Compositions and methods for inhibition of the JAK pathway

• US 9,593,082 B2
• Filed: 02/12/2008
• Issued: 03/14/2017
• Est. Priority Date: 06/08/2005
• Status: Active Grant

• Current Assignee: Rigel Pharmaceuticals, Inc.
• Original Assignee: Rigel Pharmaceuticals, Inc.
• Inventors: Argade, Ankush, Sran, Arvinder, Carroll, David, Clough, Jeffrey, Tso, Kin, Bhamidipati, Somasekhar, Thota, Sambaiah, Singh, Rajinder, Taylor, Vanessa, Li, Hui, Masuda, Esteban
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US12/030,069
• Publication Number:
  US 20080221089A1
• Time in Patent Office: 3,318 Days
• Field of Search: 544/323, 544/324, 514/275
• US Class Current: 1/1
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• 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 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 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

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

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

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

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

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 IC₅₀ of about 10 μ

M 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

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

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

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