Antiproliferative compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2016009683-A1
Application number	US-201514795837-A
Country	US
Kind code	A1
Filing date	Jul 9, 2015
Priority date	Jul 11, 2014
Publication date	Jan 14, 2016
Grant date	—

Abstract

Compounds of formula I for treating, preventing or managing cancer are disclosed. Also disclosed are methods of treating, preventing or managing cancer, such as leukemia, comprising administering the compounds. In certain embodiments, the method of treatment comprise administering a compound provided herein in combination with a second agent. Pharmaceutical compositions and single unit dosage forms comprising the compounds are also disclosed.

First claim

What is claimed is:

1 . A compound of Formula I:

or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein:
R 1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;
R 2 and R 3 are each halo;
where the substituents on R 1 , when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —R 4 OR 5 , —R 4 OR 5 —R 4 OR 5 , —R 4 N(R 6 )(R 7 ), —R 4 SR 5 , —R 4 OR 4 N(R 6 )(R 7 ), —R 4 OR 4 C(J)N(R 6 )(R 7 ), —C(J)R 9 or R 4 S(O) t R 8 ;
each R 4 is independently alkylene, alkenylene or a direct bond;
each R 5 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groups in R 5 are each independently optionally substituted with 1-3 Q 1 groups, where each Q 1 is independently alkyl, haloalkyl or halo;
R 6 and R 7 are selected as follows:
i) R 6 and R 7 are each independently hydrogen or alkyl; or
ii) R 6 and R 7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl;
R 8 is alkyl, haloalkyl, or hydroxyalkyl;
R 9 is alkyl or aryl;
J is O or S; and
t is 1 or 2.

2 . The compound of claim 1 , wherein R 1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl.

3 . The compound of claim 1 having Formula II:

or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein:
R 1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;
where the substituents on R 1 , when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, —R 4 OR 5 , —R 4 SR 5 , —R 4 N(R 6 )(R 7 ), R 4 OR 4 N(R 6 )(R 7 ) or R 4 OR 4 C(J)N(R 6 )(R 7 );
J is O or S;
each R 4 is independently alkylene, alkenylene or a direct bond;
each R 5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and
R 6 and R 7 are selected as follows:
i) R 6 and R 7 are each independently hydrogen or alkyl; or
ii) R 6 and R 7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.

4 . The compound of claim 1 , wherein R 1 is optionally substituted aryl;
where the substituents on R 1 , when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, —R 4 OR 5 , —R 4 SR 5 , —R 4 N(R 6 )(R 7 ), R 4 OR 4 N(R 6 )(R 7 ) or R 4 OR 4 C(J)N(R 6 )(R 7 ); J is O or S; each R 4 is independently alkylene, alkenylene or a direct bond; each R 5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R 6 and R 7 are selected as follows: i) R 6 and R 7 are each independently hydrogen or alkyl; or ii) R 6 and R 7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.

5 . The compound of claim 1 , wherein R 1 is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted piperidinyl, or optionally substituted pyridyl, where the substituents on R 1 , when present, are one to three groups Q, where each Q is independently halo, alkyl, —R 4 OR 5 or —R 4 N(R 6 )(R 7 ); each R 4 is independently a direct bond or alkylene; each R 5 is independently hydrogen, halo, alkyl, alkoxy, haloalkoxy or haloalkyl; and R 6 and R 7 are selected as follows:
i) R 6 and R 7 are each independently hydrogen or alkyl; or
ii) R 6 and R 7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl ring.

6 . The compound of claim 1 , wherein R 1 is optionally substituted phenyl, where the substituents on R 1 , when present, are one to three groups Q, where each Q is independently fluoro, chloro, methyl, tert butyl, —R 4 OR 5 , —R 4 SR 5 or R 4 OR 4 C(J)N(R 6 )(R 7 ); each R 4 is independently a direct bond or methylene; each R 5 is independently hydrogen, methyl, ethyl or trifluoromethyl; and R 6 and R 7 are each independently hydrogen or methyl.

7 . The compound of claim 1 , wherein the compound has formula III

or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein:
each Q 1 is independently alkyl, halo, haloalkyl, alkoxyalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, —R 4 OR 5 , —R 4 SR 5 , —R 4 N(R 6 )(R 7 ), R 4 OR 4 N(R 6 )(R 7 ) or R 4 OR 4 C(J)N(R 6 )(R 7 );
J is O or S;
each R 4 is independently alkylene, alkenylene or a direct bond;
each R 5 is independently hydrogen, alkyl, halo, alkoxy, haloalkyl or hydroxyalkyl;
R 6 and R 7 are selected as follows:
i) R 6 and R 7 are each independently hydrogen or alkyl; or
ii) R 6 and R 7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl; and
n is 0-3.

8 . The compound of claim 1 , wherein the compound has formula IV

or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein:
Q 2 is hydrogen, alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, —R 4 OR 5 , —R 4 SR 5 , —R 4 N(R 6 )(R 7 ), R 4 OR 4 N(R 6 )(R 7 ) or R 4 OR 4 C(J)N(R 6 )(R 7 );
J is O or S;
each R 4 is independently alkylene, alkenylene or a direct bond;
each R 5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and
R 6 and R 7 are each independently hydrogen or alkyl.

9 . The compound of claim 1 , wherein the compound has formula V

or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein:
Q 3 and Q 4 are each independently hydrogen, alkyl,

Assignees

• Celgene Corp

Inventors

• Hansen Joshua
• Correa Matthew Daniel
• Raheja Raj
• Lopez-Girona Antonia
• Rychak Emily
• Man Hon-Wah
• Muller George W
• Khalil Ehab M

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P35/00

  Antineoplastic agents · CPC title