Compositions and methods for inhibition of the JAK pathway

Patent metadata

Field	Value
Publication number	US-9732073-B2
Application number	US-201514974143-A
Country	US
Kind code	B2
Filing date	Dec 18, 2015
Priority date	Jun 8, 2005
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

The invention encompasses compounds having formula I-V and the compositions and methods using these compounds in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK3, may be therapeutically useful.

First claim

What is claimed is:

1. A compound of formula V

or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl;
each of Z 1 , Z 2 , and Z 3 independently is carbon or nitrogen, wherein if Z 1 is nitrogen then Z 2 and Z 3 are carbon, if Z 2 is nitrogen then Z 1 and Z 3 are carbon, and if Z 3 is nitrogen then Z 1 and Z 2 are carbon, wherein if Z 1 , Z 2 , or Z 3 is nitrogen then SO 2 N(R 4 )R 5 is not attached to the nitrogen;
q is 0, 1, 2 or 3;
each R 3 independently is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic and substituted heterocyclic;
R 4 and R 5 together with the nitrogen atom bound thereto, form a heterocyclic or substituted heterocyclic group;
R 7 is selected from the group consisting of hydrogen, alkyl or substituted alkyl; and
V is selected from the group consisting of C 1 -C 3 alkylene, substituted C 1 -C 3 alkylene, C 2 -C 3 alkenylene and substituted C 2 -C 3 alkenylene, wherein one or more of the carbon atoms have been replaced with a heteroatom selected from oxygen, sulfur, S(O), S(O) 2 , or NR 8 , where R 8 is selected from the group consisting of hydrogen and alkyl, or is a bond participating in a —N═C< site of unsaturation.

2. The compound of claim 1 , wherein the compound has formula VA

or a pharmaceutically acceptable salt thereof;
X is fluoro or methyl;
q is 0, 1, 2 or 3;
each R 3 independently is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic and substituted heterocyclic;
R 4 and R 5 together with the nitrogen atom bound thereto, form a heterocyclic or substituted heterocyclic group;
R 7 is selected from the group consisting of hydrogen, alkyl or substituted alkyl; and
V is selected from the group consisting of C 1 -C 3 alkylene, substituted C 1 -C 3 alkylene, C 2 -C 3 alkenylene and substituted C 2 -C 3 alkenylene, wherein one or more of the carbon atoms have been replaced with a heteroatom selected from oxygen, sulfur, S(O), S(O) 2 , or NR 8 , where R 8 is selected from the group consisting of hydrogen and alkyl, or is a bond participating in a —N═C< site of unsaturation.

3. The compound of claim 1 , wherein the compound has a formula VB

or a pharmaceutically acceptable salt thereof;
X is fluoro or methyl;
q is 0, 1, 2 or 3;
each R 3 independently is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl or substituted cycloalkyl, halo, heterocyclic and substituted heterocyclic;
R 4 and R 5 together with the nitrogen atom bound thereto, form a heterocyclic or substituted heterocyclic group;
R 7 is selected from the group consisting of hydrogen, alkyl or substituted alkyl; and
V is selected from the group consisting of C 1 -C 3 alkylene, substituted C 1 -C 3 alkylene, C 2 -C 3 alkenylene and substituted C 2 -C 3 alkenylene, wherein one or more of the carbon atoms have been replaced with a heteroatom selected from oxygen, sulfur, S(O), S(O) 2 , or NR 8 , where R 8 is selected from the group consisting of hydrogen and alkyl, or is a bond participating in a —N═C< site of unsaturation.

4. A compound, selected from:
N2-(3-Aminosulphonyl-4-methylphenyl)-5-fluoro-N4-[3-oxo-4-(2-pyridylmethyl)-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;
N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-[3-oxo-4-(2-pyridylmethyl)-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;
N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxybenzyl)-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;
N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxybenzyl)-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;
N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;
N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;
N2-(3-Aminosulphonyl-4-methylphenyl)-5-fluoro-N4-[3-oxo-4-cyanomethyl-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine;
N2-(3-Aminosulphonyl-4-methylphenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxybenzyl)-benzo[1,4]thiazin-6-yl]-2,4-pyrimidinediamine;
N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxybenzyl)-benzo[1,4]thiazin-6-yl]-2,4-pyrimidinediamine;
N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulphonyl-4-methylphenyl)-5-fluoro-N4-(3-oxo-4-cyanomethyl-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulphonylphenyl)-5-fluoro-N4-(2,2,4-trimethyl-1,1,3-trioxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(4-Aminosulphonylphenyl)-5-fluoro-N4-(2,2,4-trimethyl-1,1,3-trioxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3,4-dihydro-(1H)-quinolin-2-one-6-yl]-5-fluoro-2,4-pyrimidinediamine;
N2-(3-Aminosulphonyl-4-methylphenyl)-5-methyl-N4-(3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;
N2-(4-Aminosulphonylphenyl)-5-methyl-N4-(3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulphonylphenyl)-5-methyl-N4-(3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulphonyl-4-methylphenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(4-Aminosulphonylphenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulphonylphenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulphonyl-4-methylphenyl)-5-fluoro-N4-(3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulfonyl-4-methoxy-5-methylphenyl)-N4-(2,2-difluoro-4H-benz[1,4]oxazin-3-on-6-yl)-5-fluoro-2,4-pyrimidinediamine;
5-Amino-N2-(3-amionsulfonylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;
N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-(4-methyl-3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-methyl-3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulfonylphenyl)-N4-[2,2,4-trimethyl-3-oxo-benz[1,4]oxazin-6-yl]-5-fluoro-2,4-pyrimidinediamine;
N2-(4-Aminosulfonylphenyl)-N4-[2,2,4-trimethyl-3-oxo-benz[1,4]oxazin-6-yl]-5-fluoro-2,4-pyrimidinediamine;
N2-(3-Aminosulphonyl-4-methyl-phenyl)-5-fluoro-N4-(3-oxo-4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulphonyl-4-methyl-phenyl)-5-fluoro-N4-(4-methyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulphonyl-4-methylphenyl)-N4-cyanomethyl-5-fluoro-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(4-Aminosulphonylphenyl)-N4-cyanomethyl-5-fluoro-N4-[3-oxo-4-methyl-benzo[1,4]thiazin-6-yl]-2,4-pyrimidinediamine;
N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-(4-methyl-3-oxo-benz[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-(4-methyl-3-oxo-benz[1,4]thiazin-6-yl)-2,4-pyrimidinediamine; or
5-

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Li Hui
• Thota Sambaiah
• Carroll David
• Argade Ankush
• Tso Kin
• Sran Arvinder
• Clough Jeffrey
• Keim Holger
• Bhamidipati Somasekhar
• Taylor Vanessa
• Cooper Robin
• Singh Rajinder
• Wong Brian

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/08

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

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title