Compositions useful for treating disorders related to kit

Patent metadata

Field	Value
Publication number	US-9334263-B2
Application number	US-201414517480-A
Country	US
Kind code	B2
Filing date	Oct 17, 2014
Priority date	Oct 17, 2013
Publication date	May 10, 2016
Grant date	May 10, 2016

Abstract

Compounds and compositions useful for treating disorders related to KIT and PDFGR are described herein.

First claim

We claim:

1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, cycloalkyl and heterocyclyl;
each X and Y is independently selected from CR 1 and N;
Z is selected from C 1 -C 6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclic heterocyclylalkyl; wherein each of C 1 -C 6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclic heterocyclylalkyl is substituted with 0-5 independent occurrences of R C ;
L is selected from a bond, —(C(R 2 )(R 2 )) m —, —(C 2 -C 6 alkynylene)-, —(C 2 -C 6 alkenylene)-, —(C 1 -C 6 haloalkylene)-, —(C 1 -C 6 heteroalkylene)-, —(C 1 -C 6 hydroxyalkylene)-, —C(O)—, —O—, —S—, —S(O), —SO 2 —, —N(R 2 )—, —O—(C 1 -C 6 alkylene)-, —(C 1 -C 6 alkylene)-O—, —N(R 2 )—CO—, —CO—N(R 2 )—, —(C 1 -C 6 alkylene)-N(R 2 )—, —N(R 2 )—(C 1 -C 6 alkylene)-, —N(R 2 )—CO—(C 1 -C 6 alkylene)-, —CO—N(R 2 )—(C 1 -C 6 alkylene)-, —N(R 2 )—SO 2 —, —SO 2 —N(R 2 )—, —N(R 2 )—SO 2 —(C 1 -C 6 alkylene)-, and —SO 2 —N(R 2 )—(C 1 -C 6 alkylene)-;
each R A and R B is independently selected from C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, monocyclic or bicyclic aralkyl, —N(R 2 )(R 2 ), cyano, and —OR 2 ;
each R C is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkynyl, halo, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano, —C(O)R 2 , —OC(O)R 2 , —C(O)OR 2 , —SR 2 , —S(O) 2 R 2 , —S(O) 2 —N(R 2 )(R 2 ), —(C 1 -C 6 alkylene)-S(O) 2 —N(R 2 )(R 2 ), —N(R 2 )(R 2 ), —C(O)—N(R 2 )(R 2 ), —N(R 2 )(R 2 )—C(O)R 2 , —(C 1 -C 6 alkylene)-N(R 2 )—C(O)R 2 , —NR 2 S(O) 2 R 2 , —P(O)(R 2 )(R 2 ), and —OR 2 ; wherein each of heteroalkyl, haloalkyl, haloalkoxy, alkyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is substituted with 0-5 occurrences of R a ; or 2 R C together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring substituted with 0-5 occurrences of R a ;
each R 1 is independently selected from hydrogen, C 1 -C 6 alkyl, monocyclic aralkyl, C 1 -C 6 hydroxyalkyl, halo, C 1 -C 6 haloalkyl, —N(R 2 )(R 2 ), and —OR 2 ;
each R 2 is independently selected from hydrogen, hydroxyl, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each of C 1 -C 6 alkyl, cycloalkyl and heterocyclyl is substituted with 0-5 occurrences of R b , or 2 R 2 together with the carbon or nitrogen atom to which they are attached form a cycloalkyl or heterocyclyl ring;
each R a and R b is independently selected from halo, hydroxyl, —C(O)R′, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, —NR′R′, and cycloalkyl; wherein cycloalkyl is substituted with 0-5 occurrences of R′;
R′ is hydrogen, hydroxyl, or C 1 -C 6 alkyl; and
m, p, and q are each independently 0, 1, 2, 3, or 4.

2. The compound of claim 1 , wherein L is —(C(R 2 )(R 2 )) m —.

3. The compound of claim 2 , wherein X and Y are CR 1 .

4. The compound of claim 2 , wherein Z is phenyl.

5. The compound of claim 2 , wherein Z is pyridinyl.

6. The compound of claim 2 , wherein Z is isoxazolyl.

7. The compound of claim 2 , wherein Z is pyrazolyl.

8. The compound of claim 2 , wherein Z is dihydroisoquinolinyl.

9. The compound of claim 1 , wherein the compound is a compound of Formula II(a):

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 , wherein Z is phenyl.

11. The compound of claim 9 , wherein Z is pyridinyl.

12. The compound of claim 9 , wherein Z is isoxazolyl.

13. The compound of claim 9 , wherein Z is pyrazolyl.

14. The compound of claim 9 , wherein Z is dihydroisoquinolinyl.

15. The compound of claim 9 , wherein R C is piperidinyl.

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 .

17. A method of treating mastocytosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 16 .

18. A method of treating gastrointestinal stromal tumor, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 16 .

19. A method of treating acute myeloid leukemia, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 16 .

20. The method of claim 17 , wherein the mastocytosis is selected from cutaneous mastocytosis (CM) and systemic mastocytosis (SM).

21. The method of claim 20 , wherein the systemic mastocytosis is selected from indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), aggressive systemic mastocytosis (ASM), SM with associated hematologic non-mast cell lineage disease (SM-AHNMD), and mast cell leukemia (MCL).

Assignees

• Hodous Brian L
• Kim Joseph L
• Miduturu Chandrasekhar V
• Wilson Douglas
• Zhang Yulian
• Blueprint Medicines Corp

Inventors

• Hodous Brian L
• Kim Joseph L
• Miduturu Chandrasekhar V
• Wilson Douglas
• Zhang Yulian

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D251/18

  with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines · CPC title