Heteroaryl substituted pyrazole derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis

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Quick Facts

Patent No.: US 8,796,253
App. No.: 12/600,640
Granted: Aug 5, 2014
Kind: B2

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Abstract

This invention relates to novel heteroaryl substituted pyrazole compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients or therapeutic measures.

Claims (68)

1. A compound having the formula:

or a physiologically acceptable salt thereof, wherein:

A is heteroaryl optionally substituted with halogen or phenyl, or is heterocyclyl;

n is an integer from 0-3;

R 1 at each occurrence is independently halogen, —NR 6 C(O)R 7 , —C(O)R 6 , —C(O)OR 6 , —OC(O)R 6 , —OR 6 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , cyano, nitro, —C(O)NR 6 R 7 , —SO 2 NR 6 R 7 , or —NR 6 R 7 ,

R 1 is independently aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl each optionally substituted with one or more halogen, OR 6 or NR 6 R 7 groups;

R 2 is aryl optionally substituted with 1, 2 or 3 R 8 groups or heteroaryl optionally substituted with 1, 2 or 3 R 8 groups, when A is mono- or bicyclic heteroaryl or mono- or bicyclic heterocyclyl,

R 2 is hydrogen, halogen, cyano, alkyl optionally substituted with up to 3 fluoro atoms, alkyloxy optionally substituted with up to 3 fluoro atoms, cycloalkyl, aryloxy, aroyl, aralkyl optionally substituted with halogen, or heterocyclyl optionally substituted with alkyl, when A is bi- or tricyclic heteroaryl or mono-, bi- or tricyclic heterocyclyl;

R 3 and R 4 are each independently hydrogen, halogen, —OR 6 , —SR 6 , —NR 6 R 7 , alkyl optionally substituted with one or more halogen, R 6 , —OR 6 or —NR 6 R 7 groups, or cycloalkyl optionally substituted with one or more halogen, R 6 , —OR 6 or —NR 6 R 7 groups;

R 5 is hydrogen, oxo, or alkyl optionally substituted with one or more halogen, —OR 6 or —NR 6 R 7 groups;

each occurrence of R 6 or R 7 may be the same or different and is independently hydrogen, or aryl, heteroaryl, heterocyclyl, alkyl, or cycloalkyl each of which may be optionally substituted with one or more hydrogen, halogen, —OR 9 or —NR 9 R 10 groups;

each occurrence of R 8 may be the same or different and is independently

hydrogen, halogen, —NR 9 C(O)R 10 , —NR 9 C(O)OR 10 , —C(O)R 9 , —C(O)OR 9 , —OC(O)R 9 , —OR 9 , —SR 9 , —S(O)R 9 , —SO 2 R 9 , cyano, nitro, —C(O)NR 9 R 10 , —SO 2 NR 9 R 10 , —NR 9 R 10 , or

aryl, heteroaryl, heterocyclyl, alkyl, or cycloalkyl, each of which may be optionally substituted with one or more halogen, R 11 , —OR 9 or —NR 9 R 10 groups;

each occurrence of R 9 and R 10 may be the same or different and is independently hydrogen, or aryl, heteroaryl, heterocyclyl, alkyl, cycloalkyl, aralkyl, or heterocyclylalkyl each of which may be optionally substituted with one or more hydrogen, halogen, hydroxyl, alkyloxy, cycloalkyloxy, aryloxy, amino, alkylamino, cycloalkylamino, arylamino, alkyl, cycloalkyl, alkylcarbonyl or alkoxycarbonyl groups;

each occurrence of R 11 may be the same or different and is independently hydrogen, oxo, aryl, heteroaryl, heterocyclyl, alkyl, cycloalkyl, —C(O)R 9 , —C(O)OR 9 , —NR 12 C(O)R 13 , —N[C(O)R 13 ] 2 , —NR 12 C(O)OR 13 , or —N[C(O)OR 13 ] 2 ;

R 12 is hydrogen or alkyl; and

R 13 is alkyl.

2. The compound of claim 1 , wherein

A is heteroaryl or heterocyclyl;

n is an integer from 0-3;

R 1 at each occurrence is independently halogen, —NR 6 C(O)R 7 , —C(O)R 6 , —C(O)OR 6 , —OC(O)R 6 , —OR 6 , —SR 6 , cyano, nitro, —C(O)NR 6 R 7 , —SO 2 NR 6 R 7 , or —NR 6 R 7 ,

R 1 is independently aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl each optionally substituted with one or more halogen, OR 6 or NR 6 R 7 groups;

R 2 is aryl optionally substituted with 1, 2 or 3 R 8 groups or heteroaryl optionally substituted with 1, 2 or 3 R 8 groups;

R 5 is hydrogen, oxo, or alkyl optionally substituted with one or more halogen, —OR 6 or —NR 6 R 7 groups;

each occurrence of R 8 may be the same or different and is independently

hydrogen, halogen, —NR 9 C(O)R 10 , —C(O)R 9 , —C(O)OR 9 , —OC(O)R 9 , —OR 9 , —SR 9 , cyano, nitro, —C(O)NR 9 R 10 , —SO 2 NR 9 R 10 , —NR 9 R 10 , or

aryl, heteroaryl, heterocyclyl, alkyl, or cycloalkyl each of which may be optionally substituted with one or more halogen, R 11 , —OR 9 or —NR 9 R 10 groups; and

each occurrence of R 9 and R 10 may be the same or different and is independently hydrogen, or aryl, heteroaryl, heterocyclyl, alkyl, or cycloalkyl each of which may be optionally substituted with one or more hydrogen, halogen, hydroxyl, alkyloxy, cycloalkyloxy, aryloxy, amino, alkylamino, cycloalkylamino, or arylamino groups;

each occurrence of R 11 may be the same or different and is independently hydrogen, halogen, aryl, oxo, heteroaryl, heterocyclyl, alkyl, cycloalkyl, hydroxyl, alkyloxy, cycloalkyloxy, aryloxy, amino, alkylamino, cycloalkylamino, or arylamino groups.

3. The compound of claim 2 having the formula

4. The compound of claim 3 , wherein