Compounds and compositions useful for treating disorders related to NTRK

Inventors: Steven Mark Wenglowsky (Cambridge, MA); Natasja Brooijmans (Boston, MA); Chandrasekhar V. Miduturu (Cambridge, MA); Neil Bifulco, Jr. (Sudbury, MA)

C07D487/04 A61K31/519 A61P35/02 A61P35/04

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Quick Facts

Patent No.: US 11,046,697
App. No.: 16/027,166
Granted: Jun 29, 2021
Kind: B2

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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):

Claims (39)

1. A method for treating a patient suffering from a tumor by inhibiting neurotrophic tyrosine receptor kinase (NTRK) activity, the method comprising administering to the patient a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is selected from aryl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocyclyl;

Ring B is selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl;

L 1 is selected from —C(O)—, —N(R 1 )—, —N(R 1 )—C(O)-†, —C(O)—N(R 1 )-†, -(C 1 -C 6 alkylene)-N(R 1 )-†, —N(R 1 )—(C 1 -C 6 alkylene)-†, —N(R 1 )—C(O)-(C 1 -C 6 alkylene)-†, and —C(O)—N(R 1 )—(C 1 -C 6 alkylene)-†, wherein “t” represents a portion of L 1 bound to ring A and each alkylene portion of L 1 is independently substituted with 0-5 occurrences of R′;

L 2 is selected from —C(O)—, —C(O)—N(R 1 )-*, —N(R 1 )—C(O)-(C 1 -C 6 alkylene)-*, and —C(O)—N(R 1 )—(C 1 -C 6 alkylene)-*, wherein “*” represents a portion of L 2 bound to ring B and each alkylene portion of L 2 is independently substituted with 0-5 occurrences of R′;

each R A is independently selected from hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, halo, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, —C(O)R 1 , —OC(O)R 1 , —C(O)OR 1 , -(C 1 -C 6 alkylene)-C(O)R 1 , —SR 1 , —S(O) 2 R 1 , —S(O) 2 -N(R 1 )(R 1 ), -(C 1 -C 6 alkylene)-S(O) 2 R 1 , —(C 1 -C 6 alkylene)-S(O) 2 -N(R 1 )(R 1 ), —N(R 1 )(R 1 ), —C(O)—N(R 1 )(R 1 ), —N(R 1 )—C(O)R 1 , —N(R 1 )—C(O)OR 1 , —(C 1 -C 6 alkylene)-N(R 1 )—C(O)R 1 , —N(R 1 )S(O) 2 R 1 , and —P(O)(R 1 )(R 1 ), wherein each alkyl, alkenyl, alkynyl, alkoxyl, heteroalkyl, haloalkyl, haloalkoxyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl portion of each R A is independently substituted with 0-5 occurrences of R a , or 2 R A together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of R a ;

each R B is independently selected from oxo, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, halo, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, —C(O)R 1 , —OC(O)R 1 , —C(O)OR 1 , —(C 1 -C 6 alkylene)-C(O)R 1 , —SR 1 , —S(O) 2 R 1 , —S(O) 2 -N(R 1 )(R 1 ), —(C 1 -C 6 alkylene)-S(O) 2 R 1 , —(C 1 -C 6 alkylene)-S(O) 2 -N(R 1 )(R 1 ), —N(R 1 )(R 1 ), —C(O)—N(R 1 )(R 1 ), —N(R 1 )—C(O)R 1 , —N(R 1 )—C(O)OR 1 , —(C 1 -C 6 alkylene)-N(R 1 )—C(O)R 1 , —N(R 1 )S(O) 2 R 1 , and —P(O)(R 1 )(R 1 ), wherein each alkyl, alkenyl, alkynyl, alkoxyl, heteroalkyl, haloalkyl, haloalkoxyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl portion of each R B is independently substituted with 0-5 occurrences of R a , or 2 R B together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of R a ;

each R 1 is independently selected from hydrogen, hydroxyl, halo, thiol, C 1 -C 6 alkyl, C 1 -C 6 thioalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each alkyl, thioalkyl, alkoxyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl portion of R 1 is independently substituted with 0-5 occurrences of R b , or 2 R 1 together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of R b ;

each R a and R b is independently selected from C 1 -C 6 alkyl, halo, hydroxyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyl, cycloalkyl, heterocyclyl, and cyano, wherein each alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxyl, cycloalkyl, and heterocyclyl portion of R a and R b is independently substituted with 0-5 occurrences of R′;

each R′ is independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, hydroxyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl and cyano; or 2 R′ together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring; and

p is 0, 1, 2, 3, 4, or 5; and

q is 0, 1, 2, 3, or 4.

2. The method of claim 1 , wherein the compound is a compound of Formula (Ia):