Substituted 3-amino-pyrrolidino-4-lactams
The invention provides compounds of formula (1), and the pharmaceutically acceptable salt thereof, wherein R 1 , n and R 2 are as described herein; compositions thereof; and uses thereof.
1. A compound having the formula
or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is independently selected from H or F;
n is 1 or 2;
R 2 is
wherein W is O, N or S and R 21 is halo, —(C 1 -C 6 )alkyl, or —(C 1 -C 6 )alkoxy, or R 2 is a heteroaryl, wherein said heteroaryl is optionally substituted with one R 3 and is optionally substituted with one to two R 4 ;
R 3 is heterocycloalkyl, heteroaryl, benzyl-O—, phenyl, phenyl-O—, phenyl-S— or phenyl-S(O) 2 O—, wherein R 3 is optionally, independently substituted independently with one to four hydroxy, cyano, halo, nitro, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )haloalkoxy, —(C 1 -C 6 )alkoxy, —NH(CO)(C 1 -C 6 )alkyl, —S(O) T (C 1 -C 6 )alkyl, —S(O) 2 —NR 5 R 6 , —NH(CO)(C 1 -C 6 )haloalkyl, oxo or R 7 -E-, wherein R 7 is phenyl or pyridinyl and E is —O— or a covalent bond and wherein said R 7 is optionally, independently substituted with —(C 1 -C 3 )alkyl, halo, cyano, OH or methoxy;
T is 0 or 2;
each R 4 is independently cyano, halo, nitro, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )haloalkyl, —(C 3 -C 6 )cycloalkyl, —(C 1 -C 6 )alkyl-CN, —OR 5 , —SR 5 , —OS(O) 2 R 5 or —NR 5 R 6 ; and
R 5 and R 6 are each independently hydrogen, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, or —(C 3 -C 6 )cycloalkyl.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 2.
3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is pyrimidinyl, quinazolinyl, triazinyl or phthalazinyl which is optionally substituted with one R 3 and optionally substituted with one to two R 4 .
4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 3 is pyrrolidinyl, piperidinyl, pyridinyl, phenyl, dihdyroisoindolinyl, dihydroisoquinolinyl, 6,7-dihydroisoxazolo[4,3-c]pyridin-5(4H)-yl, benzyl-O—, phenyl, phenyl-O—, phenyl-S—, phenyl-S(O) 2 O—, wherein R 3 is optionally substituted with one to four halo, —S(O) T (C 1 -C 6 )alkyl, —S(O) 2 —NR 5 R 6 or R 7 -E-.
5. A compound of claim 4 having the formula
or a pharmaceutically acceptable salt thereof, wherein
R 1 is H or F;
Q is —N—, —CH— or —CF—;
R 41 is H or —(C 1 -C 3 )alkyl, —(C 1 -C 3 )haloalkyl, —S—(C 1 -C 3 )alkyl or cyclopropyl;
Z is —CH 2 — or —(CH 2 ) 2 —; and
each R 8 , R 9 and R 10 is independently H or F.
6. A compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein Z is —CH 2 —.
7. A compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 are each F.
8. A compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 41 is H.
9. A compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is F.
10. A compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein Q is —N—.
11. 1-((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one or a pharmaceutically acceptable salt thereof.
12. A compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein Q is —CH—.
13. A pharmaceutical composition comprising:
(a) a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and
(b) a pharmaceutically acceptable carrier, vehicle, diluent or excipient.
14. A pharmaceutical composition of claim 13 , comprising
(a) a compound of claim 5 , or a pharmaceutically acceptable salt thereof; and
(b) a pharmaceutically acceptable carrier, vehicle, diluent or excipient.
15. A pharmaceutical composition comprising
(a) 1-((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one, or a pharmaceutically acceptable salt thereof; and
(b) a pharmaceutically acceptable carrier, vehicle, diluent or excipient.
16. A method of treating Type 2 diabetes in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
17. A method of claim 16 comprising administering to said mammal a therapeutically effective amount of a compound of claim 5 , or a pharmaceutically acceptable salt thereof.
18. A method of treating Type 2 diabetes in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of 1-((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one, or a pharmaceutically acceptable salt thereof.
19. The method of claim 18 wherein said mammal is a human.