Compounds, compositions and methods for prevention and treatment of inflammatory and immunoregulatory disorders and diseases
View Patent ↗Compounds are provided having the formula: wherein variables R a , R 1 , R 2 , R 3 , R 4 , A 1 , A 4 , L, Q, X and subscript n as described herein. The subject compounds are useful for treatment of inflammatory and immune conditions and diseases. Compositions and methods of treatment using the subject compounds are also provided. For example, the subject methods are useful for treatment of inflammatory and immune disorders and disease such as multiple sclerosis, rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
1. A compound having the formula (I):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
A 1 is C(R b );
A 4 or N;
Q is a member selected from the group consisting of a bond, (C 1 -C 8 )alkylene, (C 2 -C 8 )heteroalkylene, —C(O)—, —OC(O)—, —CH 2 CO—, —CH 2 SO— and —CH 2 SO 2 —;
L is a bond or (C 1 -C 5 )alkylene;
X is —CH 2 —, or —C(O)—;
R a is selected from the group consisting of hydrogen, —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O) 2 R′, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —CN and —NO 2 ;
R b is selected from the group consisting of hydrogen, —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O) 2 R′, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —R′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —CN and —NO 2 ;
the subscript n is 0, 1 or 2:
each R′, R″ and R′″ independently is H, unsubstituted (C 1 -C 8 )alkyl, heteroalkyl, unsubstituted aryl, or substituted aryl;
R 1 is heteroaryl or aryl;
R 2 is a member selected from the group consisting of hydrogen, halogen, (C 1 -C 10 )alkyl, (C 2 -C 10 )heteroalkyl, hetero(C 1 -C 10 )cycloalkyl, (C 1 -C 10 )alkylaryl, and (C 2 -C 10 )heteroalkylaryl;
R 3 is a member selected from the group consisting of —S(O) m R 5 , —S(O) m N(R 8 )R 9 , —S(O) m N(R 8 )CH 2 R 6 , —N(R 8 )SO 2 R 5 ,
R 4 is a member selected from the group consisting of (C 1 -C 20 )alkyl, (C 2 -C 20 )heteroalkyl, heteroaryl, aryl, heteroaryl(C 1 -C 6 )alkyl, heteroaryl(C 2 -C 6 )heteroalkyl, aryl(C 1 -C 6 )alkyl and aryl(C 2 -C 6 )heteroalkyl;
R 5 is selected from the group consisting of (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, aryl and heteroaryl;
R 6 and R 7 independently are hydrogen, (C 1 -C 8 )alkyl or (C 2 -C 8 )heteroalkyl;
R 8 is hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, heteroaryl or aryl;
R 9 is (C 1 -C 8 )alkyl;
Z is CH or N;
X 1 is a bond, (C 1 -C 6 )alkylene or (C 1 -C 6 )heteroalkylene;
Y 1 is (C 1 -C 6 )alkylene; and
the subscript m is 0, 1 or 2.
2. The compound according to claim 1 , wherein R 3 is a member selected from the group consisting of —SO 2 CH 3 , —SO 2 CH 2 CH 3 ,
3. The compound according to claim 1 , having the formula (Ia):
or a pharmaceutically acceptable salt or prodrug thereof.
4. The compound of claim 3 , wherein X is —C(O)—.
5. The compound of claim 3 , wherein R 1 is a unsubstituted or a meta- or para-substituted phenyl, wherein the substituent is a halogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, (C 1 -C 8 )alkoxy, or (C 1 -C 8 )heteroalkoxy.
6. The compound of claim 3 , wherein R 2 is a member selected from the group consisting of
7. The compound of claim 3 , wherein Q is —C(O)—.
8. The compound of claim 3 , wherein L is a bond, —CH 2 — or —CH 2 CH 2 —.
9. The compound according to claim 3 , wherein -L-R 3 when taken together is
10. The compound of claim 3 , wherein -Q-R 4 is
11. The compound of claim 3 , wherein R 1 is para-cyanophenyl.
12. The compound of claim 3 having the formula (II):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 11 is hydrogen, (C 1 -C 8 )alkyl or (C 2 -C 8 )heteroalkyl.
13. The compound of claim 12 , wherein R 11 is —H, —CH 3 , —CH 2 CH 3 , or —CH 2 CF 3 .
14. The compound of claim 12 , wherein X is —C(O)—.
15. The compound of claim 12 , wherein R 2 is methyl and -L-R 3 is
16. The compound of claim 12 , wherein R 3 is a member selected from the group consisting of —SO 2 CH 3 , —SO 2 CH 2 CH 3 ,
17. The compound of claim 12 , wherein -Q-R 4 is
18. The compound of claim 17 , wherein R 3 is a member selected from the group consisting of —SO 2 CH 3 , —SO 2 CH 2 CH 3 ,
19. The compound of claim 1 , wherein the compound is selected from the group consisting of
20. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
21. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier, diluent or excipient.
22. A pharmaceutical composition comprising the compound of claim 3 and a pharmaceutically acceptable carrier, diluent or excipient.
23. A pharmaceutical composition comprising the compound of claim 19 and a pharmaceutically acceptable carrier, diluent or excipient.