Sulfonamide and sulfinamide prodrugs of fumarates and their use in treating various diseases
The present invention provides compounds and pharmaceutical compositions for treating neurological diseases such as multiple sclerosis.
1. A pharmaceutical composition comprising:
(i) a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is C 1 -C 6 alkyl;
L a is C 1 -C 6 alkyl, C 3 -C 10 carbocycle, C 6 -C 10 aryl, heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, wherein the alkyl, carbocycle, aryl, heterocycle, or heteroaryl groups are optionally, independently substituted one or more times with halogen;
R 2 is C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OH, C 6 -C 10 aryl, C 3 -C 10 carbocycle, heterocycle comprising one or two member 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, wherein the alkyl, alkenyl, alkynyl, aryl, carbocycle, heterocycle, or heteroaryl groups are optionally, independently substituted one or more times with C 1 -C 6 alkyl, OH, O(C 1 -C 6 alkyl), oxo, halogen, NH 2 , N(H)(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , SO 2 H, SO 2 (C 1 -C 6 alkyl), CHO, CO 2 H, CO 2 (C 1 -C 6 alkyl), or CN;
R 3 is H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, SO 2 R 4 , or S(O)R 4 , wherein the alkyl, alkenyl, or alkynyl groups are optionally, independently substituted one or more times with C 1 -C 6 alkyl, OH, O(C 1 -C 6 alkyl), oxo, halogen, NH 2 , N(H)(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , SO 2 H, SO 2 (C 1 -C 6 alkyl), CHO, CO 2 H, CO 2 (C 1 -C 6 alkyl), or CN;
R 4 is C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OH, C 6 -C 10 aryl, C 3 -C 10 carbocycle, heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, wherein the alkyl, alkenyl, alkynyl, aryl, carbocycle, heterocycle, or heteroaryl groups are optionally, independently substituted one or more times with C 1 -C 6 alkyl, OH, O(C 1 -C 6 alkyl), oxo, halogen, NH 2 , N(H)(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , SO 2 H, SO 2 (C 1 -C 6 alkyl), CHO, CO 2 H, CO 2 (C 1 -C 6 alkyl), or CN;
or alternatively, R 2 and R 3 , together with the atoms to which they are attached, form a cyclic moiety comprising one or two 5- or 6-membered rings, and optionally further comprising 1-5 additional heteroatoms selected from N, O and S, wherein the rings can be optionally substituted with oxo; and
n is 1 or 2; and
(ii) a pharmaceutically acceptable carrier or excipient.
2. A pharmaceutical composition comprising:
(i) a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is C 1 -C 6 alkyl;
L a is a C 1 -C 6 alkyl;
R 2 is C 1 -C 10 alkyl optionally substituted by halo, or C 6 -C 10 aryl optionally substituted by C 1 -C 10 alkyl, OH, O(C 1 -C 6 alkyl), or halo;
R 3 is H, C 1 -C 10 alkyl, SO 2 R 4 , or S(O)R 4 ;
R 4 is C 1 -C 10 alkyl optionally substituted by halo, or C 6 -C 10 aryl optionally substituted by C 1 -C 10 alkyl;
or alternatively, R 2 and R 3 , together with the atoms to which they are attached, form a cyclic moiety comprising one or two 5- or 6-membered rings, and optionally further comprising 1-5 additional heteroatoms selected from N, O and S, wherein the rings can be optionally substituted with oxo; and
n is 1 or 2; and
(ii) a pharmaceutically acceptable carrier or excipient.
3. The pharmaceutical composition of claim 1 , wherein R 1 is methyl.
4. The pharmaceutical composition of claim 2 , wherein R 1 is methyl.
5. The pharmaceutical composition of claim 1 , wherein R 2 is C 1 -C 10 alkyl, or phenyl optionally substituted one or more times with C 1 -C 6 alkyl, OH, or O(C 1 -C 6 alkyl).
6. The pharmaceutical composition of claim 1 , wherein R 3 is H or C 1 -C 10 alkyl.
7. The pharmaceutical composition of claim 1 , wherein R 2 and R 3 , together with the atoms to which they are attached, form a cyclic moiety comprising one or two 5- or 6-membered rings, and optionally further comprising 1-5 additional heteroatoms selected from N, O and S, wherein the rings can be optionally substituted with oxo.
8. The pharmaceutical composition of claim 1 , wherein R 4 is C 1 -C 10 alkyl optionally substituted by halo, or C 6 -C 10 aryl optionally substituted by C 1 -C 6 alkyl.
9. The pharmaceutical composition of claim 1 , wherein L a is a C 1 -C 6 alkyl.
10. The pharmaceutical composition of claim 4 , wherein R 2 is C 1 -C 10 alkyl and R 3 is H or C 1 -C 10 alkyl.
11. The pharmaceutical composition of claim 2 , wherein the compound of Formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
12. The pharmaceutical composition of claim 11 , wherein the compound of Formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13. The pharmaceutical composition of claim 12 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
14. The pharmaceutical composition of claim 12 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
15. The pharmaceutical composition of claim 12 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.