Pyrrolopyridine-aniline compounds for treatment of dermal disorders
Provided herein are compounds, pharmaceutical compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds and compositions in treating diseases or disorders in a subject where the subject is in need of an inhibitor of MEK where the Compound is according to Formula (I), where X 1 , R 1 , R 2 , R 2a , R 3 , R 3a , and R 3b are as described herein.
1. A compound of Formula (I):
or an N-oxide, a stereoisomer, mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof,
wherein
R 1 is —OR 4 , —NR 5 R 5a , or an N-linked heterocycloalkyl wherein the N-linked heterocycloalkyl is optionally substituted with one or two R 10 ;
R 2a is halo or C 1 -C 6 alkyl;
R 2 is —S—C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or halo;
X 1 is C 1 -C 6 alkyl;
R 3 , R 3a , and R 3b are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —S—C 1 -C 6 alkyl, halo, C 1 -C 6 alkoxy, C 3 -C 8 -cycloalkyloxy, heterocycloalkyloxy, heteroaryloxy, or phenoxy wherein each phenyl and heteroaryl is independently optionally substituted with 1, 2, or 3 R 6 ;
R 4 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 alkoxyalkyl;
R 5 is hydrogen; C 1 -C 6 alkyl optionally substituted with one heterocycloalkyl; C 3 -C 8 cycloalkyl; C 3 -C 8 cycloalkyl-C 1 -C 6 -alkyl-; C 1 -C 6 hydroxyalkyl; C 1 -C 6 alkoxy-C 1 -C 6 -alkyl; or —OR 5b ;
R 5a is hydrogen or C 1 -C 6 alkyl;
R 5b is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 alkoxy-C 1 -C 6 -alkyl;
each R 6 is independently selected from the group consisting of carboxy, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 3 -C 8 cycloalkyl, heterocycloalkyl, —OC(O)R 7 , —OS(O) 2 R 7 , —O—C 1 -C 6 -haloalkyl, C 3 -C 8 cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, amino, C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino, —NR 8a S(O) 2 R 8 , —NR 8a C(O)R 8 , —S(O) 2 R 8 , —S(O) 2 NR 8a R 8 , —C(O)R 8 , —C(O)NR 8a R 8 , and —C 1 -C 6 -alkylene-R 6a ;
each R 6a is independently selected from the group consisting of C 3 -C 8 cycloalkyl, heterocycloalkyl, —NH 2 , —NH(C 1 -C 6 -alkyl), —N(C 1 -C 6 -alkyl) 2 , —NR 9a S(O) 2 R 9 , —NR 9a C(O)R 9 , —S(O) 2 R 9 , —S(O) 2 NR 9a R 9 , —C(O)R 9 , and —C(O)NR 9a R 9 ;
each R 7 is independently selected from the group consisting of amino, C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 -alkoxy, heterocycloalkyl, aryl, and heteroaryl;
each R 8a and R 9a is independently H or C 1 -C 6 alkyl;
each R 8 and R 9 is independently C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, or heterocycloalkyl; and
each R 10 is independently hydrogen, halo, hydroxy, oxo, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 8 cycloalkyl, heterocycloalkyl, or heteroaryl.
2. The compound of claim 1 , wherein X 1 is —CH 3 .
3. The compound of claim 1 , wherein R 3 and R 3b are each hydrogen and R 3a is C 1 -C 6 alkyl, halo, or C 1 -C 6 alkoxy.
4. The compound of claim 1 , wherein R 3 and R 3b are each hydrogen and R 3a is methyl, fluoro, or methoxy.
5. The compound of claim 1 , wherein R 3 , R 3a , and R 3b are hydrogen.
6. The compound of claim 1 , wherein R 2 is —S—C 1 -C 6 alkyl.
7. The compound of claim 6 , wherein R 2 is —SCH 3 .
8. The compound of claim 1 , wherein R 2 is C 2 -C 6 alkynyl.
9. The compound of claim 8 , wherein R 2 is C 2 -C 3 alkynyl.
10. The compound of claim 1 , wherein R 2 is halo.
11. The compound of claim 10 , wherein R 2 is iodo.
12. The compound of claim 1 , wherein R 2a is C 1 -C 6 alkyl.
13. The Compound of claim 12 , wherein R 2a is methyl.
14. The compound of claim 1 , wherein R 2a is halo.
15. The Compound of claim 14 , where R 2a is fluoro.
16. The compound of claim 1 , wherein R 1 is —NR 5 R 5a and R 5 is C 1 -C 6 hydroxyalkyl.
17. The compound of claim 1 , wherein R 1 is —NR 5 R 5a and R 5 is —OR 5b .
18. The compound of claim 17 , wherein R 5b is C 3 -C 8 cycloalkyl-C 1 -C 6 -alkyl.
19. The compound of claim 17 , wherein R 5b is cyclopropylmethyl.
20. The compound of claim 17 , wherein R 5b is C 1 -C 6 hydroxyalkyl.
21. The compound of claim 20 , wherein R 5b is an unbranched C 1 -C 6 hydroxyalkyl.
22. The compound of claim 20 , wherein the C 1 -C 6 alkyl in C 1 -C 6 hydroxyalkyl is substituted with one hydroxy.
23. The compound of claim 1 , wherein R 1 is —NR 5 R 5a and R 5a is hydrogen.
24. The compound of claim 1 , wherein R 1 is —NH—O—CH 2 CH 2 OH.
25. The compound of claim 1 , wherein R 1 is —NH—O—CH 2 (cyclopropyl).
26. The compound of claim 1 , selected from the group consisting of:
or a stereoisomer, mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
28. The compound of claim 1 , selected from the group consisting of: