IP Library › Granted Patent US 9,593,082

Granted Patent B2

US 9,593,082 · App. 12/030,069 · Granted Mar 14, 2017

Compositions and methods for inhibition of the JAK pathway

Inventors: Ankush Argade (Foster City, CA); Arvinder Sran (Fremont, CA); David Carroll (San Francisco, CA); Jeffrey Clough (Redwood City, CA); Kin Tso (San Francisco, CA); Somasekhar Bhamidipati (Foster City, CA); Sambaiah Thota (Fremont, CA); Rajinder Singh (Belmont, CA); Vanessa Taylor (San Francisco, CA); Hui Li (Santa Clara, CA); Esteban Masuda (Menlo Park, CA)

Assignee: Rigel Pharmaceuticals, Inc.

C07D239/48 A61K31/505 C07D401/12 C07D401/14 C07D403/12 C07D407/12 C07D413/12 C07D417/12

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Quick Facts

Patent No.: US 9,593,082
App. No.: 12/030,069
Granted: Mar 14, 2017
Kind: B2

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Abstract

The invention encompasses compounds having formula I 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, are therapeutically useful.

Claims (301)

1. A compound selected from the group consisting of:

I-1: N4-(3-Acetylamino-4-hydroxyphenyl)-N2-(3-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;

I-2: N4-(3-Acetylamino-4-hydroxyphenyl)-N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine;

I-3: N4-(3-Acetylamino-4-hydroxyphenyl)-N2-(4-aminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;

I-4: N4-(3-Chloro-4-methoxyphenyl)-N2-(3-N,N-dimethylaminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;

I-5: N4-(3-Chloro-4-methoxyphenyl)-N2-(4-N,N-dimethylaminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;

I-6: N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;

I-7: N2-(3-Aminosulfonyl-4-chlorophenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;

I-8: 5-Fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;

I-9: N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;

I-10: N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-methyl-4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;

I-11: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3-chloro-4-(prop-2-ynyloxy)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-12: N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-fluoro-4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;

I-13: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(but-2-ynyloxy)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-14 N2-(4-methyl-3-propionylaminosulfonylphenyl)-5-fluoro-N4[-14-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;

I-15: N2-[3-Aminosulfonyl-4-(2-propyl)phenyl]-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;

I-16: N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynylamino)phenyl]-2,4-pyrimidinediamine;

I-17: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-{4-[bis(prop-2-ynyl)amino]phenyl}-5-fluoro-2,4-pyrimidinediamine;

I-18: 5-Fluoro-N2-(4-methyl-3-methylaminosulfonylphenyl)-N4-{4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;

I-19: 5-Fluoro-N2-{[4-methyl-3-((1-methylpiperidin-4-yl)aminosulfonyl)]phenyl}-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;

I-20: N2-[3-Aminosulfonyl-4-(1-methylpiperazin-4-yl)phenyl]-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;

I-21: N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-{4-[(prop-2-ynyloxy)carbonylaminomethyl]phenyl}-2,4-pyrimidinediamine;

I-22: N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-{4-[(prop-2-ynyloxy)carbonylaminomethyl]phenyl}-2,4-pyrimidinediamine;

I-23: N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;

I-24: N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;

I-25: N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;

I-26 5-Fluoro-N2-[3-(prop-2-ynylaminosulfonyl)phenyl]-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine;

I-27: N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;

I-28: N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;

I-29: N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[3-(prop-2-ynylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;

I-30: N2-(3-Aminosulfonyl-4-methylphenyl)-5-methyl-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-31: N2-(3-Aminosulfonylphenyl)-5-methyl-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-32: N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-33: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(2-propynyloxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;

I-34: N2-(3-Aminosulfonyl-4-methylphenyl)-5-chloro-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-35: N2-(4-Aminosulfonylphenyl)-5-chloro-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-36: N2-(3-Aminosulfonylphenyl)-5-chloro-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-37: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(3-butynyloxy)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-38: N2-(4-Aminosulfonylphenyl)-N4-[4-(3-butynyloxy)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-39: N2-(3-Aminosulfonylphenyl)-N4-[4-(3-butynyloxy)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-40: N2-(3-Aminosulfonyl-4-methylphenyl)-5-cyano-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-41: N2-(3-Aminosulfonylphenyl)-5-cyano-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-42: N2-(4-Aminosulfonylphenyl)-5-cyano-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-43: N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-44: N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-45: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(3-butynyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-46: N2-(3-Aminosulfonylphenyl)-N4-[4-(2-propynyloxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;

I-47: N2-(4-Aminosulfonylphenyl)-N4-[4-(2-propynyloxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;

I-48: N2-(3-Aminosulfonyl-4-methylphenyl)-5-cyclopropyl-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-49: 5-Fluoro-N2-[4-methyl-3-(N-propionylaminosulfonyl)phenyl]-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine Potassium Salt;

I-50: 5-Fluoro-N2-[4-methyl-3-(N-propionylaminosulfonyl)phenyl]-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine Calcium Salt;

I-51: N2-(4-Aminosulfonylphenyl)-N4- [4-(3-butynyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-52: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4(1-benzyl-1H-1,2,3-triazol-4-yl)1)methoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-53: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4((1-cyclohexyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-54: 5-Fluoro-N2-[3-(N-methoxyaminosulfonyl)phenyl]-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-55: 5-Fluoro-N2-[3((2-methyl-2-propoxy)aminosulfonyl)phenyl]-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-56: 5-Fluoro-N2-[4-methyl-3-(N-propionylaminosulfonyl)phenyl]-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine Arginine Salt;

I-57: 5-Fluoro-N2-[4-methyl-3-(N-propionylaminosulfonyl)phenyl]-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine Choline Salt;

I-59: N2-(3-Aminosulfonylphenyl)-N4-[4-(1H-benzimidazol-2-yl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-60: N2-(4-Aminosulfonylphenyl)-N4-[4-(1H-benzimidazol-2-yl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-61: N2-(3-Aminosulfonylphenyl)-N4-[4-(1H-benzimidazol-2-yl)phenyl]-5-methyl-2,4-pyrimidinediamine;

I-62: N2-(4-Aminosulfonylphenyl)-N4-[4-(1H-benzimidazol-2-yl)phenyl]-5-methyl-2,4-pyrimidinediamine;

I-63: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(1H-benzimidazol-2-yl)phenyl]-5-methyl-2,4-pyrimidinediamine;

I-64: N2-(3-Aminosulfonylphenyl)-N4-[4-(1H-benzimidazol-2-ylmethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-65: N2-(4-Aminosulfonylphenyl)-N4-[4-(1H-benzimidazol-2-ylmethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-66: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(1H-benzimidazol-2-ylmethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-67: N2-(3-Aminosulfonylphenyl)-N4-[4-(1H-benzimidazol-2-ylmethyl)phenyl]-5-methyl-2,4-pyrimidinediamine;

I-68: N2-(4-Aminosulfonylphenyl)-N4-[4-(1H-benzimidazol-2-ylmethyl)phenyl]-5-methyl-2,4-pyrimidinediamine;

I-69: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(1H-benzimidazol-2-ylmethyl)phenyl]-5-methyl-2,4-pyrimidinediamine;

I-70: N2-(3-Aminosulfonylphenyl)-N4-[3-(1H-benzimidazol-2-ylmethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-71: N2-(4-Aminosulfonylphenyl)-N4-[3-(1H-benzimidazol-2-ylmethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-72: N2-(3-Aminosulfonylphenyl)-N4-[3-(1H-benzimidazol-2-ylmethyl)phenyl]-5-methyl-2,4-pyrimidinediamine;

I-73: N2-(4-Aminosulfonylphenyl)-N4-[3-(1H-benzimidazol-2-ylmethyl)phenyl]-5-methyl-2,4-pyrimidinediamine;

I-74: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3-(4-cyanophenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-75: N2-(3-Aminosulfonylphenyl)-N4-[4-(3-cyanophenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

L-76: N2-(4-Aminosulfonylphenyl)-N4-[3-(4-cyanophenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-77: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(3-cyanophenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-78: N4-[4-(3-Cyanophenyl)phenyl]-5-fluoro-N2-[4-methyl-3-(N-methylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;

I-79: N2-(3-Aminosulfonylphenyl)-N4-[3-(4-cyanophenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-80: N4-[3-(4-Cyanophenyl)phenyl]-5-fluoro-N2-[4-methyl-3-(N-methylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;

I-81: N2-(4-Aminosulfonylphenyl)-N4-[4-(3-cyanophenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-82: N2-(3-Aminosulfonylphenyl)-5-methyl-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;

I-83: N2-(3-Aminosulfonyl-4-methylphenyl)-5-methyl-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;

I-84: 5-Methyl-N2-[4-methyl-3-(N-methylaminosulfonyl)phenyl]-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;

I-85: N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;

I-86: N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine Hydrogen Chloride Salt;

I-87: 5-Fluoro-N2-[4-methyl-3-(N-methylaminosulfonyl)phenyl]-N4-[4-(3-pyridinylmethylenethio)phenyl]-2,4-pyrimidinediamine;

I-88: N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;

I-89: N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[4-(3-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;

I-90: 5-Methyl-N2-[4-(N-propionylaminosulfonyl)phenyl]-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-91: 5-Methyl-N244-(N-propionylaminosulfonyl)phenyll-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine Sodium Salt;

I-92: N2-(3-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;

I-93: N2-(3-Aminosulfonylphenyl)-5-methyl-N4-[4-(3-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;

I-94: N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(3-pyridinylmethylenethio)phenyl]-2,4-pyrimidinediamine;

I-95: N2-(4-Aminosulfonylphenyl)-5-fluoro-N4-[4-(3-pyridinylmethylenethio)phenyl]-2,4-pyrimidinediamine;

I-96: N2-(3-Aminosulfonylphenyl)-5-methyl-N4-[4-(3-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-97: N2-(3-Aminosulfonyl-4-methylphenyl)-5-methyl-N4-[4-(3-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-98: 5-Methyl-N2-[4-methyl-3-(N-methylaminosulfonyl)phenyl]-N4-[4-(3-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-99: N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[4-(3-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-100: N2-(3-Aminosulfonylphenyl)-5-methyl-N4-[4-(4-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-101: 5-Methyl-N2-[4-(N-propionylaminosulfonyl)phenyl]-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine Hydrogen Chloride Salt;

I-102: N2-(3-Aminosulfonyl-4-methylphenyl)-5-methyl-N4-[4-(4-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-103: 5-Methyl-N2-[4-methyl-3-(N-methylaminosulfonyl)phenyl]-N4-[4-(5-pyrimidinyloxy)phenyl] -2,4-pyrimidinediamine;

I-104: N2-(3-Aminosulfonylphenyl)-N4-(4-ethynylphenyl)-5-methyl-2,4-pyrimidinediamine;

I-105: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-ethynylphenyl)-5-methyl-2,4-pyrimidinediamine;

I-106: N2-(4-Aminosulfonylphenyl)-N4-(4-ethynylphenyl)-5-methyl-2,4-pyrimidinediamine;

I-107: N2-(3-Aminosulfonylphenyl)-5-methyl-N4-[4-(5-pyrimidinyloxy)phenyl]-2,4-pyrimidinediamine;

I-108: N4-(4-Ethynylphenyl)-5-methyl-N2-[4-methyl-3-(N-methylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;

I-109: N2-(3-Aminosulfonylphenyl)-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;

I-110: N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[4-(5-pyrimidinyloxy)phenyl]-2,4-pyrimidinediamine;

I-111: N2-(4-Aminosulfonylphenyl)-5-methyl-N4[4-(4-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-112: N2-(4-Aminosulfonylphenyl)-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine;

I-113: N2-[3-(N,N-Dimethylaminosulfonyl)phenyl]-5-methyl-N4-[4-(3-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-114: N2-[4-(N,N-Dimethylaminosulfonyl)phenyl]-5-methyl-N4-[4-(3-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-115: N2-[4-(N,N-Dimethylaminosulfonyl)phenyl]-5-fluoro-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-116: N2-(3-Aminosulfonyl-4-methylphenyl)-5-methyl-N4-[4-(5-pyrimidinyloxy)phenyl]-2,4-pyrimidinediamine;

I-117: N2-[3-(N-Cyclopropylaminosulfonyl)phenyl]-5-methyl-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-118: N2-(4-Aminosulfonylphenyl)-N4-(3-ethynylphenyl)-5-methyl-2,4-pyrimidinediamine;

I-119: N2-[4-(N-Cyclopropylaminosulfonyl)phenyl]-5-methyl-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-120: N2-[3-(N-Cyclopropylaminosulfonyl)phenyl]-5-methyl-N4-[4-(3-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-121: N2-[3-(N-Cyclopropylaminosulfonyl)phenyl]-5-methyl-N4-[4-(5-pyrimidinyloxy)phenyl]-2,4-pyrimidinediamine;

I-122: N2-[4-(N-Cyclopropylaminosulfonyl)phenyl]-5-methyl-N4-[4-(5-pyrimidinyloxy)phenyl]-2,4-pyrimidinediamine;

I-123: N2-[4-(N-Cyclopropylaminosulfonyl)phenyl]-5-methyl-N4-[4-(3-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-124: N2-(3-Aminosulfonylphenyl)-N4-(3-ethynylphenyl)-5-methyl-2,4-pyrimidinediamine;

I-125: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(3-ethynylphenyl)-5-methyl-2,4-pyrimidinediamine;

I-126: N4-(3-Ethynylphenyl)-5-methyl-N2-[4-methyl-3-(N -methylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;

I-127: N2-[3-(N,N-Dimethylaminosulfonyl)phenyl]-5-fluoro-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-128: N2-(4-Aminosulfonylphenyl)-5-cyclopropyl-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-129: N2-(3-Aminosulfonylphenyl)-5-cyclopropyl-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-130: N2-[3-(N-Cyclopropylaminosulfonyl)phenyl]-5-methyl-N4-[4-(3-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;

I-131: N2-[3-N-(Cyclopropylaminosulfonyl)phenyl]-5-fluoro-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-132: N2-[4-(N-Cyclopropylaminosulfonyl)phenyl]-5-fluoro-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-133: N2-[3-(N-Cyclopropylaminosulfonyl)phenyl]-5-methyl-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;

I-134: N2-[4-(N-Cyclopropylaminosulfonyl)phenyl]-5-methyl-N4-[4-(4-pyridinylmethyl)phenyl]-2,4-pyrimidinediamine;

I-135: N2-[4-(N-Cyclopropylmethylaminosulfonyl)phenyl]-5-methyl-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-136: N2-[4-(N-Cyclopropylmethylaminosulfonyl)phenyl]-5-methyl-N4-[4-(3-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-137: N2-[3-(N-Cyclopropylmethylaminosulfonyl)phenyl]-5-methyl-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-138: N2-[3-(N-Cyclopropylmethylaminosulfonyl)phenyl]-5-methyl-N4-[4-(3-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-139: N2-[4-(N-Cyclopropylmethylaminosulfonyl)phenyl]-5-methyl-N4-[4-(5-pyrimidinyloxy)phenyl]-2,4-pyrimidinediamine;

I-140: N2-[3-(N-Cyclopropyl-N-propionylaminosulfonyl)phenyl]-5-methyl-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-141: N2-[3-(N-Cyclopropyl-N-propionylaminosulfonyl)phenyl]-5-methyl-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine Hydrogen Chloride Salt;

I-142: 5-Chloro-N2-[3-(N-cyclopropylaminosulfonyl)phenyl]-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-143: 5-Chloro-N2- [4-(N-cyclopropylmethylaminosulfonyl)phenyl]-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-144: 5-Chloro-N2-[4-(N-cyclopropylaminosulfonyl)phenyl]-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-145: 5-Chloro-N2-[3-(N-cyclopropylmethylaminosulfonyl)phenyl]-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-146: N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[4-(2-pyridinylmethylenethio)phenyl]-2,4-pyrimidinediamine;

I-147: N2-(3-Aminosulfonylphenyl)-5-methyl-N4-[4-(2-pyridinylmethylenethio)phenyl]-2,4-pyrimidinediamine;

I-148: N2-(3-Aminosulfonyl-4-methylphenyl)-5-methyl-N4-[4-(2-pyridinylmethylenethio)phenyl]-2,4-pyrimidinediamine;

I-149: N2-[3-(N-Cyclopropylaminosulfonyl)phenyl]-5-methyl-N4-[4-(2-pyridinylmethylenethio)phenyl]-2,4-pyrimidinediamine;

I-150: N2-[4-(N-Cyclopropylaminosulfonyl)phenyl]-5-methyl-N4-[4-(2-pyridinylmethylenethio)phenyl]-2,4-pyrimidinediamine;

I-151: N2-[3,5-Bis(aminosulfonyl)phenyl]-N4-[4-(2-cyanoethyl)phenyl]-5-fluoro-2,-4-pyrimidinediamine;

I-152: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[3-(2-cyanoethyl)-5-trifluoromethy-phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-153: N2-(3-Aminosulfonylphenyl)-N4-[3-(2-cyanoethyl)-5-trifluoromethylphenyl]-5-fluoro-2,4-pyrimidinediamine;

I-154: N2-(4-Aminosulfonylphenyl)-N4-[3-(2-cyanoethyl)-5-trifluoromethylphenyl]-5-fluoro-2,4-pyrimidinediamine;

I-155: N4-[4-(2-Cyanoethyl)phenyl]-5-methyl-N2-[4(N-propionylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;

I-156: N4-[4-(2-Cyanoethyl)phenyl]-5-methyl-N2-[4-(N-propionylaminosulfonyl)phenyl]-2,4-pyrimidinediamine Sodium Salt;

I-157: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[4-(2-cyanoethyl)-3-methylphenyl]-5-methyl-2,4-pyrimidinediamine;

I-158: N2-(3-Aminosulfonylphenyl)-N4-[4-(2-cyanoethyl)-3-methylphenyl]-5-methyl-2,4-pyrimidinediamine;

I-159: N2-(4-Aminosulfonylphenyl)-N4-[4-(2-cyanoethyl)-3-methylphenyl]-5-methyl-2,4-pyrimidinediamine;

I-160: N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-((1-methyl-1H-pyrazol-3-yl)aminocarbonylmethylene)phenyl]-2,4-pyrimidinediamine;

I-161: N2-(3-Aminosulfonylphenyl)-N4-(4-N,N-dimethylaminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;

I-162: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-(4-N,N-dimethylaminosulfonylphenyl)-5-fluoro-2,4-pyrimidinediamine;

I-163: N2-(4-Aminosulfonylphenyl)-5-chloro-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-164: N2-(3-Aminosulfonylphenyl)-5-chloro-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-165: N2-(3-Aminosulfonyl-4-methylphenyl)-5-chloro-N4-[4-(2-pyridinylmethyleneoxy)phenyl]-2,4-pyrimidinediamine;

I-166: N2-(3-(N-butyrylsulfamoyl)-4-methylphenyl)-5-fluoro-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-167: N2-(3-(N-isobutyrylsulfamoyl)-4-methylphenyl)-5-fluoro-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-168: N2-(3-(N-butyrylsulfamoyl)-4-methylphenyl)-5-fluoro-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine sodium salt;

I-169: N2-(3-(N-isobutyrylsulfamoyl)-4-methylphenyl)-5-fluoro-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine sodium salt;

I-170: N2-(3-(N-hexanoylsulfamoyl)-4-methylphenyl)-5-fluoro-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-171: N2-(3-(N-pentanoylsulfamoyl)-4-methylphenyl)-5-fluoro-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine;

I-172: N2-(3-(N-hexanoylsulfamoyl)-4-methylphenyl)-5-fluoro-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine sodium salt;

I-173: N2-(3-(N-pentanoylsulfamoyl)-4-methylphenyl)-5-fluoro-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine sodium salt;

or a pharmaceutically acceptable salt thereof.

2. 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 wherein the compound has formula I

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, fluoro, chloro, iodo, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;

Y is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, substituted amino, and halo;

R is hydrogen;

ring A is phenyl;

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

each R 2 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted carboxyl, carboxyl ester, hydroxyl, acylamino, aminosulfonyl, alkynyl, substituted alkynyl, alkylthio, substituted alkylthio, aminocarbonyl, acyl, oxo, and halo;

each R 3 independently is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, halo, and aminosulfonyl;

R 4 and R 5 together with the nitrogen atom bound thereto, form a heterocyclic or substituted heterocyclic group;

provided that:

if q=2 and each of R 2 is methoxy, halo, trihalomethyl or trihalomethoxy, then R 4 and R 5 are not one hydrogen and one methyl; and

if q=1 and R 2 is chloro, then R 4 and R 5 are not one hydrogen and one methyl;

the compound is selected from the compounds of claim 1 .

3. A method of inhibiting an activity of a JAK kinase, comprising contacting in vitro, a JAK3 kinase with an amount of a compound effective to inhibit an activity of the JAK kinase wherein the compound has formula I

or a pharmaceutically acceptable salt thereof, wherein:

Y is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, substituted amino, and halo;

R is hydrogen;

ring A is phenyl;

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

each R 3 independently is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, halo, and aminosulfonyl;

R 4 and R 5 together with the nitrogen atom bound thereto, form a heterocyclic or substituted heterocyclic group;

provided that:

if q=2 and each of R 2 is methoxy, halo, trihalomethyl or trihalomethoxy, then R 4 and R 5 are not one hydrogen and one methyl; and

if q =1 and R 2 is chloro, then R 4 and R 5 are not one hydrogen and one methyl;

the compound is selected from the compounds of claim 1 .

4. 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 effective to treat the autoimmune disease wherein the compound has formula I

or a pharmaceutically acceptable salt thereof, wherein:

Y is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, substituted amino, and halo;

R is hydrogen;

ring A is phenyl;

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

each R 3 independently is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, halo, and aminosulfonyl;

R 4 and R 5 together with the nitrogen atom bound thereto, form a heterocyclic or substituted heterocyclic group;

provided that:

if q=2 and each of R 2 is methoxy, halo, trihalomethyl or trihalomethoxy, then R 4 and R 5 are not one hydrogen and one methyl; and

if q =1 and R 2 is chloro, then R 4 and R 5 are not one hydrogen and one methyl;

the compound is selected from the compounds of claim 1 .

5. The method of claim 4 in which the compound is administered in combination with, or adjunctively to, a compound that inhibits Syk kinase with an IC 50 of about 10 μM or less.

6. A method of treating or preventing allograft transplant rejection in a transplant recipient, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the allograft transplant rejection wherein the compound has formula I

or a pharmaceutically acceptable salt thereof, wherein:

Y is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, substituted amino, and halo;

R is hydrogen;

ring A is phenyl;

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

each R 3 independently is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, halo, and aminosulfonyl;

R 4 and R 5 together with the nitrogen atom bound thereto, form a heterocyclic or substituted heterocyclic group;

provided that:

if q=2 and each of R 2 is methoxy, halo, trihalomethyl or trihalomethoxy, then R 4 and R 5 are not one hydrogen and one methyl; and

if q =1 and R 2 is chloro, then R 4 and R 5 are not one hydrogen and one methyl;

the compound is selected from the compounds of claim 1 .

7. The method of claim 6 , wherein the compound is administered to a tissue or an organ prior to transplanting the tissue or organ in the allograft transplant recipient.

8. The method of claim 6 in which the allograft transplant rejection is acute rejection.

9. The method of claim 6 in which the allograft transplant rejection is chronic rejection.

10. The method of claim 6 in which the allograft transplant rejection is mediated by HVGR or GVHR.

11. The method of claim 6 in which the transplant recipient receives an allograft transplant organ selected from a kidney, a heart, a liver and a lung.

12. The method of claim 6 in which the compound is administered in combination with, or adjunctively to, an immunosuppressant.

13. The method of claim 12 in which the immunosuppressant is selected from cyclosporine, tacrolimus, sirolimus, an inhibitor of IMPDH, mycophenolate, mycophanolate mofetil, an anti-T-Cell antibody and OKT3.

14. A method of treating or preventing a Type IV hypersensitivity reaction, comprising administering to a subject an amount of a compound effective to treat or prevent the hypersensitivity reaction wherein the compound has formula I

or a pharmaceutically acceptable salt thereof, wherein:

Y is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, substituted amino, and halo;

R is hydrogen;

ring A is phenyl;

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

each R 3 independently is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, halo, and aminosulfonyl;

R 4 and R 5 together with the nitrogen atom bound thereto, form a heterocyclic or substituted heterocyclic group;

provided that:

if q=2 and each of R 2 is methoxy, halo, trihalomethyl or trihalomethoxy, then R 4 and R 5 are not one hydrogen and one methyl; and

if q =1 and R 2 is chloro, then R 4 and R 5 are not one hydrogen and one methyl;

the compound is selected from the compounds of claim 1 .

15. The method of claim 13 wherein the compound and the immunosuppressant are administered prophylactically.

16. A method of inhibiting a signal transduction cascade in which JAK3 kinase plays a role, comprising contacting a cell expressing a receptor involved in said signaling cascade with a compound wherein the compound has formula I

or a pharmaceutically acceptable salt thereof, wherein:

Y is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, substituted amino, and halo;

R is hydrogen;

ring A is phenyl;

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

each R 3 independently is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, halo, and aminosulfonyl;

R 4 and R 5 together with the nitrogen atom bound thereto, form a heterocyclic or substituted heterocyclic group;

provided that:

if q=2 and each of R 2 is methoxy, halo, trihalomethyl or trihalomethoxy, then R 4 and R 5 are not one hydrogen and one methyl; and

if q =1 and R 2 is chloro, then R 4 and R 5 are not one hydrogen and one methyl;

the compound is selected from the compounds of claim 1 .

17. A method of treating or preventing a JAK kinase-mediated disease selected from HVGR or GVHR, acute allograft rejection and chronic allograft rejection, comprising administering to a subject an amount of compound effective to treat or prevent the JAK kinase-mediated disease wherein the compound has formula I

or a pharmaceutically acceptable salt thereof, wherein:

Y is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, substituted amino, and halo;

R is hydrogen;

ring A is phenyl;

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

each R 3 independently is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, halo, and aminosulfonyl;

R 4 and R 5 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, cycloalkyl, substituted cycloalkyl, and acyl; or R 4 and R 5 together with the nitrogen atom bound thereto, form a heterocyclic or substituted heterocyclic group;

provided that:

if q=2 and each of R 2 is methoxy, halo, trihalomethyl or trihalomethoxy, then R 4 and R 5 are not one hydrogen and one methyl; and

if q =1 and R 2 is chloro, then R 4 and R 5 are not one hydrogen and one methyl;

the compound is selected from the compounds of claim 1 .

Assignments (2)

SECURITY INTEREST Recorded Aug 25, 2022

From: RIGEL PHARMACEUTICALS, INC.

To: MIDCAP FINANCIAL TRUST

Reel/Frame 061327/0712 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 15, 2011

From: ARGADE, ANKUSH; SRAN, ARVINDER; CARROLL, DAVID; CLOUGH, JEFFREY; TSO, KIN; BHAMIDIPATI, SOMASEKHAR; THOTA, SAMBAIAH; SINGH, RAJINDER; TAYLOR, VANESSA; LI, HUI; MASUDA, ESTEBAN

To: RIGEL PHARMACEUTICALS, INC.

Reel/Frame 026601/0895 →

Continuity (5)

Continuation 11678429 · Feb 23, 2007

Continuation In Part 11450901 · Jun 8, 2006

Provisional Application 60776636 · Feb 24, 2006

Provisional Application 60871098 · Dec 20, 2006

Related Publication 20080221089A1 · Sep 11, 2008