Aminoacylindazole immunomodulators for treatment of autoimmune diseases

1. A compound of formula I or formula II:

wherein

R 1 is an optionally substituted bicyclic ring system chosen from an optionally substituted indole, isoindole, oxindole, tetrahydroindole, tetralin, indoline, isoindoline, tetrahydroquinoline, tetrahydroisoquinoline, 3,4-dihydro-1H-isochromene, 3,4-dihydro-2H-chromene, benzofuran, dihydrobenzofuran, tetrahydrobenzofuran, benzothiophene, tetrahydrobenzothiophene, indazole, tetrahydroindazole, 2,3-dihydro-1H-indene, naphthalene, tetrahydronaphthalene, and isochroman, said ring system attached to the carbonyl through a carbon, or, when R 2 is amino, R 1 may additionally be meta- or para-substituted phenyl or an optionally substituted monocyclic heteroaryl ring; wherein R 1 is optionally substituted with one or more of halogen, hydroxy, amino, cyano, (C 1 -C 8 )hydrocarbyl, (C 1 -C 8 )hydrocarbyloxy, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, (C 1 -C 4 )acylamino, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )fluoroalkyl, (C 1 -C 4 )fluoroalkoxy, (C 1 -C 6 )oxaalkyl, (C 3 -C 6 )carbocycle, and (C 1 -C 4 )alkenyl;

R 2 is chosen from hydrogen, amino and methyl; and

R 3 and R 4 are chosen independently from hydrogen, halogen, hydroxy, amino, cyano, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, (C 1 -C 7 )acylamino, ((C 1 -C 7 )hydrocarbyloxy)carbonylamino, (C 1 -C 4 )fluoroalkyl, (C 1 -C 4 )fluoroalkoxy, and (C 1 -C 6 )oxaalkyl, or, taken together, R 3 and R 4 on adjacent carbons form a double bond.

2. A compound according to claim 1 wherein R 1 is an optionally substituted bicyclic ring system.

3. A compound according to claim 2 wherein R 1 is optionally substituted indole, benzofuran, or benzothiophene.

4. A compound according to claim 1 wherein, when R 1 is substituted with one or more (C 1 -C 8 )hydrocarbyl, said (C 1 -C 8 )hydrocarbyl substituent is chosen from straight chain (C 1 -C 8 )alkyl, branched (C 1 -C 8 )alkyl, (C 3 -C 6 )cycloalkyl, and (C 3 -C 6 )cycloalkyl(C 1 -C 3 )alkyl.

5. The compound of claim 1 , wherein R 1 is

wherein

R 10 is —H, halogen, —O—(C 1 -C 8 )hydrocarbyl, or —(C 1 -C 8 )hydrocarbyl;

Y is chosen from S, O, NH, and N(C 1 -C 8 )hydrocarbyl; and

R 11 is —H, halogen, —(C 1 -C 8 )hydrocarbyl, or —O(C 1 -C 8 )hydrocarbyl.

6. The compound of claim 5 , wherein R 1 is

wherein

R 10 is chosen from —H, —(C 1 -C 4 )alkyl, and (C 3 -C 6 )cycloalkyl; and

R 11 is chosen from —H and —O(C 1 -C 4 )alkyl.

7. The compound of claim 1 , wherein R 1 is

wherein

R 13 is —H, halogen, —O—(C 1 -C 8 )hydrocarbyl, or —(C 1 -C 8 )hydrocarbyl; and

Y is chosen from S, O, NH, and N(C 1 -C 8 )hydrocarbyl.

8. The compound of claim 7 , wherein R 1 is

wherein

R 13 is chosen from —H, —(C 1 -C 4 )alkyl, and (C 3 -C 6 )cycloalkyl.

9. The compound of claim 1 , wherein R 1 is

wherein

Y is chosen from S, O, NH, and N(C 1 -C 8 )hydrocarbyl; and

R 12 is chosen from —H, —(C 1 -C 8 )hydrocarbyl and —O(C 1 -C 8 )hydrocarbyl.

10. The compound of claim 9 , wherein R 1 is

wherein R 12 is —H or (C 1 -C 4 )alkyl.

11. The compound of claim 1 , wherein R 1 is chosen from optionally substituted naphthalene, tetralin, tetrahydrobenzofuran, benzothiophene, tetrahydrobenzothiophene, tetrahydroindole, tetrahydroquinoline and 3,4-dihydro-1H-isochromene.

12. A compound according to claim 1 , wherein R 2 is —NH 2 .

13. A compound according to claim 12 of formula V

14. A compound according to claim 12 of formula III

15. A compound according to claim 1 , wherein R 3 and R 4 are chosen independently from hydrogen, halogen, hydroxy, amino, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, (C 1 -C 4 )acylamino, (C 1 -C 4 )fluoroalkyl, (C 1 -C 4 )fluoroalkoxy, and (C 1 -C 6 )oxaalkyl.

16. A compound according to claim 11 wherein R 1 is

and R 15 and R 16 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )fluoroalkyl, and (C 1 -C 4 )fluoroalkoxy.

17. A compound of at least 80% e.e. according to claim 1 of formula

wherein AB is an optionally substituted 6,5-5,6- or 6,6 bicycle in which ring A is non-aromatic and ring B is aromatic, wherein said 6,5-5,6- or 6,6 bicycle is optionally substituted with one or more of halogen, hydroxy, amino, cyano, (C 1 -C 8 )hydrocarbyl, (C 1 -C 8 )hydrocarbyloxy, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, (C 1 -C 4 )acylamino, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )fluoroalkyl, (C 1 -C 4 )fluoroalkoxy, (C 1 -C 6 )oxaalkyl, (C 3 -C 6 )carbocycle, and (C 1 -C 4 )alkenyl and the carbon at its point of attachment is of a single absolute configuration.

18. A method for treating autoimmune inflammatory diseases of the CNS in a patient, said method comprising administering to said patient a therapeutically effective amount of a compound according to claim 1 .