Compositions useful for treating disorders related to kit

Patent metadata

Field	Value
Publication number	US-9688680-B2
Application number	US-201514817931-A
Country	US
Kind code	B2
Filing date	Aug 4, 2015
Priority date	Aug 4, 2014
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

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

First claim

I claim:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
X is selected from CH or N;
L is a bond, —(CR c R c ) n —, —(CR c R c ) n NR b —, —NR b (CR c R c ) n —, —S(O) 2 —, —S(O)—, —C(O)—, —OC(O)—, —C(O)O—, —(CR c R c ) n —OC(O)—, —OC(O)—(CR c R c ) n —, —(CR c R c ) n —C(O)—, —C(O)—(CR c R c ) n —, —NR b C(O)(CR c R c ), —C(O)NR b —(CR c R c ), where the two R c 's, together with the carbon to which they are attached, can form a carbocycle, —C(O)NR b —(CR c R b ), —(CR c R c ) n NR b —(CR c R c ), —NR b C(S)—, —C(S)NR b —, —NR b C(O)—, —C(O)NR b —, —NR b S(O) 2 , -or —S(O) 2 NR b —;
R 1 is alkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl each of which is substituted with 0-5 occurrences of R d ;
R 2 is H, halo, aryl, alkenyl, heteroaryl, carbocyclyl, or heterocyclyl, wherein each of aryl, alkenyl, heteroaryl, carbocyclyl, and heterocyclyl is substituted with 0-5 occurrences of R d ;
R 3 is H, alkyl, heteroalkyl, haloalkyl, haloalkoxyl, —OR c , —C(O)OR c , —C(O)NR a R b , —(CR c R c ) n NR b —(CR c R c )—H, —NR a R b , or cyano, wherein each of alkyl, heteroalkyl, haloalkyl, and haloalkoxyl is substituted with 0-5 occurrences of R d ;
R a and R b are each independently H, alkyl, heteroalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, wherein each of alkyl, heteroalkyl, aryl, aralkyl, heterocyclyl, and heterocyclylalkyl is substituted with 0-5 occurrences of R d ; or R a and R b together with the nitrogen atom to which they are attached form a heterocyclyl substituted with 0-5 occurrences of R d ;
R c is H or alkyl;
each R d is independently halo, heteroalkyl, haloalkyl, haloalkoxyl, alkyl, alkynyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, nitro, cyano, hydroxyl, —C(O)R a1 , —OC(O)R a1 , —C(O)OR a1 , —SR a1 , —S(O) 2 R a1 , —NR a1 R b1 , —C(O)NR a1 R b1 , —NR a1 S(O) 2 R a1 , or —OR a1 ; wherein each of heteroalkyl, haloalkyl, haloalkoxyl, alkyl, alkynyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl is substituted with 0-5 occurrences of R c1 ; or two R d together with the atoms to which they are attached form a carbocyclyl or heterocyclyl, each optionally substituted with halo or alkyl;
R a1 and R b1 are each independently H, alkyl, aralkyl, carbocyclyl, heteroaryl, or heterocyclyl; or R a1 and R b1 together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted with halo or alkyl;
each R c1 is independently halo, —OR c2 , —NR a1 R b1 , alkyl, cyano, heteroalkyl, haloalkyl, haloalkoxyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, aryl, or aralkyl;
R c2 is H or alkyl;
p and r are each independently 1 or 2; and
n is 1, 2, 3 or 4.

2. The compound of claim 1 , wherein L is a bond, —(CR c R c ) n —, —(CR c R c ) n NR b —, —NR b (CR c R c ) n —, —(CR c R c ) n —C(O)—, —C(O)—(CR c R c ) n —, —C(O)NR b —(CR c R c ), where the two Rc's, together with the C to which they are attached, can form a carbocycle, —C(O)NR b —(CR c R b ), —(CR c R c ) n NR b —(CR c R c ), —NR b C(O)—, —C(O)NR b —, -or —S(O) 2 NR b —.

3. The compound of claim 1 , wherein L is —(CR c R c ) n NR b —, —NR b (CR c R c ) n —, —NR b C(O)—, or —C(O)NR b —.

4. The compound of claim 1 , wherein R 1 is aryl, carbocyclyl, carbocyclylalkyl, heterocyclyl, or heterocyclylalkyl, each of which is substituted with 0-5 occurrences of R d .

5. The compound of claim 1 , wherein R 2 is alkenyl, aryl, carbocyclyl, heteroaryl, or heterocyclyl, each of which is substituted with 0-5 occurrences of R d .

6. The compound of claim 1 , wherein R 2 is a 5- or 6-membered heterocyclyl substituted with 0-5 occurrences of R d .

7. The compound of claim 1 , wherein R 2 is a 5- or 6-membered heteroaryl substituted with 0-5 occurrences of R d .

8. The compound of claim 1 , wherein R 2 is selected from pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, thiophenyl, isoxazolyl, phenyl, dihydropyranyl, and tetrahydropyridinyl, each optionally substituted with 0-5 occurrences of R d .

9. The compound of claim 1 , wherein R 3 is H, alkyl, —OR c , or —NR a R b .

10. The compound of claim 1 , wherein each R d is independently selected from halo, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, hydroxyl, —C(O)R a1 , —C(O)OR a1 , —S(O) 2 R a1 , —NR a1 R b1 , —C(O) NR a1 R b1 , and —OR a1 ; wherein each of alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl is substituted with 0-5 occurrences of R c1 ; or two R d together with the atoms to which they are attached form a carbocyclyl or heterocyclyl, each optionally substituted with halo or alkyl.

11. The compound of claim 1 , wherein p is 1 and r is 1.

12. The compound of claim 1 , wherein the compound is a compound of Formula II:

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein the compound is a compound of Formula III:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein the compound is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof.

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

16. A method of treating mastocytosis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .

17. 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 .

18. 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 .

19. The method of claim 16 , wherein the mastocytosis is selected from cutaneous mastocytosis (CM) and systemic mastocytosis (SM).

20. The method of claim 19 , 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).

21. The compound of claim 1 selected from any one of the compounds below, or a pharmaceutically acceptable salt thereof:

#
Structure

1

2

Assignees

• Blueprint Medicines Corp

Inventors

• Hodous Brian L

Classifications

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title