Pyrazolopyridine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9029546-B2
Application number	US-201314030153-A
Country	US
Kind code	B2
Filing date	Sep 18, 2013
Priority date	Jul 23, 2008
Publication date	May 12, 2015
Grant date	May 12, 2015

Abstract

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

First claim

We claim:

1. A compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —H, halogen, —OR′, —N(R′) 2 , —C(O)OR′, —C(O)N(R′) 2 , —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO 2 , C1-C10 aliphatic optionally and independently substituted with one or more J a , or C3-C8 cycloaliphatic optionally and independently substituted with one or more J b ;
R 2 is —H, halogen, —OR′, —N(R′) 2 , —C(O)OR′, —C(O)N(R′) 2 , —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO 2 , C1-C10 aliphatic optionally and independently substituted with one or more J a , or C3-C8 cycloaliphatic optionally and independently substituted with one or more J b ;
Q is —N—, —O—, or —S—;
ring B is a 6-membered monocyclic heteroaromatic ring optionally fused to an aromatic or non-aromatic ring; and ring B is optionally substituted with one Y and independently further optionally and independently substituted with one or more J c ;
Y is —Y1-Q1;
Y1 is absent, or C1-10 aliphatic, wherein up to three methylene units of Y1 are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O) p —; and Y1 is optionally and independently substituted with one or more J d ;
Q1 is absent, or a C3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q1 is optionally and independently substituted with one or more J b ; wherein when B is substituted with Y then Y1 and Q1 are not both absent;
R 3 is absent, —H, or C1-C6 alkyl optionally and independently substituted with one or more J a ;
R 4 is a C1-10 aliphatic, wherein up to three methylene units of R 4 are optionally and independently replaced by G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O) p —; and R 4 is optionally and independently substituted with one or more J a ; each R′ is independently —H, or C1-C6 alkyl optionally and independently substituted with one or more J a ;
each J a is independently halogen, —OR, —N(R) 2 , —C(O)R, —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)OR, —CN, —NO 2 , or oxo;
each J b is independently halogen, —OR, —N(R) 2 , —C(O)R, —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)OR, —CN, —NO 2 , oxo, or C1-C6 alkyl optionally and independently substituted with one or more J a ;
each J c is independently halogen, —OR′, —N(R′) 2 , —C(O)R, —C(O)OR′, —C(O)N(R′) 2 , —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO 2 , or C1-C10 aliphatic optionally and independently substituted with one or more J a , or C3-C8 cycloaliphatic optionally and independently substituted with one or more J b ;
each J a is independently halogen, —OH, —NH 2 , —C(O)H, —C(O)OH, —C(O)NH 2 , —NHC(O)H, —NHC(O)OH, —CN, or —NO 2 ;
each R is independently —H or C1-C6 alkyl; and
each p is independently 0, 1, or 2.

2. A compound of claim 1 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —H, halogen, —OR′, —N(R′) 2 , —C(O)OR′, —C(O)N(R′) 2 , —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO 2 , C1-C10 aliphatic optionally and independently substituted with one or more J a , or C3-C8 cycloaliphatic optionally and independently substituted with one or more J b ;
R 2 is —H, halogen, —OR′, —N(R′) 2 , —C(O)OR′, —C(O)N(R′) 2 , —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO 2 , C1-C10 aliphatic optionally and independently substituted with one or more J a , or C3-C8 cycloaliphatic optionally and independently substituted with one or more J b ;
Q is —N—, —O—, or —S—;
ring B is a 6-membered monocyclic heteroaromatic ring optionally fused to an aromatic or non-aromatic ring; and ring B is optionally substituted with one Y and independently further optionally and independently substituted with one or more J c ;
Y is —Y1-Q1;
Y1 is absent, or C1-10 aliphatic, wherein up to three methylene units of Y1 are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O) p —; and Y1 is optionally and independently substituted with one or more J d ;
Q1 is absent, or a C3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q1 is optionally and independently substituted with one or more J b ; wherein when B is substituted with Y then Y1 and Q1 are not both absent;
R 3 is absent, —H, or C1-C6 alkyl optionally and independently substituted with one or more J a ;
R 4 is a C1-10 aliphatic, wherein up to three methylene units of R 4 are optionally and independently replaced by G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O) p —; and R 4 is optionally and independently substituted with one or more J a ; each R′ is independently —H, or C1-C6 alkyl optionally and independently substituted with one or more J a ;
each J a is independently halogen, —OR, —N(R) 2 , —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)OR, —CN, —NO 2 , or oxo;
each J b is independently halogen, —OR, —N(R) 2 , —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)OR, —CN, —NO 2 , oxo, or C1-C6 alkyl optionally and independently substituted with one or more J a ;
each J c is independently halogen, —OR′, —N(R′) 2 , —C(O)OR′, —C(O)N(R′) 2 , —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO 2 , or C1-C10 aliphatic optionally and independently substituted with one or more J a , or C3-C8 cycloaliphatic optionally and independently substituted with one or more J b ;
each J d is independently halogen, —OH, —NH 2 , —C(O)H, —C(O)OH, —C(O)NH 2 , —NHC(O)H, —NHC(O)OH, —CN, or —NO 2 ;
each R is independently —H or C1-C6 alkyl; and
each p is independently 0, 1, or 2.

3. A compound of claim 2 represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —H, halogen, —OR′, —N(R′) 2 , —C(O)OR′, —C(O)N(R′) 2 , —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO 2 , C1-C10 aliphatic optionally and independently substituted with one or more J a , or C3-C8 cycloaliphatic optionally and independently substituted with one or more J b ;
R 2 is —H, halogen, —OR′, —N(R′) 2 , —C(O)OR′, —C(O)N(R′) 2 , —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO 2 , C1-C10 aliphatic optionally and independently substituted with one or more J a , or C3-C8 cycloaliphatic optionally and independently substituted with one or more J b ;
Q is —N—, —O—, or —S—;
ring B is a 6-membered monocyclic heteroaromatic ring optionally fused to an aromatic or non-aromatic ring; and ring B is optionally substituted with one Y and independently further optionally and independently substituted with one or more J c ;
Y is —Y1-Q1;
Y1 is absent, or C1-10 aliphatic, wherein up to three methylene units of Y1 are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O) p —; and Y1 is optionally and independently substituted with one or more J d ;
Q1 is absent, or a C3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q1 is optionally and independently substituted with one or more J b ; wherein Y1 and Q1 are not both absent;
R 3 is absent, —H, or C1-C6 alkyl optionally and independently substituted with one or more J a ;
R 4 is a C1-10 aliphatic, wherein up to three methylene units of R 4 are optionally and independently replaced by G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O) p —; and R 4 is optionally and independently substituted with one or more J a ;
each R′ is independently —H, or C1-C6 alkyl optionally and independently substituted with one or

Assignees

• Vertex Pharma

Inventors

• Boyall Dean
• Brenchley Guy
• Fraysse Damien
• Jimenez Juan-Miguel
• Settimo Luca

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P31/18

  for HIV · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title