Pyrazole compound and preparation method therefor and use thereof
The present invention relates to a pyrazole compound and a preparation method therefor and a use thereof. In particular, the present invention relates to a compound shown in Formula I, a pharmaceutical composition containing same or a pharmaceutically acceptable form thereof, a pharmaceutical composition thereof, a preparation method therefor, and a use thereof. The compound can be used as a drug for treating cancer or fibrosis disease,
1 . A compound having the structure of Formula I or a pharmaceutically acceptable form thereof, wherein the pharmaceutically acceptable form is selected from the group consisting of a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, and prodrug;
wherein,
R 1 is selected from the group consisting of
R 2 is
R 3 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 1-6 alkoxyl and C 1-6 alkylamino; and
R 4 is selected from the group consisting of hydrogen, C 3-8 cycloalkyl-C 1-6 alkylamino, 3- to 8-membered heterocyclylamino, C 1-6 alkylamino, C 1-6 haloalkylamino, C 3-8 cycloalkylamino, phenylamino, benzylamino, 5- to 10-membered heteroarylamino and 5- to 10-membered heteroarylalkylamino; wherein the C 3-8 cycloalkyl-C 1-6 alkylamino, 3- to 8-membered heterocyclylamino, C 1-6 alkylamino, C 1-6 haloalkylamino, C 3-8 cycloalkylamino, phenylamino, benzylamino, 5- to 10-membered heteroarylamino and 5- to 10-membered heteroarylalkylamino are each optionally substituted with one or more groups independently selected from the group consisting of: C 1-6 alkyl, halogen, cyano, amido, carbamoyl, mono- or di-C 1-6 alkyl-substituted carbamoyl, sulfonyl, phenyl, halophenyl and 4- to 6-membered heterocyclyl.
2 . The compound according to claim 1 , or a pharmaceutically acceptable form thereof, wherein,
R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy and C 1-6 alkylamino; and
R 4 is selected from the group consisting of hydrogen, C 3-8 cycloalkyl-C 1-6 alkylamino, 3- to 8-membered heterocyclylamino, C 1-6 alkylamino, C 1-6 haloalkylamino, C 3-8 cycloalkylamino, phenylamino, benzylamino, 5- to 6-membered heteroarylamino and 5- to 6-membered heteroarylalkylamino; wherein the C 3-8 cycloalkyl-C 1-6 alkylamino, 3- to 8-membered heterocyclylamino, C 1-6 alkylamino, C 1-6 haloalkylamino, C 3-8 cycloalkylamino, phenylamino, benzylamino, 5- to 6-membered heteroarylamino, and 5- to 6-membered heteroarylalkylamino are each optionally substituted with one or more groups independently selected from the group consisting of: C 1-6 alkyl, halogen, cyano, amido, carbamoyl, mono- or di-C 1-6 alkyl-substituted carbamoyl, sulfonyl, phenyl, halophenyl, C 3-6 cycloalkyl and 4- to 6-membered heterocyclyl.
3 . The compound according to claim 1 , or a pharmaceutically acceptable form thereof, wherein the compound has the structure of Formula I-1,
wherein:
R 1 , R 2 and R 3 are as defined in claim 1 .
4 . The compound according to claim 1 , or a pharmaceutically acceptable form thereof, wherein the compound has the structure of Formula I-4,
wherein R 1 , R 2 and R 3 are as defined in claim 1 ; and
R 10 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, 3- to 8-membered heterocyclyl, benzyl, 5- to 6-membered heteroarylalkyl, phenyl and 5- to 6-membered heteroaryl; wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3 -cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, 3- to 8-membered heterocyclyl, benzyl, 5- to 6-membered heteroarylalkyl, phenyl and 5- to 6-membered heteroaryl are each optionally substituted with one or more groups independently selected from the group consisting of C 1-6 alkyl, halogen, cyano amido, carbamoyl, mono- or di-C 1-6 alkyl-substituted carbamoyl, sulfonyl, phenyl, halophenyl and 4- to 6-membered heterocyclyl.
5 . The compound according to claim 1 , or a pharmaceutically acceptable form thereof, wherein,
R 3 is selected from the group consisting of hydrogen and C 1-6 alkyl.
6 . The compound according to claim 1 , or a pharmaceutically acceptable form thereof, wherein,
R 3 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, difluoroethyl, C 1-6 alkoxy and C 1-6 alkylamino;
R 4 is selected from the group consisting of hydrogen and —NHR 10 ;
R 10 is selected from:
7 . The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, or prodrug thereof, wherein the compound is selected from:
8 . A pharmaceutical composition, which comprises at least one compound according to claim 1 , or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.
9 . A kit product, which comprises:
a) at least one compound according to claim 1 or a pharmaceutically acceptable form thereof as a first therapeutic agent, or pharmaceutical composition as a first pharmaceutical composition.
10 . A pharmaceutical composition, which comprises at least one compound according to claim 7 , or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.
11 . A kit product, which comprises:
a) at least one compound according to claim 7 or a pharmaceutically acceptable form thereof as a first therapeutic agent, or a pharmaceutical composition comprising the same as a first pharmaceutical composition.
12 . The compound of claim 3 , wherein R 3 is hydrogen or C 1-6 alkyl.
13 . The compound of claim 4 , where R 10 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, 3- to 6-membered heterocyclyl, benzyl, 5- to 6-membered heteroarylalkyl, phenyl and 5- to 6-membered heteroaryl; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, 3- to 6-membered heterocyclyl, benzyl, 5- to 6-membered heteroarylalkyl, phenyl and 5- to 6-membered heteroaryl are each optionally substituted with one or more groups independently selected from the group consisting of C 1-6 alkyl, halogen, cyano, amido, carbamoyl, mono- or di-C 1-4 alkyl-substituted carbamoyl and sulfonyl.
14 . The compound of claim 4 , wherein R 10 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, benzyl, pyridyl and pyrazolyl; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, benzyl, pyridyl and pyrazolyl are each optionally substituted with one or more groups independently selected from the group consisting of methyl, fluoro, chloro, bromo, and cyano.
15 . The compound of claim 5 , wherein R 1 is
16 . The compound of claim 5 , wherein R 3 is selected from the group consisting of hydrogen, methyl, ethyl, propyl and isopropyl.
17 . The compound of claim 5 , wherein R 3 is selected from the group consisting of hydrogen and isopropyl.
18 . The compound of claim 5 , wherein R 3 is hydrogen.
19 . The compound of claim 5 , wherein R 3 is isopropyl.
20 . The compound according to claim 1 , or a pharmaceutically acceptable form thereof, wherein,
R 4 is selected from the group consisting of hydrogen, C 1-6 alkylamino, C 3-8 cycloalkylamino, benzylamino and 5- to 10-membered heteroarylalkylamino, wherein the C 1-6 alkylamino, C 3-8 cycloalkylamino, benzylamino and 5- to 10-membered heteroarylalkylamino are each optionally substituted with one or more groups independently selected from the group consisting of the followings: C 1-6 alkyl, halogen and cyano.
21 . The compound of claim 20 , wherein R 4 is selected from the group consisting of hydrogen, C 1-6 alkylamino, C 3-6 cycloalkylamino, benzylamino and 5- to 6-membered heteroaryl-C 1-4 alkylamino, and the C 1-6 alkylamino, C 3-6 cycloalkylamino, benzylamino and 5- to 6-membered heteroaryl-C 1-4 alkylamino are each optionally substituted with one or more groups selected from the group consisting of the followings: C 1-6 alkyl, halogen and cyano.
22 . The compound of claim 20 , wherein R 4 is selected from the group consisting of hydrogen and —NHR 10 ; wherein R 10 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, benzyl and 5- to 6-membered heteroaryl-C 1-4 alkyl, and the C 1-6 alkyl, C 3-6 cycloalkyl, benzyl and 5- to 6-membered heteroaryl-C 1-4 alkyl are each optionally substituted with one or more groups independently selected from the group consisting of the followings: C 1-6 alkyl, fluoro, chloro, bromo, and cyano.
23 . The compound of claim 20 , wherein R 4 is selected from the group consisting of hydrogen and —NHR 10 ; wherein R 10 is selected from the group consisting of C 1-6 alkyl, benzyl and pyridylmethyl, and the benzyl and pyridylmethyl are each optionally substituted with one or more groups independently selected from the group consisting of the followings: C 1-6 alkyl, fluoro, chloro, bromo, and cyano.
24 . The compound of claim 23 , wherein R 10 is selected from the group consisting of C 1-6 alkyl, benzyl and pyridylmethyl, and the benzyl and pyridylmethyl are each optionally substituted with one or more groups independently selected from the group consisting of the followings: methyl and fluoro.
25 . The compound of claim 20 , wherein R 4 is selected from the group consisting of hydrogen and —NHR 10 ; R 10 is selected from:
26 . The compound of claim 20 , wherein R 4 is selected from the group consisting of hydrogen and —NHR 10 ; R 10 is selected from:
27 . The kit of claim 9 , wherein the kit further comprises b) at least one additional therapeutic agent as a second therapeutic agent, or a pharmaceutical composition comprising the additional therapeutic agent as a second pharmaceutical composition.
28 . The kit of claim 11 , wherein the kit further comprises b) at least one additional therapeutic agent as a second therapeutic agent, or a pharmaceutical composition comprising the additional therapeutic agent as a second pharmaceutical composition.
29 . The compound of claim 1 , wherein R 3 is selected from the group consisting of C 1-6 alkoxyl and C 1-6 alkylamino.
30 . The compound of claim 1 , wherein R 4 is selected from the group consisting of C 1-6 alkylamino and C 1-6 haloalkylamino.