Antiproliferative compounds, and their pharmaceutical compositions and uses

Patent metadata

Field	Value
Publication number	US-9938254-B2
Application number	US-201715400208-A
Country	US
Kind code	B2
Filing date	Jan 6, 2017
Priority date	Jan 8, 2016
Publication date	Apr 10, 2018
Grant date	Apr 10, 2018

Abstract

Compounds of formula A-I and B-I, compositions comprising the compounds, methods of making the compounds and methods of their uses are disclosed.

First claim

What is claimed is:

1. A compound of formula A-I:

or a stereoisomer or mixture of stereoisomers, tautomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, isotopologue or polymorph thereof, wherein:
each R is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl;
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, 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 or 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.

2. The compound of claim 1 , wherein the compound is of Formula A-II:

or a stereoisomer or mixture of stereoisomers, tautomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, isotopologue or polymorph thereof, wherein:
each R is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl;
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 each independently hydrogen or alkyl or 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.

3. The compound of claim 1 , wherein each R is independently H or (C 1 -C 6 )alkyl; 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 halo, alkyl, —R 4 OR 5 , —R 4 SR 5 or R 4 OR 4 C(O)N(R 6 )(R 7 ); each R 4 is independently a direct bond or alkylene; each R 5 is independently hydrogen, halo, alkyl or haloalkyl; and R 6 and R 7 are each independently hydrogen or alkyl.

4. The compound of claim 1 , wherein each R is independently is H or (C 1 -C 6 )alkyl; and 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 fluoro, chloro, methyl, —R 4 OR 5 , —R 4 N(R 6 )(R 7 ), —R 4 SR 5 or R 4 OR 4 C(O)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.

5. The compound of claim 1 , wherein each R is independently H or (C 1 -C 6 )alkyl and 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 N(R 6 )(R 7 ), —R 4 SR 5 or R 4 OR 4 C(O)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.

6. The compound of claim 1 , wherein the compound is of Formula A-III:

or a stereoisomer or mixture of stereoisomers, tautomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, isotopologue or polymorph thereof, wherein:
each R is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl;
each Q 1 is independently alkyl, halo, haloalkyl, alkoxyalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylakyl, 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;
R 6 and R 7 are each independently hydrogen or alkyl or 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.

7. The compound of claim 1 , wherein the compound is selected from the group consisting of:

8. A compound of Formula B-I:

or a stereoisomer or mixture of stereoisomers, tautomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, isotopologue or polymorph thereof, wherein:
each R′ is independently H or optionally substituted alkyl; or optionally substituted cycloalkyl;
R′ is H or optionally substituted alkyl;
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, 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 or 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.

9. The compound of claim 8 , wherein the compound is of Formula B-II:

or a stereoisomer or mixture of stereoisomers, tautomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, isotopologue or polymorph thereof, wherein:
each R is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl;
each R′ is independently is H or optionally substituted alkyl;
R 1

Assignees

• Celgene Corp

Inventors

• Alexander Matthew D
• Correa Matthew D
• Hansen Joshua
• Raheja Raj Kumar
• Sapienza John

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07F9/65583

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title