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US 10,370,379 B2Granted
Compounds and compositions useful for treating disorders related to NTRK
AssigneeBlueprint Medicines Corporation
InventorsSteven Mark Wenglowsky, Chandrasekhar V. Miduturu, Neil Bifulco, Jr., Joseph L. Kim
Life of this patent
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Abstract
This disclosure relates to inhibitors of NTRK that are active against wild-type NTRK and its resistant mutants, such as compounds of Formula I:
Claims12
A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:
- Ring A is selected from cycloalkyl and heterocyclyl;
- each RA is independently selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, C1-C6 alkyl, C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, —N(R1)(R1), cyano, —C(O)R1, —OC(O)R1, —C(O)OR1, —SR1, —S(O)2R1, —S(O)2—N(R2)(R2), —(C1-C6 alkylene)—S(O)2—N(R2)(R2), —C(O)—N(R2)(R2), —N(R2)(R2)—C(O)R1, —(C1-C6 alkylene)—N(R2)—C(O)R1, —NR2S(O)2R1, —P(O)(R1)(R1), and —OR1, wherein:
- each of aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 heteroalkyl is independently substituted with 0-5 occurrences of Ra;
- and
- wherein at least one RA is halo;
- each RB is independently selected from halo;
- each R1 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Rb;
- each R2 is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 heteroalkyl;
- or 2 R2 together with the nitrogen to which they are attached form a heterocyclyl ring substituted with 0-5 occurrences of Rb;
- each Ra is independently selected from halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, —N(R″)(R″), —C(O)—N(R″)(R″), —N(R″)(R″)—C(O)R′, and —(C1-C6 alkylene)—N(R″)—C(O)R′;
- each Rb is independently selected from halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, —N(R″)(R″), —C(O)—N(R″)(R″), N(R″)(R″)—C(O)R′, and —(C1-C6 alkylene)-N(R″)—C(O)R′;
- each R′ is independently selected from hydrogen, C1-C6 alkyl and C1-C6 hydroxyalkyl;
- each R″ is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 hydroxyalkyl;
- m is 1, 2, 3, 4 or 5;
- and
- n is 0, 1 or 2.
13 more elements
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 RA is independently selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, C1-C6 alkyl, C1-C6 alkoxyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, —N(R1)(R1), cyano, —C(O)R1, —OC(O)R1, —C(O)OR1, —SR1, —S(O)2R1, —S(O)2—N(R2)(R2), —(C1-C6 alkylene)—S(O)2—N(R2)(R2), —C(O)—N(R2)(R2), —N(R2)(R2)—C(O)R1, —(C1-C6 alkylene)—N(R2)—C(O)R1, —NR2S(O)2R1, —P(O)(R1)(R1), and —OR1, wherein:
- each of aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 heteroalkyl is independently substituted with 0-5 occurrences of Ra;
- and
- wherein at least one RA is halo;
- each RB is independently selected from halo;
- each R1 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Rb;
- each R2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl;
- or 2 R2 together with the nitrogen to which they are attached form a heterocyclyl ring substituted with 0-5 occurrences of Rb;
- each Ra is independently selected from halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, —N(R″)(R″), —C(O)—N(R″)(R″), —N(R″)(R″)—C(O)R′, and —(C1-C6 alkylene)—N(R″)—C(O)R′;
- each Rb is independently selected from halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, —N(R″)(R″), —C(O)—N(R″)(R″), N(R″)(R″)—C(O)R′, and —(C1-C6 alkylene) —N(R″) —C(O)R′;
- each R′ is independently selected from hydrogen and C1-C6 alkyl or C1-C6 hydroxyalkyl;
- each R″ is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 hydroxyalkyl;
- m is 1, 2, 3, 4 or 5;
- and
- n is 0, 1 or 2.
13 more elements
A compound selected from
- and pharmaceutically acceptable salts thereof.
A compound selected from
- and pharmaceutically acceptable salts thereof.
A compound selected from
- and pharmaceutically acceptable salts thereof.
A compound selected from
- and pharmaceutically acceptable salts thereof.
A compound selected from
- and pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.