Compounds and compositions useful for treating disorders related to NTRK
This disclosure relates to inhibitors of NTRK that are active against wild-type NTRK and its resistant mutants, such as compounds of Formula I:
1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:
Ring A is selected from cycloalkyl and heterocyclyl;
each R A is independently selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, —N(R 1 )(R 1 ), cyano, —C(O)R 1 , —OC(O)R 1 , —C(O)OR 1 , —SR 1 , —S(O) 2 R 1 , —S(O) 2 —N(R 2 )(R 2 ), —(C 1 -C 6 alkylene)—S(O) 2 —N(R 2 )(R 2 ), —C(O)—N(R 2 )(R 2 ), —N(R 2 )(R 2 )—C(O)R 1 , —(C 1 -C 6 alkylene)—N(R 2 )—C(O)R 1 , —NR 2 S(O) 2 R 1 , —P(O)(R 1 )(R 1 ), and —OR 1 , wherein:
each of aryl, heteroaryl, cycloalkyl, heterocyclyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, and C 1 -C 6 heteroalkyl is independently substituted with 0-5 occurrences of R a ; and
wherein at least one R A is halo;
each R B is independently selected from halo;
each R 1 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R b ;
each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 heteroalkyl; or 2 R 2 together with the nitrogen to which they are attached form a heterocyclyl ring substituted with 0-5 occurrences of R b ;
each R a is independently selected from halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, —N(R″)(R″), —C(O)—N(R″)(R″), —N(R″)(R″)—C(O)R′, and —(C 1 -C 6 alkylene)—N(R″)—C(O)R′;
each R b is independently selected from halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, —N(R″)(R″), —C(O)—N(R″)(R″), N(R″)(R″)—C(O)R′, and —(C 1 -C 6 alkylene)-N(R″)—C(O)R′;
each R′ is independently selected from hydrogen, C 1 -C 6 alkyl and C 1 -C 6 hydroxyalkyl;
each R″ is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 hydroxyalkyl;
m is 1, 2, 3, 4 or 5; and
n is 0, 1 or 2.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having Formula (Ia-1):
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having Formula (Ib):
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein one R A is halo and one R A is monocyclic or bicyclic arl or monocyclic or bicyclic heteroaryl.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the compounds in the table below:
Compound
Number
Structure
1
2
3
4
6
7
8
9
10
11
12
13
15
17
18
6. A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein:
Ring A is selected from cycloalkyl and heterocyclyl;
each R A is independently selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, —N(R 1 )(R 1 ), cyano, —C(O)R 1 , —OC(O)R 1 , —C(O)OR 1 , —SR 1 , —S(O) 2 R 1 , —S(O) 2 —N(R 2 )(R 2 ), —(C 1 -C 6 alkylene)—S(O) 2 —N(R 2 )(R 2 ), —C(O)—N(R 2 )(R 2 ), —N(R 2 )(R 2 )—C(O)R 1 , —(C 1 -C 6 alkylene)—N(R 2 )—C(O)R 1 , —NR 2 S(O) 2 R 1 , —P(O)(R 1 )(R 1 ), and —OR 1 , wherein:
each of aryl, heteroaryl, cycloalkyl, heterocyclyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, and C 1 -C 6 heteroalkyl is independently substituted with 0-5 occurrences of R a ; and
wherein at least one R A is halo;
each R B is independently selected from halo;
each R 1 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R b ;
each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl; or 2 R 2 together with the nitrogen to which they are attached form a heterocyclyl ring substituted with 0-5 occurrences of R b ;
each R a is independently selected from halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, —N(R″)(R″), —C(O)—N(R″)(R″), —N(R″)(R″)—C(O)R′, and —(C 1 -C 6 alkylene)—N(R″)—C(O)R′;
each R b is independently selected from halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, —N(R″)(R″), —C(O)—N(R″)(R″), N(R″)(R″)—C(O)R′, and —(C 1 -C 6 alkylene) —N(R″) —C(O)R′;
each R′ is independently selected from hydrogen and C 1 -C 6 alkyl or C 1 -C 6 hydroxyalkyl;
each R″ is independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 hydroxyalkyl;
m is 1, 2, 3, 4 or 5; and
n is 0, 1 or 2.
7. A compound selected from
and pharmaceutically acceptable salts thereof.
8. A compound selected from
and pharmaceutically acceptable salts thereof.
9. A compound selected from
and pharmaceutically acceptable salts thereof.
10. A compound selected from
and pharmaceutically acceptable salts thereof.
11. A compound selected from
and pharmaceutically acceptable salts thereof.
12. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein each R A is independently selected from halo.