Naphthyridinone-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 R 1 , R 2 , R 2a , R 3 , R 3a , R 3b , and subscript n are as described herein.
1. A compound of formula (I):
or a stereoisomer, mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:
subscript n is an integer from 0 to 2;
bond “a” is a single or double bond;
R 1 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, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, amino-C 1 -C 6 alkyl, C 1 -C 6 alkylamino-C 1 -C 6 alkyl, di-(C 1 -C 6 alkyl) amino-C 1 -C 6 alkyl, heterocycloalkyl, heterocycloalkyl-C 1 -C 6 alkyl, R 5 —C(O)—C 1 -C 6 alkyl, or —OR 4 , wherein each of the C 3 -C 8 cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R 6 ;
R 2 is halo, C 1 -C 6 alkyl, —S—C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 2a is halo or C 1 -C 6 alkyl;
each R 3 is independently halo or C 1 -C 6 alkyl;
R 3a and R 3b are each independently hydrogen, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 4 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, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, amino-C 1 -C 6 alkyl, C 1 -C 6 alkylamino-C 1 -C 6 alkyl, di-(C 1 -C 6 alkyl) amino-C 1 -C 6 alkyl, heterocycloalkyl, heterocycloalkyl-C 1 -C 6 alkyl, or R 5 —C(O)—C 1 -C 6 alkyl, wherein each of the C 3 -C 8 cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R 6 ;
R 5 is hydroxy, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di-(C 1 -C 6 alkyl) amino, hydroxyamino, or N—C 1 -C 6 alkyl hydroxyamino; and
each R 6 is independently halo, hydroxy, oxo, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 haloalkyl, amino, C 1 -C 6 alkylamino, di-(C 1 -C 6 alkyl)amino, amino-C 1 -C 6 alkyl, C 1 -C 6 alkylamino-C 1 -C 6 alkyl, or di-(C 1 -C 6 alkyl)amino-C 1 -C 6 alkyl.
2. The compound of claim 1 , wherein the compound is formula (Ia):
3. The compound of claim 1 , wherein the compound is formula (Ib):
4. The compound of claim 1 , wherein subscript n is 0.
5. The compound of claim 1 , wherein R 3a and R 3b are each hydrogen.
6. The compound of claim 1 , wherein R 2 is halo.
7. The compound of claim 1 , wherein R 2 is iodo.
8. The compound of claim 1 , wherein R 2a is halo.
9. The compound of claim 1 , wherein R 2a is fluoro.
10. The compound of claim 1 , wherein
R 1 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, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, amino-C 1 -C 6 alkyl, C 1 -C 6 alkylamino-C 1 -C 6 alkyl, di-(C 1 -C 6 alkyl) amino-C 1 -C 6 alkyl, or heterocycloalkyl-C 1 -C 6 alkyl, wherein each of the C 3 -C 8 cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R 6 and each R 6 is independently hydroxy or C 1 -C 6 alkyl; or
R 1 is R 5 —C(O)—C 1 -C 6 alkyl and R 5 is hydroxy, C 1 -C 6 alkoxy, amino, or hydroxyamino.
11. The compound of claim 1 , wherein R 1 is C 1 -C 6 hydroxyalkyl.
12. The compound of claim 1 , wherein R 1 is —OR 4 and R 4 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, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, amino-C 1 -C 6 alkyl, C 1 -C 6 alkylamino-C 1 -C 6 alkyl, di-(C 1 -C 6 alkyl) amino-C 1 -C 6 alkyl, heterocycloalkyl, or heterocycloalkyl-C 1 -C 6 alkyl, wherein each of the C 3 -C 8 cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R 6 and each R 6 is independently hydroxy or C 1 -C 6 alkyl.
13. The compound of claim 1 , wherein R 1 is —OR 4 and R 4 is C 1 -C 6 hydroxyalkyl.
14. The compound of claim 1 , wherein R 1 is selected from the group consisting of hydrogen, —OH,
15. The compound of claim 1 , selected from the group consisting of:
or a stereoisomer, mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
17. A method of treating a MEK-inhibitor responsive dermal disorder in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of claim 1 , or a stereoisomer, mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, to the patient.
18. The method of claim 17 , wherein the MEK-inhibitor responsive dermal disorder is selected from the group consisting of dermal rasopathy, neurofibromatosis type 1, dermal neurofibroma, subdermal neurofibroma, and superficial plexiform neurofibroma.
19. The method of claim 18 , 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, and Multiple lentigines syndrome (formerly called Leopard syndrome).
20. The method of claim 17 , wherein the compound is administered topically, transdermally, or intralesionally.
21. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.