Substituted 2-hydrogen-pyrazole derivative serving as anticancer drug

Patent metadata

Field	Value
Publication number	US-9969719-B2
Application number	US-201615557210-A
Country	US
Kind code	B2
Filing date	Mar 10, 2016
Priority date	Mar 11, 2015
Publication date	May 15, 2018
Grant date	May 15, 2018

Abstract

Disclosed is a substituted 2H-pyrazole derivative serving as a selective CDK4/6 inhibitor. Specifically, disclosed is a compound of formula (I) or a pharmaceutically acceptable salt thereof which serves as a selective CDK4/6 inhibitor.

First claim

What is claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof

wherein

is selected from the group consisting of

and

R 1 is selected from the group consisting of H, halogen, OH, NH 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkenylalkyl and C 3-7 cycloalkyl;
R 2 is selected from the group consisting of H, halogen, C 1-8 alkyl, C 3-7 cycloalkyl, aryl group and heteroaryl group;
R 3 is selected from the group consisting of H, halogen, —OR 8 , —SR 8 ,—N(R 8 )(R 9 ) and C 1-3 alkyl;
R 4 , R 5 and R 6 are each independently selected from the group consisting of H, halogen, OH, NH 2 , CN, NO 2 and ═O, or selected from the group consisting of C 1-8 alkyl, C 1-8 alkylamino, N,N-di(C 1-8 alkyl)amino, C 1-8 alkoxyl-C 1-8 alkyl-, C 1-8 hydroxyalkyl ,C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl and a 3- to 7-membered heterocycloalkyl group, each of which is optionally substituted with 1, 2 or 3 Rs;
optionally, any two of R 4 , R 5 and R 6 form a 3- to 7-membered ring together;
R 7 is selected from the group consisting of H, halogen, —OR 8 , —SR 8 , —N(R 8 )(R 9 ) and C 3-7 cycloalkyl;
X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of N and C(R 10 );
X 7 is selected from the group consisting of carbonyl and C(R 11 )(R 12 );
W is selected from the group consisting of O, S and a single bond;
T is selected from the group consisting of N and C(R 10 ), and T is not N when W is O or S;
Q is selected from the group consisting of N and C(R 10 );
m and n are each independently selected from the group consisting of 0, 1 and 2;
R 8 and R 9 are each independently selected from the group consisting of H, C 1-8 alkyl and C 3-7 cycloalkyl;
R is selected from the group consisting of F, Cl, Br, I, NH 2 , CN, OH, CF 3 , CHF 2 , CH 2 F, NHCH 3 and N(CH 3 ) 2 ;
optionally, R 8 and R 9 are linked to the same one atom and form a 3- to 7-membered ring with 1-4 heteroatoms;
the term “hetero” or “heteroatom” represents O, S, S(═O), S(═O) 2 , or N;
R 10 is selected from the group consisting of H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxyl, C 3-5 cycloalkyl, CN, —OR 8 , —SR 8 , —N(R 8 )(R 9 ),—C(═O)R 8 , —C(═O)OR 8 , —C(═O)N(R 8 )(R 9 ), —S(═O)R 8 , —S(═O) 2 R 8 , —S(═O)N(R 8 )(R 9 ) and —S(═O) 2 N(R 8 )(R 9 );
R 11 and R 12 are each independently selected from the group consisting of H, OH, halogen, C 1-8 alkyl and C 3-7 cycloalkyl;
optionally, R 4 and R 10 are linked to the same one atom and form a 3- to 7-membered ring.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is selected from the group consisting of isopropyl, 2-propenyl and allyl.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is selected from the group consisting of methyl and phenyl.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is F.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 , R 5 and R 6 are each independently selected from the group consisting of H, halogen, OH, NH 2 ,

Me, Et, CN, NO 2 ,

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 7 is selected from the group consisting of H, F and Cl.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the structural unit

is selected from the group consisting of

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 10 is selected from the group consisting of H, OH, NH 2 , F, Cl, CN,

and Me.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein X 4 is selected from the group consisting of N and CH.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the structural unit

is selected from the group consisting of

11. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the structural unit

is selected from the group consisting of

12. A compound selected from the group consisting of

and pharmaceutically acceptable salts thereof.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof

wherein

is selected from the group consisting of

and

R 1 is selected from the group consisting of H, halogen, OH, NH 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkenylalkyl and C 3-7 cycloalkyl;
R 2 is selected from the group consisting of H, halogen, C 1-8 alkyl, C 3-7 cycloalkyl, aryl group and heteroaryl group;
R 3 is selected from the group consisting of H, halogen, —OR 8 , —SR 8 , —N(R 8 )(R 9 ) and C 1-3 alkyl;
R 4 , R 5 and R 6 are each independently selected from the group consisting of H, halogen, OH, NH 2 , CN, NO 2 and ═O, or selected from the group consisting of C 1-8 alkyl, C 1-8 alkylamino, N,N-di(C 1-8 alkyl)amino, C 1-8 alkoxyl-C 1-8 alkyl-, C 1-8 hydroxyalkyl ,C 2-8 alkenyl, C 2-8 alkenyl, C 3-7 cycloalkyl and a 3- to 7-membered heterocycloalkyl group,

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd
• Medshine Discovery Inc

Inventors

• Ding Charles Z
• Chen Shuhui
• Zhao Baoping
• Xu Zhaobing
• Liu Yingchun
• Lin Ruibin
• Wang Fei
• Li Jian

Classifications

• A61K31/416

  condensed with carbocyclic ring systems, e.g. indazole · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title