Inhibitors of histone deacetylase

• US 8,598,168 B2
• Filed: 04/05/2007
• Issued: 12/03/2013
• Est. Priority Date: 04/07/2006
• Status: Expired due to Fees

• Current Assignee: 92229129 Quebec Inc.
• Original Assignee: MethylGene, Inc.
• Inventors: Moradei, Oscar, Paquin, Isabelle, Frechette, Sylvie, Mallais, Tammy, Roy, Simon, Machaalani, Roger, Vaisburg, Arkadii, Tessier, Pierre, Smil, David, Leit, Silvana, Dziel, Robert, Besterman, Jeffrey M
• Primary Examiner(s): RICCI, CRAIG D
• Application Number:
  US11/696,880
• Publication Number:
  US 20080132503A1
• Time in Patent Office: 2,434 Days
• Field of Search: None
• US Class Current: 514/235.5
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 235/56 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/40 having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 271/28 to a carbon atom of a non-condensed six-membered aromatic ring
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 207/325 with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/61 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/89 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 267/08 having the hetero atoms in positions 1 and 4
• CPC Class Codes: C07D 277/28 Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 277/36 Sulfur atoms
• CPC Class Codes: C07D 295/155 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/52 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 317/58 Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 333/20 by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 333/28 : Halogen atoms
• CPC Class Codes: C07D 333/36 : Nitrogen atoms
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/70 : attached in position 2
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 487/08 : Bridged systems

Abstract

The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

Claims

1. A compound of Formula I_O:

3. The compound of claim 1, wherein —

Z—

R is

12. The compound of claim 1 of the formula:

13. A composition comprising a compound according to any one of claims 1, 2, or 4-3, and a pharmaceutically acceptable carrier, excipient, or diluent.

2. A compound having formula III

6. The compound of claim 2, wherein X is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, oxo, hydroxy, C₁-C₃-hydrocarbyl, methoxy, HalCH₂—

O—

, Hal₂CH—

O—

, Hal₃C—

O—

(preferably F₃C—

O—

), NH₂—

, —

N(C₁-C₃alkyl)₂, —

CN, —

S(O)_0-2—

C₁-C₄alkyl, —

CF₃, and mono-, di-, or tri-halo substituted alkyl, or, when there are two optional substituents bonded to adjacent atoms of the phenyl, thienyl, or pyridyl they, together with the atoms to which they are bonded, optionally form a 5- or 6-membered cycloalkyl or heteroalkyl having 1, 2, or 3 annular heteroatoms.

7. The compound of claim 2, wherein Ar is optionally substituted with one or two substituents independently selected from the group consisting of halo, nitro, hydroxy, C₁-C₃-hydrocarbyl, methoxy, HalCH₂—

O—

, Hal₂CH—

O—

, Hal₃C—

O—

(preferably F₃C—

O—

), and mono-, di-, or tri-halo substituted alkyl.

8. The compound of claim 2, wherein X^a—

Y^a—

is selected from the group consisting of CH₃—

SO₂—

, CF₃—

C(O)—

NH—

, CH₃—

C(O)—

NH—

, ((CH₃)₂N)₂—

C═

N—

, (CH₃)₂N—

, CH₃—

O—

CH₂—

C(O)—

NH—

, (CH₃)₂N—

CH₂—

C(O)—

NH—

, CH₃CH₂—

N(CH₃)—

, CF₃CH₂—

NH—

, H—

, HO—

, CH₃—

O—

C(O)—

NH—

, H₂N—

, CH₃CH₂—

NH—

, H₂N—

C(O)—

, phenyl-CH₂—

O—

C(O)—

N(CH₂CH₃)—

, CH₃CH₂—

NH—

, F, CH₃—

O—

CH₂—

C(O)—

NH—

, heterocyclyl-heterocyclyl, heterocyclyl-heteroaryl, aryl-NH—

, heteroaryl-NH—

, (CH₃)₂N—

CH₂—

C(O)—

NH— and

HO—

CH₂CH₂—

NH—

.

9. The compound of claim 2 of the formula:

10. The compound of claim 2 of the formula:

11. The compound of claim 2 of the formula:

4. A compound that is

N-(4,4′

-diaminobiphenyl-3-yl)-4-(pyridin-3-yl)benzamide,

N-(4-amino-4′

-fluorobiphenyl-3-yl)-4-(pyridin-3-yl)benzamide,

N-(4-aminobiphenyl-3-yl)-4-(morpholinomethyl)benzamide,

N-(4-aminobiphenyl-3-yl)-4-(pyridin-3-yl)benzamide,

N-(4-amino-4′

-hydroxybiphenyl-3-yl)-4-(morpholinomethyl)benzamide,

(R)—

N-(4-aminobiphenyl-3-yl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)benzamide,

(R)—

N-(4-amino-4′

-hydroxybiphenyl-3-yl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)benzamide,

N-(4-amino-4′

-chlorobiphenyl-3-yl)-4-(morpholinomethyl)benzamide,

2-(dimethylamino)ethyl 4-(4-amino-4′

-chloro-3′

-fluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-3′

-fluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-3′

,4′

-dichlorobiphenyl-3-ylcarbamoyl)phenylcarbamate,

4-(4-amino-3′

,4′

-dichlorobiphenyl-3-ylcarbamoyl)phenyl acetate,

2-(dimethylamino)ethyl 4-(4-amino-3′

,4′

-difluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,

4-(4-amino-3′

,4′

-difluorobiphenyl-3-ylcarbamoyl)phenyl acetate,

2-(dimethylamino)ethyl 4-(4-aminobiphenyl-3-ylcarbamoyl)phenylcarbamate,

(S)—

N-(4-aminobiphenyl-3-yl)-4-(3-aminopyrrolidin-1-yl)benzamide,

2-morpholinoethyl 4-(4-aminobiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-3′

-(trifluoromethoxy)biphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-4′

-(trifluoromethoxy)biphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-3′

-fluoro-4′

-methoxybiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-4′

-fluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-4′

-chlorobiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-3′

-fluoro-4′

-hydroxybiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-2′

,4′

-difluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-4′

-(trifluoromethyl)biphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-2′

-fluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-4′

-hydroxybiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-3′

,4′

,5′

-trifluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-4′

-(dimethylamino)biphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-4′

-(methylthio)biphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-4′

-cyanobiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-2′

-fluoro-4′

-methoxybiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-3′

-fluoro-4′

-methylbiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-2′

,4′

,5′

-trifluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-4′

-(methylsulfinyl)biphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-2′

-fluoro-4′

-(trifluoromethyl)biphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-4′

-(methylsulfonyl)biphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4,4′

-diaminobiphenyl-3-ylcarbamoyl)phenylcarbamate,

2-(dimethylamino)ethyl 4-(4-amino-4′

-ethoxybiphenyl-3-ylcarbamoyl)phenylcarbamate,

(S)-4-(3-acetamidopyrrolidin-1-yl)-N-(4-aminobiphenyl-3-yl)benzamide,

(S)-4-(3-acetamidopyrrolidin-1-yl)-N-(4-amino-4′

-fluorobiphenyl-3-yl)benzamide,

2-(dimethylamino)ethyl 4-(4-amino-4′

-cyano-3′

-fluorobiphenyl-3-ylcarbamoyl)phenylcarbamate,

(S)—

N-(4-amino-4′

-fluorobiphenyl-3-yl)-4-(3-aminopyrrolidin-1-yl)benzamide,

(S)—

N-(4-aminobiphenyl-3-yl)-4-(3-(bis(dimethylamino)methyleneamino)pyrrolidin-1-yl)benzamide,

(S)—

N-(4-amino-4′

-fluorobiphenyl-3-yl)-4-(3-(bis(dimethylamino)methyleneamino)pyrrolidin-1-yl)benzamide,

N-(4-amino-3′

,4′

-difluorobiphenyl-3-yl)-4-(1,3-dioxoisoindolin-2-yl)benzamide,

N-(4-aminobiphenyl-3-yl)-3-(pyridin-3-yl)benzamide,

(S)—

N-(4-aminobiphenyl-3-yl)-4-(3-(methylsulfonamido)pyrrolidin-1-yl)benzamide,

N-(4-aminobiphenyl-3-yl)-4-(4-methylpiperazin-1-yl)benzamide,

N-(4-aminobiphenyl-3-yl)-4-(pyrrolidin-1-yl)benzamide,

(R)—

N-(4-aminobiphenyl-3-yl)-4-(3-aminopyrrolidin-1-yl)benzamide,

(S)—

N-(4-aminobiphenyl-3-yl)-4-(3-(2,2,2-trifluoroacetamido)pyrrolidin-1-yl)benzamide,

N-(4-aminobiphenyl-3-yl)-4-(4-methylpiperazin-1-ylsulfonyl)benzamide,

(S)—

N-(4-aminobiphenyl-3-yl)-4-(3-(dimethylamino)pyrrolidin-1-yl)benzamide,

(R)—

N-(4-aminobiphenyl-3-yl)-4-(3-hydroxypyrrolidin-1-yl)benzamide,

(S)-methyl 1-(4-(4-aminobiphenyl-3-ylcarbamoyl)phenyl)pyrrolidin-3-ylcarbamate,

N-(4-aminobiphenyl-3-yl)-4-(4-ethylpiperazin-1-yl)benzamide,

N-(4-aminobiphenyl-3-yl)-4-(4-aminopiperidin-1-yl)benzamide,

N-(4-aminobiphenyl-3-yl)-4-(3-oxopiperazin-1-yl)benzamide,

(S)—

N-(4-aminobiphenyl-3-yl)-4-(3-hydroxypyrrolidin-1-yl)benzamide,

(S)—

N-(4-aminobiphenyl-3-yl)-4-(3-(ethylamino)pyrrolidin-1-yl)benzamide,

N-(4-aminobiphenyl-3-yl)-4-(1H-imidazol-1-yl)benzamide,

(R)—

N-(4-amino-4′

-fluorobiphenyl-3-yl)-4-(3-aminopyrrolidin-1-yl)benzamide,

1-(4-(4-aminobiphenyl-3-ylcarbamoyl)phenyl)piperidine-4-carboxamide,

(S)—

N-(4-aminobiphenyl-3-yl)-4-(3-fluoropyrrolidin-1-yl)benzamide,

N-(4-aminobiphenyl-3-yl)-4-(3,3-difluoropyrrolidin-1-yl)benzamide,

(R)—

N-(4-amino-4′

-fluorobiphenyl-3-yl)-4-(3-(2-methoxyacetamido)pyrrolidin-1-yl)benzamide,

(R)—

N-(4-amino-4′

-fluorobiphenyl-3-yl)-4-(3-(methylsulfonamido)pyrrolidin-1-yl)benzamide,

(S)—

N-(4-aminobiphenyl-3-yl)-4-(3-(2-methoxyacetamido)pyrrolidin-1-yl)benzamide,

(S)—

N-(4-aminobiphenyl-3-yl)-4-(3-(2-(dimethylamino)acetamido)pyrrolidin-1-yl)benzamide,

(R)-4-(3-acetamidopyrrolidin-1-yl)-N-(4-amino-4′

-fluorobiphenyl-3-yl)benzamide,

(R)-methyl 1-(4-(4-amino-4′

-fluorobiphenyl-3-ylcarbamoyl)phenyl)pyrrolidin-3-ylcarbamate,

N-(4-aminobiphenyl-3-yl)-4-(piperazin-1-yl)benzamide,

(S)—

N-(4-aminobiphenyl-3-yl)-4-(3-(2-hydroxyethylamino)pyrrolidin-1-yl)benzamide,

(S)—

N-(4-aminobiphenyl-3-yl)-4-(3-(2,2,2-trifluoroethylamino)pyrrolidin-1-yl)benzamide,

(R)—

N-(4-aminobiphenyl-3-yl)-4-(3-(dimethylamino)pyrrolidin-1-yl)benzamide,

(R)—

N-(4-aminobiphenyl-3-yl)-4-(3-(ethylamino)pyrrolidin-1-yl)benzamide,

N-(4-aminobiphenyl-3-yl)-4-(hydroxymethyl)benzamide,

(R)—

N-(4-aminobiphenyl-3-yl)-4-(3-methoxypyrrolidin-1-yl)benzamide,

N-(4-aminobiphenyl-3-yl)-4-(3-hydroxyazetidin-1-yl)benzamide,

N-(4-amino-4′

-fluorobiphenyl-3-yl)-4-(3-hydroxyazetidin-1-yl)benzamide,

(S)—

N-(4-amino-4′

-fluorobiphenyl-3-yl)-4-(3-hydroxypyrrolidin-1-yl)benzamide,

or a pharmaceutically acceptable salt thereof.

5. A compound that is

N-(4-aminobiphenyl-3-yl)-4-(morpholinomethyl)benzamide;

2-(dimethylamino)ethyl 4-(4-amino-3′

,4′

-difluorobiphenyl-3-ylcarbamoyl)phenylcarbamate;

2-(dimethylamino)ethyl 4-(4-amino-3′

-fluoro-4′

-methoxybiphenyl-3-ylcarbamoyl)phenylcarbamate;

2-(dimethylamino)ethyl 4-(4-amino-4′

-fluorobiphenyl-3-ylcarbamoyl)phenylcarbamate;

2-(dimethylamino)ethyl 4-(4-amino-2′

,4′

-difluorobiphenyl-3-ylcarbamoyl)phenylcarbamate;

(S)—

N-(4-aminobiphenyl-3-yl)-4-(3-hydroxypyrrolidin-1-yl)benzamide;

(R)—

N-(4-amino-4′

-fluorobiphenyl-3-yl)-4-(3-(2-methoxyacetamido)pyrrolidin-1-yl)benzamide;

N-(4-amino-4′

-fluorobiphenyl-3-yl)-4-(3-hydroxyazetidin-1-yl)benzamide;

(S)—

N-(4-amino-4′

-fluorobiphenyl-3-yl)-4-(3-hydroxypyrrolidin-1-yl)benzamide;

or a pharmaceutically acceptable salt thereof.