Src kinase inhibitor compounds

• US 6,498,165 B1
• Filed: 06/26/2000
• Issued: 12/24/2002
• Est. Priority Date: 06/30/1999
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Armstrong, Helen M., Beresis, Richard, Holmes, Mark A., Zaller, Dennis M., Wong, Frederick, Steiner, Mark G., Sinclair, Peter J., Parsons, William H., Mills, Sander G., Goulet, Joung L., Hong, Xingfang
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): TRUONG, TAMTHOM NGO
• Application Number:
  US09/604,305
• Time in Patent Office: 911 Days
• Field of Search: 514/258.1, 514/275, 514/256, 544/330, 544/331
• US Class Current: 514/275
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• 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 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Pyrimidine compounds (Formula I), or their pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers, and pharmaceutical compositions including the same, which are inhibitors of tyrosine kinase enzymes, and as such are useful in the prophylaxis and treatment of protein tyrosine kinase-associated disorders, such as immune diseases, hyperproliferative disorders and other diseases in which inappropriate protein kinase action is believed to play a role, such as cancer, angiogensis, atheroscelerosis, graft rejection, rheumatoid arthritis and psoriasis.

Claims

1. The compound of Formula I

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein

R¹ and R² are independently:

a) H,

b) halo (Br, Cl, I or F)

c) OH,

d) SH,

e) CN,

f) NO₂,

g) R¹¹,

h) OR¹¹,

i) OC(═

O)R¹¹,

j) OC(═

O)OR ¹¹,

k) OC(═

O)NHR¹¹,

l) OC(═

O)NR ¹¹R¹²,

m) SR¹¹,

n) SOR¹¹,

o) SO₂R¹¹,

p) C(═

O)R¹¹,

q) C(═

O)OR ¹¹,

r) C(═

O)NHR¹¹,

s) C(═

O)NR ¹¹R¹²,

t) NH₂,

u) NHR¹¹,

v) NR¹¹R¹²,

w) NHC(═

O)R¹¹,

x) NR¹¹C(═

O)R¹²,

y) NR¹¹C(═

O)NHR¹²,

z) NR¹¹C(═

O)NR¹²R¹³,

aa) SO₂NHR¹¹,

ab) SO₂NR¹¹R¹²,

ac) NHSO₂R¹¹,

ad) NR¹¹SO₂R¹²,

R³ and R⁵ independently are;

a) H,

b) C₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, X′

, Y′ and

Z′

,

c) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substituents selected from;

X′

, Y′ and

Z′

, or

d) R³ and R⁵ taken together can represent ═

O;

e) R³ or R⁵ can represent a 2 or 3 carbon methylene bridge forming a ring of 5 to 8 atoms fused to the A ring;

R⁴ is;

a) H, or

b) C₁-C₆-alkyl, or

c) C₁-C₆-alkoxyl;

X⁵ and X⁶ are independently CR^a or N;

R^a is;

H, or C₁-C₆-alkyl;

n is 0, 1 or 2;

—

X¹—

X²—

X³—

X⁴—

is;

a) —

CR⁶═

CR⁶—

CR^6a═

CR⁶—

,

b) —

CR^6a═

CR⁶—

CR⁶═

CR⁶—

,

c) —

CR⁶═

CR^6a—

CR⁶═

CR⁶—

,

d) —

CR⁶═

CR⁶—

CR⁶═

CR^6a—

,

e) —

N═

CR⁶—

CR⁶═

CR⁶—

,

f) —

CR⁶═

N—

CR⁶═

CR⁶—

,

g) —

CR⁶═

CR⁶—

N═

CR⁶—

,

h) —

CR⁶═

CR⁶—

CR⁶═

N—

,

i) —

N═

CR⁶—

N═

CR⁶—

,

j) —

CR⁶═

N—

CR⁶═

N—

,

k) —

CR⁶═

N—

N═

CR⁶—

, or

l) —

N═

CR⁶—

CR⁶═

N—

;

R⁶ and R^6a are independently;

a) H,

b) halo(Br, Cl, I, or F)

c) OH,

d) SH,

e) CN,

f) NO₂,

g) N₃,

h) N₂+BF₄—

,

i) R¹¹,

j) OR¹¹,

k) OC(═

O)R¹¹,

l) OC(═

O)OR¹¹,

m) OC(═

O)NHR¹¹,

n) OC(═

O)NR¹¹R¹²,

o) SR¹¹,

p) SOR¹¹,

q) SO₂R¹¹,

r) C₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R¹¹,R¹², and R¹³,

s) C(═

O)R¹¹,

t) C(═

O)OR¹¹,

u) C(═

O)NHR¹¹,

v) C(═

O)NR¹¹R¹²,

w) C(═

O)N(OR¹¹)R¹²,

x) NH₂,

y) NHR¹¹,

z) NHC₁-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R¹¹,R¹², and R¹³,

aa) NR¹¹R¹²,

ab) NHC(═

O)R¹¹,

ac) NR¹¹C(═

O)R¹²,

ad) NHC(═

O)NHR¹¹,

ae) NR¹¹C(═

O)NHR¹²,

af) NR¹¹C(═

O)NR¹²R¹³,

ag) SO₂NH₂,

ah) SO₂NHR₁₁,

ai) SO₂NR₁₁R₁₂,

aj) NHSO₂R₁₁,

ak) NR¹¹SO₂R¹²,

al) NHP(═

O)(OC₁-C₆-alkyl)₂, or

am) R⁶ and R^6a when on adjacent carbons can be joined to form a 5- or 6-membered ring having the following bridging atoms;

i) —

CH═

CH—

CH═

CH—

,

ii) —

OCH₂O—

,

iii) —

C(O)N(R¹¹)C(O)—

,

iv) —

CH₂N(R¹¹)CH₂—

,

v) —

N═

CHNHC(O)—

,

vi) —

C(O)NHCH═

N—

,

vii) —

C(O)OC(O)—

,

viii) —

NHC(O)NHC(O)—

,

ix) —

C(O)NHC(O)NH—

,

x) —

N═

CHNH—

,

xi) —

NHCH═

N—

,

xii) —

N═

CHNR¹¹,

xiii) —

NR¹¹CH═

N—

,

xiv)

xv)

 

represents;

a) phenyl,

b) naphthyl,

c) pyridyl,

d) pyrazinyl,

e) pyrimidinyl,

f) pyrrolyl,

g) thienyl,

h) oxazolyl,

i) isoxazolyl,

j) thiazolyl,

k) pyrazolyl,

l) triazolyl,

m) tetrazolyl,

n) furanyl,

o) benzothienyl,

p) benzofuranyl,

q) indolyl,

r) imidazolyl,

s) benzimidazolyl, or

t) thiadiazolyl,

R⁷, R⁸, R⁹, and R¹⁰ independently are selected from;

a) H,

b) halo(Br, Cl, I, or F)

c) OH,

d) SH,

e) CN,

f) NO₂,

g) N₃

h) N₂+BF₄—

i) R¹¹,

j) OR¹¹,

k) SR¹¹,

l) SOR¹¹,

m) SO₂R¹¹,

n) C₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R¹¹R¹², and R¹³,

o) C₁-C₆-perfluoroalkyl,

p) C(═

O)R¹¹,

q) C(═

O)OR¹¹,

r) C(═

O)NHR¹¹,

s) C(═

O)NR¹¹R¹²,

t) NH₂,

u) NHR¹¹,

v) NHC₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R¹¹,R¹², and R¹³,

w) NR¹¹R¹²,

x) NHC(═

O)R¹¹,

y) NR¹¹C(═

O)R¹²,

z) NR¹¹C(═

O)NHR¹²,

aa) NR¹¹C(═

O)NR¹²R¹³,

ab) SO₂NHR¹¹,

ac) SO₂NR¹¹R¹²,

ad) NHSO₂R¹¹,

ae) NR¹¹SO₂R¹², or

af) two of R⁷, R⁸, R⁹, and R¹⁰ when on adjacent carbons join together to form a methylenedioxy bridge;

R¹¹, R¹², and R¹³ independently are selected from;

a) C₁-C₆-perfluoroalkyl,

b) C₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, X′

, Y′ and

Z′

,

c) C₂-C6-alkenyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, X′

, Y′ and

Z′

,

d) C₂-C6-alkynyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, X′

, Y′ and

Z′

,

e) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two, or three substituents selected from X′

, Y′ and

Z′

,

f) heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with one, two, three or four substituents selected from oxo, X′

, Y′

, and Z′

, or

g) C₃-C6-cycloalkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, X′

, Y′ and

Z′

;

X′

, Y′ and

Z′

independently are selected from;

a) H,

b) halo,

c) CN,

d) NO₂,

e) hydroxy,

f) C₁-C₆-perfluoroalkyl,

g) C₁-C₆-alkoxyl, alkoxyl unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl,

h) (C═

O)(C₁-C₆-alkyl), alkyl unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl,

i) (C═

O)O(C₁-C₆-alkyl), alkyl unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl,

j) (C═

O)NH(C₁-C₆-alkyl),

k) (C═

O)N(C₁-C₆-alkyl)₂,

l) NH₂,

m) NHC₁-C₆-alkyl, wherein alkyl is unsubstituted or substituted with aryl or NH₂,

n) N(C₁-C₆-alkyl)₂,

o) NHaryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two, or three substituents selected from halo, phenyl, CN, NO₂,hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxyl, NH₂,NHC₁-C₆-alkyl, N(C₁-C₆-alkyl)₂, (C═

O)(C₁-C₆-alkyl), (C═

O)O(C₁-C₆-alkyl), (C═

O)NH(C₁-C₆-alkyl), (C═

O)N(C₁-C₆-alkyl)₂, NH(C═

O)(C₁-C₆-alkyl),

p) NHheterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from halo, phenyl, oxo, CN, NO₂, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkyl substituted with C₃-C₇-cycloalkyl, C₁-C₆-alkoxyl, NH₂, NHC₁-C₆-alkyl, N(C₁-C₆-alkyl)₂, (C═

O)(C₁-C₆-alkyl), (C═

O)O(C₁-C₆-alkyl), (C═

O)OCH₂phenyl, (C═

O)NH(C₁-C₆-alkyl), (C═

O)N(C₁-C₆-alkyl)₂, NH(C═

O)(C₁-C₆-alkyl),

q) NHCHO,

r) NH(C═

O)(C₁-C₆-alkyl),

s) NH(C═

O)(OC₁-C₆-alkyl),

t) aryl, wherein aryl is as defined above in o,

u) C₁-C₆-alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, C₃-C₇-cycloalkyl, aryl or heterocyclyl, wherein aryl is defined as above in o and heterocyclyl is as defined above in p,

v) heterocyclyl, wherein heterocyclyl is as defined above in p,

w) when two of X′

, Y′ and

Z′

are on adjacent carbons they can join to form a methylenedioxy bridge,

x) NH(C═

O)aryl,

y) —

NR¹⁴NHR¹⁵,

z) —

S(O)x C₁-C₆-alkyl,

aa) SO₂NH C₁-C₆-alkyl, or

ab) CO₂H;

R¹⁴ and R¹⁵ are independently;

H, C₁-C₆-alkyl, aryl or C₁-C₆-alkylaryl;

or

x is 0, 1 or 2.

31. A method of treating a protein tyrosine kinase-associated disorder, comprising the administration of a therapeutically effective amount of at least one compound of the Formula I, or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, as recited in claim 1, to a subject in need of such treatment.

32. The method of claim 31, wherein the protein tyrosine kinase-associated disorder is transplant rejection.

33. The method of claim 31, wherein the protein tyrosine kinase-associated disorder is rheumatoid arthritis.

34. The method of claim 31, wherein the protein tyrosine kinase-associated disorder is psoriasis.

35. The method of claim 31, wherein the protein tyrosine kinase-associated disorder is inflammatory bowel disease.

36. A method of treating a protein tyrosine kinase-associated disorder, comprising the simultaneous or sequential administration of a therapeutically effective amount of at least one compound of the Formula I, or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, as recited in claim 1, with an antiinflammatory, antiproliferative chemotherapeutic agent, immunosuppressant or a protein tyrosine kinase inhibitor, other than a compound of the Formula I, to a subject in need of such treatment.

37. A method for treating a T-cell mediated disorder, comprising the administration of a therapeutically effective amount of at least one compound of the Formula I, or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof, as recited in claim 1, to a subject in need of such treatment.

38. A pharmaceutical composition for the treatment of a protein tyrosine kinase-associated disorder, comprising a pharmaceutically acceptable carrier and at least one compound of Formula I or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms or an individual diastereomer thereof, as recited in claim 1.

39. A process for making a pharmaceutical composition comprising a combination of a compound of the Formula I, or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof, as recited in claim 1 and a pharmaceutically acceptable carrier.

2. A compound of Formula I

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein

R¹ and R² are independently:

a) H,

b) halo (Br, Cl, I, or F)

c) OH,

d) SH,

e) CN,

f) NO₂,

g) R¹¹,

h) OR¹¹,

i) OC(═

O)R¹¹,

j) OC(═

O)OR¹¹,

k) OC(═

O)NHR¹¹,

l) OC(═

O)NR¹¹R¹²,

m) SR¹¹,

n) SOR¹¹,

o) SO₂R¹¹,

p) C(═

O)R¹¹,

q) C(═

O)OR¹¹,

r) C(═

O)NHR¹¹,

s) C(═

O)NR¹¹R¹²,

t) NH₂,

u) NHR¹¹,

v) NR¹¹R¹²,

w) NHC(═

O)R¹¹,

x) NR¹¹C(═

O)R¹²,

y) NR¹¹C(═

O)NHR¹²,

z) NR¹¹C(═

O)NR¹²R¹³,

aa) SO₂NHR¹¹,

ab) SO₂NR¹¹R¹²,

ac) NHSO₂R¹¹,

ad) NR¹¹SO₂R¹²,

R³ and R⁵ independently are;

a) H,

b) C₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, X′

, Y′ and

Z′

,

c) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with one, two or three substituents selected from;

X′

, Y′ and

Z′

, or

d) R³ and R⁵ taken together can represent ═

O;

e) R³ or R⁵ can represent a 2 or 3 carbon methylene bridge forming a ring of 5 to 8 atoms fused to the A ring;

R⁴ is;

a) H, or

b) C₁-C₆-alkyl, or

c) C₁-C₆-alkoxyl;

X⁵ and X⁶ are independently CR^a or N;

R^a is;

H, or C₁-C₆-alkyl;

n is 0, 1 or 2;

—

X¹—

X²—

X³—

X⁴—

is;

a) —

CR⁶═

CR⁶—

CR^6a═

CR⁶—

,

b) —

CR^6a═

CR⁶—

CR⁶═

CR⁶—

,

c) —

N═

CR⁶—

CR⁶═

CR⁶—

,

d) —

CR⁶═

N—

CR⁶═

CR⁶—

,

e) —

CR⁶═

CR⁶—

N═

CR⁶—

,

f) —

CR⁶═

CR⁶—

CR⁶═

N—

,

g) —

N═

CR⁶—

N═

CR⁶—

,

h) —

CR⁶═

N—

CR⁶═

N—

,

i) —

CR⁶═

N—

N═

CR⁶—

, or

j) —

N═

CR⁶—

CR⁶═

N—

;

R⁶ and R^6a are independently;

a) H,

b) halo(Br, Cl, I, or F)

c) OH,

d) SH,

e) CN,

f) NO₂,

g) N₃,

h) N₂+BF₄—

,

i) R¹¹,

j) OR¹¹,

k) OC(═

O)R₁₁,

l) OC(═

O)OR¹¹,

m) OC(═

O)NHR¹¹,

n) OC(═

O)NR¹¹¹²,

o) SR¹¹,

p) SOR¹¹,

q) SO₂R¹¹,

r) C₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R¹¹,R¹², and R¹³,

s) C(═

O)R¹¹,

t) C(═

O)OR¹¹,

u) C(═

O)NHR¹¹,

v) C(═

O)NR¹¹R¹²,

w) C(═

O)N(OR¹¹)R¹²,

x) NH₂,

y) NHR¹¹,

z) NHC₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R¹¹, R¹², and R¹³,

aa) NR¹¹R¹²,

ab) NHC(═

O)R¹¹,

ac) NR¹¹C(═

O)R¹²,

ad) NHC(═

O)NHR¹¹,

ae) NR¹¹C(═

O)NHR¹²,

af) NR¹¹C(═

O)NR¹²R¹³,

ag) SO₂NH₂,

ah) SO₂NHR¹¹,

ai) SO₂NR¹¹R¹²,

aj) NHSO₂R¹¹,

ak) NR¹¹SO₂R¹²,

al) NHP(═

O)(OC₁-C₆-alkyl)₂, or

am) R⁶ and R^6a when on adjacent carbons can be joined to form a 5- or 6-membered ring having the following bridging atoms;

i) —

CH═

CH—

CH═

CH—

,

ii) —

OCH₂O—

,

iii) —

C(O)N(R¹¹)C(O)—

,

iv) —

CH₂N(R¹¹)CH₂—

,

v) —

N═

CHNHC(O)—

,

vi) —

C(O)NHCH═

N—

,

vii) —

C(O)OC(O)—

,

viii) —

NHC(O)NHC(O)—

,

ix) —

C(O)NHC(O)NH—

,

x) —

N═

CHNH—

, or

xi) —

N═

CHNR¹¹—

, or

xii)

 

represens;

a) phenyl,

b) naphthyl,

c) pyridyl,

d) pyrazinyl,

e) pyrimidinyl,

f) pyrrolyll

g) thienyl,

h) oxazolyl,

i) isoxazolyl,

j) thiazolyl,

k) pyrazolyl,

l) triazolyl,

m) tetrazolyl,

n) furanyl,

o) benzothienyl,

p) benzofuranyl,

q) indolyl,

r) imidazolyl,

s) benzimidazolyl, or

t) thiadiazolyl,

R⁷, R⁸, R⁹, and R¹⁰ independently are selected from;

a) H,

b) halo(Br, Cl, I, or F)

c) OH,

d) SH,

e) CN,

f) NO₂,

g) N₃

h) N₂+BF₄—

i) R₁₁,

j) OR¹¹,

k) SR¹¹,

l) SOR¹¹,

m) SO₂R¹¹,

n) C₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R¹¹, R¹², and R¹³,

o) C₁-C₆-perfluoroalkyl,

p) C(═

O)R₁₁,

q) C(═

O)OR¹¹,

r) C(═

O)NHR¹¹,

s) C(═

O)NR¹¹R¹²,

t) NH₂,

u) NHR¹¹,

v) NHC₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R¹¹, R¹², and R¹³,

w) NR¹¹R¹²,

x) NHC(═

O)R¹¹,

y) NR¹¹C(═

O)R¹²,

z) NR¹¹C(═

O)NHR¹²,

aa) NR¹¹C(═

O)NR¹²R¹³,

ab) SO₂NHR¹¹,

ac) SO₂NR¹¹R¹²,

ad) NHSO₂R¹¹,

ae) NR¹¹SO₂R¹², or

af) two of R⁷, R⁸, R⁹, and R¹⁰ when on adjacent carbons join together to form a methylenedioxy bridge;

R¹¹, R¹², and R¹³ independently are selected from;

a) C₁-C₆-perfluoroalkyl,

b) C₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, X′

, Y′ and

Z′

,

c) C₂-C₆-alkenyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, X′

, Y′ and

Z′

,

d) C₂-C₆-alkynyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, X′

, Y′ and

Z′

,

e) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two, or three substituents selected from X′

, Y′ and

Z′

,

f) heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from oxo, X′

, Y′

, and Z′

;

g) C₃-C₆-cycloalkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, X′

, Y′ and

Z′

,

X′

, Y′ and

Z′

independently are selected from;

a) H,

b) halo,

c) CN,

d) NO₂,

e) hydroxy,

f) C₁-C₆-perfluoroalkyl,

g) C₁-C₆-alkoxyl, alkoxyl unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl,

h) (C═

O)(C₁-C₆-alkyl), alkyl unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl,

i) (C═

O)O(C₁-C₆-alkyl), alkyl unsubstituted or substituted with aryl, wherein aryl is defined as phenyl or naphthyl,

j) (C═

O)NH(C₁-C₆-alkyl),

k) (C═

O)N(C₁-C₆-alkyl)₂,

l) NH₂,

m) NHC₁-C₆-alkyl,

n) N(C₁-C₆-alkyl)₂,

o) NHaryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with one, two, or three substituents selected from halo, phenyl, CN, NO₂hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxyl, NH₂, NHC₁-C₆-alkyl, N(C₁-C₆-alkyl)₂, (C═

O)(C₁-C₆-alkyl), (C═

O)O(C₁-C₆-alkyl), (C═

O)NH(C₁-C₆-alkyl), (C═

O)N(C₁-C₆-alkyl)₂, NH(C═

O)(C₁-C₆-alkyl),

p) NHheterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from halo, phenyl, oxo, CN, NO₂,hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxyl, NH₂, NHC₁-C₆-alkyl, N(C₁-C₆-alkyl)₂,(C═

O)(C₁-C₆-alkyl), (C═

O)O(C₁-C₆-alkyl), (C═

O)OCH₂phenyl, (C═

O)NH(C₁-C₆-alkyl), (C═

O)N(C₁-C₆-alkyl)₂, NH(C═

O)(C₁-C₆-alkyl),

q) NHCHO,

r) NH(C═

O)(C₁-C₆-alkyl),

s) NH(C═

O)(OC₁-C₆-alkyl),

t) aryl, wherein aryl is as defined above in o,

u) C₁-C₆-alkyl, wherein alkyl is unsubstituted or substituted with aryl or heterocyclyl, wherein aryl is defined as above in o and heterocyclyl is as defined above in p,

v) heterocyclyl, wherein heterocyclyl is as defined above in p, or

w) when two of X′

, Y′ and

Z′

are on adjacent carbons they can join to form a methylenedioxy bridge.

3. The compound of Formula Ia:

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein R¹, R², and R³ are as defined below and all other substituents are as recited in claim 2,

R¹ and R² are independently;

a) H,

b) R¹¹,

c) NH₂,

d) NHR¹¹, or

e) NR¹¹R¹²; and

R³ is;

a) H, or

b) C₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from oxo, X′

, Y′ and

Z′

.

4. The compound of Formula Ib:

or a pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein R¹ and —

X¹—

X²—

X³—

X⁴—

are as defined below and all other substituents are as recited in claim 3,

R¹ is;

a) H,

b) R¹¹,

c) NH₂,

d) NHR¹¹, or

e) NR¹¹R¹²; and

—

X¹—

X²—

X³—

X⁴—

is;

a) —

CR⁶═

CR⁶—

CR^6a═

CR⁶—

, or

b) —

R^6a═

CR⁶—

CR⁶═

CR⁶.

5. The compound of Formula Ic:

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein R⁶ and R^6a are as defined below and all other substituents are as recited in claim 4,

R⁶ and R^6a are independently;

a) H,

b) halo (Br, Cl, I, or F),

c) R¹¹,

d) OR¹¹,

e) C₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R⁹, R¹⁰, and R¹¹,

f) NH₂,

g) NHR¹¹,

h) NHC₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R⁹, R¹⁰, and R¹¹,

i) NR¹¹R¹²,

j) NHC(═

O)R¹¹,

k) NR¹¹C(═

O)R¹²,

l) NR¹¹C(═

O)NHR¹²,

m) NR¹¹C(═

O)NR¹²R¹³,

n) NHSO₂R¹¹, or

o) NR¹¹SO₂R¹².

j) imidazolyl, unsubstituted or substituted with one, two or three substituents selected from X′

, Y′

, and Z′

,

k) imidazolidinyl, unsubstituted or substituted with one, two or three substituents selected from oxo, X′

, Y′

, and Z′

,

l) 1,3-diazobicyclo[3.3.0]octan-2-onyl,

m) 1,3-diazobicyclo[4.3.0]nonan-2-onyl,

n) NH₂,

o) NHR¹¹,

p) NHC₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R¹¹, R¹², and R¹³,

q) NR¹¹R¹²,

r) NHC(═

O)R¹¹,

s) NR¹¹C(═

O)R12,

t) NR¹¹C(═

O)NHR¹²,

u) NR¹¹C(═

O)NR¹²R¹³,

v) NHSO₂R¹¹ or

w) NR¹¹SO₂R¹².

6. The compound of Formula Ic:

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein R¹ is H, aryl, or heterocyclyl, and all other substituents are as recited in claim 5.

7. The compound of Formula Ic:

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein A is defined as phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, tetrazolyl, imidazolyl, thiadiazolyl, and all other substituents are as recited in claim 6.

8. The compound of Formula Id:

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein the substituents are as recited in claim 7, except that R⁶ is attached to the 5- or 6-position of the benzimidazole.

9. The compound of Formula Ie:

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein R⁶ is as defined below and all other substituents are as recited in claim 2,

R⁶ is;

a) H,

b) phenyl, unsubstituted or substituted with one, two, or three substituents selected from X′

, Y′ and

Z′

,

c) pyridyl, unsubstituted or substituted with one, two or three substituents selected from X′

, Y′

, and Z′

,

d) pyridazinyl, unsubstituted or substituted with one, two or three substituents selected from X′

, Y′

, and Z′

,

e) pyrimidinyl, unsubstituted or substituted with one, two or three substituents selected from X′

, Y′

, and Z′

,

f) thiazolyl, unsubstituted or substituted with one, two, or three substituents selected from X′

, Y′

, and Z′

,

g) thiadiazolyl, unsubstituted or substituted with one, two or three substituents selected from X′

, Y′

, and Z′

,

h) thienyl, unsubstituted or substituted with one, two or three substituents selected from X′

, Y′

, and Z′

,

i) pyrazinyl, unsubstituted or substituted with one, two or three substituents selected from X′

, Y′

, and Z′

,

j) imidazolyl, unsubstituted or substituted with one, two or three substituents selected from X′

, Y′

, and Z′

,

k) imidazolidinyl, unsubstituted or substituted with one, two or three substituents selected from oxo, X′

, Y′

, and Z′

,

l) 1,3-diazobicyclo[3.3.0]octan-2-onyl,

m) 1,3-diazobicyclo[4.3.0]nonan-2-onyl,

n) NH₂,

o) NHR⁸,

p) NHC₁-C6-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R⁸, R⁹, and R¹⁰,

q) NR⁸R⁹,

r) NHC(═

O)R⁸,

s) NR⁸C(═

O)R⁹,

t) NR⁸C(═

O)NHR⁹,

u) NR⁸C(═

O)NR⁹R¹⁰,

v) NHSO₂R⁸, or

w) NR⁸SO₂R⁹.

10. The compound of Formula If:

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein R⁶ is as defined below and all other substituents are as recited in claim 9,

R⁶ is;

a) H,

b) phenyl, unsubstituted or substituted with one, two, or three substituents selected from X′

, Y′ and

Z′

,

c) pyridyl, unsubstituted or substituted with one, two or three substituents selected from X′

, Y′

, and Z′

,

d) pyridazinyl, unsubstituted or substituted with one, two or three substituents selected from X′

, Y′

, and Z′

,

e) pyrimidinyl, unsubstituted or substituted with one, two or three substituents selected from X′

, Y′

, and Z′

,

f) imidazolidinyl, unsubstituted or substituted with one, two or three substituents selected from oxo, X′

, Y′

, and Z′

,

g) 1,3-diazobicyclo[3.3.0]-octan-2-onyl,

h) 1,3-diazobicyclo[4.3.0]-nonan-2-onyl,

i) NH₂,

j) NHR¹¹,

k) NHC₁-C₆-alkyl, unsubstituted or substituted with one, two, or three substituents selected from R¹¹, R¹², and R¹³,

l) NR¹¹R¹²,

m) NHC(═

O)R¹¹,

n) NR¹¹C(═

O)R¹²,

o) NR¹¹C(═

O)NHR¹²,

p) NR¹¹C(═

O)NR¹²R¹³,

q) NHSO₂R¹¹, or

r) NR¹¹SO₂R¹².

11. The compound of Formula If:

or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, wherein A is phenyl, naphthyl, pyridyl, pyrimidinyl, thienyl, or thiazolyl, and all other substituents are as recited in claim 10.

12. The compound of Formula I as recited in claim 2, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and individual diastereomers thereof, which is selected from the group consisting of:

2-[(S)-1-Phenylethylamino]-4-[5-methylbenzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[6-methylbenzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[6-aminobenzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-N,N-(dimethyl)-amninobenzimidazol-1-yl]pyrimidine;

2-((S)-1-(3-nitro-phenyl)ethylamino)-4-[5-methyl-benzimidazol-1-yl]pyrimidine;

2-((S)-1-(3-nitro-phenyl)ethylamino)-4-[6-methyl-benzimidazol-1-yl]pyrimidine;

2-((R)-1-(3-nitro-phenyl)ethylamino)-4-[5-methyl-benzimidazol-1-yl]pyrimidine;

2-((R)-1-(3-nitro-phenyl)ethylamino)4-[6-methyl-benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-N-((morpholin-2-yl)methyl)-aminobenzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-N-((piperazin-2-yl)methyl)-aminobenzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-N-(2-aminoethyl)-aminobenzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-N-((pyrrolidin-2-yl)methyl)-aminobenzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-N-(((R)-piperidin-2-yl)methyl)-aminobenzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(1,3-diazobicyclo[3.3.0]-octan-3-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(1,3-diazobicyclo[3.3.0]-octan-2-one-3-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(1,3-diazobicyclo[4.3.0]-nonan-2-one-3-yl)benzimidazol-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-N-(N-methylcarbamoyl)-aminobenzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-N-(N-ethylcarbamoyl)-aminobenzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-N-(N-propylcarbamoyl)-aminobenzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-N-(N-((1-methyl)ethylcarbamoyl)amino-benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(tetrazol-1-yl)-benzimidazol-1-yl]pyrimidine;

2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-N-(pyrrolidin-2-yl)methyl)-aminobenzimidazol-1-yl]pyrimidine;

2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-N-((pyrrolidin-2-yl)methyl)-aminobenzimidazol-1-yl]pyrimidine;

2-[(S)-1-(3Nitrophenyl)ethylamino]-4-[5-(1,3-diazobicyclo[3.3.0]-octan-2-one-3-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(1,3-diazobicyclo[3.3.0]octan-2-one-3-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-(3Nitrophenyl)ethylamino]-4-[5-(1,3-diazobicyclo[3.3.0]-octan-3-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(1,3-diazobicyclo[3.3.0]octan-3-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-phenylbenzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(thiazol-2-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(furan-2-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[benzimidazol-1-yl]-6-(2-methyl-phenyl)pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(pyridin-2-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(thiophen-3-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(pyrimidin-5-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(pyridin-3-yl)-benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(4-methoxyphenyl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(3-chlorophenyl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(3-methoxyphenyl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(4-(pyrrol-1-yl)phenyl)benzimidazol-1-yl]-pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(4-methylphenyl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(pyrimidin-2-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(3-methylphenyl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(thiophen-3-yl-carbonyl)benzimidazol-1-yl]-pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(2-aminopyridine-5-yl)benzimidazol-1-yl]-pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(2-aminopyridin-5-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(4-pyridyl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(3-methoxypyridazin-6-yl)benzimidazol-1-yl]-pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(3-chloropyridazin-6-yl)benzimidazol-1-yl]-pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(6-methylpyridazin-3-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(pyridazin-3-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(3-N,N-dimethylaminopyridazin-6-yl)-benzimidazol-1-yl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]-pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(2-aminopyridin-4-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol -1-yl]pyrimidine;

2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(pyridazin-3-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(pyridazin-3-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(3-N,N-dimethylpyridazin-6-yl)benzimidazol-1-yl]pyrimidine;

2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(3-N,N-dimethylpyridazin-6-yl)benzimidazol-1-]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(2-amninopyrimidin-4-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(pyridazin-3-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(3-N,N-dimethylpyridazin-6-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(pyridazin-3-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;

2-[(S)-1-Phenylethylamino]-4-[5-(3-N,N-dimethylpyridazin-6-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;

2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;

2-[(S)-1-(3-Nitromethylphenyl)ethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;

2-[(S)-1-(3-Trifluorophenyl)ethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;

2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine;

2-[(S)-1-(3-Nitrophenyl)ethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine;

2-[(S)-1-(3-Nitromethylphenyl)ethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine;

2-[(S)-1-(3-Trifluorophenyl)ethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine; and

2-[(S)-1-(3-Trifluoromethylphenyl)ethylamino]-4-[5-(pyridin-4-yl)benzimidazol-1-yl]-6-[2-methylphenyl]pyrimidine.

13. A method of treating a protein tyrosine kinase-associated disorder, comprising the administration of a therapeutically effective amount of at least one protein tyrosine kinase inihibitor compound of the Formula I, or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, as recited in claim 2, to a subject in need of such treatment.

14. The method of claim 13, wherein the protein tyrosine kinase-associated disorder is transplant rejection.

15. The method of claim 13, wherein the protein tyrosine kinase-associated disorder is rheumatoid arthritis.

16. The method of claim 13, wherein the protein tyrosine kinase-associated disorder is psoriasis.

17. The method of claim 13, wherein the protein tyrosine kinase-associated disorder is inflammatory bowel disease.

18. The method of claim 13, wherein the protein tyrosine kinase is Lck.

19. The method of claim 13, wherein the protein tyrosine kinase is Fyn(T) or Fyn(B).

20. The method of claim 13, wherein the protein tyrosine kinase is Lyn.

21. The method of claim 13, wherein the protein tyrosine kinase is Hck.

22. The method of claim 13, wherein the protein tyrosine kinase is Fgr.

23. The method of claim 13, wherein the protein tyrosine kinase is Src.

24. The method of claim 13, wherein the protein tyrosine kinase is Blk.

25. The method of claim 13, wherein the protein tyrosine kinase is Yes.

26. A method of treating a protein tyrosine kinase-associated disorder, comprising the simultaneous or sequential administration of a therapeutically effective amount of at least one protein tyrosine kinase inihibitor compound of the Formula I, or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, as recited in claim 2, with an antiinflammatory, antiproliferative chemotherapeutic agent, immunosuppressant or a protein tyrosine kinase inhibitor, other than a compound of the formula I, to a subject in need of such treatment.

27. The method of claim 26, wherein the protein tyrosine kinase inihibitor compound of Formula I or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof is administered with one or more of another PTK inhibitor, cyclosporin A;

CTLA4-Ig;

antibodies selected from anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, and anti-CD86;

agents blocking the interaction between CD40 and gp39;

fusion proteins constructed from CD40 and gy39;

inhibitors of NF-kappa B function;

nuclear translocation inhibitors;

cholesterol biosynthesis inhibitors;

HMG CoA reductase inhibitors;

non-steroidal antiinflammatory drugs (NSAIDs);

cyclooxygenase inhibitors;

steroids;

gold compounds;

antiproliferative agents;

FK506 (tacrolimus, Prograf);

mycophenolate mofetil;

cytotoxic drugs;

TNF-□

inhibitors;

anti-TNF antibodies or soluble TNF receptor; and

rapamycin (sirolimus or Rapamune) or derivatives thereof.

28. A method for treating a T-cell mediated disorder, comprising the administration of a therapeutically effective amount of at least one compound of the Formula I, or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof, as recited in claim 2, to a subject in need of such treatment.

29. A pharmaceutical composition for the treatment of a protein tyrosine kinase-associated disorder, comprising a pharmaceutically acceptable carrier and at least one compound of Formula I or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms or an individual diastereomer thereof, as recited in claim 2.

30. A process for making a pharmaceutical composition comprising a combination of a compound of the Formula I, or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof, as recited in claim 2 and a pharmaceutically acceptable carrier.