Substituted pyrrolopyridines as inhibitors of activin receptor-like kinase
Described herein are compounds that inhibit ALK2 and its mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
ring A is chosen from monocyclic aryl, monocyclic heteroaryl, quinolinyl, and bicyclic heterocyclyl, wherein only one ring of said bicyclic heterocyclyl is aromatic;
each R 1 is independently chosen from halo, cyano, oxo, C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkyl), —C(O)—O—(C 1 -C 4 alkyl), —C(O)—N(R 8 )—(C 1 -C 4 alkyl), —N(R 8 ) 2 , —N(R 8 )—C(O)—(C 1 -C 4 alkyl), —S(O) p —(C 1 -C 4 alkyl), —O—(C 1 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —O—(C 1 -C 4 alkylene)-N(R 8 ) 2 , —O—(C 1 -C 4 alkylene)-C(O)—N(R 8 ) 2 , —Si(R 9 )(C 1 -C 4 alkyl) 2 , C 3 -C 8 carbocyclyl, —C(O)—(C 3 -C 5 carbocyclyl), —O—(C 0 -C 4 alkylene)-(C 3 -C 8 carbocyclyl), —O—(C 0 -C 4 alkylene)-C(O)—(C 3 -C 5 carbocyclyl), —(C 0 -C 4 alkylene)-aryl, —O—(C 0 -C 4 alkylene)-aryl, heterocyclyl, —C(O)-heterocyclyl, —O—(C 0 -C 4 alkylene)-heterocyclyl, and —O—(C 0 -C 4 alkylene)-C(O)-heterocyclyl, wherein:
any said alkyl or said alkylene portion of R 1 is optionally substituted with one to five substituents independently chosen from halo, cyano, hydroxyl, and O—(C 1 -C 4 alkyl); and
any said carbocyclyl, said aryl, or said heterocyclyl portion of R 1 is optionally substituted with one to five substituents independently chosen from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, cyano, hydroxyl, —O—(C 1 -C 4 alkyl), heterocyclyl, —N(R 8 ) 2 , and —N(R 8 )—C(O)—O—(C 1 -C 4 alkyl);
R 2 is a bond or —O—;
R 3 is chosen from C 1 -C 6 alkyl, —(C 0 -C 6 alkylene)-(C 3 -C 8 carbocyclyl), and —(C 0 -C 6 alkylene)-(monocyclic —O— or S-containing heterocyclyl), wherein:
a carbon atom of said monocylic heterocyclyl is the attachment point for said monocylic heterocyclyl;
any said alkyl or said alkylene portion of R 3 is optionally substituted with one to five substituents independently chosen from halo, cyano, hydroxyl, C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —O—(C 3 -C 8 cycloalkyl), and —S(O) p —(C 1 -C 4 alkyl); and
any said carbocyclyl or said heterocyclyl portion of R 3 is optionally substituted with one to five substituents independently chosen from halo, cyano, oxo, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—(C 1 -C 4 —O—(C 1 -C 4 haloalkyl), —C(O)—(C 1 -C 4 alkyl), —C(O)—O—(C 1 -C 4 —S(O) p —(C 1 -C 4 alkyl), —O-phenyl, —(C 1 -C 4 alkyl)-phenyl, and morpholin-4-yl;
R 4 is chosen from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, —C(O)—(C 1 -C 4 alkyl), halo, and cyano, wherein:
any said alkyl portion of R 4 is optionally substituted with hydroxyl;
each R 8 is independently chosen from hydrogen and C 1 -C 4 alkyl, or two R 8 together with the nitrogen atom to which they are joined form a heterocyclyl;
each R 9 is independently chosen from hydrogen, C 1 -C 4 alkyl, and hydroxyl;
n is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from 6-membered monocyclic aryl, 5-membered heteroaryl, 6-membered monocyclic heteroaryl, 9-membered bicyclic heterocyclyl, and 10-membered bicyclic heterocyclyl.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from phenyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiophenyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from
wherein:
X is chosen from O, N, and S(O) p ;
Y is CH or N;
W is chosen from CH, N, S, and O;
Z is chosen from CH, NH, S, and 0; and
p is 0, 1, or 2.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from
wherein:
R 1B is chosen from hydrogen, halo, cyano, C 1 -C 4 alkyl, —O—(C 1 -C 4 —C(O)—(C 1 -C 4 alkyl), —C(O)—(C 3 -C 6 cycloalkyl), —C(O)—O—(C 1 -C 4 alkyl), —N(R 8 )—C(O)—(C 1 -C 4 —S(O) p —(C 1 -C 4 alkyl), C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclyl, wherein:
any said alkyl portion of R 1B is optionally substituted with one to five substituents independently chosen from halo and cyano;
any said cycloalkyl or said heterocyclyl portion of R 1B is optionally substituted with one to five substituents independently chosen from halo, —N(R 8 ) 2 , C 1 -C 4 alkyl, heterocyclyl, and C 1 -C 4 haloalkyl;
p is 0, 1, or 2; and
when R 18 is hydrogen, then n1 is 0, 1, 2, 3, 4, or 5 and, when R 18 is not hydrogen, then n1 is 0, 1, 2, 3, or 4.
6. The compound of claim 1 or a pharmaceutically acceptable salt, wherein ring A is chosen from
wherein:
R 18 is chosen from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, —(C 0 -C 4 alkylene)-aryl, heterocyclyl, and —S(O) p —(C 1 -C 4 alkyl), wherein:
any said alkyl portion of R 1B is optionally substituted with one to five substituents independently chosen from halo and cyano;
p is 0, 1, or 2;
each R 1 is independently chosen from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, halo, cyano, and —N(R 8 ) 2 , wherein:
any said alkyl portion of R 1B is optionally substituted with one to five substituents independently chosen from halo and cyano;
each R 8 is independently chosen from C 1 -C 4 alkyl; and
when R 18 is hydrogen, then n1 is 0, 1, 2, or 3, and, when R 18 is not hydrogen, then n1 is 0, 1, or 2.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from
wherein:
each R 1 is independently chosen from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, —O—(C 1 -C 4 alkyl), —C(O)-heterocyclyl, and cyano, wherein:
any said alkyl portion of R 1 is optionally substituted with one to five substituents independently chosen from halo, hydroxyl, and cyano.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from
wherein:
each R 1 is independently chosen from C 1 -C 4 alkyl optionally substituted with one to five substituents independently chosen from halo, hydroxyl, and cyano.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is chosen from
wherein:
each R 1 is independently chosen from C 1 -C 4 alkyl and cyano, wherein:
any said alkyl portion of R 1 is optionally substituted with one to five substituents independently chosen from halo, hydroxyl, and cyano.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently chosen from tetrahydropyranyl, tetrahydrofuranyl, 3,6-dihydro-2H-pyranyl, piperidinyl, piperazinyl, oxetanyl, cyano, C 1 -C 4 alkyl, —S(O)—(C 1 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkyl), —C(O)-heterocyclyl, —O—(C 1 -C 4 alkyl), halo, C 3 -C 6 cycloalkyl, —O—(C 3 -C 6 cycloalkyl), —N(CH 3 ) 2 , Si(CH 3 ) 2 OH, —NH—C(O)—CH 3 , —O—(C 0 -C 4 alkylene)-aryl, and morpholinyl, wherein
said piperidinyl is optionally substituted with one substituent chosen from morpholinyl, —O—(C 1 -C 4 alkyl), C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl or one or two substituents independently chosen from halo;
said tetrahydropyranyl or tetrahydrofuranyl is optionally substituted with one substituent chosen from hydroxyl and —O—(C 1 -C 4 alkyl);
said oxetanyl is optionally substituted with one substitutent chosen from C 1 -C 4 alkyl;
said piperazinyl is optionally substituted with one substituent chosen from C 1 -C 4 alkyl and halo;
any said cycloalkyl portion of R 1 is optionally substituted with one substituent chosen from cyano and hydroxyl;
any said alkyl portion of R 1 is optionally substituted with one to five substituents independently chosen from halo, cyano, hydroxyl, and —O—(C 1 -C 4 alkyl).
11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 3 is chosen from C 1 -C 6 alkyl, —(C 0 -C 3 alkylene)-(C 3 -C 6 carbocyclyl), and —(C 0 -C 3 alkylene)-(monocyclic 0- or S-heterocyclyl), wherein:
any said alkyl or said alkylene portion of R 3 is optionally substituted with one to five substituents independently chosen from halo, cyano, and hydroxyl; and
any said carbocyclyl or said heterocyclyl portion of R 3 is optionally substituted with one to four substituents independently chosen from halo, cyano, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—(C 1 -C 4 alkyl), —O—(C 1 -C 4 haloalkyl), —C(O)—(C 1 -C 4 alkyl), —C(O)—O—(C 1 -C 4 alkyl), —S(O) p —(C 1 -C 4 alkyl), —O-phenyl, —(C 1 -C 4 alkyl)-phenyl, and morpholin-4-yl.
12. A pharmaceutical composition comprising at least one compound chosen from the compounds of claim 1 and pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.
13. A method of inhibiting aberrant ALK2 activity in a subject in need thereof, the method comprising the step of administering to the subject a pharmaceutically effective amount of at least one compound chosen from the compounds of claim 1 and pharmaceutically acceptable salts thereof.
14. The method of claim 13 , wherein the aberrant ALK2 activity is caused by a mutation in an ALK2 gene that results in the expression of an ALK2 enzyme having at least one amino acid modification chosen from L196P, PF197-8L, R2021, R206H, Q207E, R258S, R258G, G328A, G328V, G328W, G328E, G328R, G356D, and R375P.
15. A compound chosen from any one of the following compounds
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 15 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 15 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 15 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
19. A compound chosen from any one of the following compounds:
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or a pharmaceutically acceptable salt thereof.