Indazolinone compositions useful as kinase inhibitors

• US 20040167121A1
• Filed: 10/27/2003
• Published: 08/26/2004
• Est. Priority Date: 10/25/2002
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Li, Pan, Lauffer, David J., Aronov, Alex, Li, Huan Qui, Tomlinson, Ronald Charles
• Granted Patent: US 7,262,200 B2
• Time in Patent Office: Days
• US Class Current: 514/217.07
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention provides compounds of formula I:

These compounds, and pharmaceutically acceptable compositions thereof, are useful generally as kinase inhibitors, particularly as inhibitors of PRAK, GSK3, ERK2, CDK2, MK2, SRC, SYK, and Aurora-2. Accordingly, compounds and compositions of the invention are useful for treating or lessening the severity of a variety of disorders, including, but not limited to, heart disease, diabetes, Alzheimer'"'"'s disease, immunodeficiency disorders, inflammatory diseases, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases and viral diseases.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein Z is CR and the compound has the structure (Ia):

3. The compound of claim 1, wherein Z is CR⁶ and the compound has the structure (Ib):

4. The compound of claim 1, wherein either of R³ or R⁴ is -Q¹-A-Q²-Y, wherein A is a substituted or unsubstituted aryl or heteroaryl moiety and compounds have the general formula IIa or IIb:

5. The compound of claim 4, wherein A represents one of the following moieties:

6. The compound of claim 5, wherein ring A is one of formulas i, ii, iii or x.

7. The compound of claim 4, wherein Ring A is one of groups II-A through II-DD, wherein Z¹ is nitrogen or CR^V, Z² is nitrogen or CR^W, and p is 0-4:

8. The compound of claim 7, wherein ring A is one of II-A, II-B, II-C, II-D, II-E, II-F, II-H, II-I, II-J, II-K, II-L, II-N, II-O, or II-DD.

9. The compound of claim 7, wherein ring A is one of II-A, II-B, II-C, II-D, II-E, II-H, or II-K.

10. The compound of claim 7, wherein ring A is one of II-A or II-B.

11. The compound of claim 7, wherein Z¹ is CR^V and Z² is CR^W.

12. The compound of claim 7, wherein Z¹ is N and Z² is N.

13. The compound of claim 7, wherein Z¹ is N and Z² is CR^W.

14. The compound of claim 7, wherein Z¹ is CR^V and Z² is N.

15. The compound of claim 4, wherein A is a monocyclic ring system and R^X groups, when present, include hydrogen, alkyl- or dialkylamino, acetamido, or a C_1-4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl;

R^Y groups, when present, include hydrogen, an optionally substituted group selected from C_1-6 aliphatic, C_1-6 heteroaliphatic, aryl, or heteroaryl, -Q_(n)N(R⁷)₂, -Q_(n)OR⁷, -Q_(n)SR⁷, -Q_(n)C(O)N(R⁷)₂, -Q_(n)C(O)N(R⁷)₂, -Q_(n)NHC(O)R⁷, -Q_(n)NHSO₂R⁷, or -Q(f)SO₂N(R⁷)₂, wherein n is 0 or 1, and wherein Q is preferably —

-(C(R″

)₂)—

, wherein R″

is hydrogen or C_1-3alkyl, and wherein each occurrence of R⁷ is independently hydrogen, optionally substituted aliphatic, heteroaliphatic, aryl or heteroaryl, or two occurrences of R⁷ on the same nitrogen atom are taken together with the nitrogen atom to form an optionally group selected from a 5-8 membered heterocyclic or 5-8 membered heteroaryl ring.

16. The compound of claim 15, wherein R^Y is one of the following groups:

optionally substituted 5-6 membered heteroaryl or heterocyclyl rings, such as 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl;

optionally substituted aryl or cycloalkyl rings such as phenyl, halogen substituted phenyl, alkoxy substituted phenyl, trifluoromethyl substituted phenyl, nitro substituted phenyl, methyl substituted phenyl;

optionally substituted C_1-6 aliphatic, such as methyl, ethyl, cyclopropyl, cyclopentyl, cyclohexyl, amino substituted cycloalkyl, acetamido substituted cycloalkyl, isopropyl, or t-butyl;

alkoxyalkylamino such as methoxyethylamino;

alkoxyalkyl such as methoxymethyl or methoxyethyl;

aminoalkyl such as aminoethyl, dimethylaminoethyl;

alkyl- or dialkylamino such as ethylamino or dimethylamino;

alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy;

alkyl- or dialkylaminoalkoxyalkyl such as dimethylaminoethoxymethyl;

or acetamido.

17. The compound of claim 4, wherein A is a bicyclic ring system and the bicyclic ring system A may be substituted by one or more occurrences of oxo, R⁸ or R⁹, wherein R⁸ is —

R⁷, halo, —

O(CH₂)_2-4—

N(R⁷)₂, —

O(CH₂)_2-4—

R⁷, —

OR⁷, —

N(R⁷)—

(CH₂)₂₄—

N(R⁷)₂, —

N(R⁷)—

(CH₂)₂₄—

R⁷, —

C(═

O)R⁷, —

CO₂R⁷, —

COCOR⁷, —

NO₂, —

CN, —

S(O)R⁷, —

SO₂R⁷, —

SR⁷, —

N(R⁷)₂, —

CON(R⁷)₂, —

SO₂N(R⁷)₂, —

OC(═

O)R⁷, —

N(R⁷)COR⁷, —

N(R⁷)CO₂(optionally substituted C_1-6 aliphatic), —

N(R⁷)N(R⁷)₂, —

C═

NN(R⁷)₂, —

C═

N—

OR, —

NHOR⁷, —

N(R⁷)CON(R⁷)₂, —

N(R⁷)SO₂N(R⁷)₂, —

N(R⁷)SO₂R⁷, or —

OC(═

O)N(R⁷)₂, wherein each occurrence of R⁷ is independently hydrogen, an optionally substituted group selected from aliphatic, heteroaliphatic, aryl or heteroaryl, or two occurrences of R⁷ on the same nitrogen atom are taken together with the nitrogen atom to form an optionally substituted group selected from a 5-8 membered heterocyclic or 5-8 membered heteroaryl ring.

18. The compound of claim 17 wherein each occurrence of R⁸ is independently -halo, —

R⁷, —

OR⁷, —

COR⁷, —

CO₂R⁷, —

CON(R⁷)₂, —

O(C═

O)N(R⁷)₂, —

CN, —

O(CH₂)_2-4—

N(R⁷)₂, —

O(CH₂)₂₄—

R⁷, —

NO₂—

N(R⁷)₂, —

NR⁷COR⁷, —

NR⁷SO₂R⁷, —

SO₂N(R⁷)₂ wherein each occurrence of R⁷ is independently hydrogen, an optionally substituted group selected from aliphatic, heteroaliphatic, aryl or heteroaryl, or two occurrences of R⁷ on the same nitrogen atom are taken together with the nitrogen atom to form an optionally substituted group selected from a 5-8 membered heterocyclic or 5-8 membered heteroaryl ring.

19. The compound of claim 4, wherein Y is an optionally substituted heteroaryl moiety.

20. The compound of claim 4, wherein Y is selected from one of the following heteroaryl moieties a-y:

21. The compound of claim 20, wherein Y is one of the following heteroaryl moieties:

22. The compound of claim 20, wherein Y is a pyrazole moiety, h.

23. The compound of claim 20, wherein each R¹⁰ is independently hydrogen, C_1-4aliphatic, alkoxycarbonyl, optionally substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, or (N-heterocycle)carbonyl.

24. The compound of claim 20, wherein each occurrence of R¹⁰ is independently methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═

CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇), CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, or CO(piperidin-1-yl).

25. The compound of claim 20, wherein, Y is a pyrazole moiety, h′

, wherein the pyrazole is substituted with two occurrences of R¹⁰ (R^10a and R^10b)

26. The compound of claim 20, wherein two occurrences of R¹⁰ (R^10a and R^10b as depicted in formula h′

) taken together may represent a substituted or unsubstituted cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety and comprises one of the following groups;

27. The compound of claim 4, wherein when R³ is -Q¹-A-Q²-Y, R⁴ is hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl.

28. The compound of claim 27, wherein R⁴ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂.

29. The compound of claim 4, wherein when R⁴ is -Q¹-A-Q²-Y, R³ is preferably hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl.

30. The compound of claim 29, wherein R³ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂.

31. The compound of claim 4, wherein R⁵ is hydrogen, halogen, —

NO₂, —

CN, hydroxy, optionally substituted C_1-3alkyl, optionally substituted alkoxy, —

SO₂NH₂, or —

C(O)alkyl.

32. The compound of claim 31 wherein R⁵ is C₁, CF₃, OCF₃, CH₃, —

CN, —

SO₂NH₂ or —

C(O)Me.

33. The compound of claim 4, wherein Q¹ is NH and Q² is NH, and compounds are defined by the general formula IIa(i) or IIb(i):

34. The compound of claim 4, wherein Q¹ is S and Q² is NH, and compounds are defined by the general formula IIa(ii) or IIb(ii):

35. The compound of claim 4, wherein Q¹ is 0 and Q² is NH, and compounds are defined by the general formula IIa(iii) or IIb(iii):

36. The compound of claim 4, wherein Q² is NH, and compounds are defined by the general formula IIa(iv) or IIb(iv):

37. The compound of claim 4, wherein Q² is NH and Y is an optionally substituted heteroaryl moiety, and compounds are defined by the general formula IIa(v) or IIb(v):

38. The compound of any one of claims 33, 34, 35, 36 or 37, wherein:

i. Z is CR⁶ or N;

ii. R², R¹, R⁴ and R⁵ are each hydrogen and wherein Z is CHR⁶ and R⁶ is hydrogen;

or R¹, R²R³ and R⁵ are each hydrogen and wherein Z is CHR⁶ and R⁶ is hydrogen;

iii. ring A is defined according to one of the following groups;

a. ring A is one of formulas i, ii, iii, iv, v, vi, vii, viii, ix, or x;

b. ring A is one of formulas II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-I, II-J, II-K, II-L, II-M, II-N, II-O, II-P, II-Q, II-R, II-S, II-T, II-U, II-V, II-W, II-X, II-Y, II-Z, II-AA, II-BB, II-CC, or II-DD;

c. ring A is one of formulas II-A, II-B, II-C, II-D, II-E, II-F, II-H, II-I, II-J, II-K, II-L, II-N, II-O, or II-DD;

d. ring A is one of formulas II-A, II-B, II-C, II-D, II-E, II-H, or II-K;

e. ring A is one of formulas II-A or II-B;

f. ring A is II-A and Z¹ is CR^V and Z² is CR^W;

g. ring A is II-A and Z¹ is N and Z² is N;

h. ring A is II-A and Z¹ is N and Z² is CR^W;

i. ring A is II-A and Z¹ is CR^V and Z² is N;

j. ring A is an optionally substituted aryl or heteroaryl moiety of formula i, ii, i or x;

k. ring A is a monocyclic ring system and R^V and R^W, when present, are hydrogen or amino;

R^X groups, when present, is hydrogen, alkyl- or dialkylamino, acetamido, or a C_1-4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl;

R^Y groups, when present, is hydrogen, an optionally substituted group selected from hydrogen, C_1-6 aliphatic, C_1-6 heteroaliphatic, aryl, or heteroaryl, -Q_(n)N(R⁷)₂, -Q_(n)OR⁷, -Q_(n)SR⁷, -Q_(n)(C═

O)O(R⁷), -Q_(n)C(O)N(R⁷)₂, -Q_(n)NHC(O)R⁷, -Q_(n)NHSO₂R⁷, or -Q(f)SO₂N(R⁷)₂, wherein n is 0 or 1, and wherein Q is preferably —

(C(R″

)₂)—

, wherein R″

is hydrogen or C_1-3alkyl, and wherein each occurrence of R⁷ is independently hydrogen, an optionally substituted group selected from aliphatic, heteroaliphatic, aryl or heteroaryl, or two occurrences of R⁷ on the same nitrogen atom are taken together with the nitrogen atom to form an optionally substituted group selected from a 5-8 membered heterocyclic or 5-8 membered heteroaryl ring;

l. ring A is a monocyclic ring system and R^V, R^W and R^X groups, when present, are hydrogen or amino;

R^Y groups include groups selected from optionally substituted 5-6 membered heteroaryl or heterocyclyl rings, such as 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl;

optionally substituted aryl or cycloalkyl rings such as phenyl, halogen substituted phenyl, alkoxy substituted phenyl, trifluoromethyl substituted phenyl, nitro substituted phenyl, methyl substituted phenyl;

optionally substituted C_1-6 aliphatic, such as methyl, ethyl, cyclopropyl, cyclopentyl, cyclohexyl, amino substituted cycloalkyl, acetamido substituted cycloalkyl, isopropyl, or t-butyl;

alkoxyalkylamino such as methoxyethylamino;

alkoxyalkyl such as methoxymethyl or methoxyethyl;

aminoalkyl such as aminoethyl, dimethylaminoethyl;

alkyl- or dialkylamino such as ethylamino or dimethylamino;

alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy;

alkyl- or dialkylaminoalkoxyalkyl such as dimethylaminoethoxymethyl; and

acetamido;

m. ring A system is a bicyclic ring system and the ring formed when R^x and R^y are taken together may be substituted or unsubstituted;

n. ring A system is a bicyclic ring system formed by R^X and R^Y taken together and substituted by one or more occurrences of R⁸ or R⁹, wherein each occurrence of R⁸ is independently —

R⁷, halo, —

O(CH₂)₂₄—

N(R⁷)₂, —

O(CH₂)_2-4—

R⁷, —

OR⁷, —

N(R⁷)—

(CH₂)₂₄—

N(R⁷)₂, —

N(R⁷)—

(CH₂)₂₄—

R⁷, —

C(═

O)R⁷, —

CO₂R⁷, —

COCOR⁷, —

NO₂, —

CN, —

S(O)R⁷, —

SO₂R⁷, —

SR⁷, —

N(R⁷)₂, —

CON(R⁷)₂, —

SO₂N(R⁷)₂, —

OC(═

O)R⁷, —

N(R⁷)COR⁷, —

N(R⁷)CO₂(optionally substituted C_1-6 aliphatic), —

N(R⁷)N(R⁷)₂, —

C═

NN(R⁷)₂, —

C═

N—

OR, —

NHOR⁷, —

N(R⁷)CON(R⁷)₂, —

N(R⁷)SO₂N(R⁷)₂, —

N(R⁷)SO₂R⁷, or —

OC(═

O)N(R⁷)₂, wherein each occurrence of R⁷ is independently hydrogen, an optionally substituted group selected from aliphatic, heteroaliphatic, aryl or heteroaryl, or two occurrences of R⁷ on the same nitrogen atom are taken together with the nitrogen atom to form an optionally substituted group selected from a 5-8 membered heterocyclic or 5-8 membered heteroaryl ring; and

each occurrence of R⁹ is independently hydrogen, —

R′

, —

COR′

, —

CO₂(R′

), —

CON(R′

)₂, or —

SO₂R′

, wherein each occurrence of R′

is independently hydrogen, an optionally substituted group selected from aliphatic, heteroaliphatic, aryl or heteroaryl, or two occurrences of R′

on the same nitrogen atom are taken together with the nitrogen to form an optionally substituted group selected from a 5-8 membered heterocyclic or 5-8 membered heteroaryl ring,

iv. Y is defined according to one of the following groups;

a. Y is an optionally substituted heteroaryl moiety;

b. Y is selected from one of the heteroaryl moieties a-y;

c. Y is selected from one of the following heteroaryl moieties;

wherein q is 0-4, R¹⁰ is —

R, wherein —

R is defined generally above and in classes and subclasses herein, and wherein each occurrence of R¹¹ is independently hydrogen, —

R′

, —

COR′

, —

CO₂(R′

), —

CON(R′

)₂, or —

SO₂R′

, wherein each occurrence of R′

is independently hydrogen, an optionally substituted group selected from aliphatic, heteroaliphatic, aryl or heteroaryl, or two occurrences of R on the same nitrogen atom are taken together with the nitrogen to form an optionally substituted group selected from a 5-8 membered heterocyclic or 5-8 membered heteroaryl ring;

d. Y is a pyrazole moiety, h;

e. Y is one of a, b, f, h or o, optionally substituted with one or more R¹⁰ groups, wherein each occurrence of R¹⁰ is independently hydrogen, C_1-4aliphatic, alkoxycarbonyl, optionally substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylamiinocarbonyl, and (N-heterocycle)carbonyl;

f. Y is one of a, b, f, h or o, optionally substituted with one or more R¹⁰ groups, wherein each occurrence of R¹⁰ is independently hydrogen, methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═

CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇), CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, and CO(piperidin-1-yl).

g. Y is a pyrazole moiety, h′

, wherein the pyrazole is substituted with two occurrences of R¹⁰ (R^10a and R^10b as depicted),

wherein each occurrence of R^10a is hydrogen, C_1-4aliphatic, alkoxycarbonyl, optionally substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (N-heterocycle)carbonyl, and R^10b is hydrogen;

h. Y is a pyrazole moiety, h′

, wherein the pyrazole is substituted with two occurrences of R¹⁰ (R^10a and R^10b as depicted),

wherein each occurrence of R^10a is hydrogen, methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═

CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇), CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, and CO(piperidin-1-yl, and R^10b is hydrogen;

i. Y is heteroaryl moiety substituted by at least two occurrences of R¹⁰ and where two occurrences of R¹⁰ taken together may represent an optionally substituted group selected from cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl;

j. Y represents one of the following heteroaryl moieties;

wherein r is 0-4 and R¹² is hydrogen, -halo, —

N(R⁷)₂, —

C_1-3 alkyl, —

C_1-3 haloalkyl, —

NO₂, —

O(C_1-3 alkyl), —

CO₂(C_1-3 alkyl), —

CN, —

SO₂(C_1-3 alkyl), —

SO₂NH₂, —

OC(O)NH₂, —

NH₂SO₂(C_1-3 alkyl), —

NHC(O)(C_1-3 alkyl), —

C(O)NH₂, and —

CO(C_1-3 alkyl), wherein the (C_1-3 alkyl) is most preferably methyl;

v. for compounds of formula IIa(i), R⁴ is defined according to one of the following groups;

a. R⁴ is hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl, or

b. R⁴ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂;

vi. for compounds of formula IIb(i), R³ is defined according to one of the following groups;

a. R³ is hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl, or

b. R³ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂; and

vii. R⁵ is defined according to one of the following groups;

a. hydrogen, halogen, —

NO₂, —

CN, hydroxy, optionally substituted C_1-3alkyl, optionally substituted alkoxy, —

SO₂NH₂, or —

C(O)alkyl, or

b. R⁵ is hydrogen, C₁, CF₃, OCF₃, CH₃, —

CN, —

SO₂NH₂ or —

C(O)Me.

39. The compound of claim 1, wherein either of R³ or R⁴ is -Q¹-A-Q²-Y, wherein A is an optionally substituted cycloaliphatic or heterocycloaliphatic moiety and compounds have the general formula IIIa or IIIb:

40. The compound of claim 39, wherein ring A is selected from the following group:

41. The compound of claim 40, wherein x is 0 or 1 and R¹⁴ is -halo, —

N(R⁷)₂, —

C_1-3 alkyl, —

C_1-3 haloalkyl, —

NO₂, —

O(C_1-3 alkyl), —

CO₂(C_1-3 alkyl), —

CN, —

SO₂(C_1-3 alkyl), —

SO₂NH₂, —

OC(O)NH₂, —

NH₂SO₂(C_1-3 alkyl), —

NHC(O)(C_1-3 alkyl), —

C(O)NH₂, and —

CO(C_1-3 alkyl), wherein the (C_1-3 alkyl) is most preferably methyl.

42. The compound of claim 40, wherein R¹³ is hydrogen or C_1-4alkyl.

43. The compound of claim 39, wherein ring A is selected from one of xi, xii or xvi and x is 0.

44. The compound of claim 39, wherein Y is an optionally substituted heteroaryl moiety.

45. The compound of claim 39, wherein Y is selected from one of the following heteroaryl moieties a-y:

46. The compound of claim 45, wherein Y is one of the following heteroaryl moieties:

47. The compound of claim 45, wherein each R¹⁰ is independently hydrogen, C_1-4aliphatic, alkoxycarbonyl, optionally substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, or (N-heterocycle)carbonyl.

48. The compound of claim 45, wherein each occurrence of R¹⁰ is independently methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═

CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇), CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, or CO(piperidin-1-yl).

49. The compound of claim 45, wherein, Y is a pyrazole moiety, h′

, wherein the pyrazole is substituted with two occurrences of R¹⁰ (R^10a and R^10b)

51. The compound of claim 49, wherein two occurrences of R¹⁰ (R^10a and R^10b as depicted in formula h′

) taken together may represent a substituted or unsubstituted cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety and comprises one of the following groups;

52. The compound of claim 39, wherein when R³ is -Q¹-A-Q²-Y, R⁴ is hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl.

53. The compound of claim 51, wherein R⁴ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂.

54. The compound of claim 39, wherein when R⁴ is -Q¹-A-Q²-Y, R³ is preferably hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl.

55. The compound of claim 53, wherein R³ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂.

56. The compound of claim 39, wherein R⁵ is hydrogen, halogen, —

NO₂, —

CN, hydroxy, optionally substituted C_1-3alkyl, optionally substituted alkoxy, —

SO₂NH₂, or —

C(O)alkyl.

57. The compound of claim 55 wherein R is C₁, CF₃, OCF₃, CH₃, —

CN, —

SO₂NH₂ or —

C(O)Me.

58. The compound of claim 39, wherein Q¹ is NH and Q² is NH, and compounds are defined by the general formula IIIa(i) or IIIb(i):

59. The compound of claim 39 wherein Q¹ is S, and Q² is NH, and compounds are defined by the general formula IIIa(ii) or IIIb(ii):

60. The compound of claim 39 wherein Q¹ is O and Q² is NH, and compounds are defined by the general formula IIIa(iii) or IIIb(iii):

61. The compound of claim 39, wherein Q² is NH, and compounds are defined by the general formula IIIa(iv) or IIIb(iv):

62. The compound of claim 39, wherein Q² is NH, and compounds are defined by the general formula IIIa(v) or IIIb(v):

63. The compound of any one of claims 57, 58, 59, 60 or 61, wherein:

i. Z is CR⁶ or N;

ii. R¹, R², R⁴ and R⁵ are each hydrogen and wherein Z is CHR⁶ and R⁶ is hydrogen;

or R¹, R², R³ and R⁵ are each hydrogen and wherein Z is CHR⁶ and R⁶ is hydrogen;

iii. ring A is defined according to one of the following groups;

a. ring A is selected from one of the groups;

wherein R¹³ is hydrogen, —

R′

, —

COR′

, —

CO₂(R′

), —

CON(R′

)₂, or —

SO₂R′

, wherein each occurrence of R′

is independently hydrogen, an optionally substituted group selected from aliphatic, heteroaliphatic, aryl or heteroaryl, or two occurrences of R′

on the same nitrogen atom are taken together with the nitrogen to form an optionally substituted group selected from a 5-8 membered heterocyclic or 5-8 membered heteroaryl ring;

R¹⁴ is oxo or —

R; and

x is 0-4;

or

b. ring A is selected from one of xi, xii or xvi and x is 0 or 1;

R¹⁴ is -halo, —

N(R⁷)₂, —

C_1-3 alkyl, —

C_1-3 haloalkyl, —

NO₂, —

O(C_1-3 alkyl), —

CO₂(C_1-3 alkyl), —

CN, —

SO₂(C_1-3 alkyl), —

SO₂NH₂, —

OC(O)NH₂, —

NH₂SO₂(C_1-3 alkyl), —

NHC(O)(C_1-3 alkyl), —

C(O)NH₂, and —

CO(C_1-3 alkyl), wherein the (C_1-3 alkyl) is most preferably methyl; and

R¹³ is hydrogen or C_1-4alkyl;

iv. Y is defined according to one of the following groups;

a. Y is an optionally substituted heteroaryl moiety;

b. Y is selected from one of the heteroaryl moieties a-y;

c. Y is selected from one of the following heteroaryl moieties;

wherein q is 0-4, R¹⁰ is —

R, wherein —

R is defined generally above and in classes and subclasses herein, and wherein each occurrence of R¹¹ is independently hydrogen, —

R′

, —

COR′

, —

CO₂(R′

), —

CON(R′

)₂, or —

SO₂R, wherein each occurrence of R′

is independently hydrogen, an optionally substituted group selected from aliphatic, heteroaliphatic, aryl or heteroaryl, or two occurrences of R′

on the same nitrogen atom are taken together with the nitrogen to form an optionally substituted group selected from a 5-8 membered heterocyclic or 5-8 membered heteroaryl ring;

c. Y is a pyrazole moiety, h;

d. Y is one of a, b, f, h or o, optionally substituted with one or more R¹⁰ groups, wherein each occurrence of R¹⁰ is independently hydrogen, C_1-4aliphatic, alkoxycarbonyl, optionally substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (N-heterocycle)carbonyl;

e. Y is one of a, b, f, h or o, optionally substituted with one or more R¹⁰ groups, wherein each occurrence of R¹⁰ is independently hydrogen, methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═

CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇), CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, and CO(piperidin-1-yl);

f. Y is a pyrazole moiety, h′

, wherein the pyrazole is substituted with two occurrences of R¹⁰ (R^10a and R^10b as depicted),

wherein each occurrence of R^10a is hydrogen, C_1-4aliphatic, alkoxycarbonyl, optionally substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (N-heterocycle)carbonyl, and R^10b is hydrogen;

g. Y is a pyrazole moiety, h′

, wherein the pyrazole is substituted with two occurrences of R¹⁰ (R^10a and R^10b as depicted),

wherein each occurrence of R^10a is hydrogen, methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═

CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇), CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, and CO(piperidin-1-yl, and R^10b is hydrogen;

h. Y is heteroaryl moiety substituted by at least two occurrences of R¹⁰ and where two occurrences of R¹⁰ taken together may represent an optionally substituted group selected from cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl;

i. Y represents one of the following heteroaryl moieties;

wherein r is 0-4 and R¹² is hydrogen, -halo, —

N(R⁷)₂, —

C_1-3 alkyl, —

C_1-3 haloalkyl, —

NO₂, —

O(C_1-3 alkyl), —

CO₂(C_1-3 alkyl), —

CN, —

SO₂(C_1-3 alkyl), —

SO₂NH₂, —

OC(O)NH₂, —

NH₂SO₂(C_1-3 alkyl), —

NHC(O)(C_1-3 alkyl), —

C(O)NH₂, and —

CO(C_1-3 alkyl), wherein the (C_1-3 alkyl) is most preferably methyl;

v. R is defined according to one of the following groups;

a. R⁴ is hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl, or

b. R⁴ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂;

vi. R³ is defined according to one of the following groups;

a. R³ is hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl, or

b. R³ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂; and

vii. R⁵ is defined according to one of the following groups;

a. hydrogen, halogen, —

NO₂, —

CN, hydroxy, optionally substituted C_1-3alkyl, optionally substituted alkoxy, —

SO₂NH₂, or —

C(O)alkyl, or

b. R⁵ is hydrogen, C₁, CF₃, OCF₃, CH₃, —

CN, —

SO₂NH₂ or —

C(O)Me.

64. The compound of claim 1, wherein either of R³ or R⁴ is -Q¹-A-Q²-Y, wherein A is an optionally substituted C_2-4alkylidene unit (represented by A¹-A²-A³-A⁴) and compounds have the general formula IVa or IVb:

65. The compound of claim 63, wherein one of A¹, A², A³ or A⁴ is absent, and the remaining three are each independently selected from an optionally substituted methylene unit, wherein each methylene unit is optionally replaced by —

O—

or —

CO—

, wherein the one or more of the methylene units is unsubstituted or is substituted with an aryl, aralkyl or C_1-6aliphatic group, or wherein two substituents on the same methylene unit, or two substituents on two adjacent methylene units taken together form a 3-6-membered carbocyclic or heterocyclic ring.

66. The compound of claim 63, wherein Y is an optionally substituted heteroaryl moiety.

67. The compound of claim 63, wherein Y is selected from one of the following heteroaryl moieties a-y:

68. The compound of claim 66, wherein Y is one of the following heteroaryl moieties:

69. The compound of claim 66, wherein Y is a pyrazole moiety, h.

70. The compound of claim 66, wherein each R¹⁰ is independently hydrogen, C_1-4aliphatic, alkoxycarbonyl, optionally substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, or (N-heterocycle)carbonyl.

71. The compound of claim 66, wherein each occurrence of R¹⁰ is independently methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═

CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇), CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, or CO(piperidin-1-yl).

72. The compound of claim 66, wherein, Y is a pyrazole moiety, h′

, wherein the pyrazole is substituted with two occurrences of R¹⁰ (R^10a and R^10b)

73. The compound of claim 71, wherein two occurrences of R¹⁰ (R^10a and R^10b as depicted in formula h′

) taken together may represent a substituted or unsubstituted cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety and comprises one of the following groups;

74. The compound of claim 63, wherein when R³ is -Q¹-A-Q′

-Y, R⁴ is hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl.

75. The compound of claim 74, wherein R⁴ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂.

76. The compound of claim 63, wherein when R⁴ is -Q¹-A-Q²-Y, R³ is preferably hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl.

77. The compound of claim 76, wherein R³ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂.

78. The compound of claim 63, wherein R⁵ is hydrogen, halogen, —

NO₂, —

CN, hydroxy, optionally substituted C_1-3alkyl, optionally substituted alkoxy, —

SO₂NH₂, or —

C(O)alkyl.

79. The compound of claim 78 wherein R⁵ is Cl, CF₃, OCF₃, CH₃, —

CN, —

SO₂NH₂ or —

C(O)Me.

80. The compound of claim 63, wherein Q¹ is NH and Q² is NH and have the general formula IVa(i) or IVb(i).

81. The compound of claim 63, wherein Q¹ is O and Q² is NH, and have the general formula IVa(ii) or IVb(ii).

82. The compound of claim 63, wherein Q¹ is S and Q² is NH, and have the general formula IVa(iii) or IVb(iii).

83. The compound of claim 63, wherein Q¹ is an optionally substituted methylene unit —

(C(R^A)₂)— and

Q² is NH, and have the general formula IVa(iv) or IVb(iv).

84. The compound of any one of claims 79, 80, 81 or 82, wherein:

i. Z is CR⁶ or N;

ii. R¹, R², R⁴ and R⁵ are each hydrogen and wherein Z is CHR⁶ and R⁶ is hydrogen;

or R¹, R², R³ and R⁵ are each hydrogen and wherein Z is CHR⁶ and R⁶ is hydrogen;

iii. A is defined according to one of the following groups;

a. only one of A¹, A², A³ or A⁴ is absent;

b. only one of A¹, A², A³ or A 4 is absent, and the remaining three are each independently selected from an optionally substituted methylene unit, wherein each methylene unit is optionally replaced by —

O—

or —

CO—

;

c. only one of A¹, A², A³ or A⁴ is absent, and the remaining three are each independently selected from an optionally substituted methylene unit, wherein each methylene unit is optionally replaced by —

O—

or —

CO—

;

wherein one or more of the methylene units represented by A¹, A², A³ or A⁴ is unsubstituted or is substituted with an aryl, aralkyl or C_1-6aliphatic group;

d. only one of A¹, A², A³ or A⁴ is absent, and the remaining three are each independently selected from an optionally substituted methylene unit, wherein each methylene unit is optionally replaced by —

O—

or —

CO—

; and

wherein two substituents on the same methylene unit, or two substituents on adjacent methylene units, taken together form an optionally substituted 3-6-membered carbocyclic or heterocyclic ring;

iv. Y is defined according to one of the following groups;

a. Y is an optionally substituted heteroaryl moiety;

b. Y is selected from one of the heteroaryl moieties a-y;

c. Y is selected from one of the following heteroaryl moieties;

wherein q is 0-4, R¹⁰ is —

R, wherein —

R is defined generally above and in classes and subclasses herein, and wherein each occurrence of R¹¹ is independently hydrogen, —

R′

, —

COR′

, —

CO₂(R′

), —

CON(R′

)₂, or —

SO₂R′

, wherein each occurrence of R′

is independently hydrogen, an optionally substituted group selected from aliphatic, heteroaliphatic, aryl or heteroaryl, or two occurrences of R on the same nitrogen atom are taken together with the nitrogen to form an optionally substituted group selected from a 5-8 membered heterocyclic or 5-8 membered heteroaryl ring.

d. Y is a pyrazole moiety, h;

e. Y is one of a, b, f, h or o, optionally substituted with one or more R¹⁰ groups, wherein each occurrence of R¹⁰ is independently hydrogen, C_1-4aliphatic, alkoxycarbonyl, optionally substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (N-heterocycle)carbonyl;

f. Y is one of a, b, f, h or o, optionally substituted with one or more R¹⁰ groups, wherein each occurrence of R¹⁰ is independently hydrogen, methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═

CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇), CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, and CO(piperidin-1-yl).

g. Y is a pyrazole moiety, h′

, wherein the pyrazole is substituted with two occurrences of R¹⁰ (R^10a and R^10b as depicted),

wherein each occurrence of R^10a is hydrogen, C_1-4aliphatic, alkoxycarbonyl, optionally substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (N-heterocycle)carbonyl, and R^10b is hydrogen;

h. Y is a pyrazole moiety, h′

, wherein the pyrazole is substituted with two occurrences of R¹⁰ (R^10a and R^10b as depicted),

wherein each occurrence of R^10a is hydrogen, methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═

CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇), CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, and CO(piperidin-1-yl, and R^10b is hydrogen;

i. Y is heteroaryl moiety substituted by at least two occurrences of R¹⁰ and where two occurrences of R¹⁰ taken together may represent an optionally substituted group selected from cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl;

j. Y represents one of the following heteroaryl moieties;

wherein r is 0-4 and R¹² is hydrogen, -halo, —

N(R⁷)₂, —

C_1-3 alkyl, —

C_1-3 haloalkyl, —

NO₂, —

O(C_1-3 alkyl), —

CO₂(C_1-3 alkyl), —

CN, —

SO₂(C_1-3 alkyl), —

SO₂NH₂, —

OC(O)NH₂, —

NH₂SO₂(C_1-3 alkyl), —

NHC(O)(C_1-3 alkyl), —

C(O)NH₂, and —

CO(C_1-3 alkyl), wherein the (C_1-3 alkyl) is most preferably methyl;

v. R is defined according to one of the following groups;

a. R⁴ is hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl, or

b. R⁴ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂;

vi. R³ is defined according to one of the following groups;

a. R³ is hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl, or

b. R³ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂; and

vii. R⁵ is defined according to one of the following groups;

a. hydrogen, halogen, —

NO₂, —

CN, hydroxy, optionally substituted C_1-3alkyl, optionally substituted alkoxy, —

SO₂NH₂, or —

C(O)alkyl, or

b. R⁵ is hydrogen, C₁, CF₃, OCF₃, CH₃, —

CN, —

SO₂NH₂ or —

C(O)Me.

85. A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

86. The composition according to claim 85, further comprising an additional therapeutic agent.

87. A method of inhibiting a PRAK, GSK3, ERK2, CDK2, MK2, SRC, SYK, or Aurora-2 family kinase activity in a biological sample comprising the step of contacting said biological sample with:

a) a composition according to claim 85;

or

b) a compound of claim 1 or a pharmaceutically acceptable derivative thereof.

88. A method of treating or lessening the severity of a PRAK, GSK3, ERK2, CDK2, MK2, SRC, SYK, or Aurora-2-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to claim 85.

89. A method of treating or lessening the severity of a disease or condition selected from cardiovascular diseases, diabetes, neurological disorders, immunodeficiency disorders, inflammatory diseases, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases and viral diseases comprising the step of administering to said patient a composition according to claim 84.

90. The method according to claim 89, comprising the additional step of administering to said patient an additional therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an anti-infective agent, an antiviral agent, or an agent for treating cardiovascular disease, wherein:

said additional therapeutic agent is appropriate for the disease being treated; and

said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.