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): wherein X 1 , R 1 , R 2 , R 2a , R 3 , R 3a , and R 3b are as described herein.
1. A method of treating a MEK-inhibitor responsive disorder, MEK-inhibitor responsive dermal disorder, MEK-mediated disorder, or a MEK-mediated dermal disorder comprising administering to a subject in need thereof, a therapeutically effective amount of 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 method of claim 1 , wherein the MEK-inhibitor responsive dermal disorder or a MEK-mediated dermal disorder is selected from the group consisting of a dermal rasopathy, a neurofibromatosis type 1, a cutaneous neurofibroma, a subdermal neurofibroma, and a superficial plexiform neurofibroma.
3. The method of claim 2 , wherein the dermal rasopathy is selected from the group consisting of psoriasis, keratocanthoma (KA), hyperkeratosis, papilloma, Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), Costello syndrome (faciocutaneoskeletal syndrome or FCS syndrome), oculoectodermal syndrome, cafe au lait spots, pyogenic granuloma, sebaceous gland hyperplasia, cutaneous neurofibromas, seborrheic keratosis, sebaceous hyperplasia, seborrheic keratosis, and Multiple lentigines syndrome (formerly called Leopard syndrome).
4. The method of claim 1 , wherein the compound is administered topically, subcutaneously, transdermally, intradermally, or intralesionally.
5. The method of claim 1 , wherein X 1 is —CH 3 .
6. The method 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.
7. The method of claim 1 , wherein R 3 and R 3b are each hydrogen and R 3a is methyl, fluoro, or methoxy.
8. The method of claim 1 , wherein R 3 , R 3a , and R 3b are hydrogen.
9. The method of claim 1 , wherein R 2 is —S—C 1 -C 6 alkyl.
10. The method of claim 9 , wherein R 2 is —SCH 3 .
11. The method of claim 1 , wherein R 2 is C 2 -C 6 alkynyl.
12. The method of claim 11 , wherein R 2 is C 2 -C 3 alkynyl.
13. The method of claim 1 , wherein R 2 is halo.
14. The method of claim 13 , wherein R 2 is iodo.
15. The method of claim 1 , wherein R 2a is C 1 -C 6 alkyl.
16. The method of claim 15 , wherein R 2a is methyl.
17. The method of claim 1 , wherein R 2a is halo.
18. The method of claim 17 , wherein R 2a is fluoro.
19. The method of claim 1 , wherein R 1 is —NR 5 R 5a and R 5 is C 1 -C 6 hydroxyalkyl.
20. The method of claim 1 , wherein R 1 is —NR 5 R 5a and R 5 is —OR 5b .
21. The method of claim 20 , wherein R 5b is C 3 -C 8 cycloalkyl-C 1 -C 6 -alkyl.
22. The method of claim 20 , wherein R 5b is cyclopropylmethyl.
23. The method of claim 20 , wherein R 5b is C 1 -C 6 hydroxyalkyl.
24. The method of claim 23 , wherein R 5b is an unbranched C 1 -C 6 hydroxyalkyl.
25. The method of claim 23 , wherein the C 1 -C 6 alkyl in C 1 -C 6 hydroxyalkyl is substituted with one hydroxy.
26. The method of claim 1 , wherein R 1 is —NR 5 R 5a and R 5a is hydrogen.
27. The method of claim 1 , wherein R 1 is —NH—O—CH 2 CH 2 OH.
28. The method of claim 1 , wherein R 1 is —NH—O—CH 2 (cyclopropyl).
29. The method of claim 1 , wherein the compound is selected from the group consisting of:
or a stereoisomer, mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof.
30. The method of claim 1 , wherein the compound is selected from the group consisting of:
31. The method of claim 1 , wherein the subject is a human.
32. The method of claim 31 , wherein the MEK-inhibitor responsive dermal disorder or a MEK-mediated dermal disorder is a neurofibromatosis type 1.
33. The method of claim 32 , wherein the compound is: