IP Library › Granted Patent US 8,293,757

Granted Patent B2

US 8,293,757 · App. 12/674,416 · Granted Oct 23, 2012

5-(4-(haloalkoxy)phenyl) pyrimidine-2-amine compounds and compositions as kinase inhibitors

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,293,757
App. No.: 12/674,416
Granted: Oct 23, 2012
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention provides compounds of formula (1) and pharmaceutical compositions thereof, which are useful as protein kinase inhibitors, as well as methods for using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated kinase activity. In some embodiments, the invention provides methods for using such compounds to treat, ameliorate or prevent diseases or disorders that involve abnormal activation of c-kit, PDGFRα, PDGFRβ, CSF1R, AbI, BCR-AbI, CSK, JNK1, JNK2, p38, p70S6K, TGFβ, SRC, EGFR, trkB, FGFR3. Fes, Lck, Syk, RAF, MKK4, MKK6, SAPK2β, BRK, Fms, KDR, c-rapor b-raf kinases.

Claims (164)

1. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof;

wherein:

R 1 is a haloalkyl having 1-6 fluorine atoms;

R 2 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, each of which may be optionally substituted with halo, amino or hydroxyl groups; halo, cyano, nitro, (CR 2 ) k OR 7 , (CR 2 ) k O(CR 2 ) 1-4 R 7 , (CR 2 ) k SR 7 , (CR 2 ) k NR 9 R 10 , (CR 2 ) k C(O)O 0-1 R 7 , OC(O)R 7 , (CR 2 ) k C(S)R 7 , (CR 2 ) k C(O)NR 9 R 10 , (CR 2 ) k C(O)NR(CR 2 ) 0-6 C(O)O 0-1 R 7 , (CR 2 ) k NRC(O)O 0-1 R 7 , (CR 2 ) k S(O) 1-2 NR 9 R 10 , (CR 2 ) k S(O) 1-2 R 8 , (CR 2 ) k NRS(O) 1-2 R 8 or (CR 2 ) k R 6 ; or any two adjacent R 2 groups together may form an optionally substituted 5-8 membered carbocyclic, heterocyclic, aryl or heteroaryl ring;

R 3 is selected from the group consisting of

R 9 and R 10 are independently H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, each of which may be optionally substituted with halo, amino, hydroxyl, alkoxy, cyano, carboxyl or R 6 ; (CR 2 ) k CN, (CR 2 ) 1-6 NR 7 R 7 , (CR 2 ) 1-6 OR 7 , (CR 2 ) k C(O)O 0-1 R 7 , (CR 2 ) k C(O)NR 7 R 7 or (CR 2 ) k —R 6 ;

R 6 is an optionally substituted C 3-7 cycloalkyl, C 6-10 aryl, or a 5-10 membered heteroaryl or 5-7 membered heterocyclic ring;

R 7 and R 8 are independently (CR 2 ) k— R 6 or C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, each of which may be optionally substituted with halo, amino, amido, or hydroxyl, alkoxy, cyano, carboxyl or R 6 ;

or R 7 is H;

each R is H or C 1-6 alkyl;

each k is 0-6; and

j and m are independently 0-4.

2. The compound of claim 1 , wherein R 1 is —CHF 2 , —CF 3 , —CH 2 CF 3 , —CF 2 CH 3 , or —CH 2 CF 3 .

3. The compound of claim 2 , wherein R 1 is —CHF 2 .

4. The compound of claim 1 , wherein R 2 if present, is halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy or CO 2 R 7 and R 7 is H or C 1-6 alkyl.

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

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-methylpiperidine-2-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1S,2R,5R)-N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)piperidine-2-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-5-oxopyrrolidine-2-carboxamide;

(R)-N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-5-oxopyrrolidine-2-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-6-oxopiperidine-3-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-6-fluoropyridine-3-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1H-imidazole-5-carboxamide;

N-(2-methyl-5-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-5-oxopyrrolidine-2-carboxamide;

(S)-N-(2-methyl-5-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-5-oxopyrrolidine-2-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-cyclopropyl-5-oxopyrrolidine-3-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-ethyl-6-oxopiperidine-3-carboxamide;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-N-(2-fluoroethyl)-3-hydroxypropanamide;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one;

(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one;

(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-hydroxypiperidin-1-yl)propan-1-one;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-(2-hydroxypropyl)propanamide;

(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamide;

(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((R)-2-hydroxypropyl)propanamide;

(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide;

(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((S)-2-hydroxypropyl)propanamide;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-(4-hydroxycyclohexyl)propanamide;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1r,4r)-4-hydroxycyclohexyl)propanamide;

(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1r,4R)-4-hydroxycyclohexyl)propanamide;

(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1r,4R)-4-hydroxycyclohexyl)propanamide;

(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4S)-4-hydroxycyclohexyl)propanamide;

(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4S)-4-hydroxycyclohexyl)propanamide;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1s,4s)-4-hydroxycyclohexyl)propanamide;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(3-hydroxypiperidin-1-yl)propan-1-one;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one;

(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one;

(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((S)-3-hydroxypiperidin-1-yl)propan-1-one;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one;

(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one;

(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-((R)-3-hydroxypiperidin-1-yl)propan-1-one;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-(2-hydroxycyclopentyl)propanamide;

(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1R,2R)-2-hydroxycyclopentyl)propanamide;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide;

(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1R,2R)-2-hydroxycyclopentyl)propanamide;

(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide;

(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide;

(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2S)-2-hydroxycyclopentyl)propanamide;

(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-N-((1S,2R)-2-hydroxycyclopentyl)propanamide;

2-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(4-hydroxypiperidin-1-yl)prop-2-en-1-one;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(4-hydroxypiperidin-1-yl)ethanone;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-one;

(R)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-one;

(S)-2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(4-methylpiperazin-1-yl)propan-1-one;

2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxy-1-(3-(trifluoromethyl)piperazin-1-yl)propan-1-one;

2-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(3-(trifluoromethyl)-4-methylpiperazin-1-yl)-3-hydroxypropan-1-one;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methanesulfonyl -piperazine-1-carboxamide;

1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(1,3-dimethyl-1H-pyrazol-5-yl)urea;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethyl)piperazine-1-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-4,7-diazaspiro[2.59]octane-7-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethy)-4,7-diazaspiro[2.5]octane-7-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(trifluoromethyl)piperazine-1-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-3-(trifluoromethyl)piperazine-1-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-3-oxopiperazine-1-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethyl)-3-oxopiperazine-1-carboxamide;

4-(4-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)-1-methylpiperazin-2-one;

4-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)-1-(2-hydroxyethyl)piperazin-2-one;

4-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoyl)piperazin-2-one; and

(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)(3-(trifluoromethyl)piperazin-1-yl)methanone.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure of Formula (1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:

wherein:

R 1 is a haloalkyl having 1-6 fluorine atoms;

R 3 is selected from the group consisting of

R 9 and R 10 are independently H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, each of which may be optionally substituted with halo, amino, hydroxyl, alkoxy, cyano, carboxyl or R 6 ; (CR 2 ) k CN, (CR 2 ) 1 - 6 NR 7 R 7 , (CR 2 ) 1-6 OR 7 , (CR 2 ) k C(O)O 0-1 R 7 , (CR 2 ) k C(O)NR 7 R 7 or (CR 2 ) k— R 6 ;

R 6 is an optionally substituted C 3-7 cycloalkyl, C 6-10 aryl, or a 5-10 membered heteroaryl or 5-7 membered heterocyclic ring;

or R 7 is H;

each R is H or C 1-6 alkyl;

each k is 0-6; and

j and m are independently 0-4.

7. The pharmaceutical composition of claim 6 , wherein the compound is selected from the group consisting of:

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-1-methylpiperidine-2-carboxamide;

N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-azabicyclol[3.1.0]hexane-2-carboxamide;

(1S,2R,5R)-N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-azabicyclol[3.1.0]hexane-2-carboxamide;