, 210.47 μmol). The reaction mixture was stirred at 120 °C for 1 hour. LC-MS monitoring was performed to ensure complete reaction of the starting material and the formation of the desired product. After the reaction was complete, the reaction solution was filtered, the filtrate was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 2), the organic phase was washed with saturated brine (20 mL × 2), and dried over anhydrous sodium sulfate. The solution was filtered, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (petroleum ether:tetrahydrofuran (V / V) = 10:1-5:1, gradient elution) to obtain methyl 5-cyano-2-fluoro-3-methylbenzoate (107 mg).

[0281] LC-MS, M / Z (ESI): 194.1 [M+H] + .

[0282] Step 3: Synthesis of methyl 3-(bromomethyl)-5-cyano-2-fluorobenzoate

[0283]

[0284] Under nitrogen protection, methyl 5-cyano-2-fluoro-3-methylbenzoate (107 mg, 553.90 μmol) was dissolved in carbon tetrachloride (2 mL), followed by the addition of N-bromosuccinimide (118.30 mg, 664.69 μmol) and dibenzoyl peroxide (17.12 mg, 276.95 μmol, 14.76 μL). The reaction mixture was stirred at 80 °C for 16 hours. LC-MS monitoring was performed to ensure complete reaction of the starting material and the formation of the desired product. After the reaction was complete, the reaction solution was filtered, the filtrate was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 2), the organic phase was washed with saturated brine (20 mL × 2), and dried over anhydrous sodium sulfate. The crude product was obtained by filtration and vacuum concentration. The crude product was then purified by silica gel column chromatography (petroleum ether: tetrahydrofuran (V / V) = 10:1-5:1, gradient elution) to obtain methyl 5-cyano-2-fluoro-3-methylbenzoate (50 mg).

[0285] LC-MS, M / Z (ESI): 271.9 [M+H] + .

[0286] Step 4: Synthesis of methyl 5-cyano-3-(2,4-dichloro-3,5-difluorophenoxy)methyl-2-fluorobenzoate

[0287]

[0288] Under nitrogen protection, methyl 3-(bromomethyl)-5-cyano-2-fluorobenzoate (50 mg, 183.78 μmol) and 2,4-dichloro-3,5-difluorophenol (43.88 mg, 220.53 μmol) were dissolved in acetonitrile (2 mL), followed by the addition of potassium carbonate (38.10 mg, 275.66 μmol). The reaction mixture was stirred at 25 °C for 16 hours. LC-MS monitoring was performed to ensure complete reaction of the starting materials and the formation of the desired product. After the reaction was complete, the filtrate was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2), and the organic phase was washed with saturated brine (10 mL × 2) and dried over anhydrous sodium sulfate. The crude product was obtained by filtration and vacuum concentration. The crude product was then purified by silica gel column chromatography (petroleum ether: tetrahydrofuran (V / V) = 5:1-1:1, gradient elution) to obtain methyl 5-cyano-3-(2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorobenzoate (30 mg).

[0289] LC-MS, M / Z (ESI): 390.3 [M+H] + .

[0290] Step 5: Synthesis of 5-cyano-3-(2,4-dichloro-3,5-difluorophenoxy)methyl)-2-methoxybenzoic acid

[0291]

[0292] Methyl 5-cyano-3-(2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorobenzoate (30 mg, 76.90 μmol) was dissolved in methanol (0.5 mL), tetrahydrofuran (0.5 mL), and water (0.2 mL) at 25 °C, followed by the addition of lithium hydroxide (5.52 mg, 230.69 μmol). The reaction mixture was stirred at 25 °C for 1 hour. LC-MS was used to monitor the reaction until the starting material was completely reacted and the desired product was formed. After the reaction was complete... The pH was adjusted to 4 with 1N hydrochloric acid, extracted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product. The crude product was subjected to reversed-phase preparative HPLC (Welch Ultimate 10 μm 21.2*250 mm; 60% MeCN was gradient eluted to 72% MeCN in water containing 0.1% formic acid within 15 minutes) to obtain 5-cyano-3-(2,4-dichloro-3,5-difluorophenoxy)methyl)-2-methoxybenzoic acid (2.9 mg, yield 7.71%).

[0293] 1 H-NMR(400MHz,CD3OD)δ7.35(d,J=2.2Hz,1H),7.24(s,1H),6.41-6.38(m,1H),4.45(s,2H),3.18(s,3H)

[0294] LC-MS, M / Z (ESI): 388.1 [M+H] + .

[0295] Example 12: Synthesis of 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)benzoic acid (compound 32)

[0296] The synthetic route for compound 32 is as follows:

[0297]

[0298] Step 1: Synthesis of methyl 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)benzoate

[0299]

[0300] To a solution of methyl 3-(bromomethyl)benzoate (300 mg, 1.31 mmol) in acetonitrile (3 mL), 2,4-dichloro-3,5-difluorophenol (287 mg, 1.44 mmol) and potassium carbonate (543 mg, 3.93 mmol) were added, and the mixture was stirred at 60 °C for 18 h. Water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 - 2 / 1) to obtain methyl 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)benzoate (320 mg, yield 70.4%).

[0301] LC-MS, M / Z (ESI): 348.3 [M+H]+

[0302] Step 2: Synthesis of 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)benzoic acid

[0303]

[0304] Sodium hydroxide (173 mg, 4.32 mmol) was added to a solution of methyl 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)benzoate (300 mg, 0.86 mmol) in tetrahydrofuran (3 mL) and water (3 mL), and the mixture was stirred at room temperature for 3 h. Water (10 mL) was added to the reaction mixture, and the pH was adjusted to 4–5 with 1 N hydrochloric acid solution, followed by extraction with ethyl acetate (3 mL x 3). The organic phase was washed with saturated brine (3 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to reverse-phase preparation (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%) to obtain 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)benzoic acid (244.1 mg, purity 99.67%, yield 84%).

[0305] 1 H NMR (400MHz, DMSO-d6) δ13.09(s,1H),8.05(s,1H),7.93(d,J=7.8Hz,1H),7.71(d ,J=7.7Hz,1H),7.56(t,J=7.7Hz,1H),7.45(dd,J=11.4,2.1Hz,1H),5.34(s,2H).

[0306] LC-MS, M / Z (ESI): 330.9 [M-1]-

[0307] Example 13: Synthesis of 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-5-fluorobenzoic acid (compound 34)

[0308] The synthetic route for compound 34 is as follows:

[0309]

[0310] Step 1: Methyl 3-fluoro-5-methylbenzoate

[0311]

[0312] Under ice bath cooling, concentrated sulfuric acid (3.18 g, 0.0325 mol) (1.73 mL) was slowly added dropwise to a methanol (10 mL) solution of 3-fluoro-5-methylbenzoic acid (1 g, 0.0065 mol) and reacted at 70 °C for 20 hours. The reaction was monitored by TLC. After no raw material remained, the reaction solution was concentrated to remove most of the methanol, and ethyl acetate (50 mL) and water (20 mL) were added. The mixture was allowed to stand and separate into layers. The organic phase was collected, washed twice with water (20 mL), once with saturated brine (20 mL), dried over anhydrous ammonium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain methyl 3-fluoro-5-methylbenzoate (1.1 g, yield 100.8%).

[0313] Step 2: Methyl 3-(bromomethyl)-5-fluorobenzoate

[0314]

[0315] Under ice bath cooling, N-bromosuccinimide (1.38 g, 0.0078 mol) and benzoyl peroxide (0.14 g, 0.0006 mol) were added sequentially to methyl 3-fluoro-5-methylbenzoate (1.1 g, 0.0065 mol) in 1,2-dichloroethane (11 mL) solvent, and the reaction was carried out at 80 °C for 5 hours. The reaction was monitored by TLC. After no starting material remained, the reaction solution was cooled to room temperature. The reaction solution was concentrated to remove most of the solvent, and ethyl acetate (50 mL) and water (20 mL) were added. After thorough mixing, the mixture was allowed to stand for separation. The organic phase was collected, washed twice with water (20 mL), and once with saturated brine (20 mL). After concentration, the mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain methyl 3-(bromomethyl)-5-fluorobenzoate (1.6 g, yield 99%).

[0316] Step 3: Methyl 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-5-fluorobenzoate

[0317]

[0318] At room temperature, potassium carbonate (414 mg, 0.003 mol) and 2,4-dichloro-3,5-difluorophenol (199 mg, 0.001 mol) were added sequentially to a 5 mL solution of methyl 3-(bromomethyl)-5-fluorobenzoate (250 mg, 0.001 mol) in acetonitrile (5 mL). The reaction was carried out at 60 °C for 16 hours. The reaction was monitored by LCMS. After no starting material remained, the reaction solution was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain methyl 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-5-fluorobenzoate (340 mg, yield 92%).

[0319] Step 4: 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-5-fluorobenzoic acid

[0320]

[0321] Sodium hydroxide (180 mg, 0.0045 mol) was added to a solution of methyl 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-5-fluorobenzoate (340 mg, 0.0009 mol) in tetrahydrofuran (3.4 mL) and water (3.4 mL) under ice bath cooling, and the reaction was carried out at 25 °C for 3 hours. The reaction was monitored by LCMS. After no raw material remained, the reaction solution was cooled to room temperature. The reaction solution was concentrated to remove most of the tetrahydrofuran. Hydrochloric acid aqueous solution (2M) was added dropwise under ice bath cooling to adjust the pH of the system to 3-4. Ethyl acetate (40ml) was added and mixed evenly. After standing, the organic phase was collected. The organic phase was washed twice with water (10mL) and once with saturated brine (10mL). It was dried over anhydrous sodium sulfate and concentrated. The mixture was then separated by preparative high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10um; solvent: A = water + formic acid (0.05%), B = acetonitrile; gradient: 52%-82%) to obtain 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-5-fluorobenzoic acid (155mg, yield 47.4%).

[0322] LC-MS, M / Z (ESI): 348.65 [M-1] -

[0323] 1 H NMR (400MHz, DMSO-d6): δ13.39(s,1H),7.87(s,1H),7.63-7.60(m,1H),7.53(d,J=9.2Hz,1H),7.40(dd,J=11.3,2.1Hz,1H),5.32(s,2H).

[0324] Example 14: Synthesis of 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-5-methylbenzoic acid (compound 35)

[0325] The synthetic route for compound 35 is as follows:

[0326]

[0327] Step 1: Synthesis of methyl 3-(bromomethyl)-5-methylbenzoate

[0328]

[0329] N-bromosuccinimide (195 mg, 1.10 mmol) and benzoyl peroxide (30 mg, 0.12 mmol) were added to a solution of methyl 3,5-dimethylbenzoate (200 mg, 1.22 mmol) in 1,2-dichloroethane (2 mL), and the mixture was stirred at 80 °C for 18 h. The reaction solution was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-5 / 1) to give methyl 3-(bromomethyl)-5-methylbenzoate (100 mg, yield 33%).

[0330] LC-MS, M / Z (ESI): 245.2 [M+H]+

[0331] Step 2: Synthesis of methyl 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-5-methylbenzoate

[0332]

[0333] To a solution of methyl 3-(bromomethyl)-5-methylbenzoate (100 mg, 0.41 mmol) in acetonitrile (1 mL), 2,4-dichloro-3,5-difluorophenol (90 mg, 0.45 mmol) and potassium carbonate (171 mg, 1.23 mmol) were added, and the mixture was stirred at 60 °C for 18 h. Water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 - 2 / 1) to give methyl 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-5-methylbenzoate (120 mg, yield 80.8%).

[0334] LC-MS, M / Z (ESI): 362.3 [M+H] +

[0335] Step 3: Synthesis of 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-5-methylbenzoic acid

[0336]

[0337] Sodium hydroxide (66 mg, 1.65 mmol) was added to a solution of methyl 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-5-methylbenzoate (120 mg, 0.33 mmol) in tetrahydrofuran (1.2 mL) and water (1.2 mL), and the mixture was stirred at room temperature for 6 h. Water (10 mL) was added to the reaction mixture, and the pH was adjusted to 4–5 with 1 N hydrochloric acid solution, followed by extraction with ethyl acetate (3 mL x 3). The organic phase was washed with saturated brine (3 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to reverse-phase preparation (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%) to obtain 3-((2,4-dichloro-3,5-difluorophenoxy)methyl)-5-methylbenzoic acid (51.2 mg, purity 99.42%, yield 44%).

[0338] 1 H NMR (400MHz, DMSO-d6) δ12.98(s,1H),7.85(s,1H),7.75(s,1H),7.51(s,1H),7.43(dd,J=11.4,2.1Hz,1H),5.29(s,2H),2.38(s,3H).

[0339] LC-MS, M / Z (ESI): 344.9 [M-1] -

[0340] Example 15: Synthesis of 3-cyano-5-((2,4-dichloro-3,5-difluorophenoxy)methyl)benzoic acid (compound 36)

[0341] The synthetic route for compound 36 is as follows:

[0342]

[0343] Step 1: Synthesis of methyl 3-(bromomethyl)-5-cyanobenzoate

[0344]

[0345] N-bromosuccinimide (366 mg, 2.06 mmol) and benzoyl peroxide (41 mg, 0.17 mmol) were added to a solution of methyl 3-cyano-5-methylbenzoate (300 mg, 1.71 mmol) in 1,2-dichloroethane (3 mL), and the mixture was stirred at 80 °C for 18 h. The reaction solution was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-5 / 1) to give methyl 3-(bromomethyl)-5-cyanobenzoate (300 mg, yield 69%).

[0346] LC-MS, M / Z (ESI): 256.2 [M+H]+

[0347] Step 2: Synthesis of methyl 3-cyano-5-((2,4-dichloro-3,5-difluorophenoxy)methyl)benzoate

[0348]

[0349] To a solution of methyl 3-(bromomethyl)-5-cyanobenzoate (300 mg, 1.18 mmol) in acetonitrile (3 mL), 2,4-dichloro-3,5-difluorophenol (282 mg, 1.42 mmol) and potassium carbonate (490 mg, 3.54 mmol) were added, and the mixture was stirred at 60 °C for 18 h. Water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 - 2 / 1) to obtain methyl 3-cyano-5-((2,4-dichloro-3,5-difluorophenoxy)methyl)benzoate (210 mg, yield 47.8%).

[0350] LC-MS, M / Z (ESI): 373.3 [M+H]+

[0351] Step 3: Synthesis of 3-cyano-5-((2,4-dichloro-3,5-difluorophenoxy)methyl)benzoic acid

[0352]

[0353] Sodium hydroxide (107 mg, 2.70 mmol) was added to a solution of methyl 3-cyano-5-((2,4-dichloro-3,5-difluorophenoxy)methyl)benzoate (200 mg, 0.54 mmol) in tetrahydrofuran (2 mL) and water (2 mL), and the mixture was stirred at room temperature for 3 h. Water (10 mL) was added to the reaction mixture, and the pH was adjusted to 4–5 with 1 N hydrochloric acid solution, followed by extraction with ethyl acetate (3 mL x 3). The organic phase was washed with saturated brine (3 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to reverse-phase preparation (column: Phenomenex Synergi C). 18 100*25mm*4μm; Solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; Gradient: 5%-95%) to obtain 3-cyano-5-((2,4-dichloro-3,5-difluorophenoxy)methyl)benzoic acid (96.6 mg, purity 99.63%, yield 50%).

[0354] 1 H NMR (400MHz, DMSO-d6) δ13.38(s,1H),8.30(d,J=17.3Hz,2H),8.14(s,1H),7.44(dd,J=11.2,2.0Hz,1H),5.38(s,2H).

[0355] LC-MS, M / Z (ESI): 356.0 [M-1]-

[0356] Example 16: Synthesis of 6-((2,4-dichloro-3,5-difluorophenoxy)methyl)pyridine-2-carboxylic acid (compound 37)

[0357] The synthetic route for compound 37 is as follows:

[0358]

[0359] Step 1: Synthesis of methyl 6-((2,4-dichloro-3,5-difluorophenoxy)methyl)pyridine-2-carboxylate

[0360]

[0361] To a solution of methyl 6-(bromomethyl)pyridine-2-carboxylate (200 mg, 0.87 mmol) in acetonitrile (2 mL), 2,4-dichloro-3,5-difluorophenol (190 mg, 0.96 mmol) and potassium carbonate (360 mg, 2.61 mmol) were added, and the mixture was stirred at 60 °C for 18 h. Water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 - 2 / 1) to give methyl 6-((2,4-dichloro-3,5-difluorophenoxy)methyl)pyridine-2-carboxylate (220 mg, yield 72.7%).

[0362] LC-MS, M / Z (ESI): 349.3 [M+H] +

[0363] Step 2: Synthesis of 6-((2,4-dichloro-3,5-difluorophenoxy)methyl)pyridine-2-carboxylic acid

[0364]

[0365] Sodium hydroxide (115 mg, 2.87 mmol) was added to a solution of methyl 6-((2,4-dichloro-3,5-difluorophenoxy)methyl)pyridine-2-carboxylate (200 mg, 0.57 mmol) in tetrahydrofuran (2 mL) and water (2 mL), and the mixture was stirred at room temperature for 3 h. Water (10 mL) was added to the reaction mixture, and the pH was adjusted to 4–5 with 1 N hydrochloric acid solution, followed by extraction with ethyl acetate (3 mL x 3). The organic phase was washed with saturated brine (3 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to reverse-phase preparation (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%) to obtain 6-((2,4-dichloro-3,5-difluorophenoxy)methyl)pyridine-2-carboxylic acid (129.4 mg, purity 98.96%, yield 67%).

[0366] 1 H NMR (400MHz, DMSO-d6) δ13.28(s,1H),8.14–7.94(m,2H),7.78(d,J=7.5Hz,1H),7.50(dd,J=11.2,1.6Hz,1H),5.39(s,2H).

[0367] LC-MS, M / Z (ESI): 331.7 [M-1]-

[0368] Example 17: Synthesis of 5-(3-((2,4-dichloro-3,5-difluorophenoxy)methyl)phenyl)-1H-tetrazole (compound 38)

[0369] The synthetic route for compound 38 is as follows:

[0370]

[0371] Step 1: 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]benzonitrile

[0372]

[0373] Following the first step of Example 5, 2,4-dichloro-3,5-difluorophenol was prepared. At room temperature, 2,4-dichloro-3,5-difluorophenol (200 mg, 1.01 mmol) was dissolved in acetonitrile (4 mL), followed by the addition of potassium carbonate (208 mg, 1.51 mmol) and 3-(bromomethyl)benzonitrile (217 mg, 1.11 mmol). The reaction was carried out at 60 °C for 12 hours. After the reaction was complete, the mixture was diluted with water (10 mL). Extraction was then performed with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated sodium chloride solution, dried, filtered, and concentrated. The crude product was subjected to column chromatography (PE:EA = 100:1 to 1:1) to obtain compound 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]benzonitrile (250 mg, yield 78.8%). LC / MS (ESI) (m / z): 311.6 (MH) +

[0374] Step 2: 5-(3-((2,4-dichloro-3,5-difluorophenoxy)methyl)phenyl)-1H-tetrazazole

[0375]

[0376] At room temperature, 3-[(2,4-dichloro-3,5-difluorophenoxy)methyl]benzonitrile (100 mg, 0.320 mmol) was dissolved in toluene (2 mL), followed by the addition of tri-n-butyltin azide (158 mg, 0.480 mmol) and ammonium chloride (26.0 mg, 0.480 mmol). The reaction mixture was then reacted at 130 °C for 24 hours. After the reaction was complete, the reaction solution was cooled to room temperature and diluted with ethyl acetate (20 mL). The solution was washed with saturated ammonium chloride solution (20 mL) and saturated sodium chloride solution (20 mL), dried, and concentrated. The crude product was purified by column chromatography (PE:EA = 100 / 1 to 0 / 1) to give compound 5-(3-((2,4-dichloro-3,5-difluorophenoxy)methyl)phenyl)-1H-tetrazole (4.70 mg, yield 4.1%).

[0377] LC / MS (ESI) (m / z): 354.7 (MH) + ;

[0378] 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),8.01–7.97(m,1H),7.63(dd,J=4.0,1.6Hz,2H),7.46(dd,J=11.2,2.0Hz,1H),5.36(s,2H).

[0379] Example 18: Synthesis of 2-fluoro-3-[(pentafluorophenoxy)methyl]benzoic acid (compound 39)

[0380] The synthetic route for compound 39 is as follows:

[0381]

[0382] Step 1: Methyl 2-fluoro-3-[(pentafluorophenoxy)methyl]benzoate

[0383]

[0384] At room temperature, pentafluorophenol (100 mg, 0.540 mmol) was dissolved in anhydrous acetonitrile (1 mL), followed by the addition of methyl 3-(bromomethyl)-2-fluorobenzoate (148 mg, 0.600 mmol) and potassium carbonate (83.0 mg, 0.60 mmol). The reaction mixture was then incubated at 25 °C for 12 hours. After the reaction was complete, the reaction mixture was slowly poured into water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed successively with saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL), dried, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:1 to 5:1) to give methyl 2-fluoro-3-[(pentafluorophenoxy)methyl]benzoate (180 mg, yield 87.8%).

[0385] 1 H NMR (400MHz, CDCl3) δ7.98–7.91(m,1H),7.71–7.64(m,1H),7.25(d,J=6.4Hz,1H),5.26(s,2H),3.93(s,3H).

[0386] Step 2: 2-Fluoro-3-[(pentafluorophenoxy)methyl]benzoic acid

[0387]

[0388] Methyl 2-fluoro-3-[(pentafluorophenoxy)methyl]benzoate (180 mg, 0.510 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (1 mL), and water (1 mL) at room temperature, followed by the addition of lithium hydroxide monohydrate (109 mg, 2.57 mmol). The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the organic solvent was removed using a rotary evaporator, and the mixture was diluted with water (1.5 mL). The pH was adjusted to approximately 4 using 1 N HCl at 0 °C. Filtration yielded 2-fluoro-3-[(pentafluorophenoxy)methyl]benzoic acid (128 mg, 74.8% yield).

[0389] LC / MS (ESI) (m / z): 334.7 (MH) + ;

[0390] 1 H NMR (400MHz, DMSO-d6) δ13.42(s,1H),7.90(t,J=6.4Hz,1H),7.74(t,J=6.4Hz,1H),7.32(t,J=7.6Hz,1H),5.31(s,2H).

[0391] Example 19: Synthesis of 2-fluoro-3-[(2,3,5,6-tetrafluorophenoxy)methyl]benzoic acid (compound 40)

[0392] The synthetic route for compound 40 is as follows:

[0393]

[0394] Step 1: Methyl 2-fluoro-3-[(2,3,5,6-tetrafluorophenoxy)methyl]benzoate

[0395]

[0396] At room temperature, 2,3,5,6-tetrafluorophenol (100 mg, 0.600 mmol) was dissolved in anhydrous acetonitrile (1 mL), followed by the addition of methyl 3-(bromomethyl)-2-fluorobenzoate (156 mg, 0.630 mmol) and potassium carbonate (87.0 mg, 0.630 mmol). The reaction mixture was then incubated at 25 °C for 12 hours. After the reaction was complete, the reaction mixture was slowly poured into water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed successively with saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL), dried, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:1 to 5:1) to give methyl 2-fluoro-3-[(2,3,5,6-tetrafluorophenoxy)methyl]benzoate (190 mg, yield 95.0%).

[0397] 1 H NMR (400MHz, CDCl3) δ7.93 (dd, J=10.4, 4.4Hz, 1H), 7.70 (t, J=7.2Hz, 1H), 7.23 (d ,J=8.4Hz,1H),6.79(dq,J=10.4,7.2Hz,1H),5.33(s,2H),3.93(d,J=0.8Hz,3H).

[0398] Step 2: 2-Fluoro-3-[(2,3,5,6-tetrafluorophenoxy)methyl]benzoic acid

[0399]

[0400] Methyl 2-fluoro-3-[(2,3,5,6-tetrafluorophenoxy)methyl]benzoate (190 mg, 0.570 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (1 mL), and water (1 mL) at room temperature, followed by the addition of lithium hydroxide monohydrate (120 mg, 2.86 mmol). The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the organic solvent was removed using a rotary evaporator, and the mixture was diluted with water (1.5 mL). The pH was adjusted to approximately 4 using 1 N HCl at 0 °C. Filtering yielded 2-fluoro-3-[(2,3,5,6-tetrafluorophenoxy)methyl]benzoic acid (123 mg, 67.9% yield). LC / MS (ESI) (m / z): 316.7 (MH) + ;

[0401] 1 H NMR (400MHz, DMSO-d6) δ7.89(td,J=7.6,1.6Hz,1H),7.76–7.72(m,1H),7.66(ddd,J=10.8,9.2,5.6Hz,1H),7.32(t,J=7.6Hz,1H),5.37(s,2H).

[0402] Example 20: Synthesis of 2-fluoro-3-((4-(pentafluoride thio)phenoxy)methyl)benzoic acid (compound 41)

[0403] The synthetic route for compound 41 is as follows:

[0404]

[0405] Step 1: Methyl 2-fluoro-3-((4-(pentafluoride sulfo)phenoxy)methyl)benzoate

[0406]

[0407] At room temperature, potassium carbonate (138 mg, 1.0 mmol) and methyl 3-(bromomethyl)-2-fluorobenzoate (148 mg, 0.6 mmol) were added to a solution of 4-pentafluoride thiophenol (110 mg, 0.5 mmol) in N,N-dimethylformamide (5 mL). After stirring for 4 hours, the mixture was washed with saturated ammonium chloride solution (10 mL), extracted twice with ethyl acetate (20 mL), and the organic phases were separated and combined. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 90:10) to give methyl 2-fluoro-3-((4-(pentafluoride thio)phenoxy)methyl)benzoate (190 mg, yield 98.4%).

[0408] LC / MS (ESI) (m / z): 387.05 (M+H)+

[0409] Step 2: 2-Fluoro-3-((4-(pentafluoride thio)phenoxy)methyl)benzoic acid

[0410]

[0411] Methyl 2-fluoro-3-((4-(pentafluoridesulfo)phenoxy)methyl)benzoate (560 mg, 1.45 mmol), THF / H₂O (10 mL, v:v = 1:1), and sodium hydroxide (290 mg, 7.25 mmol) were added sequentially to a 100 mL single-necked flask, and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then subjected to reverse-phase preparation (column: YMC-Triart Prep C18 (30 mm × 40 cm, 7 μm); mobile phase: A = 0.1% formic acid, B = acetonitrile; gradient: 10%-100%) to obtain 2-fluoro-3-((4-(pentafluoridesulfo)phenoxy)methyl)benzoic acid (287 mg, yield 53%).

[0412] LC / MS (ESI) (m / z): 373.03 (M+H) +

[0413] 1 H NMR (400MHz, CDCl3) δ8.03(t,J=7.2Hz,1H),7.77-7.67(M,3H),7.29(t,J=7.6Hz,1H),7.01(d,J=8.8Hz,2H),5.23(s,2H).

[0414] Example 21: Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(difluoromethoxy)benzoic acid (compound 42)

[0415] The synthetic route for compound 42 is as follows:

[0416]

[0417] Step 1: Synthesis of methyl 3-hydroxy-5-methylbenzoate

[0418]

[0419] 3-Hydroxy-5-methylbenzoic acid (2 g, 13.15 mmol) was dissolved in methanol (20 mL), and concentrated H₂SO₄ (1.48 g, 15.12 mmol) with a mass fraction of 98% was added dropwise at 0 °C. After addition, the mixture was stirred at 70 °C for 16 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude product. Purification was performed by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1-10:1, gradient elution) to give methyl 3-hydroxy-5-methylbenzoate (1.5 g, yield 68.72%).

[0420] LC-MS, M / Z (ESI): 167.1 [M+H] + .

[0421] Step 2: Synthesis of methyl 3-(difluoromethoxy)-5-methylbenzoate

[0422]

[0423] Methyl 3-hydroxy-5-methylbenzoate (1.30 g, 7.82 mmol) was dissolved in ultradry DMF (20 mL), and sodium dichlorofluoroacetate (3.58 g, 23.47 mmol) and cesium carbonate (5.10 g, 15.65 mmol) were added. After addition, the reaction mixture was stirred at 90 °C for 3 hours. After the reaction was completed, the reaction mixture was diluted with ice water (20 mL), then extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (20 mL × 3), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran (V / V) = 20:1-10:1, gradient elution) to give methyl 3-(difluoromethoxy)-5-methylbenzoate (700.00 mg, yield 41.39%).

[0424] LC-MS, M / Z (ESI): 217.2 [M+H] + .

[0425] Step 3: Synthesis of methyl 3-(bromomethyl)-5-(difluoromethoxy)benzoate

[0426]

[0427] Methyl 3-(difluoromethoxy)-5-methylbenzoate (700.00 mg, 3.24 mmol) and BPO (34.31 mg, 555.09 μmol) were dissolved in carbon tetrachloride (5 mL), and NBS (543.38 mg, 3.05 mmol) was added. After addition, the mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the mixture was concentrated to obtain a crude product. The crude product was eluted with a solvent (petroleum ether:tetrahydrofuran (V / V) = 10:1-8:1, gradient elution) to give methyl 3-(bromomethyl)-5-(difluoromethoxy)benzoate (650.00 mg, yield 79.37%).

[0428] LC-MS, M / Z (ESI): 295.0 [M+H] + .

[0429] Step 4: Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(difluoromethoxy)benzoate

[0430]

[0431] Methyl 3-(bromomethyl)-5-(difluoromethoxy)benzoate (650 mg, 2.20 mmol) and potassium carbonate (455.98 mg, 3.30 mmol) were dissolved in ACN (14 mL), and 2-chloro-4-(trifluoromethyl)phenol (519.57 mg, 2.64 mmol) was added. After addition, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product. Purification was performed by silica gel column chromatography (petroleum ether:tetrahydrofuran (V / V) = 7:1-5:1, gradient elution) to give compound methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(difluoromethoxy)benzoate (570.00 mg, yield 63.00%).

[0432] LC-MS, M / Z (ESI): 411.3 [M+H] + .

[0433] Step 5: Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(difluoromethoxy)benzoic acid

[0434]

[0435] Methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(difluoromethoxy)benzoate (5) (50 mg, 121.74 μmol) was dissolved in a mixed solvent of methanol (0.5 mL) and THF (0.5 mL). An aqueous solution of lithium hydroxide monohydrate (10.23 mg, 243.48 μmol) (1 mL) was added dropwise under ice bath conditions. After addition, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL) under ice bath conditions and acidified to pH 4-5 with 1 M hydrochloric acid. The acidified reaction mixture was extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (20 mL × 2), dried over sodium sulfate, and concentrated to dryness to obtain the crude product. The reaction solution was purified by separation using a C-18 reversed-phase column (0.1% formic acid water: acetonitrile (V / V) = 2:1-1:1, gradient elution) to give compound 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(difluoromethoxy)benzoic acid (5.20 mg, yield 31.47%).

[0436] 1 H-NMR (400MHz, CDCl3) δ8.06(s,1H),7.84(s,1H),7.69(d,J=1.6Hz,1H),7.56-7.49(m,2H),7.03(d,J=8.5Hz,1H),6.61(t,J=73.0Hz,1H),5.26(s,2H)

[0437] LC-MS, M / Z (ESI): 395.0 [MH] - .

[0438] Example 22: Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(difluoromethoxy)-2-fluorobenzoic acid (compound 43)

[0439] The synthetic route for compound 43 is as follows:

[0440]

[0441] Step 1: Synthesis of 5-bromo-2-fluoro-3-methylbenzoic acid

[0442]

[0443] 4-Bromo-1-fluoro-2-methylbenzene (10 g, 52.90 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). Under nitrogen protection, a 2.0 M, 26.45 mL solution of LDA in THF was added dropwise to the reaction mixture at -65 °C. After addition, the mixture was stirred at -65 °C for 2 hours. Excess CO2 gas was bubbled into the reaction mixture, which was then stirred for 30 minutes and allowed to warm naturally to room temperature. After the reaction was complete, the reaction mixture was quenched with a saturated ammonium chloride aqueous solution (200 mL) in an ice bath, followed by extraction with ethyl acetate (100 mL × 3). The organic layers were combined, washed with saturated brine (100 mL × 3), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran (V / V) = 5:1–4:1, gradient elution) to give 5-bromo-2-fluoro-3-methylbenzoic acid (2.4 g, yield 19.47%).

[0444] LC-MS, M / Z (ESI): 233.10 [M+H] + .

[0445] Step 2: Synthesis of 2-fluoro-5-hydroxy-3-methylbenzoic acid

[0446]

[0447] 5-Bromo-2-fluoro-3-methylbenzoic acid (500 mg, 2.15 mmol) and sodium carbonate (568.59 mg, 5.36 mmol) were dissolved in water (10 mL), and an aqueous solution (1 mL) of (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (61.04 mg, 429.12 μmol) and CuBr2 (47.92 mg, 214.56 μmol) was added dropwise. After addition, the mixture was stirred at 95 °C under nitrogen protection for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (30 mL) in an ice bath and acidified to pH 4-5 with 1 M hydrochloric acid aqueous solution. The acidified reaction mixture was extracted with ethyl acetate (30 mL × 2), the organic layers were combined, the organic phase was washed with saturated brine (20 mL × 3), dried over sodium sulfate, and concentrated to give 2-fluoro-5-hydroxy-3-methylbenzoic acid (370 mg).

[0448] LC-MS, M / Z (ESI): 171.20 [M+H] + .

[0449] Step 3: Synthesis of methyl 2-fluoro-5-hydroxy-3-methylbenzoate

[0450]

[0451] 370 mg of 2-fluoro-5-hydroxy-3-methylbenzoic acid was dissolved in 10 mL of methanol, and 1.48 g (15.12 mmol) of 98% concentrated H₂SO₄ was added dropwise at 0 °C. After addition, the mixture was stirred at 70 °C for 16 hours. After the reaction was completed, the reaction solution was directly concentrated to the crude product. Purification was achieved by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1-10:1, gradient elution) to give methyl 2-fluoro-5-hydroxy-3-methylbenzoate (300 mg).

[0452] LC-MS, M / Z (ESI): 185.1 [M+H] + .

[0453] Step 4: Synthesis of methyl 5-(difluoromethoxy)-2-fluoro-3-methylbenzoate

[0454]

[0455] Methyl 2-fluoro-5-hydroxy-3-methylbenzoate (100 mg, 542.99 μmol) was dissolved in ultra-dry DMF (3 mL), and sodium dichlorofluoroacetate (248.35 mg, 1.63 mmol) and cesium carbonate (5.10 g, 15.65 mmol) were added. After addition, the reaction mixture was stirred at 90 °C for 3 hours. After the reaction was completed, the reaction mixture was diluted with ice water (20 mL), then extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (20 mL × 3), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran (V / V) = 20:1-10:1, gradient elution) to give methyl 5-(difluoromethoxy)-2-fluoro-3-methylbenzoate (50.00 mg, yield 39.32%).

[0456] LC-MS, M / Z (ESI): 235.2 [M+H] + .

[0457] Step 5: Synthesis of methyl 3-(bromomethyl)-5-(difluoromethoxy)-2-fluorobenzoate

[0458]

[0459] Methyl 5-(difluoromethoxy)-2-fluoro-3-methylbenzoate (50 mg, 213.52 μmol) and BPO (3.96 mg, 64.06 μmol) were dissolved in carbon tetrachloride (5 mL), and NBS (41.80 mg, 234.87 μmol) was added. After addition, the mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the mixture was concentrated to obtain a crude product. The crude product was eluted with a solvent (petroleum ether:tetrahydrofuran (V / V) = 10:1-8:1, gradient elution) to give methyl 3-(bromomethyl)-5-(difluoromethoxy)-2-fluorobenzoate (30.00 mg, yield 44.88%).

[0460] LC-MS, M / Z (ESI): 313.1 [M+H] + .

[0461] Step 6: Synthesis of methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(difluoromethoxy)-2-fluorobenzoate

[0462]

[0463] Methyl 3-(bromomethyl)-5-(difluoromethoxy)-2-fluorobenzoate (30 mg, 95.83 μmol) and K₂CO₃ (19.84 mg, 143.74 μmol) were dissolved in ACN (2 mL), and 2-chloro-4-(trifluoromethyl)phenol (22.60 mg, 114.99 μmol) was added. After addition, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran (V / V) = 7:1-5:1, gradient elution) to give compound methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(difluoromethoxy)-2-fluorobenzoate (35.00 mg, 81.64 μmol, 85.20% yield).

[0464] LC-MS, M / Z (ESI): 429.3 [M+H] + .

[0465] Step 7: Synthesis of 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(difluoromethoxy)-2-fluorobenzoic acid

[0466]

[0467] Methyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(difluoromethoxy)-2-fluorobenzoate (35 mg, 81.64 μmol) was dissolved in a mixed solvent of methanol (0.5 mL) and THF (0.5 mL). An aqueous solution of lithium hydroxide monohydrate (6.86 mg, 163.28 μmol) (0.5 mL) was added dropwise under ice bath conditions. After addition, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL) under ice bath conditions and acidified to pH 4-5 with 1 M hydrochloric acid. The acidified reaction mixture was extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (20 mL × 2), dried over sodium sulfate, and concentrated to dryness to obtain the crude product. The reaction solution was purified by separation using a C-18 reversed-phase column (0.1% formic acid water: acetonitrile (V / V) = 2:1-1:1, gradient elution) to give compound 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)-5-(difluoromethoxy)-2-fluorobenzoic acid (13.86 mg, yield 40.94%).

[0468] 1 H-NMR (400MHz, CDCl3) δ7.79-7.70(m,3H),7.53(d,J=8.5Hz,1H),7.09(d,J=8.5Hz,1H),6.55(t,J=72.6Hz,1H),5.29(s,2H)

[0469] LC-MS, M / Z (ESI): 415.1 [M+H] + .

[0470] Example 23: Synthesis of 5-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluorobenzoic acid (compound 44)

[0471] The synthetic route for compound 44 is as follows:

[0472]

[0473] Step 1: Methyl 5-(bromomethyl)-2-fluorobenzoate

[0474]

[0475] Under ice bath cooling, N-bromosuccinimide (1.26 g, 0.0071 mol) and benzoyl peroxide (0.14 g, 0.0006 mol) were added sequentially to methyl 2-fluoro-5-methylbenzoate (1 g, 0.0059 mol) in 1,2-dichloroethane (10 mL) solvent, and the reaction was carried out at 80 °C for 20 hours. The reaction was monitored by TLC. After no starting material remained, the reaction solution was cooled to room temperature, concentrated to remove most of the solvent, and then ethyl acetate (50 mL) and water (20 mL) were added. After thorough mixing, the mixture was allowed to stand for separation, and the organic phase was collected. The organic phase was washed twice with water (20 mL) and once with saturated brine (20 mL). After concentration, the mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain methyl 5-(bromomethyl)-2-fluorobenzoate (1.5 g, yield 102%).

[0476] Step 2: Methyl 5-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluorobenzoate

[0477]

[0478] At room temperature, potassium carbonate (414 mg, 0.003 mol) and 2,4-dichloro-3,5-difluorophenol (199 mg, 0.001 mol) were added sequentially to a 5 mL solution of methyl 5-(bromomethyl)-2-fluorobenzoate (250 mg, 0.001 mol) in acetonitrile (5 mL). The reaction was carried out at 60 °C for 16 hours. The reaction was monitored by LCMS. After no starting material remained, the reaction solution was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain methyl 5-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluorobenzoate (350 mg, yield 94.7%).

[0479] Step 3: 5-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluorobenzoic acid

[0480]

[0481] Sodium hydroxide (200 mg, 0.005 mol) was added to a solution of methyl 5-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluorobenzoate (350 mg, 0.001 mol) in tetrahydrofuran (3.5 mL) and water (3.5 mL) under ice bath cooling, and the reaction was carried out at 25 °C for 3 hours. The reaction was monitored by LCMS. After no raw material remained, the reaction solution was cooled to room temperature. The reaction solution was concentrated to remove most of the tetrahydrofuran. Hydrochloric acid aqueous solution (2M) was added dropwise under ice bath cooling to adjust the pH of the system to 3-4. Ethyl acetate (40ml) was added and mixed evenly. After standing, the organic phase was collected. The organic phase was washed twice with water (10mL) and once with saturated brine (10mL). It was dried over anhydrous sodium sulfate and concentrated. The solution was then separated by preparative high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10um; solvent: A = water + formic acid (0.05%), B = acetonitrile; gradient: 52%-82%) to obtain 5-[(2,4-dichloro-3,5-difluorophenoxy)methyl]-2-fluorobenzoic acid (134mg, yield 39.8%).

[0482] LC-MS, M / Z (ESI): 348.70 [M-1] -

[0483] 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),7.96(dd,J=7.1,2.3Hz,1H),7.71-7.67(m,1H),7.41(d,J=10.5Hz,1H),7.34(dd,J=10.7,8.6Hz,1H),5.26(s,2H).

[0484] Example 24: Synthesis of 5-cyano-3-(2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorobenzoic acid (compound 25)

[0485] The synthetic route for compound 25 is as follows:

[0486]

[0487] At 25°C, methyl 5-cyano-3-(2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorobenzoate (53 mg, 135.85 μmol) was dissolved in tetrahydrofuran (1 ml) and water (0.2 ml), followed by the addition of lithium hydroxide (9.76 mg, 407.55 μmol). The reaction mixture was stirred at 25°C for 1 hour. LC-MS monitoring was used to ensure complete reaction of the starting material and the formation of the desired product. After the reaction was complete... The pH was adjusted to 4 with 1N hydrochloric acid, extracted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product. The crude product was subjected to reversed-phase preparative HPLC (Welch Ultimate 10 μm 21.2*250 mm; 45% MeCN was gradient eluted to 70% MeCN in water containing 0.1% formic acid within 15 minutes) to obtain 5-cyano-3-(2,4-dichloro-3,5-difluorophenoxy)methyl)-2-fluorobenzoic acid (17 mg, yield 33.27%).

[0488] 1 H-NMR (400MHz, DMSO-D6) δ8.35-8.31(m,1H),8.28-8.27(m,1H),7.57(dd,J=11.3,1.9Hz,1H),5.47(d,J=74.5Hz,2H)

[0489] LC-MS, M / Z (ESI): 376.1 [M+H] + .

[0490] Example 25: Synthesis of 5-(3-(2,4-dichloro-3,5-difluorophenoxy)methyl)-2,6-difluorophenyl)-1H-tetrazole (compound 46)

[0491] The synthetic route for compound 46 is as follows:

[0492]

[0493] Step 1: Synthesis of 2,6-difluoro-3-methylbenzamide

[0494]

[0495] Under nitrogen protection, 2,6-difluoro-3-methylbenzoic acid (4.0 g, 23.24 mmol) was dissolved in N,N-dimethylformamide (40 mL), followed by the addition of benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (13.25 g, 34.86 mmol) and N,N-diisopropylethylamine (9.01 g, 69.72 mmol, 12.14 mL). The reaction mixture was stirred at room temperature for 20 minutes, after which ammonium chloride (1.86 g, 34.86 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. LC-MS was used to monitor the reaction until complete. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), washed with saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. The crude product was obtained by filtration and vacuum concentration. The crude product was then purified by silica gel column chromatography (petroleum ether:tetrahydrofuran (V / V) = 10:1-5:1, gradient elution) to obtain 2,6-difluoro-3-methylbenzamide (2.4 g, yield: 60.35%).

[0496] LC-MS, M / Z (ESI): 172.1 [M+H] + .

[0497] Step 2: Synthesis of 2,6-difluoro-3-methylbenzonitrile

[0498]

[0499] Under nitrogen protection, 2,6-difluoro-3-methylbenzamide (2.5 g, 14.61 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of 2,4,6-trichloro-1,3,5-triazine (5.39 g, 29.22 mmol). The reaction mixture was stirred at 0 °C for 2 hours. LC-MS monitoring confirmed complete reaction of the starting material and the formation of the desired product. After the reaction was complete, the mixture was diluted with water (40 mL), extracted with ethyl acetate (40 mL × 2), washed with saturated brine (40 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:tetrahydrofuran (V / V) = 10:1-5:1, gradient elution) to give 2,6-difluoro-3-methylbenzonitrile (1.4 g, yield: 62.59%).

[0500] LC-MS, M / Z (ESI): 153.9 [M+H] + .

[0501] Step 3: Synthesis of 3-(bromomethyl)-2,6-difluorobenzonitrile

[0502]

[0503] Under nitrogen protection, 2,6-difluoro-3-methylbenzonitrile (1.5 g, 9.80 mmol) was dissolved in carbon tetrachloride (15 mL), followed by the addition of N-bromosuccinimide (2.09 g, 11.75 mmol) and azobisisobutyronitrile (321.71 mg, 1.96 mmol). The reaction mixture was stirred at 90 °C for 5 hours. LC-MS monitoring confirmed complete reaction of the starting material and the formation of the desired product. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran (V / V) = 10:1-5:1, gradient elution) to obtain 3-(bromomethyl)-2,6-difluorobenzonitrile (500 mg, yield: 22.0%).

[0504] 1 H-NMR (400MHz, DMSO-D6) δ8.03(td,J=8.7,6.7Hz,1H),7.47(t,J=8.8Hz,1H),4.74(s,2H)

[0505] Step 4: Synthesis of 3-(2,4-dichloro-3,5-difluorophenoxy)methyl-2,6-difluorobenzonitrile

[0506]

[0507] At room temperature, 3-(bromomethyl)-2,6-difluorobenzonitrile (500 mg, 2.15 mmol) and 2,4-dichloro-3,5-difluorophenol (428.80 mg, 2.15 mmol) were dissolved in acetonitrile (5 mL), followed by the addition of potassium carbonate (446.74 mg, 3.23 mmol). The reaction mixture was stirred at 25 °C for 1 hour. LC-MS monitoring confirmed complete reaction of the starting material and the formation of the desired product. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran (V / V) = 5:1-1:1, gradient elution) to obtain 3-(2,4-dichloro-3,5-difluorophenoxy)methyl-2,6-difluorobenzonitrile (400 mg, yield: 53.02%).

[0508] 1 H-NMR(400MHz,DMSO-D6)δ8.04(dd,J=15.3,8.4Hz,1H),7.58-7.47(m,2H),5.29(d,J=47.8Hz,2H)

[0509] Step 5: Synthesis of 5-(3-(2,4-dichloro-3,5-difluorophenoxy)methyl)-2,6-difluorophenyl)-1H-tetrazole

[0510]

[0511] At 25°C, the starting material 3-(2,4-dichloro-3,5-difluorophenoxy)methyl-2,6-difluorobenzonitrile (150 mg, 428.46 μmol) was dissolved in xylene (3 mL), followed by the addition of tributyltin chloride (1.12 g, 3.43 mmol) and sodium azide (222.83 mg, 3.43 mmol). The reaction mixture was stirred at 140°C for 16 hours. LC-MS monitoring was used to confirm the complete reaction of the starting material and the formation of the desired product. After the reaction was complete... The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran (V / V) = 2:1-1:1, gradient elution), and then subjected to reversed-phase preparative HPLC (Welch Ultimate 10um 21.2*250mm; 54% MeCN was gradient eluted to 54% MeCN in water containing 0.1% formic acid within 22 minutes) to obtain 5-cyano-3-(2,4-dichloro-3,5-difluorophenoxy)methyl)-2-methoxybenzoic acid (13.9 mg, yield 8.25%).

[0512] 1 H-NMR (400MHz, DMSO-d6) δ7.93(dd,J=14.8,8.5Hz,1H),7.60(dd,J=11.4,1.8Hz,1H),7.49(t,J=9.1Hz,1H),5.37(s,2H)

[0513] LC-MS, M / Z (ESI): 393.2 [M+H] + .

[0514] The preparation methods for the following compounds are as described in Example 1.

[0515]

[0516]

[0517]

[0518] The reference compounds are shown below:

[0519]

[0520] Prepared according to literature WO2020198537A1.

[0521] Test Example 1: MRGPRX4 IP-1 Measurement Test

[0522] The antagonistic effect of the compound on MRGPRX4 was determined in a stable HEK293 cell line expressing high levels of human MRGPRX4. Cells were cultured in DMEM medium containing 10% FBS at 37°C and 5% CO2. One day before the assay, the stable HEK293 cell line expressing high levels of human MRGPRX4 was seeded in 384-well plates and incubated overnight. The next day, different final concentrations of the compound were added to each well, and after incubation for a certain time, a certain amount of deoxycholic acid solution was added. The cells were incubated at 37°C in the dark for 1 hour, followed by incubation at room temperature for 30 minutes. IP-1 standard and HTRF assay reagent were added according to the IP-One-Gq kit (Cisbio) instructions, and then incubated at room temperature in the dark for 1 hour. After incubation, the emission values ​​at 665nm and 620nm under 330nm excitation light were measured using a microplate reader. The antagonistic effect (IC50) of the compound was calculated using Prism software, with compound concentration as the X-axis and fluorescence signal ratio as the Y-axis. 50 value).

[0523] Table 1. Antagonistic effects of compounds on MRGPRX4

[0524]

[0525]

[0526] The IP-1 test results of MRGPRX4 show that the compound of the present invention has a good antagonistic effect on MRGPRX4.

[0527] Test Example 2: Hepatocyte Stability Test

[0528] Hepatocyte stability assays were performed by co-incubating the compound with hepatocytes in vitro. First, a 10 mM stock solution of the test compound was prepared in DMSO solvent and diluted to an appropriate working solution. Thawed, viability-measured, and counted hepatocytes were then diluted to a concentration of 1.05 × 10⁻⁶ mM. 6Hepatocyte suspension at a density of cells / mL was prepared. The appropriate volumes of the compound working solution and hepatocyte suspension were added to pre-incubated reaction plates. All reaction plates were placed in a 37°C, 5% CO2, 95% humidity incubator with shaking at 200 rpm for the specified time. After incubation for 0, 5, 15, 30, 60, and 90 minutes, stop solution was added to each well, and the reaction was terminated by shaking at 300 rpm for 10 minutes. The samples were transferred to 96-well deep-well plates, sealed, and shaken at 500 rpm for 10 minutes, followed by centrifugation at approximately 3200 × g for 20 minutes. After centrifugation, the supernatant was collected, diluted with pure water at a 1:3 ratio, and analyzed by LC / MS / MS. The ratio of the compound peak area to the internal standard peak area at each time point was obtained. The peak area ratios at 5, 15, 30, 60, and 90 minutes were compared with the peak area ratio at 0 minutes to calculate the remaining percentage of the compound at each time point, and the T value was calculated. 1 / 2 .

[0529] Table 2 Hepatocyte stability results (T) 1 / 2 (min))

[0530] compound people monkey dog rats mice control compound 125 50 84 173 >217 Compound 24 282 158 394 381 413

[0531] Hepatocyte stability results indicate that the compounds of this invention exhibit good hepatocyte stability and good drug-like properties.

[0532] Test Example 3: Mouse Pharmacokinetic Study

[0533] Pharmacokinetic studies were conducted in mice using male ICR mice (20-25g, fasted overnight). Three mice were administered 10mg / kg orally via gavage. Blood samples were collected before administration and at 15, 30 minutes, 1, 2, 4, 8, and 24 hours after administration. 6800g of blood samples were centrifuged at 2-8℃ for 6 minutes, and plasma was collected and stored at -80℃. Plasma samples from each time point were mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4℃ for 10 minutes, and the supernatant was mixed with 3 times the volume of water. An appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software.

[0534] Table 2: Results of Pharmacokinetic Studies in Mice

[0535]

[0536] The results of the pharmacokinetic studies in mice showed that the compounds of this invention exhibited excellent pharmacokinetic properties and good drug-likeness.

[0537] Test Example 4: Rat Pharmacokinetic Test

[0538] Pharmacokinetic studies were conducted on male SD rats (180-240g) that had been fasted overnight. Three rats were administered the drug 10mg / kg orally via gavage. Blood samples were collected before administration and at 15, 30 minutes, 1, 2, 4, 8, and 24 hours after administration. 6800g of blood samples were centrifuged at 2-8℃ for 6 minutes, and plasma was collected and stored at -80℃. Plasma samples from each time point were mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4℃ for 10 minutes, and the supernatant was mixed with 3 times the volume of water. An appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software.

[0539] Table 5: Results of Rat Pharmacokinetic Study

[0540]

[0541] The results of the pharmacokinetic studies in rats showed that the compound of the present invention exhibits excellent pharmacokinetic properties and good drug-likeness.

[0542] Test Example 5: Brain Distribution Test

[0543] Pharmacokinetic studies were conducted on male SD rats (180-240g) that had been fasted overnight. Twelve rats were administered 10 mg / kg orally via gavage and divided into four groups of three. Blood and brain tissue samples were collected at four time points after administration. Whole blood samples were centrifuged at 1500g for 10 min to separate plasma, and the supernatant plasma was collected into sample tubes. Brain tissue samples were accurately weighed and homogenized with an appropriate volume of 80% methanol-water at a weight:volume ratio of 1:5. The samples were analyzed by LC / MS / MS.

[0544]

[0545] Brain distribution test results show that the compound of the present invention enters the brain less and has a lower risk of central nervous system toxicity compared to the control compound.

[0546] Test Example 6: Antipruritic Test

[0547] Male hMRGPRX4 KI mice (Shanghai Southern Model Biotechnology Co., Ltd.) were acclimatized for one week under controlled temperature and humidity conditions and a normal light cycle (on at 6:00 AM; off at 6:00 PM). Before testing, mice were placed in separate testing chambers for 20 minutes to acclimatize. After 20 minutes, mice were orally administered different doses of the drug or a blank solvent. After a certain time, the pruritus agent (SC) or saline solution was subcutaneously administered to the nape of the neck. The number of scratches by the mice over a period of time following the injection of the pruritus agent was counted, and differences between groups were statistically analyzed. Each group consisted of 10-12 animals.

[0548] As attached Figure 1 , Figure 2 The antipruritic test results shown indicate that the compound of the present invention exhibits excellent antipruritic efficacy, and its efficacy is superior to that of the control compound at the same dosage.

[0549] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. The compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs: in, A is a 6-10 membered aryl, a 3-11 membered heterocyclic alkyl, a 5-10 membered heteroaryl, or a saturated or partially unsaturated 9-12 membered fused and bicyclic heteroaryl; the heteroatoms in the heterocyclic alkyl, heteroaryl, and fused and bicyclic heteroaryl are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different; R 1 The substituent on A is a halogen, hydroxyl, amino, cyano, carbonyl, oxo, carboxyl, or C group. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 1-1 Replacement C 1-6 Alkyl, optional R 1-1 Replacement -OC 1-6 Alkyl, optional R 1-1 Replacement C 3-8 cycloalkyl, optional R 1-1 Substituted 3- to 11-membered heterocyclic alkyl groups, optionally R 1-1 Substituted 5- to 10-membered heteroaryl groups, -C(O)-NH-S(O)2-R 1 -1 -S(O)2-NH-C(O)-OR 1-1 The R 1-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 1-1 The number of substitutions can be 0, 1, 2, 3, 4, or 5; when there are multiple substituents, the substituents may be the same or different; R 2 H, halogen, cyano, carbonyl, oxo, carboxyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 2-1 Replacement C 1-6 Alkyl or optionally R 2-1 Replacement C 3-8 cycloalkyl; the R 2-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 2-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different; Z represents -O-, -S-, -N(R) 3 -CH2-, -OC(R) 3 )2-、-O-CH(R 3 )-; The R 3 For H or C 1-6 alkyl; Each R 4 Each of the following groups can be independently represented as SF5, SCF3, H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, or C. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 4-1 Replacement C 1-6 Alkyl or optionally R 4-1 Replacement C 3-8 Cycloalkyl, and wherein at least one R 4 For SF5 or SCF3, r is 1, 2, 3, 4 or 5; or when R 4 When it is a halogen, r is 4 or 5; The R 4-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 4-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different; m is selected from 0, 1, 2, 3, 4, 5, 6 or 7; n is selected from 0, 1, 2 or 3.

2. The compound of formula I as claimed in claim 1, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that, A is a 6-8 membered aryl, a 3-8 membered heterocyclic alkyl, a 5-8 membered heteroaryl, or a saturated or partially unsaturated 9-10 membered fused and bicyclic heteroaryl; the heteroatoms in the heterocyclic alkyl, heteroaryl, and fused and bicyclic heteroaryl are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different; R 1 The substituent on A is a halogen, hydroxyl, amino, cyano, carbonyl, oxo, carboxyl, or C group. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 1-1 Replacement C 1-6 Alkyl, optional R 1-1 Replacement -OC 1-6 Alkyl, optional R 1-1 Replacement C 3-8 cycloalkyl, optional R 1-1 Substituted 3- to 11-membered heterocyclic alkyl groups, optionally R 1-1 Substituted 5- to 10-membered heteroaryl groups, -C(O)-NH-S(O)2-R 1-1 -S(O)2-NH-C(O)-OR 1-1 The R 1-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 1-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different; R 2 H, halogen, cyano, carbonyl, oxo, carboxyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 2-1 Replacement C 1-6 Alkyl or optionally R 2-1 Replacement C 3-8 cycloalkyl; the R 2-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 2-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different; Z represents -O-, -S-, -N(R) 3 -CH2-, -OC(R) 3 )2-、-O-CH(R 3 )-; The R 3 For H or C 1-6 alkyl; Each R 4 Each of the following groups can be independently represented as SF5, SCF3, H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, or C. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 4-1 Replacement C 1-6 Alkyl or optionally R 4-1 Replacement C 3-8 Cycloalkyl, and wherein at least one R 4 It is SF5 or SCF3, and r is 2, 3, 4 or 5; the R 4-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 4-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different; m and n are 0, 1, 2 or 3 respectively.

3. The compound of formula I as claimed in claim 1, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that, A is a 6-8 membered aryl, a 3-8 membered heterocyclic alkyl, a 5-8 membered heteroaryl, or a saturated or partially unsaturated 9-10 membered fused and bicyclic heteroaryl; the heteroatoms in the heterocyclic alkyl, heteroaryl, and fused and bicyclic heteroaryl are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different; R 1 The substituent on A is a halogen, hydroxyl, amino, cyano, carbonyl, oxo, carboxyl, or C group. 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 1-1 Replacement C 1-6 Alkyl, optional R 1-1 Replacement -OC 1-6 Alkyl, optional R 1-1 Replacement C 3-8 cycloalkyl, optional R 1-1 Substituted 3- to 11-membered heterocyclic alkyl groups, optionally R 1-1 Substituted 5- to 10-membered heteroaryl groups, -C(O)-NH-S(O)2-R 1-1 -S(O)2-NH-C(O)-OR 1-1 The R 1-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 1-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different; R 2 H, halogen, cyano, carbonyl, oxo, carboxyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, optional R 2-1 Replacement C 1-6 Alkyl or optionally R 2-1 Replacement C 3-8 cycloalkyl; the R 2-1 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, hydroxyl, or halogen; the R 2-1 The number of substitutions is 0, 1, or 2; when there are multiple substituents, the substituents may be the same or different; Z represents -O-, -S-, -N(R) 3 -CH2-, -OC(R) 3 )2-、-O-CH(R 3 )-; The R 3 For H or C 1-6 alkyl; R 4 When it is a halogen, r is 4 or 5; m and n are 0, 1, 2 or 3 respectively.

4. The compound of Formula I as described in any one of claims 1 to 3, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that, A is a 6-8 aryl group or a 5-8 heteroaryl group; Optionally, A is a 5- or 6-membered nitrogen-containing heteroaryl group, and the number of nitrogen atoms is 1, 2, or 3; Optionally, A is phenyl, pyrazolyl, or pyridinyl; Optionally, A is a saturated or partially unsaturated 5-membered and 6-membered fused and bicyclic heteroaryl group, or a saturated or partially unsaturated 6-membered and 6-membered fused and bicyclic heteroaryl group. Optionally, one ring in A is a 5- or 6-membered saturated heterocycle, and the other ring is an unsaturated aromatic ring or a heteroaryl ring; the heteroatom in the heteroaryl ring is selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different; Optionally, both rings in A are unsaturated 5- or 6-membered aromatic rings or heteroaryl rings; the heteroatoms in the heteroaryl ring are selected from N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different; Optionally, A is Optionally, A is And / or, Selected from Among them, Ra1, Ra2, Ra3, Ra4, and Ra5 are selected from H or R. 1 Ra1, Ra2, Ra3, Ra4, and Ra5 are independent and may be the same or different; or, Selected from Among them, Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, and Rb7 are selected from H or R. 1 Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, and Rb7 are independent of each other and may be the same or different. And / or, Selected from Among them, Rc1, Rc2, Rc3, Rc4, and Rc5 are selected from R 4 Rc1, Rc2, Rc3, Rc4, and Rc5 are independent of each other and may be the same or different. And / or, the R 1 For F, Cl, cyano, -CH3, -CHF2, -CH2CF3, -COOH, -OCHF2, -OCH3, -C(O)-NH-S(O)2-CH3, -S(O)2-NH-C(O)-O-CH3, 5. The compound of Formula I as described in any one of claims 1 to 3, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that, The R 2 For H, cyano, oxo, -COOH, -CH3, And / or, the Z is -O-, -S-, -NH-, -NCH3-, -CH2-, -O-CH2-, -O-CH(CH3)-.

6. The compound of Formula I as described in any one of claims 1 to 3, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that, There are at least 2 Rs 4 And the R 4 Each can be independently SF5, SCF3, H, F, Cl, -CH3, -CH2CF3, -COOH or And at least one of them R 4 It is either SF5 or SCF3; Optional, at least 4 Rs 4 And the R 4 They are F or Cl, respectively, independently.

7. The compound of Formula I as described in any one of claims 1 to 3, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that, The compound includes:

8. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: a compound of Formula I as described in any one of claims 1-7, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and a pharmaceutically acceptable carrier.

9. Use of a compound of Formula I as described in any one of claims 1-7, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, or use of a pharmaceutical composition as described in claim 8, said use comprising: Adjust MRGPRX4; And / or, prevention and / or treatment of MRGPRX4-related diseases; And / or, to prepare a medicine, pharmaceutical composition or formulation for regulating MRGPRX4, and / or preventing and / or treating MRGPRX4-related diseases.

10. The use as described in claim 9, characterized in that, The MRGPRX4-related diseases include: pruritus-related diseases; optionally, the pruritus-related diseases include: nonhistaminergic pruritus; optionally, the nonhistaminergic pruritus includes: cholestatic pruritus, uremic pruritus.

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