Thieno[3,2-D]pyrimidine derivatives having inhibitory activity for protein kinases

Patent metadata

Field	Value
Publication number	US-RE47451-E
Application number	US-201215783240-A
Country	US
Kind code	E1
Filing date	Dec 27, 2012
Priority date	Dec 30, 2011
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

Abstract

Provided are a thieno[3,2-d]pyrimidine derivative of formula (I) or a pharmaceutically acceptable salt thereof having inhibitory activity for protein kinase, and a pharmaceutical composition comprising same for prevention and treatment of abnormal cell growth diseases.

First claim

What is claimed is:

1. A thieno[3,2-d]pyrimidine compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein,
A is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-10 aryl or, 5- to 10-membered heteroaryl,

2,3-dihydrobenzo[b][1,4]dioxin-6-yl, benzo[d][1,3]dioxol-5-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, idolin-6-yl, 1,4-diethyl-1,2,3,4,-tetrahydroquinoxalin-6-yl;, 2-methyl-1,3-dioxoisoindolin-5-yl, or 5-oxo-5,6,7,-8-tetrahydronaphthalen-2-yl;
W is O, S, S(O), S(O) 2 , NH, —NHNH— or 3- to 6-membered heterocycloalkyl;
X and Y are each independently CH or N;
Z is hydrogen, C 1-3 alkyl or NR 3 R 4 , wherein said R 3 and R 4 are each independently hydrogen, C 1-6 alkyl or —(CH 2 )q-B—, B representing NR 5 R 6 , C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl;
R 1 is hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy, wherein said alkyl or alkoxy is unsubstituted or substituted with one or more halogen atoms;
R 2 is hydrogen, halogen, ═O, —CF 3 , —NO 2 , —OH, —CN, C 1-6 alkoxy, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, —NR 7 R 8 , —NHSO 2 R 9 , —SO 2 R 10 , —C(O)R 11 , —NHC(O)R 12 , —NHC(O)OR 13 , —S(O)R 14 , C 3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl 3- to 6-membered heterocycloalkyl, C 6-10 aryl, C 6-10 aryloxy, 5- to 10-membered heteroaryl or 3- to 6-membered heteroaryloxy 5- to 10-membered heteroaryloxy, wherein said R 2 is connected to A by —(CH 2 )p- or substituted with C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkylcarbonyl or one or more halogen atoms;
R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently hydrogen, —NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being unsubstituted or substituted with one or more halogen atoms;
q is an integer ranging from 0 to 3;
p is an integer ranging from 0 to 3;
m is an integer ranging from 0 to 5; and
n is an integer ranging from 0 to 2; and
when A is hydrogen, m is 0.

2. The thieno[3,2-d]pyrimidine compound or its pharmaceutically acceptable salt of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is C 6-10 aryl or 5- to 10-membered heteroaryl.

3. The thieno[3,2-d]pyrimidine compound or its pharmaceutically acceptable salt of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is NH.

4. The thieno[3,2-d]pyrimidine compound or its pharmaceutically acceptable salt of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is NR 3 R 4 .

5. The thieno[3,2-d]pyrimidine compound or its pharmaceutically acceptable salt of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH and Y is N.

6. The A thieno[3,2-d]pyrimidine compound or its pharmaceutically acceptable salt of claim 1 , which is selected from the group consisting of:
1) 4-amino-N-(1-((4-chlorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
2) 4-amino-N-(6-methyl-1-((3-(trifluoromethyl)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
3) N-(1-((4-chlorophenyl)amino)-6-methylisoquinolin-5-yl)-4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamide;
4) 4-(cyclopropylamino)-N-(6-methyl-1-((3-(trifluoromethyl)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
5) 4-amino-N-(6-methyl-1-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
6) 4-(cyclopropylamino)-N-(6-methyl-1-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
7) 4-amino-N-(1-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
8) 4-(cyclopropylamino)-N-(1-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
9) N-(1-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-6-methylisoquinolin-5-yl)-4-(methylamino)thieno[3,2-d]pyrimidine-7-carboxamide;
10) 4-amino-N-(1-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
11) 4-amino-N-(1-((4-((4-ethylpiperazin-1-yl)methyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
12) 4-amino-N-(6-methyl-1-((3-(trifluoromethyl)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
13) 4-amino-N-(1-((4-chloro-3-(trifluoromethyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
14) 4-amino-N-(1-((2-methoxy-5-(trifluoromethyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
15) 4-amino-N-(6-methyl-1-((4-(trifluoromethyl)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
16) 4-amino-N-(1-((4-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
17) 4-amino-N-(6-methyl-1-(p-tolylamino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
18) 4-amino-N-(1-((4-isopropylphenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
19) 4-amino-N-(1-((5-(t-butyl)isoxazol-3-yl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
20) 4-amino-N-(1-((4-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
21) 4-amino-N-(6-methyl-1-(thiazol-2-ylamino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
22) 4-amino-N-(1-((4-cyanophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
23) 4-amino-N-(6-methyl-1-(quinolin-5-ylamino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
24) 4-amino-N-(1-((4-ethoxyphenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
25) 4-amino-N-(6-methyl-1-((4-phenoxyphenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
26) 4-amino-N-(1-((4-hydroxyphenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
27) 4-amino-N-(1-((4-isopropoxyphenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
28) 4-amino-N-(1-((4-(dimethylamino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide 4-amino-N-(1-((4-dimethylaminophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
29) 4-amino-N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
30) 4-amino-N-(1-((3,4-dimethoxyphenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
31) 4-amino-N-(1-((3-fluoro-4-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
32) 4-amino-N-(6-methyl-1-((3,4,5-trimethoxyphenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
33) 4-amino-N-(6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
34) 4-amino-N-(1-(benzo[d][1,3]dioxol-5-ylamino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
35) 4-amino-N-(6-methyl-1-((5,6,7,8-tetrahydronaphthalen-2-yl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
36) 4-amino-N-(4-((4-chlorophenyl)amino)-7-methylquinazolin-8-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
37) 4-(cyclopropylamino)-N-(1-((4-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
38) 4-amino-N-(1-((3-chlorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
39) 4-amino-N-(1-((3-bromophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxami

Assignees

• Hanmi Pharm Ind Co Ltd

Inventors

• Bae In Hwan
• Son Jung Beom
• Han Sang Mi
• Kwak Eun Joo
• Kim Ho Seok
• Song Ji Young
• Byun Eun Young
• Jun Seung Ah
• Ahn Young Gil
• Suh Kwee Hyun

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title