Vinyl compounds as FGFR and VEGFR inhibitors

Patent metadata

Field	Value
Publication number	US-10519133-B2
Application number	US-201615750704-A
Country	US
Kind code	B2
Filing date	Aug 3, 2016
Priority date	Aug 7, 2015
Publication date	Dec 31, 2019
Grant date	Dec 31, 2019

Abstract

FGFR and VEGFR inhibitors are provided, and compounds represented by formula (1) or formula (II) as FGFR and VEGFR inhibitors, pharmaceutically acceptable salts or tautomers thereof are specifically disclosed.

First claim

What is claimed is:

1. A compound represented by formula (I) or formula (II), a pharmaceutically acceptable salt or a tautomer thereof,

wherein, one of R 1 and R 2 is selected from the group consisting of F, Cl, Br, I, CN, OH and NH 2 , the other is selected from the group consisting of H, F, Cl, Br, I, CN, OH and NH 2 ;
B 1 is selected from the group consisting of

L 1 and L 3 are each independently selected from the group consisting of —(CRR) 0-3 —, —(CRR) 0-3 —N(R)—(CRR) 0-3 — and —(CRR) 0-3 —O—(CRR) 0-3 —;
B 2 is selected from a 5- to 10-membered aryl or heteroaryl which is optionally substituted with R;
B 4 is selected from a 5- to 6-membered aryl or heteroaryl and a 5- to 6-membered cycloalkyl or heterocycloalkyl, each of which is optionally substituted with R;
T 31-34 are each independently selected from N or C(R);
optionally, any two of T 31-34 are connected to the same atom or atom group to form a 3-6 membered ring;
n is 1;
R is selected from the group consisting of H, F, Cl, Br, I, CN, SH, NH 2 , CHO, COOH, C(═O)NH 2 , S(═O)NH 2 , S(═O) 2 NH 2 , or selected from a C 1-12 alkyl or heteroalkyl, a C 3-12 cyclocarbyl or heterocyclocarbyl, and a C 1-12 alkyl or heteroalkyl substituted with a C 3-12 cyclocarbyl or heterocyclocarbyl; and the C 1-12 alkyl or heteroalkyl and the C 3-12 cyclocarbyl or heterocyclocarbyl is optionally substituted with R′;
R′ is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH 2 , CHO, COOH, C(═O)NH 2 , S(═O)NH 2 , S(═O) 2 NH 2 , ═NH, ═O, ═S, or selected from the group optionally substituted with R″ consisting of NHC(═O)CH 3 , a C 1-12 alkyl, a C 1-12 alkylamino, N,N-di(C 1-12 alkyl)amino, a C 1-12 alkoxy, a C 1-12 alkanoyl, a C 1-12 alkoxycarbonyl, a C 1-12 alkylsulfonyl, a C 1-12 alkylsulfinyl, a 3- to 12-membered cycloalkyl, a 3- to 12-membered cycloalkylamino, a 3- to 12-membered heterocycloalkylamino, a 3- to 12-membered cycloalkyloxy, a 3- to 12-membered cycloalkylcarbonyl, a 3- to 12-membered cycloalkyloxycarbonyl, a 3- to 12-membered cycloalkylsulfonyl, a 3- to 12-cycloalkylsulfinyl, a 5- to 12-membered aryl or heteroaryl, a 5 to 12-membered aralkyl or heteroaralkyl;
R″ is selected from the group consisting of F, Cl, Br, I, CN, OH, N(CH 3 ) 2 , NH(CH 3 ), NH 2 , CHO, COOH, C(═O)NH 2 , S(═O)NH 2 , S(═O) 2 NH 2 , ═NH, ═O, ═S, trihalomethyl, dihalomethyl, monohalomethyl, aminomethyl, hydroxymethyl, methyl, methoxy, formyl, methoxycarbonyl, methanesulfonyl, methylsulfinyl;
“hetero” represents a heteroatom or a heteroatom group selected from the group consisting of —C(═O)N(R)—, —N(R)—, —C(═NR)—, —S(═O) 2 N(R)—, —S(═O)N(R)—, —O—, —S—, ═O, ═S, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)—, —S(═O) 2 — and/or —N(R)C(═O)N(R)—;
in each of the above cases, the number of R, R′, R″, heteroatoms or heteroatom groups is independently selected from 0, 1, 2 or 3.

2. The compound, the pharmaceutically acceptable salt or the tautomer thereof according to claim 1 , wherein R is selected from the group consisting of H, F, Cl, Br, I, NH 2 , CN, hydroxymethyl, hydroxyethyl, carboxypropyl, carboxymethyl, methoxy, ethoxy, propoxy, methyl, ethyl, propyl, isopropyl, monohalomethyl, dihalomethyl, trihalomethyl, methylamino, dimethylamino,

3. The compound, the pharmaceutically acceptable salt or the tautomer thereof according to claim 1 , wherein any two of T 31-34 are connected together to the same atom or atom group to form a benzene ring.

4. The compound, the pharmaceutically acceptable salt or the tautomer thereof according to claim 1 , wherein L 1 and L 3 are each independently selected from the group consisting of a single bond, NH,

5. The compound, the pharmaceutically acceptable salt or the tautomer thereof according to claim 1 , wherein B 2 is selected from the group consisting of

wherein, T is selected from N or C(R);
D is selected from the group consisting of —C(R)(R)—, —C(═O)N(R)—, —N(R)—, —C(═NR)—, —S(═O) 2 N(R)—, —S(═O)N(R)—, —O—, —S—, —C(═O)O—, —C(═O)—, C(═S)—, —S(═O)—, —S(═O) 2 — or —N(R)C(═O)N(R)—.

6. The compound, the pharmaceutically acceptable salt or the tautomer thereof according to claim 5 , wherein B 2 is selected from the group consisting of

7. The compound, the pharmaceutically acceptable salt or the tautomer thereof according to claim 1 , wherein B 4 is selected from the group consisting of phenyl, pyridyl, imidazolyl, furyl, thiazolyl, piperidinyl, piperazinyl or morpholinyl, and each of which is optionally substituted with 1, 2 or 3 R.

8. The compound, the pharmaceutically acceptable salt or the tautomer thereof according to claim 1 , wherein the structure unit

is selected from the group consisting of

9. The compound, the pharmaceutically acceptable salt or the tautomer thereof according to claim 1 , which is selected from the group consisting of

Assignees

• Medshine Discovery Inc
• Harbin Zhenbao Pharmaceutical Co Ltd

Inventors

• Chen Shuhui
• Chen Zhengxia
• Dai Meibi
• Xie Cheng
• Li Peng
• Zhang Yang
• Liang Guibai
• Wang Qiang
• Liao Jiangpeng
• Sun Fei
• Hu Guoping
• Li Jian

Classifications

• A61K31/416

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

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D401/02

  containing two hetero rings · CPC title

• C07D403/02

  containing two hetero rings · CPC title