Antiproliferative compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9968596-B2
Application number	US-201715723065-A
Country	US
Kind code	B2
Filing date	Oct 2, 2017
Priority date	Jul 11, 2014
Publication date	May 15, 2018
Grant date	May 15, 2018

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 method of synthesizing a compound of Formula I:

or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising contacting

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 Q groups, 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 method of claim 1 , further comprising reduction of

to obtain

3. The method of claim 2 , further comprising contacting

with zinc cyanide and palladium to obtain

4. The method of claim 3 , further comprising contacting

where R is alkyl, with

to obtain

5. The method of claim 4 , further comprising bromination of

to obtain

6. The method of claim 5 , further comprising esterification of

to obtain

7. The method of claim 1 comprising contacting 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate with 2-(4-chlorophenyl)-2,2-difluoroacetic acid to obtain 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide.

8. The method of claim 7 , wherein the contacting step is conducted in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate in a solvent.

9. The method of claim 8 , wherein the solvent is dimethyl formamide.

10. The method of claim 1 , wherein the reduction is performed using methanesulfonic acid, 10% dry palladium on carbon in a solvent.

11. The method of claim 10 , wherein the solvent is dry dimethylacetamide.

12. The method of claim 3 , wherein the contacting is performed in the presence of 1,1′ bis(diphenylphosphino)ferrocene, zinc cyanide and zinc acetate in a solvent, followed by tris(dibenzylideneacetone)dipalladium.

13. The method of claim 12 , wherein the solvent is dimethyl formamide.

14. The method of claim 4 , comprising contacting methyl-4-bromo-2-(bromomethyl) benzoate with 3-aminopiperidine-2,6-dione.hydrochloride to obtain 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

15. The method of claim 5 , wherein the bromination is performed using N-bromosuccinate and azo-isobutyronitrile.

16. The method of claim 6 , wherein the esterification is performed by contacting 4-bromo-2-methylbenzoic acid with methanol in presence of an acid.

17. The method of claim 16 , wherein the acid is concentrated sulfuric acid.

18. The method of claim 1 , wherein R 2 and R 3 are each fluoro.

19. The method of claim 1 , 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.

20. The method of claim 1 , 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.

21. The method of claim 1 , 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, alken

Assignees

• Celgene Corp

Inventors

• Cathers Brian E
• Correa Matthew Daniel
• Hansen Joshua
• Lopez-Girona Antonia
• Khalil Ehab M
• Macbeth Kyle
• Man Hon-Wah
• Muller George W
• Pourdehnad Michael
• Raheja Raj

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P7/00

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