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.
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0. 39. A thieno[3,2-d]pyrimidine compound having the following structure:
##STR00136##
or a pharmaceutically acceptable salt thereof.
0. 43. A thieno[3,2-d]pyrimidine compound having the following structure:
##STR00137##
or a pharmaceutically acceptable salt thereof.
0. 27. A thieno[3,2-d]pyrimidine compound having the following structure:
##STR00133##
or a pharmaceutically acceptable salt thereof.
0. 51. A thieno[3,2-d]pyrimidine compound having the following structure:
##STR00139##
or a pharmaceutically acceptable salt thereof.
0. 47. A thieno[3,2-d]pyrimidine compound having the following structure:
##STR00138##
or a pharmaceutically acceptable salt thereof.
0. 31. A thieno[3,2-d]pyrimidine compound having the following structure:
##STR00134##
or a pharmaceutically acceptable salt thereof.
0. 35. A thieno[3,2-d]pyrimidine compound having the following structure:
##STR00135##
or a pharmaceutically acceptable salt thereof.
0. 23. A thieno[3,2-d]pyrimidine compound having the following structure:
##STR00132##
or a pharmaceutically acceptable salt thereof.
0. 15. A thieno[3,2-d]pyrimidine compound selected from the group consisting of:
71) 4-amino-N-(1-((3-(dimethylcarbamoyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
72) 4-amino-N-(6-methyl-1-((3-(methylcarbamoyl)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
81) 4-amino-N-(1-((4-(2-methoxyethoxy)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
95) 4-amino-N-(1-((4-(dimethylcarbamoyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
124) 4-amino-N-(1-((3-(dimethylamino)propyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide; and
125) 4-amino-N-(6-methyl-1-(piperidin-1-yl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
or a pharmaceutically acceptable salt thereof.
0. 55. A method of preparing a thieno[3,2-d]pyrimidine compound, or a pharmaceutically acceptable salt thereof, according to reaction steps 1 to 3:
##STR00140##
wherein:
A is c6-10 aryl or 5- to 10-membered heteroaryl;
Z is hydrogen, c1-3 alkyl or NR3R4, wherein said R3 and R4 are each independently hydrogen, c1-6 alkyl or —(CH2)q-B—, B representing NR5R6, c1-6 alkoxy, c3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl;
R1 is hydrogen, halogen, c1-3 alkyl or c1-3 alkoxy, wherein said alkyl or alkoxy is unsubstituted or substituted with one or more halogen atoms;
R2 is hydrogen, halogen, —CF3, —NO2, —OH, —CN, c1-6 alkoxy, c1-6 alkyl, c2-4 alkenyl, c2-4 alkynyl, —NR7R8, —NHSO2R9, —SO2R10, —C(O)R11, —NHC(O)R12, —NHC(O)OR13, —S(O)R14, c3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, c6-10 aryl, c6-10 aryloxy, 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryloxy, wherein said R2 is connected to A by —(CH2)p- or substituted with c1-4 alkyl, c2-4alkynyl, c1-4 alkylcarbonyl or one or more halogen atoms;
R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are each independently hydrogen, —NH2, c1-6 alkyl, c1-6 alkoxy, c3-6 cycloalkyl or 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being unsubstituted or substituted with one or more halogen atoms;
m is an integer ranging from 0 to 3;
q is 0;
p is an integer ranging from 0 to 1; and
n is 0 or 1.
##STR00130##
wherein,
A is hydrogen, c1-6 alkyl, c3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, c6-10 aryl or, 5- to 10-membered heteroaryl,
##STR00131##
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, c1-3 alkyl or NR3R4, wherein said R3 and R4 are each independently hydrogen, c1-6 alkyl or —(CH2)q-B—, B representing NR5R6, c1-6 alkoxy, c3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl;
R1 is hydrogen, halogen, c1-3 alkyl or c1-3 alkoxy, wherein said alkyl or alkoxy is unsubstituted or substituted with one or more halogen atoms;
R2 is hydrogen, halogen, ═O, —CF3, —NO2, —OH, —CN, c1-6 alkoxy, c1-6 alkyl, c2-4 alkenyl, c2-4 alkynyl, —NR7R8, —NHSO2R9, —SO2R10, —C(O)R11, —NHC(O)R12, —NHC(O)OR13, —S(O)R14, c3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl 3- to 6-membered heterocycloalkyl, c6-10 aryl, c6-10 aryloxy, 5- to 10-membered heteroaryl or 3- to 6-membered heteroaryloxy 5- to 10-membered heteroaryloxy, wherein said R2 is connected to A by —(CH2)p- or substituted with c1-4 alkyl, c2-4alkynyl, c1-4 alkylcarbonyl or one or more halogen atoms;
R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are each independently hydrogen, —NH2, c1-6 alkyl, c1-6 alkoxy, c3-6 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
3. The thieno[3,2-d]pyrimidine compound or its pharmaceutically acceptable salt of
4. The thieno[3,2-d]pyrimidine compound or its pharmaceutically acceptable salt of
5. The thieno[3,2-d]pyrimidine compound or its pharmaceutically acceptable salt of
6. The A thieno[3,2-d]pyrimidine compound or its pharmaceutically acceptable salt 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-carboxamide;
40) 4-amino-N-(1-((2,4-dichlorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
41) 4-amino-N-(1-((3,4-dichlorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
42) 4-amino-N-(1-((3,5-dichlorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
43) 4-amino-N-(6-methyl-1-((3,4,5-trichlorophenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
44) 4-amino-N-(1-((4-chloro-3-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
45) 4-amino-N-(1-benzylamino-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
46) 4-amino-N-(6-methyl-1-phenoxyisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
47) 4-amino-N-(6-methyl-1-((4-morpholinophenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
48) N-(1-((4-(1H-pyrrol-1-yl)phenyl)amino)-6-methylisoquinolin-5-yl)-4-aminothieno[3,2-d]pyrimidine-7-carboxamide;
49) 4-amino-N-(6-methyl-1-(pyrimidin-4-ylamino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
50) 4-amino-N-(1-((4-(difluoromethoxy)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
51) 4-amino-N-(6-methyl-1-((4-(trifluoromethoxy)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
52) 4-amino-N-(1-((4-chlorophenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
53) 4-amino-N-(5-((4-chlorophenyl)amino)naphthalen-1-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
54) 4-amino-N-(1-((4-ethynylphenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
55) 4-amino-N-(1-(isopropylamino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
56) 4-amino-N-(1-(indolin-6-ylamino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
57) 4-amino-N-(1-((4-(fluoromethoxy)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
58) N-(1-(4-chlorophenylamino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
59) 4-amino-N-(1-((4-chloro-3-((dimethylamino)methyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
60) 4-amino-N-(1-((4-chloro-3-(pyrrolidin-1-ylmethyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
61) 4-amino-N-(1-((4-chloro-3-((diethylamino)methyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
62) 4-amino-N-(1-((1,4-diethyl-1,2,3,4-tetrahydroquinoxalin-6-yl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
63) 4-amino-N-(1-((4-chloro-3-(piperidin-1-ylmethyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
64) 4-amino-N-(1-((4-chloro-3-(morpholinomethyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
65) 4-amino-N-(1-((4-chloro-3-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
66) 4-amino-N-(1-((4-chloro-3-((diisopropylamino)methyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
67) 4-amino-N-(6-methyl-1-((3-(methylsulfonamido)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
68) tert-butyl 4-(5-((5-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-6-methylisoquinolin-1-yl)amino)-2-chlorobenzyl)piperazine-1-carboxylate;
69) 4-amino-N-(1-((4-chloro-3-(piperazin-1-ylmethyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
70) 4-amino-N-(1-((3-chloro-4-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
71) 4-amino-N-(1-((3-(dimethylcarbamoyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
72) 4-amino-N-(6-methyl-1-((3-(methylcarbamoyl)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
73) 4-amino-N-(1-((4-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
74) 4-amino-N-(1-((4-bromo-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
75) 4-amino-N-(1-((4-methoxybenzyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
76) 4-amino-N-(1-((4-chlorobenzyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
77) 4-amino-N-(1-(2-(4-chlorophenyl)hydrazinyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
78) 4-amino-N-(1-((3-((dimethylamino)methyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
79) 4-amino-N-(6-methyl-1-((4-oxo-4H-chromen-6-yl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
80) N-(1-((3-acetylphenyl)amino)-6-methylisoquinolin-5-yl)-4-aminothieno[3,2-d]pyrimidine-7-carboxamide;
81) 4-amino-N-(1-((4-(2-methoxyethoxyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
82) 4-amino-N-(6-methyl-1-((3-(trifluoromethoxy)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
83) N-(1-((4-acetylphenyl)amino)-6-methylisoquinolin-5-yl)-4-aminothieno[3,2-d]pyrimidine-7-carboxamide;
84) 4-amino-N-(6-methyl-1-((4-(methylsulfonamido)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
85) 4-amino-N-(6-methyl-1-((3-(methylsulfonyl)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
86) 4-amino-N-(1-((4-chloro-3-(methoxymethyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
87) 4-amino-N-(1-((4-methoxy-3-(methylsulfonamido)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
88) 4-amino-N-(1-((4-chloro-3-(methylsulfonamido)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
89) 4-amino-N-(1-((6-chloropyridin-3-yl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
90) 4-amino-N-(1-((2-chloropyridin-4-yl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
91) 4-amino-N-(6-methyl(4-(methylsulfonamidomethyl)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
92) 4-amino-N-(6-methyl-1-((3-(methylsulfonamidomethyl)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
93) 4-amino-N-(1-((4-chloro-3-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
94) 4-amino-N-(1-((3-bromo-4-chlorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
95) 4-amino-N-(1-((4-(dimethylcarbamoyl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
96) N-(1-((3-acetamidophenyl)amino)-6-methylisoquinolin-5-yl)-4-aminothieno[3,2-d]pyrimidine-7-carboxamide;
97) 4-amino-N-(6-methyl-1-((1-methyl-1H-indazol-6-yl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
98) 4-amino-N-(6-methyl-1-((4-(methylsulfinyl)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
99) 4-amino-N-(6-methyl-1-((2-methyl-1,3-dioxoisoindolin-5-yl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
100) 4-amino-N-(1-((6-methoxypyridin-3-yl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
101) 4-amino-N-(6-methyl-1-((3-(2,2,2-trifluoroacetyl)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
102) 4-amino-N-(6-methyl-1-((4-propionylphenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
103) 4-amino-N-(1-((4-hexanoylphenyl)amino)-6-methylisoquinolin-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
104) N-(1-((1-acetyl-1H-indazol-6-yl)amino)-6-methylisoquinolin-5-yl)-4-aminothieno[3,2-d]pyrimidine-7-carboxamide;
105) 4-amino-N-(1-((3-chloro-4-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
106) 4-amino-N-(6-methyl-1-((5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
107) 4-amino-N-(6-methyl-1-((2-methyl-2H-indazol-6-yl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
108) methyl 4-((5-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-6-methylisoquinolin-1-yl)amino)benzoate;
109) 4-amino-N-(6-methyl-1-((1-methyl-1H-indazol-5-yl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
110) 4-amino-N-(6-methyl-1-((2-methyl-2H-indazol-5-yl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
111) 4-amino-N-(6-methyl-1-((6-methylpyridin-3-yl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
112) 4-amino-N-(6-methyl-1-((1-methyl-1H-indol-6-yl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
113) tert-butyl 6-((5-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-6-methylisoquinolin-1-yl)amino)-1H-indazol-1-carboxylate;
114) N-(1-((1H-indazol-6-yl)amino)-6-methylisoquinolin-5-yl)-4-aminothieno[3,2-d]pyrimidine-7-carboxamide hydrochloride;
115) 4-amino-N-(1-((5-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
116) 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
117) 4-amino-N-(1-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
118) 4-amino-N-(1-((3-chloro-1-methyl-1H-indazol-6-yl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
119) 4-amino-N-(6-methyl-1-((4-(prop-2-yn-1-yloxy)phenyl)amino)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
120) 4-amino-N-(1-((2-methoxy-4-morpholinophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
121) 4-amino-N-(1-(benzo[d]thiazol-6-ylamino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
122) N-(1-((1H-indazol-5-yl)amino)-6-methylisoquinolin-5-yl)-4-aminothieno[3,2-d]pyrimidine-7-carboxamide; and
123) 4-amino-N-(1-((3-chloro-2,4-difluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide;
124) 4-amino-N-(1-((3-(dimethylamino)propyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide; and
125) 4-amino-N-(6-methyl-1-(piperidin-1-yl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide,
or its a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising the compound of
8. The pharmaceutical composition of
9. A pharmaceutical formulation comprising the pharmaceutical composition of
10. The pharmaceutical formulation of
11. The pharmaceutical formulation of
12. A method for manufacturing a medicament containing the compound of
13. A method for treating a cancer, which method comprises administering the compound of
14. The method of
0. 16. A pharmaceutical composition comprising a compound of claim 15, or a pharmaceutically acceptable salt thereof, as an active ingredient.
0. 17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition further comprises a drug selected from the group consisting of cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological reaction modifiers, antihormonal agents, antiandrogen, cell differentiation/proliferation/survival inhibitors, apoptosis inhibitors, inflammation inhibitors and P-glycoprotein inhibitors.
0. 18. A pharmaceutical formulation comprising the pharmaceutical composition of claim 16.
0. 19. The pharmaceutical formulation of claim 18, wherein said formulation is an oral formulation.
0. 20. The pharmaceutical formulation of claim 18, wherein said formulation is in the form of a tablet, a pill, powder, a capsule, syrup, an emulsion or a microemulsion.
0. 21. A method for treating cancer, which method comprises administering the pharmaceutical composition of claim 16 to a mammal in need thereof, wherein the cancer is liver cancer or melanoma.
0. 22. The method of claim 21, wherein the pharmaceutical composition is administered in combination with a drug selected from the group consisting of cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological reaction modifiers, antihormonal agents, antiandrogen, cell differentiation/proliferation/survival inhibitors, apoptosis inhibitors, inflammation inhibitors and P-glycoprotein inhibitors.
0. 24. A pharmaceutical composition comprising the thieno[3,2-d]pyrimidine compound of claim 23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
0. 25. A method of treating a cancer, the method comprising administering the pharmaceutical composition of claim 24 to a mammal in need thereof, wherein the cancer is liver cancer or melanoma.
0. 26. The method of claim 25 wherein the pharmaceutical composition is administered in combination with a cell signal transduction inhibitor drug.
0. 28. A pharmaceutical composition comprising the thieno[3,2-d]pyrimidine compound of claim 27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
0. 29. A method of treating a cancer, the method comprising administering the pharmaceutical composition of claim 28 to a mammal in need thereof, wherein the cancer is liver cancer or melanoma.
0. 30. The method of claim 31 wherein the pharmaceutical composition is administered in combination with a cell signal transduction inhibitor drug.
0. 32. A pharmaceutical composition comprising the thieno[3,2-d]pyrimidine compound of claim 31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
0. 33. A method of treating a cancer, the method comprising administering the pharmaceutical composition of claim 32 to a mammal in need thereof, wherein the cancer is liver cancer or melanoma.
0. 34. The method of claim 33 wherein the pharmaceutical composition is administered in combination with a cell signal transduction inhibitor drug.
0. 36. A pharmaceutical composition comprising the thieno[3,2-d]pyrimidine compound of claim 35, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
0. 37. A method of treating a cancer, the method comprising administering the pharmaceutical composition of claim 36 to a mammal in need thereof, wherein the cancer is liver cancer or melanoma.
0. 38. The method of claim 37 wherein the pharmaceutical composition is administered in combination with a cell signal transduction inhibitor drug.
0. 40. A pharmaceutical composition comprising the thieno[3,2-d]pyrimidine compound of claim 39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
0. 41. A method of treating a cancer, the method comprising administering the pharmaceutical composition of claim 40 to a mammal in need thereof, wherein the cancer is liver cancer or melanoma.
0. 42. The method of claim 41 wherein the pharmaceutical composition is administered in combination with a cell signal transduction inhibitor drug.
0. 44. A pharmaceutical composition comprising the thieno[3,2-d]pyrimidine compound of claim 43, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
0. 45. A method of treating a cancer, the method comprising administering the pharmaceutical composition of claim 44 to a mammal in need thereof, wherein the cancer is liver cancer or melanoma.
0. 46. The method of claim 45 wherein the pharmaceutical composition is administered in combination with a cell signal transduction inhibitor drug.
0. 48. A pharmaceutical composition comprising the thieno[3,2-d]pyrimidine compound of claim 47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
0. 49. A method of treating a cancer, the method comprising administering the pharmaceutical composition of claim 48 to a mammal in need thereof, wherein the cancer is liver cancer or melanoma.
0. 50. The method of claim 49 wherein the pharmaceutical composition is administered in combination with a cell signal transduction inhibitor drug.
0. 52. A pharmaceutical composition comprising the thieno[3,2-d]pyrimidine compound of claim 51, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
0. 53. A method of treating a cancer, the method comprising administering the pharmaceutical composition of claim 52 to a mammal in need thereof, wherein the cancer is liver cancer or melanoma.
0. 54. The method of claims 53 wherein the pharmaceutical composition is administered in combination with a cell signal transduction inhibitor drug.
0. 56. The method of claim 55 wherein the compound has the structure:
##STR00141##
or a pharmaceutically acceptable salt thereof.
0. 57. The method of claim 55 wherein the compound has the structure:
##STR00142##
or a pharmaceutically acceptable salt thereof.
0. 58. The method of claim 55 wherein the compound has the structure:
##STR00143##
or a pharmaceutically acceptable salt thereof.
0. 59. The method of claim 55 wherein the compound has the structure:
##STR00144##
or a pharmaceutically acceptable salt thereof.
0. 60. The method of claim 55 wherein the compound has the structure:
##STR00145##
or a pharmaceutically acceptable salt thereof.
0. 61. The method of claim 55 wherein the compound is:
##STR00146##
or a pharmaceutically acceptable salt thereof.
0. 62. The method of claim 55 wherein the compound is:
##STR00147##
or a pharmaceutically acceptable salt thereof.
0. 63. The method of claim 55 wherein the compound is:
##STR00148##
or a pharmaceutically acceptable salt thereof.
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This application
[(Ti−Tz/Tz)×100 (for Ti<Tz) [Equation 2]
In Equations 1 and 2, ‘Tz’ refers to a density of untreated cells, which is an absorbance in 0% cell growth groups. ‘C’ refers to a density of cells cultured by adding only medium, and ‘Ti’ refers to a density of cells treated with test compounds.
GI50 value is the concentration of test compound when the value of Equation 1 is 50, which indicates the concentration of test compound needed to reduce the growth of cancer cells to 50%. On each measurement, test compounds were compared with a control. Vemurafenib (PLX-4032) was used as a control, and the IC50 values of each compound were measured and shown in Table 4.
TABLE 4
Example
HepG2 (IC50, nM)
Control
>1,000
1
27
16
24
38
41
50
44
59
47
83
30
105
90
116
38
The inventive compounds having an inhibitory activity for protein kinase, thieno[3,2-d]-pyrimidine derivatives or pharmaceutically acceptable salts thereof, were tested for their inhibitory activities on proliferation of aberrant cells as follows.
N-RAS mutant cells, SK-Mel-2 cell lines (ATCC #HTB-68™), were obtained from ATCC (American Type Culture Collection: Rockville, Md.). SK-Mel-2 cell lines were incubated in a MEM medium supplemented with 10% FBS and 1% penicillin/streptomycin (Gibco BRL) under 37° C., 5% CO2 and 95% air. The cell lines were transferred into 96-well plates at a density of 5,000 cells/well, and cultured for 18 hours or more. The cells were treated with 10 μl˜0.1 nM of test compounds, and cultured for 72 hours.
To evaluate cell viabilities, SK-Mel-2 cell lines were fixed with 10% TCA (trichloroacetic acid), stained with SRB (sulfohodamine B), and an absorbance was measured at 540 nm. Then, GI50, i.e., the concentration of drug to cause 50% reduction in proliferation of cancer cells, were calculated therefrom. The growth rates of cancer cells were calculated by Equation 1 or 2.
[(Ti−Tz)/(C−Tz)]×100 (for Ti>=Tz) [Equation 1]
[(Ti−Tz/Tz)×100 (for Ti<Tz) [Equation 2]
In Equations 1 and 2, ‘Tz’ refers to a density of untreated cells, which is an absorbance in 0% cell growth groups. ‘C’ refers to a density of cells cultured by adding only medium, and ‘Ti’ refers to a density of cells treated with test compounds.
GI50 value is the concentration of a test compound when the value of Equation 1 is 50, which indicates the concentration of test compound needed to reduce the growth of cancer cells to 50%. On each measurement, test compounds were compared with a control. Vemurafenib (PLX-4032) was used as a control, and the IC50 values of each compound were measured and shown in Table 5.
TABLE 5
Example
SK-Mel-2 (IC50, nM)
Control
>1,000
1
56
16
52
38
97
50
163
59
236
83
60
105
210
116
76
As evidenced above, the inventive compounds, thieno[3,2-d]-pyrimidine derivative having inhibitory activity for protein kinases, can effectively inhibit various protein kinases including RAF, FMS, DDR1 and DDR2, and thus can be used, singly or in combination, for prevention and treatment of diseases associated with aberrant cell growth which are caused by mutation or overexpression of RAS protein or overactivation of its protein kinase.
Son, Jung Beom, Suh, Kwee Hyun, Ahn, Young Gil, Bae, In Hwan, Han, Sang Mi, Kwak, Eun Joo, Kim, Ho Seok, Song, Ji Young, Byun, Eun Young, Jun, Seung Ah
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