Compositions useful for treating disorders related to kit

Patent metadata

Field	Value
Publication number	US-9499522-B2
Application number	US-201414210526-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

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

First claim

We claim:

1. A compound having structural formula I:

or a pharmaceutically acceptable salt or a tautomer thereof, wherein:
each R 4 is independently selected from —C(O)N(R 2 )(R 2 ), —CN, —(C 0 -C 4 alkylene)-N(R 2 )(R 2 ), —O—(C 1 -C 4 alkylene)-O—(C 1 -C 3 alkyl), —(C 1 -C 4 alkylene)-O —(C 1 -C 3 alkyl), and —O—(C 0 -C 4 alkylene)-(R 1 ), wherein R 1 is selected from —C 1 -C 4 alkyl and heterocyclyl;
each R 2 is independently selected from hydrogen and unsubstituted C 1 -C 4 alkyl
each R 6 is independently selected from —C 1 -C 4 alkyl or two R 6 bound to the same carbon atom are taken together to form oxo, or two R 6 bound to different carbon atoms are taken together to form methylene, ethane-1,2-diyl, or propane-1,2-diyl forming a ring that is bridged to the piperazine-1,4-diyl portion of the compound;
each R 8 is independently selected from halo, —OH, —N(R 2 )(R 2 ), C 1 -C 4 alkyl, and —O—(C 1 -C 4 alkyl);
L is selected from a bond, —(C 1 -C 4 alkylene)-, —O—, —S—, —SO 2 —, —N(R 2 )—, —O—(C 1 -C 4 alkylene)-, —(C 1 -C 4 alkylene)-O—, —(C 1 -C 4 alkylene)-N(R 2 )—, —N(R 2 )—(C 1 -C 4 alkylene)-, —N(R 2 )—CO—(C 1 -C 4 alkylene)-, and —CO—N(R 2 )—(C 1 -C 4 alkylene)-;
n is 1, 2, or 3;
m is 0, 1, 2, 3, or 4;
p is 0, 1, or 2;
q is 0, 1, 2, or 3;
ring A is monocyclic or bicyclic aryl, heteroaryl, carbocyclyl or heterocyclyl;
each R 10 is independently selected from halo, —OH, —CN, —C(O)N(R 2 )(R 2 ), C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), and heterocyclyl, or two R 10 bound to adjacent ring carbon atoms are taken together to form methylenedioxy;
wherein unless otherwise specified any alkyl, or alkylene portion of the compound is optionally substituted.

2. The compound of claim 1 , wherein
any alkyl, or alkylene portion of the compound is optionally and independently substituted with one or more substituents independently selected from halo, —OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—(C 1 -C 4 alkyl), and ═O; and
any heterocyclyl portion of the compound is optionally and independently substituted with one or more substituents independently selected from halo, —OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—(C 1 -C 4 alkyl), and ═O.

3. The compound of claim 1 , wherein:
each R 4 is independently selected from —C(O)N(R 2 )(R 2 ), —O—(C 1 -C 4 alkylene)-O—(C 1 -C 3 alkyl), and —O—(C 0 -C 4 alkylene)-(R 1 ), wherein:
R 1 is selected from —C 1 -C 4 alkyl, and a saturated heterocyclyl;
each R 2 is independently selected from hydrogen and methyl;
each alkyl or alkylene is optionally substituted with one or more substituents independently selected from halo, —OH and —O—(C 1 -C 3 alkyl);
the saturated heterocyclyl is optionally substituted on a substitutable ring nitrogen with methyl; and
the saturated heterocyclyl is optionally substituted on a substitutable ring carbon with one or more substituents independently selected from methyl, halo, —OH.

4. The compound of claim 3 , wherein each R 4 is independently selected from C(O)NH 2 , —OCF 2 , —OCH 2 CH 3 , —OCH 3 , 1-methyl-4-fluoropiperidin-4-ylmethoxy, 1-(2-hydroxyethyl)-piperidin-4-ylmethoxy, 1-(2-hydroxyethyl)-piperidin-4-yloxy, 1-(2-hydroxyethyl)-pyrrolidin-3-yloxy, 1-methylazetidin-3-ylmethoxy, 1-methylpiperidin-3-ylethoxy, 1-methylpiperidin-3-ylmethoxy, 1-methylpiperidin-4-ylmethoxy, 1-methylpiperidin-4-yloxy, 1-methylpyrrolidin-3-ylmethoxy, 1-methylpyrrolidin-3-yloxy, 2,3-dihydroxypropoxy, 2-oxopiperidin-4-ylmethoxy, 2-oxopyrrolidin-l-ylethoxy, 3-methyloxetan-3-ylmethoxy, 4-methylmorpholin-2-ylmethoxy, 4-methylpiperazin- 1-ylethoxy, 4-methylpiperazin- 1-ylpropoxy, azetidin-3-ylmethoxy, methoxyethoxy, morpholin-2-ylmethoxy, piperidin-l-ylpropoxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, piperidin-4-yloxy, pyrrolidin-1-ylpropoxy, pyrrolidin-3-ylmethoxy, and pyrrolidin-3-yloxy.

5. The compound of claim 4 , wherein each R 4 is independently selected from OCH 2 CH 3 , OCH 3 , 1-(2-hydroxyethyl)-piperidin-4-ylmethoxy, 1-(2-hydroxyethyl)-piperidin-4-yloxy, 1-(2-hydroxyethyl)-pyrrolidin-3-yloxy, 1-methyl-4-fluoropiperidin-4-ylmethoxy, 1-methylazetidin-3-ylmethoxy, 1-methylpiperidin-3-ylethoxy, 1-methylpiperidin-3-ylmethoxy, 1-methylpiperidin-4-ylmethoxy, 1-methylpiperidin-4-yloxy, 1-methylpyrrolidin-3-ylmethoxy, 1-methylpyrrolidin-3-yloxy, 2,3-dihydroxypropoxy, 2-oxopiperidin-4-ylmethoxy, 2-oxopyrrolidin-1-yleithoxy, 3-methyloxetan-3-ylmethoxy, 4-methylmorpholin-2-ylmethoxy, 4-methylpiperazin-1-ylethoxy, 4-methylpiperazin-1-ylpropoxy, azetidin-3-ylmethoxy, methoxyethoxy, morpholin-2-ylmethoxy, piperidin-1-ylpropoxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, piperidin-4-yloxy, pyrrolidin-3-ylmethoxy, and pyrrolidin-3-yloxy.

6. The compound of claim 1 , wherein each R 6 is independently selected from C 1 -C 4 alkyl, or two R 6 bound to the same carbon atom are taken together to form oxo, or two R 6 on non-adjacent carbon ring atoms are taken together to form ethane-1,2-diyl, propane-1,3-diyl or butane-1,4-diyl thereby forming a ring that is bridged to the piperazine-1,4-diyl portion of the compound.

7. The compound of claim 6 , wherein each R 6 is independently methyl or two R 6 bound to the same carbon atom are taken together to form oxo, or two R 6 non-adjacent carbon ring atoms are taken together to form an ethane-1,2-diyl thereby forming a ring that is bridged to the piperazine-1,4-diyl portion of the compound.

8. The compound of claim 1 , wherein each R 8 is independently selected from —OH and —NH 2 .

9. The compound of claim 1 , wherein each R 10 is independently selected from —OH, —OCH 3 , —F, —CH 3 , —CN, —C(O )NH 2 , —OCF 2 , —Cl, CF 3 , —OCF 3 , and t-butyl, or two R 10 are taken together to form methylenedioxy.

10. The compound of claim 9 , wherein each R 10 is independently selected from OH, —OCH 3 , —F, —CH 3 , —CN, —C(O)NH 2 , —OCF 2 , and —Cl.

11. The compound of claim 1 , wherein L is selected from a bond, —CH 2 —, —CH 2 CH 2 —, —NH—, —O—, —S—, —CH 2 O—*, —OCH 2 —*, —OCH(CH 3 )—*, —N(CH 3 )CH 2 —*, —NHCH 2 —*, —NHC(O)CH 2 —*, —C(O)NH—*, —NHCH(CH 3 )—*, and —SO 2 —, wherein “*” represents a portion of L bound to ring A.

12. The compound of claim 11 , wherein L is selected from —CH 2 —, —CH 2 CH 2 —, —NH—, —O—, —S—, —CH 2 O—*,—N(CH 3 )CH 2 —*, —OCH(CH 3 )—*, and —OCH(CH 3 )—*.

13. The compound of claim 1 , wherein ring A is selected from phenyl, thiophenyl, indolinyl, 1,2,3,4-tetrahydroquinoline, pyridinyl, thiophenyl, and C 3 -C 6 cycloalkyl.

14. The compound of claim 13 , wherein ring A is selected from phenyl, and thiophen-2-yl.

15. A compound having the structural formula II:

or a pharmaceutically acceptable salt or tautomer thereof, wherein:
one of R 4a or R 4b is selected from, —O—CH 3 , —O—CH 2 CH 3 and —O—CH 2 CH 2 —O—CH 3 ;
the other of R 4a or R 4b is selected from —O—CH 3 , —O—CH 2 CH 3 , —O—CH 2 CH 2 —O—CH 3 and —(C 0 -C 4 alkylene)-(saturated heterocyclyl), wherein
the saturated heterocyclyl is optionally substituted on a substitutable ring nitrogen with methyl; and
the saturated heterocyclyl is optionally substituted on a substitutable ring carbon with one or more substituents independently selected from methyl, halo, and —OH;
R 6a is hydrogen;
R 6b is selected from hydrogen, and —CH 3 when ---- is a single bond, and R 6b is ═O, when ---- is a double bond; or
R 6a and R 6b are taken together with the carbon atoms to which they are

Assignees

• Dipietro Lucian V
• Hodous Brian L
• Kim Joseph L
• Miduturu Chandrasekhar V
• Wenglowsky Steven Mark
• Wilson Douglas
• Zhang Yulian
• Blueprint Medicines Corp

Inventors

• Dipietro Lucian V
• Hodous Brian L
• Kim Joseph L
• Miduturu Chandrasekhar V
• Wenglowsky Steven Mark
• Wilson Douglas
• Zhang Yulian

Classifications

• A61P17/00

  Drugs for dermatological disorders · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title