Compositions and methods for inhibition of the JAK pathway

• US 9,732,073 B2
• Filed: 12/18/2015
• Issued: 08/15/2017
• Est. Priority Date: 06/08/2005
• Status: Active Grant

• Current Assignee: Rigel Pharmaceuticals, Inc.
• Original Assignee: Rigel Pharmaceuticals, Inc.
• Inventors: Tso, Kin, Thota, Sambaiah, Keim, Holger, Taylor, Vanessa, Cooper, Robin, Wong, Brian, Li, Hui, Carroll, David, Argade, Ankush, Sran, Arvinder, Clough, Jeffrey, Bhamidipati, Somasekhar, Singh, Rajinder
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US14/974,143
• Publication Number:
  US 20160102084A1
• Time in Patent Office: 606 Days
• Field of Search: 544 12, 544324, 5142232, 514275
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/5383 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 31/695 Silicon compounds
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 285/22 : condensed with one six-membered ring
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems
• CPC Class Codes: C07F 7/0812 : comprising a heterocyclic ring
• CPC Class Codes: C07F 7/10 : containing nitrogen having a Si-N linkage

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.

Claims

1. A compound of formula V

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

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

5. A pharmaceutical formulation comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient, diluent, preservative, or stabilizer, or a combination thereof.

9. A method of treating a T-cell mediated autoimmune disease, comprising administering to a patient suffering from such an autoimmune disease an amount of a compound of claim 1 effective to treat the autoimmune disease.

10. A method of treating rheumatoid arthritis, comprising administering to a patient an amount of a compound of claim 1 effective to treat rheumatoid arthritis.

11. A method of treating or preventing a JAK kinase-mediated disease, comprising administering to a subject a compound of claim 1 in an amount effective to treat or prevent the JAK kinase-mediated disease.

12. The compound of claim 1, wherein R⁷ is selected from the group consisting of alkyl or substituted alkyl.

13. The compound of claim 1, wherein V is selected from the group consisting of C₁-C₃ alkylene, substituted C₁-C₃ alkylene, C₂-C₃ alkenylene and substituted C₂-C₃ alkenylene, wherein one or more of the carbon atoms have been replaced with a heteroatom selected from sulfur, S(O), S(O)₂, or NR⁸, where R⁸ is selected from the group consisting of hydrogen and alkyl, or is a bond participating in a —

N═

C<

site of unsaturation.

14. The compound of claim 1, wherein each R³ independently is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, halo, heterocyclic, and substituted heterocyclic.

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-Fluoro-N4-(4-methyl-3-oxo-benz[1,4]thiazin-6-yl)-N2-(3-piperidinosulfonylphenyl)-2,4-pyrimidinediamine.

15. A method of treating a T-cell mediated autoimmune disease, comprising administering to a patient suffering from such an autoimmune disease an amount of a compound of claim 4 effective to treat the autoimmune disease.

16. A method of treating rheumatoid arthritis, comprising administering to a patient an amount of a compound of claim 4 effective to treat rheumatoid arthritis.

17. A method of treating or preventing a JAK kinase-mediated disease, comprising administering to a subject a compound of claim 4 in an amount effective to treat or prevent the JAK kinase-mediated disease.

6. A method of inhibiting an activity of a JAK kinase, comprising contacting the JAK kinase with an amount of a compound effective to inhibit an activity of the JAK kinase, the compound having a formula V

7. A method of treating or preventing allograft transplant rejection in a transplant recipient, comprising administering to the transplant recipient a compound in an amount effective to treat or prevent the rejection, the compound having a formula V

8. A method of inhibiting a signal transduction cascade in which JAK3 kinase plays a role, comprising contacting a cell expressing a receptor involved in such a signaling cascade with a compound having a formula V