Bicyclic heteroaromatic compounds useful as LH agonists
View Patent ↗The invention relates to a bicyclic heteroaromatic derivative compound according to general formula (II), or a pharmaceutically acceptable salt thereof. The compounds of the invention have LH receptor activating activity and can be used in fertility regulating therapies.
1. A bicyclic heteroaromatic compound of formula II, or a pharmaceutically acceptable salt thereof,
wherein
R 1 is (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted at the ortho and/or meta-position with one or more substituents selected from R 8 , (6-14C)aryl, (4-13C)heteroaryl, (2-7C)heterocycloalkyl, (3-8C)cycloalkyl, NRR 8 , OR 8 and/or SR 8 in which R 8 is (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, (1-8C)alkyl, (2-6C)alkenyl, (2-8C)alkynyl, the alkyl group of which may be optionally substituted with one or more substituents selected from hydroxyl, (1-8C)alkoxy, (2-7C)heterocycloalkyl((1-8C)alk)oxy, (3-8C)cycloalkyl((1-8C)alk)oxy, (6-14C)aryl((1-8C)alk)oxy, (4-13C)heteroaryl((1-8C)alk)oxy, (2-7C)heterocycloalkyl, (3-8C)cycloalkyl, (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkoxycarbonyl, (6-14C)aryloxycarbonyl, (1-8C)alkylcarbonyloxy, (6-14C)arylcarbonyloxy, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, amine, (1-8C)alkylaminocarbonyl, (6-14C)arylaminocarbonyl, (1-8C)alkylcarbonylamino, (6-14C)arylcarbonylamino, (6-14C)(di)arylamino and/or (1-8C)(di)alkylamino;
R 2 is (1-8C)alkyl, (2-8C)alkenyl or (2-8C)alkynyl, all optionally substituted with one or more substituents selected from (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, (1-8C)alkylcarbonyloxy, (6-14C)arylcarbonyloxy, (6-14C)aryloxycarbonyl and/or (1-8C)alkoxycarbonyl, or R 2 is (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted with one or more substituents selected from (1-8C)alkyl, (1-8C)alkylthio, (1-8C)(di)alkylamino, (1-8C)alkoxy, (2-8C)alkenyl, or (2-8C)alkynyl;
R 3 is (1-8C)alkyl, (2-8C)alkenyl or (2-8C)alkynyl, all optionally substituted with one or more substituents selected from hydroxyl, (1-8C)alkoxy, (6-14C)aryloxy, (3-8C)cycloalkyl((1-8C)alk)oxy, (2-7C)heterocycloalkyl((1-8C)alk)oxy, (6-14C)aryl((1-8C)alk)oxy, (4-13C)heteroaryl((1-8C)alk)oxy, (2-7C)heterocycloalkyl, (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkoxycarbonyl, (6-14C)aryloxycarbonyl (1-8C)alkylcarbonyloxy, (6-14C)arylcarbonyloxy, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, amine, (1-8C)alkylaminocarbonyl, (6-14C)arylaminocarbonyl, (1-8C)alkylcarbonylamino, (6-14C)arylcarbonylamino, (6-14C)(di)arylamino or (1-8C)(di)alkylamino, or R 3 is (3-8C)cycloalkyl, (2-7C)heterocycloalkyl, or (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted with one or more substituents selected from (1-8C)alkyl, (1-8C)(di)alkylamino or (1-8C)alkoxy;
B is N(H), O, or a bond and
Y═CH or N,
with the proviso that the compound is not ethyl 5-amino-2-ethoxycarbonylmethylthio-4-(pyridine-4-yl)-thieno[2,3-d]pyrimidine-6-carboxylate, 5-amino-6-(4-methylbenzoyl)-4-phenyl-2-[(4-methylphenyl)carbonylmethylthio]-thieno[2,3-d]pyrimidine, ethyl 5-amino-4-phenyl-2-ethoxycarbonylmethylthio-thieno[2,3-d]pyrimidine-6-carboxylate, methyl 5-amino-4-phenyl-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylate, ethyl 5-amino-4-phenyl-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylate, 6-acetyl-5-amino-4-phenyl-2-(2-oxopropylthio)-thieno[2,3-d]pyrimidine, 5-amino-6-benzoyl-4-phenyl-2-phenylcarbonylmethylthio-thieno[2,3-d]pyrimidine, 5-amino-6-(4-chlorobenzoyl)-4-phenyl-2-[(4-chlorophenyl)carbonylmethylthio]-thieno[2,3-d]pyrimidine, methyl 5-amino-4-(4-methoxyphenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylate, ethyl 5-amino-4-(4-methoxyphenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylate, methyl 5-amino-4-(4-chlorophenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylate, or ethyl 5-amino-4-(4-chlorophenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylate.
2. The compound according to claim 1 , wherein B is N(H) or O.
3. The compound according to claim 2 , wherein B is N(H).
4. The compound according to claim 1 , wherein R 3 is isopropyl or tert-butyl.
5. The compound according to claim 1 , wherein Y═N.
6. The compound according to claim 1 , wherein R 2 =(1-4C)alkyl.
7. A pharmaceutical composition comprising:
a bicyclic heteroaromatic compound or a pharmaceutically acceptable salt or solvate thereof,
wherein the bicyclic heteroaromatic compound is represented by Formula II,
wherein
R 1 is (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted at the ortho and/or meta-position with one or more substituents selected from R 8 , (6-14C)aryl, (4-13C)heteroaryl, (2-7C)heterocycloalkyl, (3-8C)cycloalkyl, NHR 8 , OR 8 and/or SR 8 in which R 8 is (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, (1-8C)alkyl, (2-6C)alkenyl, (2-8C)alkynyl, the alkyl group of which may be optionally substituted with one or more substituents selected from hydroxyl, (1-8C)alkoxy, (2-7C)heterocycloalkyl((1-8C)alk)oxy, (3-8C)cycloalkyl((1-8C)alk)oxy, (6-14C)aryl((1-8C)alk)oxy, (4-13C)heteroaryl((1-8C)alk)oxy, (2-7C)heterocycloalkyl, (3-8C)cycloalkyl, (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkoxycarbonyl, (6-14C)aryloxycarbonyl, (1-8C)alkylcarbonyloxy, (6-14C)arylcarbonyloxy, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, amine, (1-8C)alkylaminocarbonyl, (6-14C)arylaminocarbonyl, (1-8C)alkylcarbonylamino, (6-14C)arylcarbonylamino, (6-14C)(di)arylamino and/or (1-8C)(di)alkylamino;.
R 2 is (1-8C)alkyl, (2-8C)alkenyl or (2-8C)alkynyl, all optionally substituted with one or more substituents selected from (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, (1-8C)alkylcarbonyloxy, (6-14C)arylcarbonyloxy, (6-14C)aryloxycarbonyl and/or (1-8C)alkoxycarbonyl, or R 2 is (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted with one or more substituents selected from (1-8C)alkyl, (1-8C)alkylthio, (1-8C)(di)alkylamino, (1-8C)alkoxy, (2-8C)alkenyl, or (2-8C)alkynyl;
R 3 is (1-8C)alkyl, (2-8C)alkenyl or (2-8C)alkynyl, all optionally substituted with one or more substituents selected from hydroxyl, (1-8C)alkoxy, (6-14C)aryloxy, (3-8C)cycloalkyl((1-8C)alk)oxy, (2-7C)heterocycloalkyl((1-8C)alk)oxy, (6-14C)aryl((1-8C)alk)oxy, (4-13C)heteroaryl((1-8C)alk)oxy, (2-7C)heterocycloalkyl, (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkoxycarbonyl, (6-14C)aryloxycarbonyl (1-8C)alkylcarbonyloxy, (6-14C)arylcarbonyloxy, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, amine, (1-8C)alkylaminocarbonyl, (6-14C)arylaminocarbonyl, (1-8C)alkylcarbonylamino, (6-14C)arylcarbonylamino, (6-14C)(di)arylamino or (1-8C)(di)alkylamino, or R 3 is (3-8C)cycloalkyl, (2-7C)heterocycloalkyl, or (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted with one or more substituents selected from (1-8C)alkyl, (1-8C)(di)alkylamino or (1-8C)alkoxy;
B is N(H), O, or a bond and
Y═CH or N, and
pharmaceutically acceptable auxiliaries.