Imidazopyrazine tyrosine kinase inhibitors

• US 20060084654A1
• Filed: 10/14/2004
• Published: 04/20/2006
• Est. Priority Date: 10/15/2003
• Status: Active Grant

• Current Assignee: Anthony Innocenzo Nigro, Arno G. Steinig, Cara Cesario, Douglas Werner, Han-Qing Dong, Jonathan Williams, Kenneth Foreman, Lydia Saroglou, Mark Joseph Mulvihill, Matthew Cox, Patricia Anne Beck, Qinghua Weng, Robin Wilkes, Yingchuan Sun
• Original Assignee: Osi Pharmaceuticals Incorporated (Astellas Pharma Incorporated)
• Inventors: Cox, Matthew, Werner, Douglas, Dong, Han-Qing, Mulvihill, Mark Joseph, Steinig, Arno G., Weng, Qinghua, Williams, Jonathan, Sun, Yingchuan, Foreman, Kenneth, Beck, Patricia Anne, Cesario, Cara, Wilkes, Robin, Nigro, Anthony Innocenzo, Saroglou, Lydia
• Granted Patent: US 7,459,554 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• 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 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 33/02 : Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• 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: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

Compounds of the formula
and pharmaceutically acceptable salts thereof, wherein Q¹ and R¹ are defined herein, inhibit the IGF-1R enzyme and are useful for the treatment and/or prevention of various diseases and conditions that respond to treatment by inhibition of tyrosine kinases.

Claims

1. A compound represented by Formula I:

2. The compound of claim 1, wherein Q¹ is aryl¹ or heteroaryl¹, any of which is optionally substituted by one or more independent G¹ substituents.

3. The compound of claim 2, wherein Q¹ is heteroaryl¹, any of which is optionally substituted by one or more independent G¹ substituents.

4. The compound of claim 3, wherein Q¹ is aryl¹, any of which is optionally substituted by one or more independent G¹ substituents.

5. The compound of claim 1, wherein G¹ is halo, —

CF₃, —

OCF₃, —

OR², —

NR²R³, —

C(O)R², —

CO₂R², —

CONR²R³, —

S(O)_j1R², —

SO₂NR²R³, NR²(C═

O)R³, NR²(C═

O)OR³, NR²(C═

O)NR²R³, NR²S(O)_j1R³, —

O(C═

O)OR², —

O(C═

O)NR²R³, C_0-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_1-10alkoxyC_1-10alkyl, C_1-10alkoxyC_2-10alkenyl, C_1-10alkoxyC_2-10alkynyl, C_1-10alkylthioC_1-10alkyl, C_1-10alkylthioC_2-10alkenyl, C_1-10alkylthioC_2-10alkynyl, cycloC_3-8alkyl, cycloC_3-8alkenyl, cycloC_3-8alkylC_1-10alkyl, cycloC_3-8alkenylC_1-10alkyl, cycloC_3-8alkylC_2-10alkenyl, cycloC_3-8alkenylC_2-10alkenyl, cycloC_3-8alkylC_2-10alkynyl, cycloC_3-8alkenylC_2-10alkynyl, heterocyclyl-C_0-10alkyl, heterocyclyl-C_2-10alkenyl, or heterocyclyl-C_2-10alkynyl, any of which is optionally substituted with one or more independent halo, oxo, —

CF₃, —

OCF₃, —

OR²²², —

NR²²²R³³³(R^333a)_j1a, —

C(O)R²²², —

CO₂R²²², —

CONR²²²R³³³, —

NO₂, —

CN, —

S(O)_j1aR²²², —

SO₂NR²²²R³³³, NR²²²(C═

O)R³³³, NR²²²(C═

O)OR³³³, NR²²²(C═

O)NR²²²R³³³, NR²²²S(O)_j1aR³³³, —

(C═

S)OR²²², —

(C═

O)SR²²², —

NR²²²(C═

NR³³³)NR^222aR^333a, —

NR²²²(C═

NR³³³)OR^222a, —

NR²²²(C═

NR³³³)SR^333a, —

O(C═

O)OR²²², —

O(C═

O)NR²²²R³³³, —

O(C═

O)SR²²², —

S(C═

O)OR²²², or —

S(C═

O)NR²²²R³³³ substituents;

or —

(X¹)_n—

(Y¹)_m—

R⁴;

or aryl-C_0-10alkyl, aryl-C_2-10alkenyl, or aryl-C_2-10alkynyl, any of which is optionally substituted with one or more independent halo, —

CF₃, —

OCF₃, —

OR²²², —

NR²²²R³³³(R^333a)_j2a, —

C(O)R²²², —

CO₂R²²², —

CONR²²²R³³³, —

NO₂, —

CN, —

S(O)_j2aR²²², —

SO₂NR²²²R³³³, NR²²²(C═

O)R³³³, NR²²²(C═

O)OR³³³, NR²²²(C═

O)NR²²²R³³³, NR²²²S(O)_j2aR³³³, —

(C═

S)OR²²², —

(C═

O)SR²²², —

NR²²²(C═

NR³³³)NR^222aR^333a, —

NR²²²(C═

NR³³³)OR^222a, —

NR²²²(C═

NR³³³)SR^333a, —

O(C═

O)OR²²², —

O(C═

O)NR²²²R³³³, —

O(C═

O)SR²²², —

S(C═

O)OR²²², or —

S(C═

O)NR²²²R³³³ substituents;

or hetaryl-C_0-10alkyl, hetaryl-C_2-10alkenyl, or hetaryl-C_2-10alkynyl, any of which is optionally substituted with one or more independent halo, —

CF₃, —

OCF₃, —

OR²²², —

NR²²²R³³³(R^333a)_j3a, —

C(O)R²²², —

CO₂R²²², —

CONR²²²R³³³, —

NO₂, —

CN, —

S(O)_j3aR²²², —

SO₂NR²²²R³³³, NR²²²(C═

O)R³³³, NR²²² (C═

O)OR³³³, NR²²²(C═

O)NR²²²R³³³, NR²²²S(O)_j3aR³³³, —

(C═

S)OR²²², —

(C═

O)SR²²², —

NR²²²(C═

NR³³³)NR^222aR^333a, —

NR²²²(C═

NR³³³)OR^222a, —

NR²²²(C═

NR³³³)SR^333a, —

O(C═

O)OR²²², —

O(C═

O)NR²²²R³³³, —

O(C═

O)SR²²², —

S(C═

O)OR²²², or —

S(C═

O)NR²²²R³³³ substituents.

6. The compound of claim 1, wherein G¹ is halo, —

OR², —

NR²R³, —

C(O)R², —

CO₂R², —

CONR²R³, —

SO₂NR²R³, NR²(C═

O)R³, NR²(C═

O)OR³, NR²(C═

O)NR²R³, NR²S(O)_j1R³, —

O(C═

O)OR², —

O(C═

O)NR²R³, C_0-10alkyl, C_2-10alkenyl, C_1-10alkoxyC_1-10alkyl, C_1-10alkoxyC_2-10alkenyl, C_1-10alkylthioC_1-10alkyl, C_1-10alkylthioC_2-10alkenyl, cycloC_3-8alkyl, cycloC_3-8alkenyl, cycloC_3-8alkylC_1-10alkyl, cycloC_3-8alkenylC_1-10alkyl, cycloC_3-8alkylC_2-10alkenyl, cycloC_3-8alkenylC_2-10alkenyl, or heterocyclyl-C_0-10alkyl, or heterocyclyl-C_2-10alkenyl, any of which is optionally substituted with one or more independent oxo, —

CF₃, —

OCF₃, —

OR²²², —

NR²²²R³³³, —

C(O)R²²², —

CO₂R²²², —

CONR²²²R³³³, —

SO₂NR²²²R³³³, NR²²²(C═

O)R³³³, NR²²²(C═

O)OR³³³, NR²²²(C═

O)NR²²²R³³³, NR²²S(O)_j1aR³³³, —

NR²²²(C═

NR³³³)NR^222aR^333a, or —

O(C═

O)NR²²²R³³³ substituents;

or —

(X¹)_n—

(Y¹)_m—

R⁴;

or aryl-C_0-10alkyl optionally substituted with one or more independent halo, —

CF₃, —

OCF₃, —

OR²²², —

NR²²²R³³³, —

C(O)R²²², —

CO₂R²²², —

CONR²²²R³³³, —

SO₂NR²²²R³³³, NR²²²(C═

O)R³³³, NR²²²(C═

O)OR³³³, NR²²²(C═

O)NR²²²R³³³, NR²²²S(O)_j2aR³³³, —

NR²²²(C═

NR³³³)NR^222aR^333a, or —

O(C═

O)NR²²²R³³³ substituents;

or hetaryl-C_0-10alkyl, optionally substituted with one or more independent halo, —

CF₃, —

OCF₃, —

OR²²², —

NR²²²R³³³, —

C(O)R²²², —

CO₂R²²², —

CONR²²²R³³³, —

SO₂NR²²²R³³³, NR²²²(C═

O)R³³³, NR²²²(C═

O)OR³³³, NR²²²(C═

O)NR²²²R³³³, NR²²²S(O)_j3aR³³³, —

NR²²²(C═

NR³³³)NR^222aR^333a, or —

O(C═

O)NR²²²R³³³ substituents.

7. The compound of claim 1, wherein G¹ is halo, —

OR², —

NR²R³, —

C(O)R², —

CO₂R², —

CONR²R³, —

SO₂NR²R³, NR²(C═

O)R³, NR²(C═

O)OR³, NR²(C═

O)NR²R³, NR²S(O)_j1R³, —

O(C═

O)OR², —

O(C═

O)NR²R³, C_0-10alkyl, C_2-10alkenyl, C_1-10alkoxyC_1-10alkyl, C_1-10alkylthioC_1-10alkyl, cycloC_3-8alkyl, cycloC_3-8alkenyl, or heterocyclyl-C_0-10alkyl, or heterocyclyl-C_2-10alkenyl, any of which is optionally substituted with one or more independent oxo, —

CF₃, —

OCF₃, —

OR²²², —

NR²²²R³³³, —

C(O)R²²², —

CO₂R²²², —

CONR²²²R³³³, —

SO₂NR²²²R³³³, NR²²²(C═

O)R³³³, NR²²²(C═

O)OR³³³, NR²²²(C═

O)NR²²²R³³³, NR²²²S(O)_j1aR³³³, —

NR²²²(C═

NR³³³)NR^222aR^333a, or —

O(C═

O)NR²²²R³³³ substituents;

or —

(X¹)_n—

(Y¹)_m—

R⁴;

or aryl-C_0-10alkyl, optionally substituted with one or more independent halo, —

CF₃, —

OCF₃, —

OR²²², —

NR²²²R³³³, —

C(O)R²²², —

CO₂R²²², —

CONR²²²R³³³, —

SO₂NR²²²R³³³, NR²²²(C═

O)R³³³, NR²²²(C═

O)OR³³³, NR²²²(C═

O)NR²²²R³³³, NR²²²S(O)_j2aR³³³, —

NR²²²(C═

NR³³³)NR^222aR^333a, or —

O(C═

O)NR²²²R³³³ substituents;

or hetaryl-C_0-10alkyl, optionally substituted with one or more independent halo, —

CF₃, —

OCF₃, —

OR²²², —

NR²²²R³³³, —

C(O)R²²², —

CO₂R²²², —

CONR²²²R³³³, —

SO₂NR²²²R³³³, NR²²²(C═

O)R³³³, NR²²²(C═

O)OR³³³, NR²²²(C═

O)NR²²²R³³³, NR²²²S(O)_j3aR³³³, —

NR²²²(C═

NR³³³)NR^222aR^333a, or —

O(C═

O)NR²²²R³³³ substituents.

8. The compound of claim 1, wherein G¹ is halo, —

OR², —

NR²R³, —

C(O)R², —

CO₂R², —

CONR²R³, —

SO₂NR²R³, NR²(C═

O)R³, NR²(C═

O)OR³, NR²(C═

O)NR²R³, NR²S(O)_j1R³, —

O(C═

O)OR², —

O(C═

O)NR²R³, C_0-10alkyl, C_2-10alkenyl, C_1-10alkoxyC_1-10alkyl, C_1-10alkylthioC_1-10alkyl, cycloC_3-8alkyl, cycloC_3-8alkenyl, or heterocyclyl-C_0-10alkyl, or heterocyclyl-C_2-10alkenyl, any of which is optionally substituted with one or more independent oxo, —

CF₃, —

OCF₃, —

OR²²², —

NR²²²R³³³, —

C(O)R²²², —

CO₂R²²², —

CONR²²²R³³³, —

SO₂ NR²²²R³³³, NR²²²(C═

O)R³³³, NR²²²(C═

O)OR³³³, NR²²²(C═

O)NR²²²R³³³, NR²²²S(O)_j1aR³³³, —

NR²²²(C═

NR³³³)NR^222aR^333a, or —

O(C═

O)NR²²²R³³³ substituents;

or —

(X¹)_n—

(Y¹)_m—

R⁴.

9. The compound of claim 1, wherein X¹ and Y¹ are each independently —

O—

, —

NR⁷—

, —

S(O)_j7—

, —

CR⁵R⁶—

, —

N(C(O)OR⁷)—

, —

N(C(O)R⁷)—

, —

N(SO₂R⁷)—

, —

CH₂O—

, —

CH₂S—

, —

CH₂N(R⁷)—

, —

CH(NR⁷)—

, —

CH₂N(C(O)R⁷)—

, —

CH₂N(C(O)OR⁷)—

, —

CH₂N(SO₂R⁷)—

, —

CH(NHR⁷)—

, —

CH(NHC(O)R⁷)—

, —

CH(NHSO₂R⁷)—

, —

CH(NHC(O)OR⁷)—

, —

CH(OC(O)R⁷)—

, —

CH(OC(O)NHR⁷)—

, —

C(O)—

, —

CH(OR⁷)—

, —

C(O)N(R⁷)—

, —

N(R⁷)C(O)—

, —

N(R⁷)S(O)—

, —

N(R⁷)S(O)₂—

—

OC(O)N(R⁷)—

, —

N(R⁷)C(O)N(R⁷)—

, —

NR⁷C(O)O—

, —

S(O)N(R⁷)—

, —

S(O)₂N(R⁷)—

, —

N(C(O)R⁷)S(O)—

, —

N(C(O)R⁷)S(O)₂—

, —

N(R⁷)S(O)N(R⁷)—

, —

N(R⁷)S(O)₂N(R⁷)—

, —

C(O)N(R⁷)C(O)—

, —

S(O)N(R⁷)C(O)—

, —

S(O)₂N(R⁷)C(O)—

, —

OS(O)N(R⁷)—

, —

OS(O)₂N(R⁷)—

, —

N(R⁷)S(O)O—

, —

N(R⁷)S(O)₂O—

, —

N(R⁷)S(O)C(O)—

, —

N(R⁷)S(O)₂C(O)—

, —

SON(C(O)R⁷)—

, —

SO₂N(C(O)R⁷)—

, —

N(R⁷)SON(R⁷)—

, —

N(R⁷)SO₂N(R⁷)—

, —

C(O)O—

, —

CH(R⁷)S(O)—

, —

CH(R⁷)S(O)₂—

, —

CH(R⁷)N(C(O)OR⁷)—

, —

CH(R⁷)N(C(O)R⁷)—

, —

CH(R⁷)N(SO₂R⁷)—

, —

CH(R⁷)O—

, —

CH(R⁷)S—

, —

CH(R⁷)N(R⁷)—

, —

CH(R⁷)N(C(O)R⁷)—

, —

CH(R⁷)N(C(O)OR⁷)—

, —

CH(R⁷)N(SO₂R⁷)—

, —

CH(R⁷)C(═

NOR⁷)—

, —

CH(R⁷)C(O)—

, —

CH(R⁷)CH(OR⁷)—

, —

CH(R⁷)C(O)N(R⁷)—

, —

CH(R⁷)N(R⁷)C(O)—

, —

CH(R⁷)N(R⁷)S(O)—

, —

CH(R⁷)N(R⁷)S(O)₂—

, —

CH(R⁷)OC(O)N(R⁷)—

, —

CH(R⁷)N(R⁷)C(O)N(R⁷)—

, —

CH(R⁷)NR⁷C(O)O—

, —

CH(R⁷)S(O)N(R⁷)—

, —

CH(R⁷)S(O)₂N(R⁷)—

, —

CH(R⁷)N(C(O)R⁷)S(O)—

, —

CH(R⁷)N(C(O)R⁷)S(O)—

, —

CH(R⁷)N(R⁷)S(O)N(R⁷)—

, —

CH(R⁷)N(R⁷)S(O)₂N(R⁷)—

, —

CH(R⁷)C(O)N(R⁷)C(O)—

, —

CH(R⁷)S(O)N(R⁷)C(O)—

, —

CH(R⁷)S(O)₂N(R⁷)C(O)—

, —

CH(R⁷)OS(O)N(R⁷)—

, —

CH(R⁷)OS(O)₂N(R⁷)—

, —

CH(R⁷)N(R⁷)S(O)O—

, —

CH(R⁷)N(R⁷)S(O)₂O—

, —

CH(R⁷)N(R⁷)S(O)C(O)—

, —

CH(R⁷)N(R⁷)S(O)₂C(O)—

, —

CH(R⁷)SON(C(O)R⁷)—

, —

CH(R⁷)SO₂N(C(O)R⁷)—

, —

CH(R⁷)N(R⁷)SON(R⁷)—

, —

CH(R⁷)N(R⁷)SO₂N(R⁷)—

, or —

CH(R⁷)C(O)O—

.

10. The compound of claim 1 wherein Q¹ is substituted by said one to five independent G¹ substituents wherein at least one of said G¹ substituents is —

(X¹)_n—

(Y¹)_m—

R⁴, and wherein X¹ and Y¹ are each independently equal to —

O—

, —

NR⁷—

, —

CR⁵R⁶—

, —

S(O)_j7—

, or —

C(O)—

, and wherein n and m are both equal to 1 and j7 is equal to 1 or 2.

11. The compound of claim 1 wherein Q¹ is substituted by said one to five independent G¹ substituents wherein at least one of said G¹ substituents is —

(X¹)_n—

(Y¹)_m—

R⁴, and wherein X¹ and Y¹ are each independently —

O—

or —

CR⁵R⁶—

, and wherein n and m are equal to 1.

12. The compound of claim 1 wherein R¹ is cycloalkyl, bicycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, or heterobicycloalkyl, any of which is optionally substituted by one or more independent G¹¹ substituents.

13. The compound of claim 1 wherein R¹ is cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclyl, any of which is optionally substituted by one or more independent G¹¹ substituents.

14. The compound of claim 1 wherein R¹ is cycloalkyl or heterocyclyl, any of which is optionally substituted by one or more independent G¹¹ substituents.

15. The compound of claim 1 wherein R¹ is cycloalkyl optionally substituted by one or more independent G¹¹ substituents.

16. The compound of claim 1 wherein R¹ is heterocyclyl optionally substituted by one or more independent G¹¹ substituents.

17. The compound of claim 1 wherein R¹ is aryl, heteroaryl, aralkyl, or heteroaralkyl, any of which is optionally substituted by one or more independent G¹¹ substituents.

18. The compound of claim 1 wherein R¹ is aryl or heteroaryl, any of which is optionally substituted by one or more independent G¹¹ substituents.

19. The compound of claim 1 wherein G¹¹ is —

OR²¹, —

NR²¹R³¹(R^31a)_j4, —

C(O)R²¹, —

CO₂R²¹, —

CONR²¹R³¹, NR²¹(C═

O)R³¹, NR²¹(C═

O)OR³¹, NR²¹(C═

O)NR²¹R³¹, NR²¹S(O)_j4R³¹, —

O(C═

O)OR²¹, —

O(C═

O)NR²¹R³¹, C_0-10alkyl, cycloC_3-8alkyl, cycloC_3-8alkenyl, heterocyclyl-C_0-10alkyl, or heterocyclyl-C_2-10alkenyl, any of which is optionally substituted with one or more independent halo, oxo, —

CF₃, —

OCF₃, —

OR²²²¹, —

NR²²²¹R³³³¹(R^333a)_j4a, —

C(O)R²²²¹, —

CO₂R²²²¹, —

CONR²²²¹R³³³¹, —

NO₂, —

CN, —

S(O)_j4aR²²²¹, —

SO₂NR²²²¹R³³³¹, NR²²²¹(C═

O)R³³³¹, NR²²²¹(C═

O)OR³³³¹, NR²²²¹(C═

O)NR²²²¹R³³³¹, NR²²²¹S(O)_j4aR³³³¹, —

(C═

S)OR²²²¹, —

(C═

O)SR²²²¹, —

NR²²²¹(C═

NR³³³¹)NR^222a1R^333a1, —

NR²²²¹(C═

NR³³³¹)OR^222a1, —

NR²²²¹(C═

NR³³³¹)SR^333a1, —

O(C═

O)OR²²²¹, —

O(C═

O)NR²²²¹R³³³¹, —

O(C═

O)SR²²²¹, —

S(C═

O)OR²²²¹, or —

S(C═

O)NR²²²¹R³³³¹ substituents;

or aryl-C_0-10alkyl, aryl-C_2-10alkenyl, or aryl-C_2-10alkynyl, any of which is optionally substituted with one or more independent halo, —

CF₃, —

OCF₃, —

OR²²²¹, —

NR²²²¹R³³³¹(R^333a1)_j5a, —

C(O)R²²²¹, —

CO₂R²²²¹, —

CONR²²²¹R³³³¹, —

NO₂, —

CN, —

S(O)_j5aR²²²¹, —

SO₂NR²²²¹R³³³¹, NR²²²¹(C═

O)R³³³¹, NR²²²¹(C═

O)OR³³³¹, NR²²²¹(C═

O)NR²²²¹R³³³¹, NR²²²¹S(O)_j5aR³³³¹, —

(C═

S)OR²²²¹, —

(C═

O)SR²²²¹, —

NR²²²¹(C═

NR³³³¹)NR^222a1R^333a1, —

NR²²²¹(C═

NR³³³¹)OR^222a1, —

NR²²²¹(C═

NR³³³¹)SR^333a1, —

O(C═

O)OR²²²¹, —

O(C═

O)NR²²²¹R³³³¹, —

O(C═

O)SR²²²¹, —

S(C═

O)OR²²²¹, or —

S(C═

O)NR²²²¹R³³³¹ substituents;

or hetaryl-C_0-10alkyl, hetaryl-C_2-10alkenyl, or hetaryl-C_2-10alkynyl, any of which is optionally substituted with one or more independent halo, —

CF₃, —

OCF₃, —

OR²²²¹, —

NR²²²¹R³³³¹(R^333a1)_j6a, —

C(O)R²²²¹, —

CO₂R²²²¹, —

CONR²²²¹R³³³¹, —

NO₂, —

CN, —

S(O)_j6aR²²²¹, —

SO₂NR²²²¹R³³³¹, NR²²²¹(C═

O)R³³³¹, NR²²²¹(C═

O)OR³³³¹, NR²²²¹(C═

O)NR²²²¹R³³³¹, NR²²²¹S(O)_j6aR³³³¹, —

(C═

S)OR²²²¹, —

(C═

O)SR²²²¹, —

NR²²²¹(C═

NR³³³¹)NR^222a1R^333a1, —

NR²²²¹(C═

NR³³³¹)OR^222a1, —

NR²²²¹(C═

NR³³³¹)SR^333a1, —

O(C═

O)OR²²²¹, —

O(C═

O)NR²²²¹R³³³¹, —

O(C═

O)SR²²²¹, —

S(C═

O)OR²²²¹, or —

S(C═

O)NR²²²¹R³³³¹ substituents.

20. The compound of claim 1 wherein G¹¹ is —

OR²¹, —

NR²¹R³¹, —

CO₂R²¹, —

C(O)R²¹, —

CONR²¹R³¹, NR²¹(C═

O)R³¹, NR²¹(C═

O)OR³¹, NR²¹(C═

O)NR²¹R³¹, NR²¹S(O)_j4R³¹, —

O(C═

O)OR²¹, —

O(C═

O)NR²¹R³¹, C_0-10alkyl, cycloC_3-8alkyl, cycloC_3-8alkenyl, heterocyclyl-C_0-10alkyl, or heterocyclyl-C_2-10alkenyl, any of which is optionally substituted with one or more independent halo, oxo, —

CF₃, —

OCF₃, —

OR²²²¹, —

NR²²²¹R³³³¹(R^333a1)_j4a, —

C(O)R²²²¹, —

CO₂R²²²¹, —

CONR²²²¹R³³³¹, —

NO₂, —

CN, —

S(O)_j4aR²²²¹, —

SO₂NR²²²¹R³³³¹, NR²²²¹(C═

O)R³³³¹, NR²²²¹(C═

O)OR³³³¹, NR²²²¹(C═

O)NR²²²¹R³³³¹, NR²²²¹S(O)_j4aR³³³¹, —

(C═

S)OR²²²¹, —

(C═

O)SR²²²¹, —

NR²²²¹(C═

NR³³³¹)NR^222a1R^333a1, —

NR²²²¹(C═

NR³³³¹)OR^222a1, —

NR²²²¹(C═

NR³³³¹)SR^333a1, —

O(C═

O)OR²²²¹, —

O(C═

O)NR²²²¹R³³³¹, —

O(C═

O)SR²²²¹, —

S(C═

O)OR²²²¹, or —

S(C═

O)NR²²²¹R³³³¹ substituents.

21. The compound of claim 1 wherein R⁴ is H, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more independent G⁴¹ substituents.

22. The compound of claim 10 wherein R⁴ is alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more independent G⁴¹ substituents.

23. The compound of claim 11 wherein R⁴ is alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more independent G⁴¹ substituents.

24. The compound of claim 1 wherein Q¹ is phenyl substituted by said one to five independent G¹ substituents wherein at least one of said G¹ substituents is —

(X¹)_n—

(Y¹)_m—

R⁴, and wherein n=1 and X¹ is 3-(—

O—

), m=1 and Y¹ is —

(—

CH₂—

), and R⁴ is aryl optionally substituted by one or more independent G⁴¹ substituents.

25. The compound of claim 24 wherein R¹ is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more independent G¹¹ substituents.

26. The compound of claim 25 wherein R¹ is cycloalkyl or heterocyclyl, optionally substituted by one or more independent G¹¹ substituents.

27. The compound of claim 26 wherein R¹ is cycloalkyl, optionally substituted by one or more independent G¹¹ substituents.

28. The compound of claim 27 wherein R¹ is cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted by one or more independent G¹¹ substituents.

29. The compound of claim 27 wherein G¹¹ is —

OR²¹, —

NR²¹R³¹, —

CO₂R²¹, —

C(O)R²¹, —

CONR²¹R³¹, NR²¹(C═

O)R³¹, NR²¹(C═

O)OR³¹, NR²¹(C═

O)NR²¹R³¹, NR²¹S(O)_j4R³¹, —

O(C═

O)OR²¹, —

O(C═

O)NR²¹R³¹, C_0-10alkyl, cycloC_3-8alkyl, cycloC_3-8alkenyl, heterocyclyl-C_0-10alkyl, or heterocyclyl-C_2-10alkenyl, any of which is optionally substituted with one or more independent halo, oxo, —

CF₃, —

OCF₃, —

OR²²²¹, —

NR²²²¹R³³³¹(R^333a1)_j4a, —

C(O)R²²²¹, —

CO₂R²²²¹, —

CONR²²²¹R³³³¹, —

NO₂, —

CN, —

S(O)_j4aR²²²¹, —

SO₂NR²²²¹R³³³¹, NR²²²¹(C═

O)R³³³¹, NR²²²¹(C═

O)OR³³³¹, NR²²²¹(C═

O)NR²²²¹R³³³¹, NR²²²¹S(O)_j4aR³³³¹, —

(C═

S)OR²²²¹, —

(C═

O)SR²²²¹, —

NR²²²¹(C═

NR³³³¹)NR^222a1R^333a1, —

NR²²²¹(C═

NR³³³¹)OR^222a1, —

NR²²²¹(C═

NR³³³¹)SR^333a1, —

O(C═

O)OR²²²¹, —

O(C═

O)NR²²²¹R³³³¹, —

O(C═

O)SR²²²¹, —

S(C═

O)OR²²²¹, or —

S(C═

O)NR²²²¹R³³³¹ substituents.

30. The compound of claim 1 wherein Q¹ is phenyl substituted by said one to five independent G¹ substituents wherein at least one of said G¹ substituents is —

(X¹)_n—

(Y¹)_m—

R⁴, and wherein n=1 and X¹ is 4-(—

O—

), m=1 and Y¹ is —

(—

CH₂—

), and R⁴ is aryl optionally substituted by one or more independent G⁴¹ substituents.

31. The compound of claim 30 wherein R¹ is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more independent G¹¹ substituents.

32. The compound of claim 31 wherein R¹ is cycloalkyl or heterocyclyl, optionally substituted by one or more independent G¹¹ substituents.

33. The compound of claim 32 wherein R¹ is cycloalkyl, optionally substituted by one or more independent G¹¹ substituents.

34. The compound of claim 33 wherein R¹ is cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted by one or more independent G¹¹ substituents.

35. The compound of claim 33 wherein G¹¹ is —

OR²¹, —

NR²¹R³¹, —

CO₂R²¹, —

C(O)R²¹, —

CONR²¹R³¹, NR²¹(C═

O)R³¹, NR²¹(C═

O)OR³¹, NR²¹(C═

O)NR²¹R³¹, NR²¹S(O)_j4R³¹, —

O(C═

O)OR²¹, —

O(C═

O)NR²¹R³¹, C_0-10alkyl, cycloC_3-8alkyl, cycloC_3-8alkenyl, heterocyclyl-C_0-10alkyl, or heterocyclyl-C_2-10alkenyl, any of which is optionally substituted with one or more independent halo, oxo, —

CF₃, —

OCF₃, —

OR²²²¹, —

NR²²²¹R³³³¹(R^333a1)_j4a, —

C(O)R²²²¹, —

CO₂R²²²¹, —

CONR²²²¹R³³³¹, —

NO₂, —

CN, —

S(O)_j4aR²²²¹, —

SO₂NR²²²¹R³³³¹, NR²²²¹(C═

O)R³³³¹, NR²²²¹(C═

O)OR³³³¹, NR²²²¹(C═

O)NR²²²¹R³³³¹, NR²²²¹S(O)_j4aR³³³¹, —

(C═

S)OR²²²¹, —

(C═

O)SR²²²¹, —

NR²²²¹(C═

NR³³³¹)NR^222a1R^333a1, —

NR²²²¹(C═

NR³³³¹)OR^222a1, —

NR²²²¹(C═

NR³³³¹)SR^333a1, —

O(C═

O)OR²²²¹, —

O(C═

O)NR²²²¹R³³³¹, —

O(C═

O)SR²²²¹, —

S(C═

O)OR²²²¹, or —

S(C═

O)NR²²²¹R³³³¹ substituents.

36. The compound of claim 1 wherein Q¹ is phenyl substituted by said one to five independent G¹ substituents wherein at least one of said G¹ substituents is —

(X¹)_n—

(Y¹)_m—

R⁴, and wherein n=1 and X¹ is 3-(—

O—

), m=0, and R⁴ is (C₀-C₈)alkyl or cycloalkyl optionally substituted by one or more independent G⁴¹ substituents.

37. The compound of claim 36 wherein R¹ is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more independent G¹¹ substituents.

38. The compound of claim 37 wherein R¹ is cycloalkyl or heterocyclyl, optionally substituted by one or more independent G¹¹ substituents.

39. The compound of claim 38 wherein R¹ is cycloalkyl, optionally substituted by one or more independent G¹¹ substituents.

40. The compound of claim 39 wherein R¹ is cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted by one or more independent G¹¹ substituents.

41. The compound of claim 39 wherein G¹¹ is —

OR²¹, —

NR²¹R³¹, —

CO₂R²¹, —

C(O)R²¹, —

CONR²¹R³¹, NR²¹(C═

O)R³¹, NR²¹(C═

O)OR³¹, NR²¹(C═

O)NR²¹R³¹, NR²¹S(O)_j4R³¹, —

O(C═

O)OR²¹, —

O(C═

O)NR²¹R³¹, C_0-10alkyl, cycloC_3-8alkyl, cycloC_3-8alkenyl, heterocyclyl-C_0-10alkyl, or heterocyclyl-C_2-10alkenyl, any of which is optionally substituted with one or more independent halo, oxo, —

CF₃, —

OCF₃, —

OR²²²¹, —

NR²²²¹R³³³¹(R^333a1)_j4a, —

C(O)R²²²¹, —

CO₂R²²²¹, —

CONR²²²¹R³³³¹, —

NO₂, —

CN, —

S(O)_j4aR²²²¹, —

SO₂NR²²²¹R³³³¹, NR²²²¹(C═

O)R³³³¹, NR²²²¹(C═

O)OR³³³¹, NR²²²¹(C═

O)NR²²²¹R³³³¹, NR²²²¹S(O)_j4aR³³³¹, —

(C═

S)OR²²²¹, —

(C═

O)SR²²²¹, —

NR²²²¹(C═

NR³³³¹)NR^222a1R^333a1, —

NR²²²¹(C═

NR³³³¹)OR^222a1, —

NR²²²¹(C═

NR³³³¹)SR^333a1, —

O(C═

O)OR²²²¹, —

O(C═

O)NR²²²¹R³³³¹, —

O(C═

O)SR²²²¹, —

S(C═

O)OR²²²¹, or —

S(C═

O)NR²²²¹R³³³¹ substituents.

42. The compounds of claim 36 wherein R⁴ is (C₀-C₆)alkyl.

43. The compound of claim 41 wherein R⁴ is (C₀-C₆)alkyl.

44. The compounds of claim 36 wherein R⁴ is H or methyl.

45. The compound of claim 43 wherein R⁴ is H or methyl.

46. The compound of claim 1 wherein Q¹ is phenyl substituted by said one to five independent G¹ substituents wherein at least one of said G¹ substituents is —

(X¹)_n—

(Y¹)_m—

R⁴, and wherein n=1 and X¹ is 3-(—

O—

), m=0, and R⁴ is aryl optionally substituted by one or more independent G⁴¹ substituents.

47. The compound of claim 46 wherein R¹ is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more independent G¹¹ substituents.

48. The compound of claim 46 wherein R¹ is cycloalkyl or heterocyclyl, optionally substituted by one or more independent G¹¹ substituents.

49. The compound of claim 48 wherein R¹ is cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted by one or more independent G¹¹ substituents.

50. The compound of claim 48 wherein G¹¹ is —

OR²¹, —

NR²¹R³¹, —

CO₂R²¹, —

C(O)R²¹, —

CONR²¹R³¹, NR²¹(C═

O)R³¹, NR²¹(C═

O)OR³¹, NR²¹(C═

O)NR²¹R³¹, NR²¹S(O)_j4R³¹, —

O(C═

O)OR²¹, —

O(C═

O)NR²¹R³¹, C_0-10alkyl, cycloC_3-8alkyl, cycloC_3-8alkenyl, heterocyclyl-C_0-10alkyl, or heterocyclyl-C_2-10alkenyl, any of which is optionally substituted with one or more independent halo, oxo, —

CF₃, —

OCF₃, —

OR²²²¹, —

NR²²²¹R³³³¹(R^333a1)_j4a, —

C(O)R²²²¹, —

CO₂R²²²¹, —

CONR²²²¹R³³³¹, —

NO₂, —

CN, —

S(O)_j4aR²²²¹, —

SO₂NR²²²¹R³³³¹, NR²²²¹(C═

O)R³³³¹, NR²²²¹(C═

O)OR³³³¹, NR²²²¹(C═

O)NR²²²¹R³³³¹, NR²²²¹S(O)_j4aR³³³¹, —

(C═

S)OR²²²¹, —

(C═

O)SR²²²¹, —

NR²²²¹(C═

NR³³³¹)NR^222a1R^333a1, —

NR²²²¹(C═

NR³³³¹)OR^222a1, —

NR²²²¹(C═

NR³³³¹)SR^333a1, —

O(C═

O)OR²²²¹, —

O(C═

O)NR²²²¹R³³³¹, —

O(C═

O)SR²²²¹, —

S(C═

O)OR²²²¹, or —

S(C═

O)NR²²²¹R³³³¹ substituents.

51. The compounds of claim 46 wherein R⁴ is phenyl optionally substituted with G⁴¹.

52. The compound of claim 1 wherein Q¹ is phenyl substituted by said one to five independent G¹ substituents wherein at least one of said G¹ substituents is —

(X¹)_n—

(Y¹)_m—

R⁴, and wherein n=1 and X¹ is 3- or 4-(—

NH—

), m=1 and Y¹ is —

(—

SO₂—

), and R⁴ is aryl optionally substituted by one or more independent G⁴¹ substituents.

53. The compound of claim 52 wherein R¹ is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more independent G¹¹ substituents.

54. The compound of claim 53 wherein R¹ is cycloalkyl or heterocyclyl, optionally substituted by one or more independent G¹¹ substituents.

55. The compound of claim 54 wherein R¹ is cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted by one or more independent G¹¹ substituents.

56. The compound of claim 54 wherein G¹¹ is —

OR²¹, —

NR²¹R³¹, —

CO₂R²¹, —

C(O)R²¹, —

CONR²¹R³¹, NR²¹(C═

O)R³¹, NR²¹(C═

O)OR³¹, NR²¹(C═

O)NR²¹R³¹, NR²¹S(O)_j4R³¹, —

O(C═

O)OR²¹, —

O(C═

O)NR²¹R³¹, C_0-10alkyl, cycloC_3-8alkyl, cycloC_3-8alkenyl, heterocyclyl-C_0-10alkyl, or heterocyclyl-C_2-10alkenyl, any of which is optionally substituted with one or more independent halo, oxo, —

CF₃, —

OCF₃, —

OR²²²¹, —

NR²²²¹R³³³¹(R^333a1)_j4a, —

C(O)R²²²¹, —

CO₂R²²²¹, —

CONR²²²¹R³³³¹, —

NO₂, —

CN, —

S(O)_j4aR²²²¹, —

SO₂NR²²²¹R³³³¹, NR²²²¹(C═

O)R³³³¹, NR²²²¹(C═

O)R³³³¹, NR²²²¹(C═

O)NR²²²¹R³³³¹, NR²²²¹S(O)_j4aR³³³¹, —

(C═

S)OR²²²¹, —

(C═

O)SR²²²¹, —

NR²²²¹(C═

NR³³³¹)NR^222a1R^333a1, —

NR²²²¹(C═

NR³³³¹)OR^222a1, —

NR²²²¹(C═

NR³³³¹)SR^333a1, —

O(C═

O)OR²²²¹, —

O(C═

O)NR²²²¹R³³³¹, —

O(C═

O)SR²²²¹, —

S(C═

O)OR²²²¹, or —

S(C═

O)NR²²²¹R³³³¹ substituents.

57. The compound of claim 56 wherein R¹ is cis- or trans-cyclobutyl substituted at the 3-position by G¹¹ wherein G¹¹ is —

OH, —

NH₂, —

N(CH₃)₂, —

NHAc, —

NH(CO)NHCH₃, —

NH(CO)OCH₃, —

CH₂OH, —

CH₂NH₂, —

CH₂NHAc, CO₂H, CONH₂, —

CH₂N(CH₃)₂, —

CH₂NH(CO)NHMe, —

CH₂NH(CO)OCH₃, CO₂CH₃, CONHCH₃,

58. The compound of claim 56 wherein R¹ is cis- or trans-cyclohexyl substituted at the 4-position by G¹¹ wherein G¹¹ is —

OH, —

NH₂, —

N(CH₃)₂, —

NHAc, —

NH(CO)NHCH₃, —

NH(CO)OCH₃, —

CH₂OH, —

CH₂NH₂, —

CH₂NHAc, CO₂H, CONH₂, —

CH₂N(CH₃)₂, —

CH₂NH(CO)NHMe, —

CH₂NH(CO)OCH₃, CO₂CH₃, CONHCH₃,

60. A method of inhibiting protein kinase activity comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof.

61. The method of claim 60 wherein said protein kinase is IGF-IR.

62. The method of claim 60 wherein the activity of said protein kinase affects hyperproliferative disorders.

63. The method of claim 60 wherein the activity of said protein kinase influences angiogenesis, vascular permeability, immune response, cellular apoptosis, tumor growth, or inflammation.

64. A method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

65. The method of claim 64 wherein said protein kinase is IGF-IR.

66. The method of claim 64 wherein the condition mediated by protein kinase activity is a hyperproliferative disorder.

67. The method of claim 64 wherein the activity of said protein kinase influences angiogenesis, vascular permeability, immune response, cellular apoptosis, tumor growth, or inflammation.

68. The method of claim 64 wherein the protein kinase is a protein serine/threonine kinase or a protein tyrosine kinase.

69. The method of claim 64 wherein the condition mediated by protein kinase activity is one or more ulcers.

70. The method of claim 69 wherein the ulcer or ulcers are caused by a bacterial or fungal infection;

or the ulcer or ulcers are Mooren ulcers;

or the ulcer or ulcers are a symptom of ulcerative colitis.

71. The method of claim 64 wherein the condition mediated by protein kinase activity is Lyme disease, sepsis or infection by Herpes simplex, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa, or toxoplasmosis.

72. The method of claim 64 wherein the condition mediated by protein kinase activity is von Hippel Lindau disease, pemphigoid, psoriasis, Paget'"'"'s disease, or polycystic kidney disease.

73. The method of claim 64 wherein the condition mediated by protein kinase activity is fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthma, exudtaes, ascites, pleural effusions, pulmonary edema, cerebral edema or edema following burns, trauma, radiation, stroke, hypoxia, or ischemia.

74. The method of claim 64 wherein the condition mediated by protein kinase activity is ovarian hyperstimulation syndrome, preeclainpsia, menometrorrhagia, or endometriosis.

75. The method of claim 64 wherein the condition mediated by protein kinase-activity is chronic inflammation, systemic lupus, glomerulonephritis, synovitis, inflammatory bowel disease, Crohn'"'"'s disease, glomerulonephritis, rheumatoid arthritis and osteoarthritis, multiple sclerosis, or graft rejection.

76. The method of claim 64 wherein the condition mediated by protein kinase activity is sickle cell anaemia.

77. The method of claim 64 wherein the condition mediated by protein kinase activity is an ocular condition.

78. The method of claim 77 wherein the ocular condition is ocular or macular edema, ocular neovascular disease, seleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser treatment complications, conjunctivitis, Stargardt'"'"'s disease, Eales disease, retinopathy, or macular degeneration.

79. The method of claim 64 wherein the condition mediated by protein kinase activity is a cardiovascular condition.

80. The method of claim 79 wherein the condition mediated by protein kinase activity is atherosclerosis, restenosis, ischemia/reperfusion injury, vascular occlusion, venous malformation, or carotid obstructive disease.

81. The method of claim 64 wherein the condition mediated by protein kinase activity is cancer.

82. The method of claim 81 wherein the cancer is a solid tumor, a sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, a rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, an hematopoietic malignancy, or malignant ascites.

83. The method of claim 82 wherein the cancer is Kaposi'"'"'s sarcoma, Hodgkin'"'"'s disease, lymphoma, myeloma, or leukemia.

84. The method of claim 64 wherein the condition mediated by protein kinase activity is Crow-Fukase (POEMS) syndrome or a diabetic condition.

85. The method of claim 84 wherein the diabetic condition is insulin-dependent diabetes mellitus glaucoma, diabetic retinopathy, or microangiopathy.

86. The method of claim 64 wherein the protein kinase activity is involved in T cell activation, B cell activation, mast cell degranulation, monocyte activation, signal transduction, apoptosis, the potentiation of an inflammatory response or a combination thereof.

87. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

88. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof;

and an anti-neoplastic, anti-tumor, anti-angiogenic, or chemotherapeutic agent.

89. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof;

and a cytotoxic cancer therapeutic agent.

90. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof;

and an angiogenesis inhibiting cancer therapeutic agent.

91. A method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to claim 87.

59. A compound selected from the group consisting of:

[1-(3-Benzyloxy-phenyl)-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine],

1-(3-Benzyloxyphenyl)-3-phenyl-imidazo[1,5-a]pyrazin-8-ylamine,

3-Benzyl-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Benzyloxyphenyl)-3-naphthalen-1-yl-imidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Benzyloxyphenyl)-3-naphthalen-2-yl-imidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Benzyloxy-phenyl)-3-cyclopentyl-imidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Benzyloxy-phenyl)-3-cyclohexyl-imidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Benzyloxy-phenyl)-3-cycloheptyl-imidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Benzyloxy-phenyl)-3-(tetrahydro-furan-3-yl)-imidazo[1,5-a]pyrazin-8-ylamine,

trans-3-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol,

1-(3-Benzyloxy-phenyl)-3-(1-methyl-piperidin-4-yl)-imidazo[1,5-a]pyrazin-8-ylamine,

cis-4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide,

trans-4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide,

cis-{4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol,

trans-{4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol,

cis-2-{4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-isoindole-1,3-dione,

trans-2-{4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-isoindole-1,3-dione,

cis-3-(4-Aminomethyl-cyclohexyl)-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-8-ylamine,

trans-3-(4-Aminomethyl-cyclohexyl)-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-8-ylamine,

cis-N-{4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-acetamide, or

trans-N-{4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-acetamide.

or pharmaceutically acceptable salts thereof.

92. A compound selected from the group consisting of:

trans-N-{4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-acetamide,

1-Biphenyl-3-yl-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Bromo-phenyl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine,

1-(4′

-t-Butylbiphenyl-3-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine,

3-Cyclobutyl-1-(4′

-methylbiphenyl-3-yl)-imidazo[1,5-a]pyrazin-8-ylamine,

3-Cyclobutyl-1-(4′

-methoxybiphenyl-3-yl)-imidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Benzyloxyphenyl)-3-cyclopentylmethylimidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Benzyloxyphenyl)-3-cyclohexylmethylimidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Benzyloxyphenyl)-3-trifluoromethylimidazo[1,5-a]pyrazin-8-ylamine,

4-[8-Amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-benzamide,

3-Cyclobutyl-1-phenylimidazo[1,5-a]pyrazin-8-ylamine,

(trans-3-(4-Azetidin-1-ylmethyl-cyclohexyl)-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-8-ylamine,

trans-1-(3-Benzyloxy-phenyl)-3-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-imidazo[1,5-a]pyrazin-8-ylamine),

trans-4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methyl ester,

(trans-4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid,

(trans-4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methylamide,

4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid ethylamide,

trans-1-(3-Benzyloxy-phenyl)-3-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-imidazo[1,5-a]pyrazin-8-ylamine,

cis-1-(3-Benzyloxy-phenyl)-3-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-imidazo[1,5-a]pyrazin-8-ylamine,

trans-3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine,

cis-3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine,

toluene-4-sulfonic acid 3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutylmethyl ester,

{3-[8-Amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol,

3-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-1-methyl-cyclobutanol,

3-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-1-ethyl-cyclobutanol,

1-Allyl-3-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol,

1-(3-Benzyloxyphenyl)-3-tert-butylimidazo[1,5-a]pyrazin-8-ylamine,

cis-1-[3-(Benzyloxy)phenyl]-3-[3-(dimethylamino) cyclobutyl]imidazo[1,5-a]pyrazin-8-amine,

3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol,

3-Cyclobutyl-1-[3-(4-fluoro-benzyloxy)-phenyl]-imidazo[1,5-a]pyrazin-8-ylamine,

trans-4-[8-Amino-1-(3-hydroxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclohexanecarboxylic acid methyl ester,

3-[8-Amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-benzamide,

{3-[8-Amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-phenyl}-methanol,

3-(3-Aminomethylphenyl)-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine,

2-{3-[8-Amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-benzyl}-isoindole-1,3-dione,

4-{8-Amino-1-[3-(2,6-difluoro-benzyloxy)-phenyl]-imidazo[1,5-a]pyrazin-3-yl}-cyclohexanecarboxylic acid methyl ester,

4-{8-Amino-1-[3-(2,6-difluoro-benzyloxy)-phenyl]-imidazo[1,5-a]pyrazin-3-yl}-cyclohexanecarboxylic acid,

cis-3-(3-Dimethylaminomethyl-cyclobutyl)-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine,

cis-3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine,

cis-3-(3-Pyrrolidin-1-ylmethylcyclobutyl)-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine,

cis-3-(3-Azidomethyl-cyclobutyl)-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine,

cis-3-(3-aminomethyl-cyclobutyl)-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine,

cis-3-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutane-carboxylic acid amide,

trans-3-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutane-carboxylic acid amide,

3-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxymethyl-cyclobutanol,

cis-Toluene-4-sulfonic acid 3-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxy-cyclobutylmethyl ester,

trans-Toluene-4-sulfonic acid 3-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxy-cyclobutylmethyl ester,

trans-3-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-1-azetidin-1-ylmethyl-cyclobutanol,

cis-3-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-1-azetidin-1-ylmethyl-cyclobutanol,

1-[3-(4-tert-Butoxy-benzyloxy)-phenyl]-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine,

2-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-Benzonitrile,

3-Cyclobutyl-1-[3-(2-nitro-benzyloxy)-phenyl]-imidazo[1,5-a]pyrazin-8-ylamine,

1-[3-(2-Bromo-benzyloxy)-phenyl]-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine,

1-[3-(3-Aminomethyl-benzyloxy)-phenyl]-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine,

3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-benzoic acid methyl ester,

3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-benzamide,

{3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-phenyl}-methanol,

2-{3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-benzyl}-isoindole-1,3-dione,

3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-benzoic acid,

3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-N-methyl-Benzamide,

1-(3-Benzyloxy-phenyl)-3-(3-methoxymethylene-cyclobutyl)-imidazo[1,5-a]pyrazin-8-ylamine,

3-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl] cyclobutanecarbaldehyde,

cis-1-(3-Benzyloxy-phenyl)-3-(4-methoxy-cyclohexyl)-imidazo[1,5-a]pyrazin-8-ylamine,

trans-1-(3-Benzyloxy-phenyl)-3-(4-methoxy-cyclohexyl)-imidazo[1,5-a]pyrazin-8-ylamine,

cis-tert-Butyl (({3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}oxy)acetate,

cis-2-{3-[8-Amino-1-(3-benzyloxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutoxy}ethanol,

cis-Toluene-4-sulfonic acid 2-{3-[8-amino-1-(3-benzyloxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutoxy}ethyl ester,

cis-1-(3-Benzyloxyphenyl)-3-[3-(2-dimethylaminoethoxy)-cyclobutyl]imidazo[1,5-a]pyrazin-8-yl amine,

cis-{3-[8-Amino-1-(3-benzyloxyphenyl)imidazo[1,5-a]pyrazin-3-yl]-cyclobutoxy}acetic acid,

cis-2-{3-[8-Amino-1-(3-benzyloxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutoxy}-N-methylacetamide,

cis-2-{3-[8-Amino-1-(3-benzyloxy-phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutoxy}acetamide,

1-(3-benzyloxy-4-methoxyphenyl)-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Benzyloxy-4-fluorophenyl)-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Benzyloxy-4-isopropoxyphenyl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine,

1-(3-Benzyloxy-4-ethoxyphenyl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine,

4-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-benzyloxyphenol,

4-{8-Amino-1-[3-(2,6-difluoro-benzyloxy)-phenyl]-imidazo[1,5-a]pyrazin-3-yl}-cyclohexanecarboxylic acid amide,

4-{8-Amino-1-[3-(2,6-difluoro-benzyloxy)-phenyl]-imidazo[1,5-a]pyrazin-3-yl}-cyclohexanecarboxylic acid methylamide,

N-{3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-phenyl}-acetamide,

or pharmaceutically acceptable salts thereof.

93. A compound selected from the group consisting of:

94. A compound selected from the group consisting of:

95. A compound selected from the group consisting of:

96. A compound selected from the group consisting of:

97. A compound selected from the group consisting of:

98. A compound selected from the group consisting of:

99. A compound selected from the group consisting of:

100. A compound selected from the group consisting of: