Inhibitors of RET

Patent metadata

Field	Value
Publication number	US-10030005-B2
Application number	US-201615340428-A
Country	US
Kind code	B2
Filing date	Nov 1, 2016
Priority date	Nov 2, 2015
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

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 having the formula (A):

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 );
each of Y 1 and Y 2 is independently selected from —CH 2 — and —O—, wherein no more than one of Y 1 or Y 2 is —O—;
each R 1 and each R 7 is independently selected from 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, —OC(O)R, —C(O)OR, -(C 1 -C 6 alkylene)-C(O)R, —SR, —S(O) 2 R, —S(O) 2 —N(R)(R), -(C 1 -C 6 alkylene)-S(O) 2 R, -(C 1 -C 6 alkylene)-S(O) 2 —N(R)(R), —N(R)(R), —C(O)—N(R)(R), —N(R)—C(O)R, —N(R)—C(O)OR, —(C 1 -C 6 alkylene)-N(R)—C(O)R, —N(R)S(O) 2 R, and —P(O)(R)(R), 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 3a , R 3b , R 4 , R 8a , and R 8b is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, hydroxyl, C 1 -C 6 heteroalkyl, and —N(R)(R), wherein each alkyl, alkoxy, and heteroalkyl is independently substituted with 0-5 occurrences of R a ;
each of R 5 and R 9 is independently selected from hydrogen, 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, C 1 -C 6 heteroalkyl, and —N(R)(R), wherein each alkyl, alkoxy, and heteroalkyl is independently substituted with 0-5 occurrences of R a ;
each R 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 alkyl, thioalkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R a , or 2 R 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 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 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 2 R′ together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;
represents a single or double bond;
m is 0, 1, or 2;
n is 0, 1, 2, or 3; and
each o is 0 when is a double bond; and
each o is 1 when is a single bond.

2. The compound of claim 1 having the formula (I):

or a pharmaceutically acceptable salt thereof, wherein;
represents a single or double bond.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
m is 1;
R 1 is located at the 5-position; and
R 1 is C 1 -C 4 alkyl optionally substituted with 0-3 occurrences of R a .

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, hydroxyl, halo, and C 1 -C 4 alkoxy.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each of R 3a , R 3b , R 8a , and R 8b is independently selected from hydrogen and C 1 -C 4 alkyl optionally substituted with 0-3 occurrences of R a .

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one pair of R 3a and R 3b or R 8a and R 8b is simultaneously hydrogen.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, wherein each alkyl portion of R 4 is optionally substituted with 0-3 occurrences of R a .

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen or C 1 -C 4 alkyl optionally substituted with 0-3 occurrences of R a .

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

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

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
n is 1; and
R 7 is pyrazol-1-yl optionally substituted with 0-3 occurrences of R a .

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen.

14. A compound having the formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is selected from N, CH, and C(halo);
X 2 is selected from N and CH;
X 3 is selected from N and CH;
R 12 is selected from hydrogen, hydroxyl, halo, and O—C 1 -C 4 alkyl;
each of R 13a , R 13b , R 18a , and R 18b is independently selected from hydrogen and C 1 -C 4 alkyl;
R 14 is selected from hydrogen, C 1 -C 4 alkyl and O—C 1 -C 4 alkyl;
R 15 is selected from hydrogen and C 1 -C 4 alkyl;
R 16 is selected from hydrogen and C 1 -C 4 alkyl;
R 17b is selected from hydrogen and halo; and
each of R 17a and R 17c is independently selected from hydrogen and C 1 -C 4 alkyl.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein:
X 1 is selected from N, CH, and C(Cl);
R 12 is selected from hydrogen, hydroxyl, fluoro, and —O—CH 3 ;
each of R 13a , R 13b , R 18a , and R 18b is independently selected from hydrogen, methyl, and ethyl, wherein at least one pair of R 13a and R 13b or R 18a and R 18b is simultaneously hydrogen;
R 14 is selected from hydrogen, —CH 3 , —CH 2 CH 3 , —OCH 3 , and —OCH 2 CH 3 ;
R 15 is selected from hydrogen and —CH 3 ;
R 16 is selected from hydrogen and —CH 3 ;
R 17b is selected from hydrogen, chloro, and fluoro;
R 17a and R 17c are simultaneously hydrogen or —CH 3 , wherein when R 17a and R 17c are simultaneously —CH 3 , R 17b is hydrogen.

16. A pharmaceutical composition comprising:
a compound of claim 1 or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier.

17. A method for treating a subject suffering from non-small cell lung cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of c

Assignees

• Blueprint Medicines Corp

Inventors

• Brubaker Jason D
• Kim Joseph L
• Wilson Kevin J
• Wilson Douglas
• Dipietro Lucian V

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title