Compounds useful for treating disorders related to RET

Patent metadata

Field	Value
Publication number	US-10227329-B2
Application number	US-201715657057-A
Country	US
Kind code	B2
Filing date	Jul 21, 2017
Priority date	Jul 22, 2016
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

Abstract

Described herein are compounds that inhibit wild-type RET and its resistant mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.

First claim

The invention claimed is:

1. A compound of structural formula (I) or a pharmaceutically acceptable salt thereof, wherein:

ring A is an aryl or heteroaryl ring;
each of X 1 and X 2 is independently selected from N and C(R 6 );
Z is

—CD(R 5 )—, or —CH(R 5 )—, wherein “1” represents a point of attachment to N(R 8 ); and “2” represents a point of attachment to ring A;
each R 1 and each R 7 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halo, C 1 -C 6 heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, —C(O)R c , —OC(O)R c , —C(O)OR d , —(C 1 -C 6 alkylene)-C(O)R c , —SR d , —S(O) 2 R c , —S(O) 2 —N(R d )(R d ), —(C 1 -C 6 alkylene)-S(O) 2 R c , —(C 1 -C 6 alkylene)-S(O) 2 —N(R d )(R d ), —N(R d )(R d ), —C(O)—N(R d )(R d ), —N(R d )—C(O)R c , —N(R d )— C(O)OR c , —(C 1 -C 6 alkylene)-N(R d )—C(O)R c , —N(R d )S(O) 2 R c , and —P(O)(R c )(R c ), wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R a , or two R 1 or two R 7 are taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of R b ;
each of R 2 , R 3 , and R 4 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, hydroxyl, cyano, C 1 -C 6 heteroalkyl, and —N(R d )(R d ), wherein each of alkyl, alkoxy, and heteroalkyl is independently substituted with 0-5 occurrences of R a ;
each of R 5 and R 8 is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, and C 1 -C 6 heteroalkyl, wherein each alkyl and heteroalkyl is independently substituted with 0-5 occurrences of R a ;
each R 6 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, cyano, C 1 -C 6 heteroalkyl, and —N(R d )(R d ), wherein each alkyl, alkoxy, and heteroalkyl is independently substituted with 0-5 occurrences of R a ;
each R a and each R b is independently selected from C 1 -C 6 alkyl, halo, hydroxyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, cycloalkyl, heterocyclyl, and cyano, wherein each of alkyl, heteroalkyl, alkoxy, cycloalkyl, and heterocyclyl 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, cycloalkyl, and cyano, or two R′ together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;
each R c is independently selected from hydrogen, hydroxyl, halo, thiol, C 1 -C 6 alkyl, C 1 -C 6 thioalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, thioalkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R a , or two R c 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 d is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R a , or two R d 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 ;
m is 0, 1, or 2; and
n is 0, 1, 2, or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof having the structural formula (Ia):

wherein:
R 1 is halo, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy; and
R 1 is substituted with 0-3 occurrences of R a .

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from hydrogen, C 1 -C 4 alkyl substituted with 0-5 occurrences of R a , C 1 -C 6 alkoxy substituted with 0-5 occurrences of R a , hydroxyl, and halo;
R 3 is hydrogen; or
R 4 is selected from hydrogen, hydroxyl, halo, cyano, C 1 -C 4 alkyl, and O—C 1 -C 4 alkyl, wherein each alkyl portion of R 4 is substituted with 0-3 occurrences of R a .

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein:
R 2 is hydrogen, fluoro, —CH 3 , —CH 2 CH 3 , —CH 2 OH, —CH 2 CN, —OCH 2 CF 3 , —OCH 2 CH 2 , or OMe; or
R 4 is selected from hydrogen, fluoro, cyano, hydroxyl, —CH 3 , —CH 2 CN, —CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —OCH 3 , —OCH 2 CF 3 , and —OCH 2 CH 3 .

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is selected from

—CH 2 —, and —CH(C 1 -C 4 alkyl)-, wherein the C 1 -C 4 alkyl is substituted with 0-3 occurrences of R a .

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
each R 6 is independently selected from hydrogen, halo, cyano, and C 1 -C 4 alkyl substituted with 0-3 occurrences of R a ; or
R 8 is hydrogen and —CH 3 .

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or a 6-membered monocyclic heteroaryl comprising at least one nitrogen ring atom.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
ring A is selected from

n is 1;
R 7 is selected from 1H-pyrazol-1-yl, azetidin-1-yl, and pyrrolidin-1-yl; and
R 7 is substituted with 0-3 occurrences of R a .

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from 3-fluoroazetidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, 3-difluoromethyl-1H-pyrazol-1-yl, 4-fluoro-1H-pyrazol-1-yl, 4-chloro-1H-pyrazol-1-yl, 3-difluoromethyl-1H-pyrazol-1-yl, 4-difluoromethyl-1H-pyrazol-1-yl, 4-cyclopropyl-1H-pyrazol-1-yl, 4-fluoro-1H-pyrazol-1-yl, 3,5-bis(difluoromethyl)-1H-pyrazolyl, 3-methyl-1H-pyrazol-1-yl, 4-methyl-1H-pyrazol-1-yl, 3,5-dimethyl-1H-pyrazol-1-yl, and pyrazol-1-yl.

11. A compound having the structural formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is selected from N and C(R 13 );
each Y 1 and Y 2 is independently selected from N and CH, wherein no more than one of Y 1 and Y 2 is N;
Q is selected from N, CH, and CH 2 ;
R 11 is C 1 -C 4 alkyl;
R 12 is selected from hydrogen and C 4 alkyl;
R 13 is selected from hydrogen, cyano, and halo;
R 14 is selected from hydrogen, halo, cyano, hydroxyl, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy;
R 15 is selected from hydrogen and C 1 -C 4 alkyl;

Assignees

• Blueprint Medicines Corp

Inventors

• Brubaker Jason D
• Guzi Timothy
• Wilson Kevin J
• Dipietro Lucian V
• Zhang Yulian
• Wilson Douglas
• Fleming Paul E

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title