Therapeutically active compositions and their methods of use

Patent metadata

Field	Value
Publication number	US-9856279-B2
Application number	US-201615130358-A
Country	US
Kind code	B2
Filing date	Apr 15, 2016
Priority date	Jun 17, 2011
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

Abstract

Provided are piperazine compounds of Formula I useful for treating cancer and methods of treating cancer comprising administering to a subject in need thereof a compound described here.

First claim

The invention claimed is:

1. A compound of Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
Y is —N(R 5 );
R 1a is hydrogen, —C 1 -C 4 alkyl, —N(R 7 )(C 1 -C 4 alkylene)-N(R 7 )(C 1 -C 4 alkyl), aryl, heterocyclyl, —C(O)N(R 7 )-aryl, —N(R 7 )C(O)-aryl, —(C 1 -C 4 alkylene)-aryl, —(C 1 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-aryl, —O—(C 0 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-heterocyclyl, —O—(C 0 -C 4 alkylene)-carbocyclyl, —N(R 7 )-aryl, N(R 7 )-heteroaryl, —N(R 9 )-aryl, —N(R 9 )-heteroaryl, —O—(C 1 -C 4 alkeylene)-N(R 7 )C(O)O—(C 1 -C 4 alkylene)-aryl, or —N(R 9 )—C(O)—(C 2 -C 4 alkenyl);
R 1b is hydrogen, —C 1 -C 4 alkyl, —N(R 7 )(C 1 -C 4 alkylene)-N(R 7 )(C 1 -C 4 alkyl), aryl, heteroaryl, heterocyclyl, —C(O)N(R 7 )-aryl, —N(R 7 )C(O)-aryl, —(C 1 -C 4 alkylene)-aryl, —(C 1 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-aryl, —O—(C 0 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-heterocyclyl, —O—(C 0 -C 4 alkylene)-carbocyclyl, —N(R 7 )-aryl, N(R 7 )-heteroaryl, —N(R 9 )-aryl, —N(R 9 )-heteroaryl, —O—(C 1 -C 4 alkylene)-N(R 7 )C(O)O—(C 1 -C 4 alkylene)-aryl, or —N(R 9 )—C(O)—(C 2 -C 4 alkenyl), wherein:
at least one of R 1a and R 1b is not hydrogen or methyl;
any alkylene moiety present in R 1a or R 1b is optionally substituted with OH or F;
each R 7 is independently selected from hydrogen and C 1 -C 4 alkyl; and
any aryl, heteroaryl, or heterocyclyl of R 1a or R 1b is optionally substituted with one or more substituents selected from -G-L-M, halo, —NO 2 , C 1 -C 6 alkyl, —C≡N, ═O, —CF 3 and —OCF 3 ;
G is a bond or a bivalent C 1 -C 6 saturated or unsaturated, straight or branched hydrocarbon chain wherein optionally one, two or three methylene units of the hydrocarbon chain are independently replaced by —NR 8 —, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—;
L is a covalent bond or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, —NR 8 —, —N(R 8 )C(O)—, —C(O)N(R 8 )—, —N(R 8 )SO 2 —, SO 2 N(R 8 )—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—;
M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -D-E, oxo, NO 2 , halogen, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
D is a covalent bond or a bivalent C 1 -C 6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of D are optionally and independently replaced by —NR 8 —, —S—, —O—, —C(O)—, —SO—, or —SO 2 —;
E is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with oxo, halogen, or CN; and
each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C 1 -C 6 alkoxy, —S(O) 2 —C 2 -C 4 alkenyl, or an optionally substituted group selected from phenyl, a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 2 is selected from phenyl, a 3-7 membered cycloalkyl, C 2 -C 4 alkyl, and CF 3 , wherein the phenyl or cycloalkyl is optionally substituted with a substituent selected from methyl or fluoro;
each R 3 is independently selected from halo, —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —C 1 -C 4 fluoroalkyl, —C(O)—O—(C 1 -C 4 alkyl), -phenyl, -heteroaryl, C 3 -C 7 cycloalkyl, —CH 2 —N(C 1 -C 4 alkyl) 2 , C(O)—N—(C 1 -C 4 alkyl) 2 , —C(O)—NH—(C 1 -C 4 alkyl), and —C 1 -C 4 alkyl optionally substituted with one or more halo or —OH;
R 4 is selected from hydrogen, —CN, halo, C 1 -C 4 alkoxy, —CH 2 NH(C 1 -C 4 alkyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), C 1 -C 4 fluoroalkyl, C(O)—N—(C 1 -C 4 alkyl) 2 , —C(O)—NH—(C 1 -C 4 alkyl), —C(O)—O—(C 1 -C 4 alkyl), —C(O)—OH, —S(O) 2 —(C 1 -C 4 alkyl), and a 5-membered heteroaryl;
R 5 is selected from: —C(O)—(C 1 -C 5 alkyl), —C(O)—(C 2 -C 6 alkenyl), —C(O)—(C 0 -C 2 alkylene)-Q, —C(O)—(C 1 -C 4 alkenylene)-Q, —C(O)—O—(C 0 -C 2 alkylene)-Q, —C(O)—(C 1 -C 2 alkylene)-O—(C 0 -C 2 alkylene)-Q, —C(O)—C(O)-Q, —S(O) 2 -Q, —C(O)—(C 1 -C 4 alkylene)-O—C(O)—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 2 alkylene)-O—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 2 alkylene)-C(O)C(O)N(R)(C 1 -C 4 alkyl), —C(O)—O—(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-O—C(O)—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 2 alkylene)-S(O) 0-2 —(C 1 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkylene)-C(O)C(O)N(R 6 ) (C 1 -C 6 alkyl), —C(O)—(C 1 -C 4 alkylene)-N(R 6 )S(O) 2 —(C 1 -C 6 alkyl), and —C(O)—(C 1 -C 4 alkylene)-N(R 6 )S(O) 2 Q, wherein:
any alkylene moiety present in R 5 is optionally substituted with OCH 3 , OH or F;
any terminal methyl moiety present in R 5 is optionally replaced with —CH 2 OH, CF 3 , —CH 2 F, —CH 2 Cl, C(O)CH 3 , C(O)CF 3 , CN, —OCH 3 , —C(O)H, —OP(O)(OH) 2 , —OP(O)(C 1 -C 4 alkoxy) 2 or CO 2 H;
each R 6 is independently selected from hydrogen and methyl;
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, wherein Q is optionally substituted with up to 3 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —C(O)O—(C 1 -C 4 alkyl)-, —(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy), —CN, —OH, fluoro, chloro, and bromo, wherein each C 1 -C 4 alkyl is optionally substituted with OH;
R 9 is selected from aryl and heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one or more substituents selected from -G-L-M, halo, C 1 -C 6 alkyl, —C≡N, ═O, —CF 3 and —OCF 3 ; and
m is 0, 1, 2 or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
Y is —N(R 5 );
R 1a is hydrogen, —C 1 -C 4 alkyl, —N(R 7 )(C 1 -C 4 alkylene)-N(R 7 )(C 1 -C 4 alkyl), aryl, heterocyclyl, —C(O)N(R 7 )-aryl, —N(R 7 )C(O)-aryl, —(C 1 -C 4 alkylene)-aryl, —(C 1 -C 4 alkylene)-heteroaryl, —O—(C 1 -C 4 alkylene)-aryl, —O—(C 1 -C 4 alkylene)-heteroaryl, —O—(C 1 -C 4 alkylene)-heterocyclyl, —N(R 7 )-aryl, or —N(R 7 )-heteroaryl;
R 1b is hydrogen, —C 1 -C 4 alkyl, —N(R 7 )(C 1 -C 4 alkylene)-N(R 7 )(C 1 -C 4 alkyl), aryl, heteroaryl, heterocyclyl, —C(O)N(R 7 )-aryl, —N(R 7 )C(O)-aryl, —(C 1 -C 4 alkylene)-aryl, —(C 1 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-aryl, —O—(C 0 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-heterocyclyl, —O—(C 0 -C 4 alkylene)-carbocyclyl, —N(R 7 )-aryl, N(R 7 )-heteroaryl, —N(R 9 )-aryl, —N(R 9 )-heteroaryl, —O—(C 1 -C 4 alkeylene)-N(R 7 )C(O)O—(C 1 -C 4 alkylene)-aryl, or —N(R 9 )—C(O)—(C 2 -C 4 alkenyl), wherein:
at least one of R 1a and R 1b is not hydrogen or methyl;
any alkylene moiety present in R 1a or R 1b is optionally substituted with OH or F;
each R 7 is independently selected from hydrogen and C 1 -C 4 alkyl; and
any aryl, heteroaryl, or heterocylyl of R 1a or R 1b is optionally substituted with one or more substituents selected from -G-L-M, halo, C 1 -C 6 alkyl, —C≡N, ═O, —CF 3 and —OCF 3 ;
G is a bond or a bivalent C 1 -C 6 saturated or unsaturated, straight or branched hydrocarbon chain wherein optionally one, two or

Assignees

• Agios Pharmaceuticals Inc
• Agios Pharmaceuticals Inc

Inventors

• Cao Sheldon
• Popovici-Muller Janeta
• Salituro Francesco G
• Saunders Jeffrey O
• Tan Xuefei
• Travins Jeremy M
• Yan Shunqi
• Ye Zhixiong

Classifications

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D401/12

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

• C07D487/04

  Ortho-condensed systems · CPC title