Pyrimidine compound
A novel and excellent method for preventing and/or treating diseases related to a cannabinoid type 2 receptor, based on an agonistic action on a cannabinoid type 2 receptor. It was found that a hetero ring derivative mainly having two substituents, for example, a pyrimidine-5-carboxamide derivative having a substituent amino group at the 2-position, exhibits a potent agonistic action on a cannabinoid type 2 receptor, and can be an agent for preventing and/or treating diseases related to a cannabinoid type 2 receptor such as inflammatory diseases, pain, and the like.
1. A compound of formula (I), or a salt thereof:
wherein
R 1 is lower alkyl, C 3-6 cycloalkyl, or halogeno-lower alkyl;
R 2 is —C(O)R 20 ;
W is —NH—;
R 3 is C 7-10 cycloalkyl which optionally has 1 to 5 substituents selected from the group consisting of lower alkyl, halogen, and —OH, on the ring;
each R 0 is the same as or different from each other, each representing H or lower alkyl;
R 20 is a nitrogen-containing saturated hetero ring group which optionally has 1 to 5 substituents selected from Group G 2 ;
Group G 2 is lower alkyl, halogen, halogeno-lower alkyl, —C(O)OR 0 , —C(O)N(R 0 ) 2 , —CN, —X—OR 0 , —O-lower alkylene-OR 0 , —O-halogeno-lower alkyl, —OC(O)-lower alkyl, —X—N(R 0 ) 2 , oxo, —X—C 3-6 cycloalkyl, —X—O—X—C 3-6 cycloalkyl, —X-phenyl, or —X-morpholinyl;
each X is the same as or different from each other, each representing a bond or lower alkylene.
2. The compound or a salt thereof as described in claim 1 , wherein R 1 is lower alkyl or C 3-6 cycloalkyl.
3. The compound or a salt thereof as described in claim 1 , wherein R 1 is halogeno-lower alkyl.
4. The compound or a salt thereof as described in claim 1 , wherein R 20 is 1-pyrrolidyl, 1-piperidyl, morpholin-4-yl, thiomorpholin-4-yl, or 1,1-dioxidothiomorpholin-4-yl, which optionally has 1 to 5 substituents selected from the group consisting of lower alkyl and halogen.
5. The compound or a salt thereof as described in claim 4 , wherein R 20 is morpholin-4-yl or 1,1-dioxidothiomorpholin-4-yl.
6. The compound or a salt thereof as described in claim 5 , wherein R 3 is C 7-10 cycloalkyl which optionally has 1 to 5 substituents selected from the group consisting of lower alkyl, halogen, and OH, on the ring and has a bridge.
7. The compound or a salt thereof as described in claim 1 , wherein said compound is selected from the group consisting of:
N-adamantan-1-yl-5-[(4,4-difluoropiperidin-1-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-amine,
rac-N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-4-isopropyl-5-(morpholin-4-ylcarbonyl)pyrimidin-2-amine,
rac-N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-4-cyclopropyl-5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]pyrimidin-2-amine,
rac-N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-4-tert-butyl-5-(morpholin-4-ylcarbonyl)pyrimidin-2-amine,
N-[(1S,2S,4R)-bicyclo[2.2.1]hept-2-yl]-4-isopropyl-5-(morpholin-4-ylcarbonyl)pyrimidin-2-amine,
N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-4-isopropyl-5-(morpholin-4-ylcarbonyl)pyrimidin-2-amine,
3-({5-[(3,3,4,4-tetrafluoropyrrolidin-1-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-yl}amino)adamantan-1-ol,
rac-N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-amine,
5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyrimidin-2-amine,
5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-N-(3,5,7-trifluoroadamantan-1-yl)-4-(trifluoromethyl)pyrimidin-2-amine,
N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-amine,
N-[(1S,2S,4R)-bicyclo[2.2.1]hept-2-yl]-5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-amine, and
N-bicyclo[2.2.2]oct-1-yl-5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-amine.
8. A pharmaceutical composition, comprising a compound or a salt thereof as described in claim 1 and a pharmaceutically acceptable excipient.
9. A pharmaceutical composition, comprising a compound or a salt thereof as described in claim 4 and a pharmaceutically acceptable excipient.
10. A pharmaceutical composition, comprising a compound or a salt thereof as described in claim 2 and a pharmaceutically acceptable excipient.
11. A pharmaceutical composition, comprising a compound or a salt thereof as described in claim 3 and a pharmaceutically acceptable excipient.
12. The compound according to claim 1 or a salt thereof, wherein said compound is rac-N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-4-isopropyl-5-(morpholin-4-ylcarbonyl)pyrimidin-2-amine.
13. The compound according to claim 1 or a salt thereof, wherein said compound is rac-N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-4-tert-butyl-5-(morpholin-4-ylcarbonyl)pyrimidin-2-amine.
14. The compound according to claim 1 or a salt thereof, wherein said compound is rac-N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-amine.
15. The compound according to claim 1 or a salt thereof, wherein said compound is 5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-N-(3,5,7-trifluoroadamantan-1-yl)-4-(trifluoromethyl)pyrimidin-2-amine.
16. The compound according to claim 1 or a salt thereof, wherein said compound is N-bicyclo[2.2.2]oct-1-yl-5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-amine.