2,4-PYRIMIDINEDIAMINE COMPOUNDS AND THEIR USES

• US 20090156622A1
• Filed: 11/18/2008
• Published: 06/18/2009
• Est. Priority Date: 02/01/2002
• Status: Active Grant

• Current Assignee: Rigel Pharmaceuticals, Inc.
• Original Assignee: Rigel Pharmaceuticals, Inc.
• Inventors: Clough, Jeffrey, Keim, Holger, Argade, Ankush, Sylvain, Catherine, Bhamidipati, Somasekhar, Li, Hui, Singh, Rajinder, Holland, Sacha J., Payan, Donald, Molineaux, Susan, Rossi, Alexander B.
• Granted Patent: US 8,334,296 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• 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 31/519 ortho- or peri-condensed with 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 31/5395 having two or more nitrogen atoms in the same ring, e.g. oxadiazines
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• 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: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 239/48 : Two nitrogen atoms
• CPC Class Codes: C07D 265/36 : 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 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 407/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/10 : linked by a carbon chain containing aromatic rings
• 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 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/14 : Ortho-condensed systems
• CPC Class Codes: C07F 5/027 : Organoboranes and organoborohydrides

Abstract

The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.

Claims

1-50. -50. (canceled)

51. A method of inhibiting cell degranulation, comprising contacting a cell with an amount of a compound effective to inhibit degranulation, wherein the compound is according to formula I:

wherein;

each of R² and R⁴, independently is phenyl substituted with one or more R⁹ groups or a heteroaryl selected from the group consisting of

wherein

at least one of R² and R⁴ is the heteroaryl;

R² is not trialkoxyphenyl;

R⁵ is selected from the group consisting of (C₁-C₆) alkyl optionally substituted with one or more of the same or different R⁸ groups, —

OR^d, —

SR^d, (C₁-C₃) haloalkyloxy, (C₁-C₃) perhaloalkyloxy, —

NR^cR^c, (C₁-C₃) haloalkyl, —

CN, —

NC, —

OCN, —

SCN, —

NO, —

NO₂, —

N₃, —

S(O)R^d, —

S(O)₂R^d, —

S(O)₂OR^d, —

S(O)NR^cR^c;

—

S(O)₂NR^cR^c, —

OS(O)R^d, —

OS(O)₂R^d, —

OS(O)₂OR^d, —

OS(O)NR^cR^c, —

OS(O)₂NR^cR^c, —

C(O)R^d, —

C(O)OR^d, —

C(O)NR^cR^c, —

C(NH)NR^cR^c, —

OC(O)R^d, —

SC(O)R^d, —

OC(O)OR^d, —

SC(O)OR^d, —

OC(O)NR^cR^c;

—

SC(O)NR^cR^c, —

OC(NH)NR^cR^c, —

SC(NH)NR^cR^c, —

[NHC(O)]_nR^d, —

[NHC(O)_nOR^d, —

[NHC(O)_nNR^cR^c, —

[NHC(NH)_nNR^cR^C, (C5-C10) aryl optionally substituted with one or more of the same or different R⁸ groups, (C₆-C₁₆) arylalkyl optionally substituted with one or more of the same or different R⁸ groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R⁸ groups and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R⁸ groups;

R³⁵ is hydrogen or R⁸;

each R⁸ independently is R^e, R^b, R^e substituted with one or more of the same or different R^a or R^b, —

OR^a substituted with one or more of the same or different R^a or R^b, —

B(OR^a)₂, —

B(NR^cR^c)₂, —

(CH₂)_m—

R^b, —

(CHR^a)_mR^b, —

O—

(CH₂)—

R^b, —

S—

CH₂)_m—

R^b, —

O—

CHR^aR^b, —

O—

CR^a(R^b)₂, —

O—

(CHR^a)_m—

R^b, —

O—

(CH₂)_m—

CH[(CH₂)_mR^b]R^b, —

S—

(CHR^a)_m—

R^b, —

C(O)NH—

(CH₂)_m—

R^b, —

C(O)NH—

(CHR^a)_m—

R^b, —

O—

(CH₂)_m—

C(O)NH—

(CH₂)_m—

R^b, —

S—

(CH₂)_m—

C(O)NH—

(CH₂)_m—

R^b, —

O—

(CHR^a)_m—

C(O)NH—

(CHR^a)_m—

R^b, —

S—

(CHR^a)_m—

C(O)NH—

(CHR^a)_m—

R^b, —

NH—

(CH₂)_m—

R^b, —

NH—

(CHR^a)_m—

R^b, —

NH[(CH₂)_mR^b], —

N[(CH₂)_mR^b]₂, —

NH—

C(O)—

NH—

(CH₂)_m—

R^b, —

NH—

C(O)—

(CH₂)_m—

CHR^bR^b and —

NH—

(CH₂)_m—

C(O)—

NH—

CH₂)_m—

R^b;

each R^a is independently selected from the group consisting of hydrogen, (C₁-C₆) alkyl, (C₃-C₈) cycloalkyl, (C₄-C₁₁) cycloalkylalkyl, (C₅-C₁₀) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;

each R^b is a suitable group independently selected from the group consisting of ═

O, —

OR^d, (C₁-C₃) haloalkyloxy, —

OCF₃, ═

S, —

SR^d, ═

NR^d, ═

NOR^d, —

NR^cR^c, halogen, —

CF₃, —

CN, —

NC, —

OCN, —

SCN, —

NO, —

NO₂, ═

N₂, —

N₃, —

S(O)R^d, —

S(O)₂R^d, —

S(O)₂OR^d, —

S(O)NR^cR^c, —

S(O)₂NR^cR^c, —

OS(O)R^d, —

OS(O)₂R^d, —

OS(O)₂OR^d, —

OS(O)₂NR^cR^c, —

C(O)R^d, C(O)OR^d, —

C(O)NR^cR^c, —

C(NH)NR^cR^c, —

C(NR^a)NR^cR^c, —

C(NOH)R^a, —

C(OH)NR^cR^c, —

OC(O)R^d, —

OC(O)OR^d, —

OC(O)NR^cR^c, —

OC(NH)NR^cR^c, —

OC(NR^a)NR^cR^c, —

[NHC(O)]_nR^d, —

[NR^aC(O)_nR^d, —

[NHC(O)_nOR^d, —

[NR^aC(O)_nOR^d, —

[NHC(O)_nNR^cR^c, —

[NR^aC(O)_nNR^cR^c, —

[NHC(NH)]_nNR^cR^c and —

[NR^aC(NR^a)_nNR^cR^c;

each R^c is independently a protecting group or R^a, or, alternatively, two R^c are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R^a or suitable R^b groups;

each R^d is independently R^a;

each R^e is independently selected from the group consisting of (C₁-C₆) alkyl, (C₃-C₈) cycloalkyl, (C4-C11) cycloalkylalkyl, (C₅-C₁₀) aryl, (C₆-C₁₆) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;

each Y¹ independently is selected from the group consisting of O, S, SO, SO, SONR³⁶, NH and NR³⁵;

each Y² independently is selected from the group consisting of CH, CH₂, O, S, N, NH and NR³⁵;

each R³⁶ independently is hydrogen or alkyl;

A is selected from the group consisting of O, NH and NR³⁸;

Q is selected from the group consisting of —

OH, OR⁸, —

NR^cR^c, NHR³⁹C(O)R⁸, —

NHR³⁹—

C(O)OR⁸, —

NR³⁹—

CHR⁴⁰—

R^b, —

NR³⁹—

(CH₂)_m—

R^b and —

NR³⁹—

C(O)—

CHR⁴⁰—

NR^cR^c;

each R³⁸ independently is selected from the group consisting of alkyl and aryl;

R⁹, R¹⁰, R¹¹ and R¹² are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R⁹ and R¹⁰ or R¹¹ and R¹², or R⁹ and R¹⁰ and R¹¹ and R¹² are taken together form an oxo group;

each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester and carbamate;

R³⁹ and R⁴⁰ are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl and NHR⁸,

each m independently is an integer from 1 to 3; and

each n independently is an integer from 0 to 3.

52. The method of claim 51 in which the cell is a human mast, basophil cell, neutrophil or eosinophil cell.

53-54. -54. (canceled)

55. A method of treating a disease characterized by, caused by or associated with mast or basophil cell degranulation, comprising administering to an animal suffering from such a disease an effective amount of a compound according to formula I:

wherein;

each of R² and R⁴, independently is phenyl substituted with one or more R⁸ groups or a heteroaryl selected from the group consisting of

wherein

at least one of R² and R⁴ is the heteroaryl

R² is not trialkoxyphenyl;

R⁵ is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more of the same or different R⁸ groups, —

OR^d, —

SR^d, (C₁-C₃) haloalkyloxy, (C₁-C₃ perhaloalkyloxy, —

NR^cR^c, (C₁-C₃) haloalkyl, —

CN, —

NC, —

OCN, —

SCN, —

NO, —

NO₂, —

N³, —

S(O)R^d, —

S(O)₂R^d, —

S(O)₂OR^d, —

S(O)NR^cR^c, —

S(O)₂NR^cR^c, —

OS(O)R^d, —

OS(O)₂R^d, —

OS(O)₂OR^d, —

OS(O)NR^cR^c, —

OS(O)₂NR^cR^c, —

C(O)R^d, —

C(O)OR^d, —

C(O)NR^cR^c, —

C(NH)NR^cR^c, —

OC(O)R^d, —

SC(O)R^d, —

OC(O)OR^d, —

SC(O)OR^d, —

OC(O)NR^cR^c;

—

SC(O)NR^cR^c, —

OC(NH)NR^cR^c, —

SC(NH)NR^cR^c, —

[NHC(O)]_nR^d, —

NHC(O)]_nOR^d, —

[NHC(O)]_nNR^cR^c, —

[NHC(NH)]_nNR^cR^C, (C5-C10) aryl optionally substituted with one or more of the same or different R⁸ groups, (C6-C16) arylalkyl optionally substituted with one or more of the same or different R⁸ groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R⁸ groups and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R⁸ groups;

R³⁵ is hydrogen or R⁸;

each R⁸ independently is R^e, R^b, R^e substituted with one or more of the same or different R^a or R^b, —

OR^a substituted with one or more of the same or different R^a or R^b, —

B(OR^a)₂, —

B(NR^cR^c)₂, —

(CH₂)_m—

R^b, —

(CHR^a)_m—

R^b, —

O—

(CH₂)_m—

R^b, —

S—

(CH₂)_m—

R^b, —

O—

CHR^aR^b, —

O—

CR^a(R^b)₂, —

O—

(CHR^a)_m—

R^b, —

O—

(CH₂)_m—

CH[(CH₂)_mR^bR^b, —

S—

(CHR^a)_m—

R^b, —

C(O)NH—

(CH₂)_m—

R^b, —

C(O)NH—

(CHR^a)_m—

R^b, —

O—

(CH₂)_m—

C(O)NH—

(CH₂)_m—

R^b, —

S—

(CH₂)_m—

C(O)NH—

(CH₂)_m—

R^b, —

O—

(CHR^a)_m—

C(O)NH—

(CHR^a)_m—

R^b, —

S—

(CHR^a)_m—

C(O)NH—

(CHR^a)_m—

R^b, —

NH—

(CH₂)_m—

R^b, —

NH—

(CHR^a)_m—

R^b, —

NH[(CH₂)_mR^d, —

N[(CH₂)_mR^b]₂, —

NH—

C(O)—

NH—

(CH₂)_m—

R^b, —

NH—

C(O)—

(CH₂)_m—

CHR^bR^b and —

NH—

(CH₂)_m—

C(O)—

NH—

(CH₂)_m—

R^b;

each R^a is independently selected from the group consisting of hydrogen, (C₁-C₆) alkyl, (C₃-C₈) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C₆-C₁₆) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl,

each R^b is a suitable group independently selected from the group consisting of ═

O, —

OR^d, (C₁-C₃) haloalkyloxy, —

OCF₃, ═

S, —

SR^d, ═

NR^d, ═

NOR^d, —

NR^cR^c, halogen, —

CF₃, —

CN, —

NC, —

OCN, —

SCN, —

NO, —

NO₂, ═

N₂, —

N₃, —

S(O)R^d, —

S(O)₂R^d, —

S(O)₂OR^d, —

S(O)NR^cR^c, —

S(O₂)₂NR^cR^c, —

OS(O)R^d, —

OS(O)₂OR^d, —

OS(O)₂NR^cR^c, —

C(O)R^d, —

C(O)OR^d, —

C(O)NR^cR^cR^c, —

C(NH)NR^cR^c, —

C(NR^a)NR^cR^c, —

C(NOH)R^a, —

C(NOH)NR^cR^c, —

OC(O)R^d, —

OC(O)OR^d, —

OC(O)NR^cR^c, —

OC(NH)NR^cR^c, —

OC(NR^a)NR^cR^c, —

[NHC(O)_mR^d, —

[NR^aC(O)]_nR^d, —

[NHC(O)]_nOR^d, —

[NR^aC(O)]_nOR^d, —

[NHC(O)_nNR^cR^c, —

[NR^aC(O)]_nNR^cR^c, —

[NHC(NH)_nNR^cR^c and —

[NR^aC(NR^a)]_nNR^cR^c);

each R^c is independently a protecting group or R^a, or, alternatively, two R^c are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R^a or suitable R^b groups;

each R^d is independently R^a;

each R^e is independently selected from the group consisting of (C₁-C₆) alkyl, (C₃-C₈) cycloalkyl, (C4-C11) cycloalkylalkyl, (C₅-C₁₀) aryl, (C₆-C₁₆) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;

each Y¹ independently is selected from the group consisting of O, S, SO, SO₂, SONR³⁶, NH and NR³⁵;

each Y² independently is selected from the group consisting of CH, CH₂, O, S, N, NH and NR³⁵;

each R³⁶ independently is hydrogen or alkyl;

A is selected from the group consisting of O, NH and NR³⁸;

Q is selected from the group consisting of —

OH, OR⁸, —

NR^cR^c, NHR³⁹C(O)R⁸, —

NHR³⁹—

C(O)OR⁸, —

NR³⁹—

CHR⁴⁰—

R^b, —

NR³⁹—

(CH₂)_m—

R^b and —

NR³⁹—

C(O)—

CHR⁴⁰—

NR^cR^c;

each R³⁸ independently is selected from the group consisting of alkyl and aryl;

R⁹, R¹⁰, R¹¹ and R¹² are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R⁹ and R¹⁰ or R¹¹ and R¹², or R⁹ and R¹⁰ and R¹¹ and R¹² are taken together form an oxo group,;

each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester and carbamate;

R³⁹ and R⁴⁰ are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl and NHR⁸;

each m independently is an integer from 1 to 3; and

each n independently is an integer from 0 to 3.

56. The method of claim 55 in which the animal is a human.

57. The method of claim 55 in which the disease is selected from the group consisting of allergic diseases, low grade scarring, diseases associated with tissue destruction, diseases associated with tissue inflammation, inflammation, and scarring.

58. The method of claim 57 in which the allergic disease is selected from the group consisting of conjunctivitis, rhinitis, asthma, atopic dermatitis and food allergies.

59. The method of claim 57 in which the low grade scarring is selected from the group consisting of scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury and post myocardial infarction.

60. The method of claim 57 in which the disease associated with tissue destruction is selected form the group consisting of COPD, cardiobronchitis and post myocardial infarction.

61. The method of claim 57 in which the disease associated with tissue inflammation is selected from the group consisting of irritable bowel, spastic colon and inflammatory colon disease.

62. A method of inhibiting a Syk kinase, comprising the step of contacting the Syk kinase or an active fragment thereof with an effective amount of a 2,4-pyrimidinediamine compound according to formula I:

wherein;

each of R² and R⁴, independently is phenyl substituted with one or more R⁸ groups or a heteroaryl selected from the group consisting of

wherein

at least one of R² and R⁴ is the heteroaryl;

R² is not trialkoxyphenyl;

R⁵ is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more of the same or different R⁸ groups, —

OR^d, —

SR^d, (C₁-C₃) haloalklloxy, (C₁-C₃) perhaloalkyloxy, —

NR^cR^c, (C₁-C₃) haloalkyl, —

CN, —

NC, —

OCN, —

SCN, —

NO, —

NO₂, —

N₃, —

S(O)R^d, —

S(O)₂R^d, —

S(O)₂OR^d, —

S(O)NR^cR^c;

—

S(O)₂NR^cR^c, —

OS(O)₂R^d, —

OS(O)₂OR^d, —

OS(O)NR^cR^c, —

OS(O)₂NR^cR^c, —

C(O)R^d, —

C(O)OR^d, —

C(O)NR^cR^c, —

C(NH)NR^cR^c, —

OC(O)R^d, —

SC(O)R^d, —

OC(O)OR^d, —

SC(O)OR^d, —

OC(O)NR^cR^c;

—

SC(O)NR^cR^c, —

OC(NH)NR^cR^c, —

SC(NH)NR^cR^c, —

[NHC(O)]_nR^d, —

[NHC(O)]_nOR^d, —

[NHC(O)]_nNR^cR^c, —

[NHC(NH)]_nNR^cR^c, (C5-C10) aryl optionally substituted with one or more of the same or different R⁸ groups, (C6-C16) arylalkyl optionally substituted with one or more of the same or different R⁸ groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R⁸ groups and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R⁸ groups;

R³⁵ is hydrogen or R⁸;

each R⁸ independently is R^e, R^b, R^e substituted with one or more of the same or different R^a or R^b, —

OR^a substituted with one or more of the same or different R^a or R^b, —

B(OR^a)₂, —

B(NR^cR^c)₂, —

(CH₂)_m—

R^b, —

(CHR^a)_m—

R^b, —

O—

(CH₂)_m—

R^b, —

S—

(CH₂)_m—

R^b, —

O—

CHR^aR^b, —

O—

CR^a(R^b)₂, —

O—

(CHR^a)_m—

R^b, —

O—

(CH₂)_m—

CH[(CH₂)_mR^b]R^b, —

S—

(CHR^a)_m—

R^b, —

C(O)NH—

(CH₂)_m—

R^b, —

C(O)NH—

(CHR^a)_m—

R^b, —

O—

(CH₂)_m—

C(O)NH—

(CH₂)_m—

R^b, —

S—

(CH₂)_m—

C(O)NH—

(CH₂)_m—

R^b, —

O—

(CHR^a)_m—

C(O)NH—

(CHR^a)_m—

R^b, —

S—

(CHR^a)_m—

C(O)NH—

(CHR^a)_m—

R^b, —

NH—

(CH₂)_m—

R^b, —

NH—

(CHR^a)_m—

R^b, —

NH[(CH₂)_mR^b], —

N[(CH₂)_mR^b]₂, —

NH—

C(O)—

NH—

(CH₂)_m—

R^b, —

NH—

C(O)—

(CH₂)_m—

CHR^bR^b and —

NH—

(CH₂)_m—

C(O)—

NH—

(CH₂)_m—

R^b;

each R^a is independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl,2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;

each R^b is a suitable group independently selected from the group consisting of ═

O, —

OR^d, (C1-C3) haloalkyloxy, —

OCF₃, ═

S, —

SR^d, ═

NR^d, ═

NOR^d, —

NR^cR^c, halogen, —

CF₃, —

CN, —

NC, —

OCN, —

SCN, —

NO, —

NO₂, ═

N₂, —

N₃, —

S(O)R^d, —

S(O)₂R^d, —

S(O)₂OR^d, —

S(O)NR^cR^c, —

S(O)₂NR^cR^c, —

OS(O)R^d, —

OS(O)₂R^d, —

OS(O)₂OR^d, —

OS(O)₂NR^cR^c, —

C(O)R^d, —

C(O)OR^d, —

C(O)NR^cR^c, —

C(NH)NR^cR^c, —

C(NR^a)NR^cR^c, —

C(NOH)R^a, —

C(NOH)NR^cR^c, —

OC(O)R^d, —

OC(O)OR^d, —

OC(O)NR^cR^c, —

OC(NH)NR^cR^c, —

OC(NR^a)NR^cR^c, —

[NHC(O)]_nR^d, —

[NR^aC(O)]_nR^d, —

[NHC(O)]_nOR^d, —

[NR^aC(O)]_nOR^d, —

[NHC(O)]_nNR^cR^c, —

[NR^aC(O)]NR^cR^c, —

[NHC(NH)]_nNR^cR^c and —

[NR^aC(NR^a)]_nNR^cR^c;

each R^c is independently a protecting group or R^a, or, alternatively, two R^c are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R^a or suitable R^b groups;

each R^d is independently R^a;

each R^e is independently selected from the group consisting of (C₁-C₆) alkyl, (C₃-C₈) cycloalkyl, (C₄-C₁₁) cycloalkylalkyl, (C₅-C₁₀) aryl, (C₆-C₁₆) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;

each Y¹ independently is selected from the group consisting of O, S, SO, SO₂, SONR³⁶, NH and NR³⁵;

each Y² independently is selected from the group consisting of CH, CH₂, O, S, N, NH and NR³⁵,

each R³⁶ independently is hydrogen or alkyl;

A is selected from the group consisting of O, NH and NR³⁸;

Q is selected from the group consisting of —

OH, OR⁸, —

NR^cR^c, NHR³⁹C(O)R⁸, —

NHR³⁹—

C(O)OR⁸, —

NR³⁹, —

CHR⁴⁰—

R^b, —

NR³⁹—

(CH₂)_m—

R^b and —

NR³⁹—

C(O)—

CHR⁴⁰—

NR^cR^c;

each R³⁸ independently is selected from the group consisting of alkyl and aryl;

R⁹, R¹⁰, R¹¹ and R¹² are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R⁹ and R¹⁰ or R¹¹ and R¹², or R⁹ and R¹⁰ and R¹¹ and R¹² are taken together form an oxo group;

each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester and carbamate;

R³⁹ and R⁴⁰ are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl and NHR⁸;

each m independently is an integer from 1 to 3; and

each n independently is an integer from 0 to 3.

63. The method of claim 62 which is practiced in vitro with an isolated or recombinant Syk kinase.

64. The method of claim 62 in which the Syk kinase is practiced in vitro with a cell or cell population that expresses an endogenous or recombinant Syk kinase.

65. The method of claim 62 which is practiced in vivo.

66. A method of inhibiting a Syk kinase in an animal, comprising the step of administering to the animal an amount of a 2,4-pyrimidinediamine compound effective to inhibit the Syk kinase, wherein the compound is according to formula I:

wherein;

each of R² and R⁴, independently is phenyl substituted with one or more R⁸ groups or a heteroaryl selected from the group consisting of

wherein

at least one of R² and R⁴ is the heteroaryl;

R² is not trialkoxyphenyl;

R⁵ is selected from the group consisting of (C₁-C₆) alkyl optionally substituted with one or more of the same or different R⁸ groups, —

OR^d, —

SR^d, (C₁-C₃) haloalkyloxy, (C₁-C₃) perhaloalkyloxy, —

NR^cR^c, (C₁-C₃) haloalkyl, —

CN, —

NC, —

OCN, —

SCN, —

NO, —

NO₂, —

N₃, —

S(O)R^d, —

S(O)₂R^d, —

S(O)₂OR^d, —

S(O)NR^cR^c;

—

S(O)₂NR^cR^c, —

OS(O)R^d, —

OS(O)₂R^d, —

OS(O)₂OR^d, —

OS(O)NR^cR^c, —

OS(O)₂NR^cR^c, —

C(O)R^d, —

C(O)OR^d, —

C(O)NR^cR^c, —

C(NH)NR^cR^c, —

OC(O)R^d, —

SC(O)R^d, —

OC(O)OR^d, —

SC(O)OR^d, —

OC(O)NR^cR^c;

—

SC(O)NR^cR^c, —

OC(NH)NR^cR^c, —

SC(NH)NR^cR^c, —

[NHC(O)]_nR^d, —

[NHC(O)_nOR^d, —

[NHC(O)_nNR^cR^c, —

[NHC(NH)_nNR^cR^C, (C5-C10) aryl optionally substituted with one or more of the same or different R⁸ groups, (C₆-C₁₆) arylalkyl optionally substituted with one or more of the same or different R⁸ groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R⁸ groups and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R⁸ groups;

R³⁵ is hydrogen or R⁸;

each R⁸ independently is R^e, R^b, R^e substituted with one or more of the same or different R^a or R^b, —

OR^a substituted with one or more of the same or different R^a or R^b, —

B(OR^a)₂, —

B(NR^cR^c)₂, —

(CH₂)_m—

R^b, —

(CHR^a)_m—

R^b, —

O—

(CH₂)_m—

R^b, —

S—

(CH₂)_m—

R^b, —

O—

CHR^aR^b, —

O—

CR^a(R^b)₂, —

O—

(CHR^a)_m-R^b, —

O—

(CH₂)_m—

CH[(CH₂)_mR^b]R^b, —

S—

(CHR^a)_m—

R^b, —

C(O)NH—

(CH₂)_m—

R^b, —

C(O)NH—

(CHR^a)_m—

R^b, —

O—

(CH₂)_m—

C(O)NH—

(CH₂)_m—

R^b, —

S—

(CH₂)_m—

C(O)NH—

(CH₂)_m—

R^b, —

O—

(CHR^a)_m—

C(O)NH—

(CHR^a)_m—

R^b, —

S—

(CHR^a)_m—

C(O)NH—

(CHR^a)_m—

R^b, —

NH—

(CH₂)_m—

R^b, —

NH—

(CHR^a)_m—

R^b, —

NH[(CH₂)_mR^b], —

N[(CH₂)_mR^b]₂, —

NH—

C(O)—

NH—

(CH₂)_m—

R^b, —

NH—

C(O)—

(CH₂)_m—

CHR^bR^b and —

NH—

(CH₂)_m—

C(O)—

NH—

(CH₂)_m—

R^b;

each R^a is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;

each R^b is a suitable group independently selected from the group consisting of ═

O, —

OR^d, (C₁-C₃) haloalkyloxy, —

OCF₃, ═

S, —

SR^d, ═

NR^d, ═

NOR^d, —

NR^cR^c, halogen, —

CF₃, —

CN, —

NC, —

OCN, —

SCN, —

NO, —

NO₂, ═

N₂, —

N₃, —

S(O)R^d, —

S(O)₂R^d, —

S(O)₂OR^d, —

S(O)NR^cR^c, —

S(O)₂NR^cR^c, —

OS(O)R^d, —

OS(O)₂R^d, —

OS(O)₂OR^d, —

OS(O)₂NR^cR^c, —

C(O)R^d, C(O)OR^d, —

C(O)NR^cR^c, —

C(NH)NR^cR^c, —

C(NR^a)NR^cR^c, —

C(NOH)R^a, —

C(OH)NR^cR^c, —

OC(O)R^d, —

OC(O)OR^d, —

OC(O)NR^cR^c, —

OC(NH)NR^cR^c, —

OC(NR^a)NR^cR^c, —

[NHC(O)]_nR^d, —

[NR^aC(O)_nR^d, —

[NHC(O)_nOR^d, —

[NR^aC(O)_nOR^d, —

[NHC(O)_nNR^cR^c, —

[NR^aC(O)_nNR^cR^c, —

[NHC(NH)]_nNR^cR^c and —

[NR^aC(NR^a)_nNR^cR^c;

each R^c is independently a protecting group or R^a, or, alternatively, two R^c are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R^a or suitable R^b groups;

each R^d is independently R^a;

each R^e is independently selected from the group consisting of (C₁-C₆) alkyl, (C₃-C₈) cycloalkyl, (C4-C11) cycloalkylalkyl, (C₅-C₁₀) aryl, (C₆-C₁₆) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;

each Y¹ independently is selected from the group consisting of O, S, SO, SO, SONR³⁶, NH and NR³⁵;

each Y² independently is selected from the group consisting of CH, CH₂, O, S, N, NH and NR³⁵;

each R³⁶ independently is hydrogen or alkyl;

A is selected from the group consisting of O, NH and NR³⁸;

Q is selected from the group consisting of —

OH, OR⁸, —

NR^cR^c, NHR³⁹C(O)R⁸, —

NHR³⁹—

C(O)OR⁸, —

NR³⁹—

CHR⁴⁰—

R^b, —

NR³⁹—

(CH₂)_m—

R^b and —

NR³⁹—

C(O)—

CHR⁴⁰—

NR^cR^c;

each R³⁸ independently is selected from the group consisting of alkyl and aryl;

R⁹, R¹⁰, R¹¹ and R¹² are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R⁹ and R¹⁰ or R¹¹ and R¹², or R⁹ and R¹⁰ and R¹¹ and R¹² are taken together form an oxo group;

each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester and carbamate;

R³⁹ and R⁴⁰ are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl and NHR⁸,

each m independently is an integer from 1 to 3; and

each n independently is an integer from 0 to 3.

69. The method of claim 66 or 67 in which the animal is a human.

68. (canceled)

70. A method of inhibiting an Fc receptor signal transduction cascade, contacting a cell comprising an Fc receptor having a gamma homodimer with an amount of a 2,4-pyrimidinediamine compound effective to inhibit its signal transduction cascades wherein the compound is according to formula I:

wherein;

each of R² and R⁴, independently is phenyl substituted with one or more R⁸ groups or a heteroaryl selected from the group consisting of

wherein

at least one of R² and R⁴ is the heteroaryl;

R² is not trialkoxyphenyl;

R⁵ is selected from the group consisting of (C₁-C₆) alkyl optionally substituted with one or more of the same or different R⁸ groups, —

OR^d, —

SR^d (C₁-C₃) haloalkyloxy, (C₁-C₃) perhaloalkyloxy, —

NR^cR^c, (C₁-C₃) haloalkyl, —

CN, —

NC, —

OCN, —

SCN, —

NO, —

NO₂, —

N₃, —

S(O)R^d, —

S(O)₂R^d, —

S(O)₂OR^d, —

S(O)NR^cR^c;

—

S(O)₂NR^cR^c, —

OS(O)R^d, —

OS(O)₂R^d, —

OS(O)₂OR^d, —

OS(O)NR^cR^c, —

OS(O)₂NR^cR^c, —

C(O)R^d, —

C(O)OR^d, —

C(O)NR^cR^c, —

C(NH)NR^cR^c, —

OC(O)R^d, —

SC(O)R^d, —

OC(O)OR^d, —

SC(O)OR^d, —

OC(O)NR^cR^c;

—

SC(O)NR^cR^c, —

OC(NH)NR^cR^c, —

SC(NH)NR^cR^c, —

[NHC(O)]_nR^d, —

[NHC(O)_nOR^d, —

[NHC(O)_nNR^cR^c, —

[NHC(NH)_nNR^cR^C, (C5-C10) aryl optionally substituted with one or more of the same or different R⁸ groups, (C₆-C₁₆) arylalkyl optionally substituted with one or more of the same or different R⁸ groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R⁸ groups and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R⁸ groups;

R³⁵ is hydrogen or R⁸;

each R⁸ independently is R^e, R^b, R^e substituted with one or more of the same or different R^a or R^b, —

OR^a substituted with one or more of the same or different R^a or R^b, —

B(OR^a)₂, —

B(NR^cR^c)₂, —

(CH₂)_m—

R^b, —

(CHR^a)_mR^b, —

O—

(CH₂)—

R^b, —

S—

CH₂)_m—

R^b, —

O—

CHR^aR^b, —

O—

CR^a(R^b)₂, —

O—

(CHR^a)_m—

R^b, —

O—

(CH₂)_m—

CH[(CH₂)_mR^b]R^b, —

S—

(CHR^a)_m—

R^b, —

C(O)NH—

(CH₂)_m—

R^b, —

C(O)NH—

(CHR^a)_m—

R^b, —

O—

(CH₂)_m—

C(O)NH—

(CH₂)_m—

R^b, —

S—

(CH₂)_m—

C(O)NH—

(CH₂)_m—

R^b, —

O—

(CHR^a)_m—

C(O)NH—

(CHR^a)_m—

R^b, —

S—

(CHR^a)_m—

C(O)NH—

(CHR^a)_m—

R^b, —

NH—

(CH₂)_m—

R^b, —

NH—

(CHR^a)_m—

R^b, —

NH[(CH₂)_mR^b], —

N[(CH₂)_mR^b]₂, —

NH—

C(O)—

NH—

(CH₂)_m—

R^b, —

NH—

C(O)—

(CH₂)_m—

CHR^bR^b and —

NH—

(CH₂)_m—

C(O)—

NH—

CH₂)_m—

R^b;

each R^a is independently selected from the group consisting of hydrogen, (C₁-C₆) alkyl, (C₃-C₈) cycloalkyl, (C₄-C₁₁) cycloalkylalkyl, (C₅-C₁₀) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;

each R^b is a suitable group independently selected from the group consisting of ═

O, —

OR^d, (C₁-C₃) haloalkyloxy, —

OCF₃, ═

S, —

SR^d, ═

NR^d, ═

NOR^d, —

NR^cR^c, halogen, —

CF₃, —

CN, —

NC, —

OCN, —

SCN, —

NO, —

NO₂, ═

N₂, —

N₃, —

S(O)R^d, —

S(O)₂R^d, —

S(O)₂OR^d, —

S(O)NR^cR^c, —

S(O)₂NR^cR^c, —

OS(O)R^d, —

OS(O)₂R^d, —

OS(O)₂OR^d, —

OS(O)₂NR^cR^c, —

C(O)R^d, C(O)OR^d, —

C(O)NR^cR^c, —

C(NH)NR^cR^c, —

C(NR^a)NR^cR^c, —

C(NOH)R^a, —

C(OH)NR^cR^c, —

OC(O)R^d, —

OC(O)OR^d, —

OC(O)NR^cR^c, —

OC(NH)NR^cR^c, —

OC(NR^a)NR^cR^c, —

[NHC(O)]_nR^d, —

[NR^aC(O)_nR^d, —

[NHC(O)_nOR^d, —

[NR^aC(O)_nOR^d, —

[NHC(O)_nNR^cR^c, —

[NR^aC(O)_nNR^cR^c, —

[NHC(NH)]_nNR^cR^c and —

[NR^aC(NR^a)_nNR^cR^c;

each R^c is independently a protecting group or R^a, or, alternatively, two R^c are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R^a or suitable R^b groups;

each R^d is independently R^a;

each R^e is independently selected from the group consisting of (C₁-C₆) alkyl, (C₃-C₈) cycloalkyl, (C4-C11) cycloalkylalkyl, (C₅-C₁₀) aryl, (C₆-C₁₆) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;

each Y¹ independently is selected from the group consisting of O, S, SO, SO, SONR³⁶, NH and NR³⁵;

each Y² independently is selected from the group consisting of CH, CH₂, O, S, N, NH and NR³⁵;

each R³⁶ independently is hydrogen or alkyl;

A is selected from the group consisting of O, NH and NR³⁸;

Q is selected from the group consisting of —

OH, OR⁸, —

NR^cR^c, NHR³⁹C(O)R⁸, —

NHR³⁹—

C(O)OR⁸, —

NR³⁹—

CHR⁴⁰—

R^b, —

NR³⁹—

(CH₂)_m—

R^b and —

NR³⁹—

C(O)—

CHR⁴⁰—

NR^cR^c;

each R³⁸ independently is selected from the group consisting of alkyl and aryl;

R⁹, R¹⁰, R¹¹ and R¹² are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R⁹ and R¹⁰ or R¹¹ and R¹², or R⁹ and R¹⁰ and R¹¹ and R¹² are taken together form an oxo group;

each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester and carbamate;

R³⁹ and R⁴⁰ are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl and NHR⁸,

each m independently is an integer from 1 to 3; and

each n independently is an integer from 0 to 3.

71. The method of claim 70 in which the Fc receptor is selected from the group consisting of Fcα

RI, FCγ

RI, FCγ

RIII and Fcε

RI.