Compounds and compositions useful for treating disorders related to ntrk

Patent metadata

Field	Value
Publication number	US-2017145018-A1
Application number	US-201615355425-A
Country	US
Kind code	A1
Filing date	Nov 18, 2016
Priority date	Nov 19, 2015
Publication date	May 25, 2017
Grant date	—

Abstract

This invention relates to inhibitors of NTRK that are active against wild-type NTRK and its resistant mutants.

First claim

We claim:

1 . A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein:

Ring A is selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, 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 ), nitro, 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, alkyl, alkoxyl, haloalkyl, hydroxyalkyl, heteroalkyl is independently substituted with 0-5 occurrences of R a ;
each R B is independently selected from 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 ), nitro, cyano, and —OR 1 ;
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 and 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′ and R″ is independently selected from hydrogen and C 1 -C 6 alkyl or C 1 -C 6 hydroxyalkyl;
m is 0, 1, 2, 3, 4 or 5; and
n is 0, 1 or 2;
provided that the compound is not (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile.

2 . The compound of claim 1 , having Formula (Ia-1):

3 . The compound of claim 1 , wherein at least one R A is halo.

4 . The compound of claim 1 , having Formula (Ib):

5 . The compound of claim 4 , wherein one R A is halo and one R A is aryl or heteroaryl.

6 . The compound of claim 1 , having Formula Ic or Ic-1:

or a pharmaceutically acceptable salt thereof, wherein:
X is N or C(R 9 );
R A1 is fluoro or —CN;
R A2 is fluoro or hydrogen;
R B1 is hydrogen or fluoro;
R 9 is selected from hydrogen, halo, —CN, —C 1 -C 4 alkyl, —C(O)N(R 11 )(R 11 ) and —S(O) 2 N(R 11 )(R 11 ), wherein any alkyl portion of R 9 is optionally substituted with one or more substituents selected from —OH and —F;
R 10 is selected from hydrogen, halo, —O—(C 1 -C 4 alkyl) optionally substituted with one or more halo, and —C(O)N(R 11 )(R 11 ); and
each R 11 is independently selected from hydrogen, and C 1 -C 4 alkyl optionally substituted with one or more substituents selected from —OH and cyclopropyl.

7 . The compound of claim 6 , wherein R 9 is selected from hydrogen, fluoro, chloro, —CN, —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , —C(O)NHCH 2 CH 2 OH, —C(OH)(CH 3 ) 2 , —S(O) 2 NH 2 , and N-(cyclopropylmethyl)carbamyl.

8 . The compound of claim 6 or 7 , wherein R 10 is selected from hydrogen, fluoro, chloro, —OCH 3 , —OCF 3 and —C(O)NH 2 .

9 . The compound of claim 1 , selected from any one of the compounds in the table below:

Compound

Number
Structure

1

2

3

4

5

6

7

8

9

10

11

Assignees

• Blueprint Medicines Corp

Inventors

• Wenglowsky Steven Mark
• Miduturu Chandrasekhar V
• Bifulco Jr Neil
• Kim Joseph L

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title