Substituted tetrahydrobenzothienopyrimidinamine compounds useful for treating hyper-proliferative disorders
View Patent ↗The present invention relates to a compound of Formula (I) and its use in treating lung and breast cancer.
1. A compound of formula
wherein
R is in each instance selected independently from H, (C 2 –C 6 )alkenyl, C(O)R 6 , hydroxy, NR 8-1 R 8-1 , and
or
R is (C 1 –C 6 )alkyl said alkyl being optionally mono-substituted with R 7 ,
with the proviso that when one R is H, the other R must be other than H or methyl, and with the further proviso that when one R is hydroxy, the other R must be other than hydroxy;
R 1 is selected from H, OH, halo, CN, NH 2 , CF 3 , OCF 3 , (C 1 –C 3 )alkyl, (C 2 –C 3 )alkynyl, and (C 1 –C 3 )alkoxy;
R 2 is selected from H, OH, halo, NH 2 , CN, CF 3 , OCF 3 , (C 1 –C 3 )alkyl, (C 2 –C 6 )alkynyl, (C 1 –C 3 )alkoxy,
(C 1 –C 3 )alkoxy-phenyl where said phenyl is optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH, and
(C 1 –C 3 )alkoxy-pyridyl, where said pyridyl is optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH,
O-phenyl optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH;
O-pyridyl optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH;
R 3 is selected from H, OH, halo, NH 2 , CN, CF 3 , OCF 3 , (C 1 –C 3 )alkyl, (C 2 –C 6 )alkynyl, (C 1 –C 3 )alkoxy,
(C 1 –C 3 )alkoxy-phenyl where said phenyl is optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH,
(C 1 –C 3 )alkoxy-pyridyl, where said pyridyl is optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH,
O-phenyl optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH,
O-pyridyl optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH;
or
R 2 and R 3 together with the carbon atoms to which they are attached form a pyrazole, where said pyrazole is optionally substituted with 1 or 2 substituents each selected independently from methyl, ethyl and benzyl or pyridylmethyl, wherein benzyl and pyridylmethyl can optionally be substituted with 1 or 2 substituents each selected independently from methyl, halo, cyano and methoxy;
R 4 is selected from H, OH, halo, CN, CF 3 , OCF 3 , NH 2 , (C 1 –C 3 )alkyl, (C 2 –C 6 )alkynyl, (C 1 –C 3 )alkoxy, trifluoromethyl, trifluoromethoxy,
(C 1 –C 3 )alkoxy-phenyl where said phenyl is optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH, and
(C 1 –C 3 )alkoxy-pyridyl, where said pyridyl is optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl,
(C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH,
O-phenyl optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH;
O-pyridyl optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH;
or
R 5 is selected from H, OH, halo, CN, CF 3 , OCF 3 , NH 2 , (C 1 –C 3 )alkyl, (C 2 –C 3 )alkynyl, and (C 1 –C 3 )alkoxy;
R 6 is selected from OH, (C 1 –C 6 )alkyl, (C 1 –C 3 )alkoxy, phenyl, pyridyl, NR 8 R 8 ,
NH(C 2 –C 6 )alkenyl, and
a five membered heterocycle optionally substituted with a substituent selected from OH, N[(C 1 –C 3 )alkyl] 2 , and (C 1 –C 3 )alkyl, said alkyl being optionally substituted with a substituent selected from OH, (C 1 –C 3 )alkoxy, and
R 7 is selected from OH, halo, (C 1 –C 4 )alkoxy, phenoxy optionally substituted with halo or amino, C(O)R 6 , halo, NR 8 R 8 , imidazolyl, phenyl, indazolyl, aminoindazolyl, —OS(O) 2 (C 1 –C 3 ),
NHC(O)NR 8 R 8 , NHS(O) 2 R 9 , NHC(O)-pyrrolidinyl,
NHC(O)-morpholinyl, and
pyrrolidinyl optionally substituted with one or two substituents selected from hydroxy, (C 1 –C 3 )alkoxy, N[(C 1 –C 3 )alkyl] 2 , and (C 1 –C 3 )alkyl optionally mono -substituted with hydroxy or (C 1 –C 3 )alkoxy;
R 8 is in each instance selected independently from H, pyridyl,
(C 1 –C 4 )alkyl optionally mono-substituted with hydroxy, (C 1 –C 3 )alkoxy, —S(O) 2 (C 1 –C 3 )alkyl, NR 10 R 10 , or
and
phenyl optionally substituted with 1, 2, or 3 substituents each independently selected from CN, OH, halo, CF 3 , NR 10 R 10 and (C 1 –C 3 )alkoxy, or
wherein n is a number from 1 to 5 and R 10 is selected from H and (C 1 –C 3 )alkyl;
R 8-1 is in each instance selected independently from H, and
(C 1 –C 4 )alkyl optionally mono-substituted with (C 1 –C 3 )alkoxy, NR 10 R 10 , or
R 9 is selected from (C 1 –C 3 )alkyl, pyridyl, thienyl, and phenyl where said phenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, CN, OH, halo, CF 3 , and NR 8 R 8 ;
R 10 is selected from H and (C 1 –C 3 )alkyl;
Z is selected from CH 2 , O, S, SO, SO 2 , and NH, and
when Z is NH, H is optionally replaced with pyridyl,
(C 1 –C 3 )alkyl optionally substituted with a substituent selected from hydroxy, (C 1 –C 3 )alkoxy and pyridyl, or
phenyl optionally substituted with 1, 2, or 3 substituents each independently selected from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, CN, halo, CF 3 , and NR 8 R 8 ;
Z 1 is selected from CH 2 , O, S, SO, SO 2 , and NH, and
when Z 1 is NH, H is optionally replaced with pyridyl,
(C 1 –C 3 )alkyl optionally substituted with a substituent selected from hydroxy, (C 1 –C 3 )alkoxy and pyridyl, or
phenyl optionally substituted with 1, 2, or 3 substituents each independently selected from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, CN, halo, CF 3 , and NR 8 R 8 ;
or a pharmaceutically acceptable salt or ester thereof, excluding the following compounds:
5,6,7,8-tetrahydro-7-methyl-N-[4-(phenylmethoxy)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine, monohydrochloride;
5,6,7,8-tetrahydro-N-(4-methoxyphenyl)-7-methyl-[1]benzothieno[2,3-]pyrimidin-4-amine, monohydrochloride;
5,6,7,8-tetrahydro-7-methyl-N-[3-(trifluoromethyl)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine;
N-(3,4-dimethylphenyl)-5,6,7,8-tetrahydro-7-methyl [1]benzothieno-[2,3-d]pyrimidin-4-amine.
2. The compound of claim 1 , wherein
R is selected independently from hydrogen and C(O)R 6 , or
R is (C 1 –C 6 )alkyl said alkyl being optionally mono-substituted with R 7 ;
with the proviso that when one R is H, the other R must be other than H or methyl;
R 1 is selected from H, OH, halo, CN, NH 2 , CF 3 , methyl, ethyl, ethynyl, methoxy, and ethoxy;
R 2 is selected from H, OH, halo, NH 2 , CN, CF 3 , (C 1 –C 3 )alkyl, (C 2 –C 6 )alkynyl, (C 1 –C 3 )alkoxy,
(C 1 –C 3 )alkoxy-phenyl where said phenyl is optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH, and
(C 1 –C 3 )alkoxy-pyridyl, where said pyridyl is optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH,
O-phenyl optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH;
R 3 is selected from H, OH, halo, NH 2 , CN, CF 3 , (C 1 –C 3 )alkyl, (C 2 –C 6 )alkynyl, (C 1 –C 3 )alkoxy,
(C 1 –C 3 )alkoxy-phenyl where said phenyl is optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH,
(C 1 –C 3 )alkoxy-pyridyl, where said pyridyl is optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH,
O-phenyl optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH,
O-pyridyl optionally substituted with 1, 2 or 3 substituents each selected independently from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, halo, CF 3 , CN, and OH; or
R 2 and R 3 together with the carbon atoms to which they are attached form a pyrazole, where said pyrazole is optionally N-substituted with 1 substituent selected from methyl, ethyl and benzyl;
R 4 is H;
R 5 is H;
R 5 is selected from NR 8 R 8 ,
NH(C 2 –C 6 )alkenyl, and
a five membered heterocycle optionally substituted with a substituent selected from OH, N[(C 1 –C 3 )alkyl] 2 , and (C 1 –C 3 )alkyl, said alkyl being optionally substituted with a substituent selected from OH, (C 1 –C 3 )alkoxy, and
R 7 is selected from phenoxy optionally substituted with halo or amino, NR 8 R 8 , imidazolyl, indazolyl, aminoindazolyl,
NHC(O)NR 8 R 8 , NHS(O) 2 R 9 , NHC(O)-pyrrolidinyl,
NHC(O)-morpholinyl, and
pyrrolidinyl optionally substituted with one substituent selected from (C 1 –C 3 )alkoxy, N[(C 1 –C 3 )alkyl] 2 , and (C 1 –C 3 )alkyl optionally mono-substituted with (C 1 –C 3 )alkoxy;
R 8 is in each instance selected independently from H, pyridyl,
(C 1 –C 4 )alkyl optionally mono-substituted with (C 1 –C 3 )alkoxy, —S(O(C 1 –C 3 )alkyl, NR 10 R 10 , or
and
phenyl optionally substituted with 1, 2, or 3 substituents each independently selected from CN, OH, halo, CF 3 , NR 10 R 10 and (C 1 –C 3 )alkoxy;
R 9 is selected from (C 1 –C 3 )alkyl, pyridyl, thienyl, and phenyl where said phenyl is optionally substituted with 1, 2, or 3 substituents each independently selected from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, CN, OH, halo, CF 3 , and NR 8 R 8 ;
R 10 is selected from H and (C 1 –C 3 )alkyl;
Z is selected from CH 2 , O, S and NH, and
when Z is NH, H is optionally replaced with pyridyl,
(C 1 –C 3 )alkyl optionally substituted with a substituent selected from hydroxy, (C 1 –C 3 )alkoxy and pyridyl, or
phenyl optionally substituted with 1, 2, or 3 substituents each independently selected from (C 1 –C 3 )alkyl, (C 1 –C 3 )alkoxy, CN, halo, CF 3 , and NR 8 R 8 ;
or a pharmaceutically acceptable salt or ester thereof, excluding the following compounds:
5,6,7,8-tetrahydro-7-methyl-N-[4-phenylmethoxy)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine, monohydrochloride;
5,6,7,8-tetrahydro-N-(4-methoxyphenyl)-7-methyl-[1]benzothieno[2,3-d]pyrimidin-4-amine, monohydrochloride;
5,6,7,8-tetrahydro-7-methyl-N-[3-(trifluoromethyl)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine;
N-(3,4-dimethylphenyl)-5,6,7,8-tetrahydro-7-methyl [1]benzothieno-[2,3-d]pyrimidin-4-amine.
3. A process for preparing a compound according to claim 1 , wherein a compound of formula (II)
wherein R has the meaning indicated in claim 1 ,
is reacted with a compound of formula (III)
wherein R 1 to R 5 have the meaning indicated in claim 1 .
4. A pharmaceutical composition comprising a compound according to claim 1 .
5. A pharmaceutical composition comprising a compound of claim 1 in combination with at least one pharmaceutically acceptable, pharmaceutically safe carrier or excipient.
6. A process for preparing a pharmaceutical composition according to claim 5 , comprising combining at least one compound according to claim 1 with at least one pharmaceutically acceptable, pharmaceutically safe carrier or excipient.
7. A method of treating lung or breast cancer in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of formula (I).