ATX INHIBITOR, AND PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

Disclosed are an ATX inhibitor, a preparation method therefor, and the use thereof, which belong to the technical field of pharmaceutical chemistry. In particular, the ATX inhibitor is a compound having the structure of formula I′, or a pharmaceutically acceptable salt, an ester, an isomer, a solvate, a prodrug or an isotope marker thereof. Compared with the existing ATX inhibitor GLPG-1690, the ATX inhibitor has higher inhibitory activity, also has excellent efficacy, in vitro/in vivo pharmacokinetic properties and safety, and has broad clinical application prospects.

Description

Claims

1. A compound of Formula I′ or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof, whereinn is any integer from 0 to 5;if present, each R1 is independently selected from the group consisting of hydrogen, deuterium, cyano, halogen, amino, hydroxyl, —COOH, —CHO, —NO2, C1-6 alkylamino, C1-6 alkoxy, and C1-6 alkyl, C3-7 cycloalkyl and 3- to 7-membered heterocycloalkyl that are unsubstituted or substituted with substituents selected from the group consisting of cyano, amino, hydroxyl, halogen, C1-6 alkyl, and C1-6 alkoxy;R2 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, hydroxyl, —COOH, —CHO, —NO2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, —C(═O)NH2, —NH(C═O)CH3, and 3- to 7-membered heterocycloalkyl;R3 is selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, C3-7 cycloalkyl, and C1-6 alkyl, C3-7 cycloalkyl and 3- to 7-membered heterocycloalkyl that are substituted with substituents selected from the group consisting of cyano, amino, hydroxyl, halogen, C1-6 alkyl, and C1-6 alkoxy;ring B is any one of the following structures: R4 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-7 cycloalkyl, and 3- to 7-membered heterocycloalkyl;X1, X2, X3 and X4 are each independently N or CR5;R5 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkyl, C3-7 cycloalkyl and 3- to 7-membered heterocycloalkyl that are substituted with substituents selected from the group consisting of cyano, amino, hydroxyl, halogen, C1-6 alkyl, and C1-6 alkoxy;ring A is selected from the group consisting of C6-10 aryl and 5- to 10-membered heteroaryl that are substituted or unsubstituted, and the substitution is a substitution with 1 to 3 substituents selected from the group consisting of hydroxyl, amino, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C1-6 alkylamino, and C1-6 alkoxy;R6 is -L1-L2-W1;L1 is selected from the group consisting of a chemical bond, C1-3 alkylene, —O—, —C(═O)—, -C(=O)C(R8)2-, —C(═O)O—, —C(═O)NH—, —OC(═O)—, —NH—, —SO2—, —NHSO2—, and —SO2NH—; wherein R8 is hydrogen or C1-6 alkyl;L2 is selected from the group consisting of a chemical bond, —O—, —C(═O)—, —C(═O)CH2—, —C(═O)O—, —OC(═O)—, —C(═O)NH—, -NR7-, —NHCH2—, —SO2—, -NR7SO2-, -SO2NR7-, -C(=O)NR7-, and -NR7C(=O)-; wherein R7 is hydrogen or C1-6 alkyl;W1 is a substituted or unsubstituted group as follows: hydrogen, deuterium, amino, cyano, C1-6 alkyl, halogen, hydroxyl, C1-6 alkoxy, C1-6 alkylamino, carboxyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-7 cycloalkyl or 3- to 7-membered heterocycloalkyl; the substitution is a substitution with 1 or 2 substituents selected from the group consisting of oxo, hydroxy, amino, hydroxymethyl, aminomethyl, cyano, C1-6 alkyl, C1-6 alkyl—C(═O)O—, and halogen.

2. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein n is any integer from 0 to 2, preferably n is 1;if present, each R1 is independently selected from the group consisting of hydrogen, cyano and halogen, preferably halogen, more preferably fluorine.

3. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein R2 is cyano.

4. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein R3 is C1-6 alkyl, preferably methyl or ethyl.

5. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein ring B is any one of the following structures: X1, X2, X3 and X4 are each independently N or CR5;R5 is selected from the group consisting of hydrogen, deuterium, halogen, methyl, and halomethyl, preferably hydrogen;R4 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, and cyclopropyl, preferably ethyl.

6. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein ring A is selected from the group consisting of phenylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, thiazolylene, thiadiazolylene, and oxadiazolylene; preferably, ring A is any one selected from the following structures: more preferably, ring A is any one selected from the following structures:.

7. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 6, wherein ring A is substituted with 1 to 3 substituents, preferably 1 substituent, the substituents being each independently selected from the group consisting of hydroxyl, amino, halogen, cyano, and C1-6 alkyl, preferably halogen and C1-6 alkyl, more preferably fluorine and methyl.

8. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein L1 is selected from the group consisting of a chemical bond, —CH2—, —CH(CH3)—, —C(CH3)2—, —C(═O)—, —SO2—, —C(═O)CH2—, and —C(═O)NH—, preferably the chemical bond, —CH2—, —C(CH3)2—, and —C(═O)CH2—.

9. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein L2 is selected from the group consisting of a chemical bond, —NH—, —C(═O)—, —SO2—, —NHCH2—, —C(═O)CH2—, —C(═O)NH—, —NHSO2—, and —N(CH3)SO2—, preferably the chemical bond, C(═O)—,NHCH2—, —C(═O)NH—, —NHSO2—, and —N(CH3)SO2—.

10. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein W1 is a substituted or unsubstituted group as follows: C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, C3-7 cycloalkyl or 3- to 7-membered heterocycloalkyl, and the substitution is a substitution with 1 or 2 substituents selected from the group consisting of oxo, hydroxy, amino, hydroxymethyl, aminomethyl, halogen, cyano, C1-6 alkyl—C(═O)O—, and C1-6 alkyl.

11. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 10, wherein W1 is C1-6 alkyl, C3-7 cycloalkyl or 3- to 7-membered heterocycloalkyl which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of hydroxy, amino, hydroxymethyl, aminomethyl, and C1-6 alkyl—C(═O)O—.

12. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 11, wherein W1 is a group as follows: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, pyrrolidinyl, oxopyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 1,1-dioxidothiomorpholinyl, 2-azaspiro[3.3]heptyl, 1,1-dioxidoisothiazolidinyl, or 1,1-dioxido-1,2-thiazinanyl which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of hydroxy, amino, hydroxymethyl, aminomethyl, and acetoxy, preferably methyl, oxopyrrolidinyl, 2-azaspiro[3.3]heptyl, 1,1-dioxidoisothiazolidinyl, or 1,1-dioxido-1,2-thiazinanyl, or preferably ethyl, azetidinyl, cyclobutyl, pyrrolidinyl, or piperidinyl which is substituted with a substituent selected from the group consisting of hydroxyl, hydroxymethyl, and acetoxy.

13. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein n is 1;R1 is fluorine;R2 is cyano;R3 is methyl or ethyl;Ring B is any one of the following structures: R4 is ethyl;X1, X2, X3 and X4 are each independently N or CH;ring A is any one selected from the following structures: ring A is unsubstituted or substituted with one fluorine or methyl;R6 is -L1-L2-W1;L1 is selected from the group consisting of a chemical bond, —CH2—, —C(CH3)2—, and —C(═O)CH2—;L2 is selected from the group consisting of a chemical bond, —C(═O)—, —NHCH2—, —C(═O)NH—, —NHSO2—, and —N(CH3)SO2—;W1 is any one of the following groups: .

14. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein the compound is a compound having a structure of Formula I, wherein n, R1, R2, R3, R4, R6, X1, X2, X3, and ring A are as defined in claim 1.

15. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein the compound is a compound having a structure of Formula I-1, wherein n, R1, R2, R3, R4, R6, and ring A are as defined in claim 1.

16. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein the compound is a compound having a structure of Formula II, wherein n, R1, R2, R3, R4, R6, X1, X2, X3, and ring A are as defined in claim 1.

17. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein the compound is a compound having a structure of Formula II-1, wherein n, R1, R2, R3, R4, R6, and ring A are as defined in claim 1.

18. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein the compound is a compound having a structure of Formula III, wherein n, R1, R2, R3, R4, R6, X1, X2, X3, and ring A are as defined in claim 1.

19. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, wherein the compound is a compound having a structure of Formula III-1, wherein n, R1, R2, R3, R4, R6, and ring A are as defined in claim 1.

20. A compound as follows or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof: .

21. A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1.

22. A pharmaceutical formulation, comprising the compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1; preferably, the pharmaceutical formulation is any one of a tablet, a capsule, an injection, a granule, a powder, a suppository, a pill, a cream, a paste, a gel, a pulvis, an oral solution, an inhalant, a suspension, a dry suspension, a patch, and a lotion.

23. Use of the compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, in preparation of a drug for preventing and/or treating a related disease with a pathologic feature of increased ATX expression; preferably, the related disease with the pathologic feature of increased ATX expression includes cancer, fibrotic diseases, metabolic diseases, myelodysplastic syndrome, respiratory diseases, cardiovascular diseases, autoimmune diseases, inflammation, dermatological diseases, nervous system diseases, or pain;more preferably, the related disease with the pathologic feature of increased ATX expression is pulmonary fibrosis, renal fibrosis, or liver fibrosis.

24. The compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1 for use in prevention and/or treatment of a related disease with a pathologic feature of increased ATX expression; preferably, the related disease with the pathologic feature of increased ATX expression includes cancer, fibrotic diseases, metabolic diseases, myelodysplastic syndrome, respiratory diseases, cardiovascular diseases, autoimmune diseases, inflammation, dermatological diseases, nervous system diseases, or pain;more preferably, the related disease with the pathologic feature of increased ATX expression is pulmonary fibrosis, renal fibrosis, or liver fibrosis.

25. A method for preventing and/or treating a related disease with a pathologic feature of increased ATX expression, comprising the step of administrating an effective amount of the compound or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labelled compound thereof according to claim 1, to a subject in need thereof.