Phenylaminopyrimidine derivatives and methods of use

• US 7,232,825 B2
• Filed: 04/09/2004
• Issued: 06/19/2007
• Est. Priority Date: 05/02/2003
• Status: Expired due to Fees

• Current Assignee: Guoqing P. Chen
• Original Assignee: Guoqing P. Chen
• Inventors: Chen, Guoqing P
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US10/821,382
• Publication Number:
  US 20040224967A1
• Time in Patent Office: 1,166 Days
• Field of Search: 544/331, 514/252.18, 514/275
• US Class Current: 514/252.18
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

Abstract

The present invention relates to phenylaminopyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states such as cancers associated with tyrosine kinases, especially Bcr-Abl, to their use as medicaments and to their use in the manufacture of medicaments for use in the production of inhibition of tyrosine kinase reducing effects in warm-blooded animals such as humans.

Claims

1. A phenylaminopyrlmidine compound of formula (I)

2. A compound of Formula (I) according to claim 1, wherein

X is oxygen or sulfur,

Y is a direct bond, oxygen, nitrogen or lower alkyl,

Z is an aliphatic, cycloaliphatic, aryl or a heterocyclyl radical,

R₁ is heterocyclyl radical,

R₂ is hydrogen, halogen, halogenlower alkyl, lower alkyl or lower alkoxyl,

R₃ is hydrogen or lower alkyl,

R₄is:

(a) oxy-lower alkyl unsubstituted, mono or disubstituted amino;

oxy-lower alkyl morpholinyl, oxy-lower alkyl pyrrolidinyl, oxy-lower alkyl piperidinyl, oxy-lower alkyl piperazinyl, oxy-pyrrolidinyl, oxy-piperidinyl,

(b) lower alkyl oxy-lower alkyl unsubstituted, mono or disubstituted amino;

lower alkyl oxy-lower alkyl morpholinyl, lower alkyl oxy-lower alkyl pyrrolidinyl, lower alkyl oxy-lower alkyl piperidinyl, lower alkyl oxy-lower alkyl piperazinyl,

(c) mono or difluoro substituted lower alkyl unsubstituted, mono or disubstituted amino;

mono or difluoro substituted lower alkyl morpholinyl, mono or difluoro substituted lower alkyl pyzrolidinyl, mono or difluoro substituted lower alkyl piperidinyl, mono or difluoro substituted lower alkyl piperazinyl,

(d) amino lower alkyl morpholinyl, amino lower alkyl pyrrolidinyl, amino lower alkyl piperidinyl, amino lower alkyl piperazinyl,

(e) lower alkylamino lower alkyl unsubstituted, mono or disubstituted amino;

lower alkylamino lower alkyl morpholinyl, lower alkylamino lower alkyl pyrrolidinyl, lower alkylamino lower alkyl piperidinyl, lower alkylamino lower alkyl piperazinyl,

or a pharmaceutically acceptable salt thereof.

3. A compound of Fonnula (I) according to claim 1, wherein

X is oxygen or sulfur,

Y is a direct bond,

Z is an aliphatic, cycloaliphatic, aryl or a heterocyclyl radical,

R₁ is heterocyclyl radical,

R₂ is hydrogen, halogen, halogenlower alkyl, lower alkyl or lower alkoxyl,

R₃ is hydrogen or lower alkyl,

R₄ is:

(a) oxy-lower alkyl unsubstituted, mono or disubstituted amino;

oxy-lower alkyl morpholinyl, oxy-lower alkyl pyrrolidinyl, oxy-lower alkyl piperidinyl, oxy-lower alkyl piperazinyl, oxy-pyrrolidinyl, oxy-piperidinyl,

(b) lower alkyl oxy-lower alkyl unsubstituted, mono or disubstituted amino;

lower alkyl oxy-lower alkyl morpholinyl, lower alkyl oxy-lower alkyl pyrrolidinyl, lower alkyl oxy-lower alkyl piperidinyl, lower alkyl oxy-lower alkyl piperazinyl,

(c) mono or difluoro substituted lower alkyl unsubstituted, mono or disubstituted amino;

mono or difluoro substituted lower alkyl morpholinyl, mono or difluoro substituted lower alkyl pyrrolidinyl, mono or difluoro substituted lower alkyl piperidinyl, mono or difluoro substituted lower alkyl piperazinyl,

(d) amino lower alkyl morpholinyl, amino lower alkyl pyrrolidinyl, amino lower alkyl piperidinyl, amino lower alkyl piperazinyl,

(e) lower alkylamino lower alkyl unsubstituted, mono or disubstituted amino;

lower alkylamino lower alkyl morpholinyl, lower alkylamino lower alkyl pyrrolidinyl, lower alkylamino lower alkyl piperidinyl, lower alkylamino lower alkyl piperazinyl,

or a pharmaceutically acceptable salt thereof.

4. A compound of Formula (I) according to claim 1, wherein

X is oxygen or sulfur,

Y is a direct bond,

Z is aryl,

R₁ is heterocyclyl radical,

R₂ is hydrogen, halogen, halogenlower alkyl, lower alkyl or lower alkoxyl,

R₃is hydrogen or lower alkyl,

R₄is:

(a) oxy-lower alkyl unsubstituted, mono or disubstituted amino;

oxy-lower alkyl morpholinyl, oxy-lower alkyl pyrrolidinyl, oxy-lower alkyl piperidinyl, oxy-lower alkyl piperazinyl, oxy-pyrrolidinyl, oxy-piperidinyl,

(b) lower alkyl oxy-lower alkyl unsubstituted, mono or disubstituted amino;

lower alkyl oxy-lower alkyl morpholinyl, lower alkyl oxy-lower alkyl pyrrolidinyl, lower alkyl oxy-lower alkyl piperidinyl, lower alky) oxy-lower alkyl piperazinyl,

(c) mono or difluoro substituted lower alkyl unsubstituted, mono or disubstituted amino;

mono or difluoro substituted lower alkyl morpholinyl, mono or difluoro substituted lower alkyl pyrrolidinyl, mono or difluoro substituted lower alkyl piperidinyl, mono or difluoro substituted lower alkyl piperazinyl,

(d) amino lower alkyl morpholinyl, amino lower alkyl pyrrolidinyl, amino lower alkyl piperidinyl, amino lower alkyl piperazinyl,

(e) lower alkylamino lower alkyl unsubstituted, mono or disubstituted amino;

lower alkylamino lower alkyl morpholinyl, lower alkylamino lower alkyl pyrrolidinyl, lower alkylamino lower alkyl piperidinyl, lower aikylamino lower alkyl piperazinyl,

or a pharmaceutically acceptable salt thereof.

5. A compound of Formula (I) according to claim 1, wherein

X is oxygen or sulfur,

Y is a direct bond,

Z Is aryl,

R₁ is heterocyclyl radical,

R₂ is halogenlower alkyl or lower alkyl,

R₃ is hydrogen or lower alkyl,

R₄ is:

(a) oxy-lower alkyl unsubstituted, mono or disubstituted amino;

oxy-lower alkyl morpholinyl, oxy-lower alkyl pyrrolidinyl, oxy-lower alkyl piperidinyl, oxy-lower alkyl piperazinyl, oxy-pyrrolidinyl, oxy-piperidinyl,

(b) lower alkyl oxy-lower alkyl unsubstituted, mono or disubstituted amino;

lower alkyl oxy-lower alkyl morpholinyl, lower alkyl oxy-lower alkyl pyrrolidinyl, lower alkyl oxy-lower alkyl piperidinyl, lower alkyl oxy-lower alkyl piperazinyl,

(c) mono or difluoro substituted lower alkyl unsubstituted, mono or disubstituted amino;

mono or difluoro substituted lower alkyl morpholinyl, mono or difluoro substituted lower alkyl pyrrolidinyl, mono or difluoro substituted lower alkyl piperidinyl, mono or difluoro substituted lower alkyl piperazinyl,

(d) amino lower alkyl morpholinyl, amino lower alkyl pyrrolidinyl, amino lower alkyl piperidinyl, amino lower alkyl piperazinyl,

(e) lower alkylamino lower alkyl unsubstituted, mono or disubstituted amino;

lower alkylamino lower alkyl morpholinyl, lower alkylamino lower alkyl pyrrolidinyl, lower alkylamino lower alkyl piperidiny, lower alkylamino lower alkyl piperazinyl,

or a pharmaceutically acceptable salt thereof.

6. A compound of Formula (I) according to claim 1, wherein

X is oxygen or sulfur,

Y is a direct bond,

Z is aryl,

R₁ is heterocyclyl radical,

R₂ is lower alkyl,

R₃ is hydrogen,

R₄is:

(a) oxy-lower alkyl unsubstituted, mono or disubstituted amino;

oxy-lower alkyl morpholinyl, oxy-lower alkyl pyrrolidinyl, oxy-lower alkyl piperidinyl, oxy-lower alkyl piperazinyl, oxy-pyrrolidinyl, oxy-piperidinyl,

(b) lower alkyl oxy-lower alkyl unsubstituted, mono or disubstituted amino;

lower alkyl oxy-lower alkyl morpholinyl, lower alkyl oxy-lower alkyl pyrrolidinyl, lower alkyl oxy-lower alkyl piperidinyl, lower alkyl oxy-lower alkyl piperazinyl,

(c) mono or difluoro substituted lower alkyl unsubstituted, mono or disubstituted amino;

mono or difluoro substituted lower alkyl morpholinyl, mono or difluoro substituted lower alkyl pyrrolidinyl mono or difluoro substituted lower alkyl piperidinyl, mono or difluoro substituted lower alkyl piperazinyl,

(d) amino lower alkyl morpholnyl, amino lower alkyl pyrrolidinyl, amino lower alkyl piperidinyl, amino lower alkyl piperazinyl,

(e) lower alkylamino lower alkyl unsubstituted, mono or disubstituted amino;

lower alkylamino lower alkyl morpholinyl, lower alkylamino lower alkyl pyrrolidinyl, lower alkylamino lower alkyl piperidinyl, lower alkylamino lower alkyl piperazinyl,

or a pharmaceutically acceptable salt thereof.

7. A compound of Formula (I) according to claim 1, wherein

X is oxygen,

Y is a direct bond,

Z is phenyl,

R₁ is:

3-pyridyl or 4-pyridyl

R₂ is;

methyl, F, Cl or hydrogen,

R₃ is hydrogen,

8. A compound of Formula (I) according to claim 1 is selected from:

[4-(2-aminoethoxy)phenyl]-N-{4-methyl-3-[(4-(3-pyridyl)-pyrimidin-2-yl)amino]phenyl}carboxamide

[4-(fluoropiperazinylmethyl)phenyl]-N-{4-methyl-3-[(4-(3-pyridy)-pyrimidin-2-yl)amino]phenyl}carboxamide

N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}-{4-[(1-methylpyrrolidin -2-yl)methoxy]phenyl}carboxamide

[4-(aminofluoromethyl)phenyl]-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}carboxamide

{4-[fluoro(4-methylpiperazinyl)methyl]phenyl}-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}carboxamide

[4-(aminodifluoromethyl)phenyl]-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}carboxamide

(4-{fluoro[(1-methylypyrrolidin)-3-yl)amino]methyl}phenyl)-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}carboxamide

{4-[fluoro(methypyrrolidin-3-ylamino)methyl]phenyl}-N-{4-methyl-3-[(4-3-pyridyl)pyrimidin-2-yl)amino]phenyl}carboxamide

[4-({[2-(dimethylamino)ethyl]amino}fluoromethyl)phenyl]-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}carboxamide

[4-(difluoropiperazinylmethyl)phenyl]-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}carboxamide

{4-[difluoro(4-methylpiperazinyl)methyl]phenyl}-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}carboxamide

[4-({[2-(dimethylamino)ethyl]amino}difluoromethyl)phenyl]-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]pbenyl}carboxamide

(4-{fluoro[methyl(1-methylpyrrolidin-3-yl)amino]methyl}-phenyl)-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}carboxamide

{4-[fluoro(pyrrolidin-3-ylamino)methyl]phenyl}-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}carboxamide

{4-[(4-ethylpipeazinyl)difluoromethyl]phenyl}-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin -2-yl)amino]phenyl}carboxamide {4-[(4-ethylpiperazinyl)fluoromethyl]phenyl}-N-{4-methyl-3-[(4-(3-(pyridyl)pyrimidin -2-yl)amino]phenyl}carboxamide

(4-{(difluoro[methyl(1-methylpyrrolidin-3-yl)amino]methyl}-phenyl)-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}carboxamide

{4-[difluoro(metlylpyrrolidin-3-ylamino)methyl]phenyl}-N-{(4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}carboxamide

[4-({[2-(dimethylamino)ethyl]amino}fluoromethyl)phenyl]-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}caxboxamide

{4-[difluoro(pyrrolidin-3-ylamino)methyl]phenyl}-N-{4-methyl-3-[(4-(3-pyridyl)pyrimidin-2-yl)amino]phenyl}caboxamide

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical acceptable salt according to any one of claims 1 to 8 is methanesulfonic acid salt.