Substituted heteroaryl compounds and methods of use

1. A compound having Formula (I):

or a stereoisomer, a tautomer, an N-oxide, a solvate, or a pharmaceutically acceptable salt thereof, wherein:

Z is C 7 -C 12 spiro bicycloalkyl, C 7 -C 12 fused bicycloalkyl, 7-12 membered spiro heterobicyclyl or 7-12 membered fused heterobicycloalkyl, wherein Z is optionally substituted by 1, 2, 3, 4 or 5 R 2 groups;

Z 1 is H, C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl or 3-12 membered heterocyclyl, wherein Z 1 is optionally substituted by 1, 2, 3, 4 or 5 R 3 groups;

A is pyrazolyl or imidazolyl, wherein A is optionally substituted by 1, 2, 3, 4 or 5 R 4 groups;

R 1 is H, F, Cl, Br, I, NO 2 , N 3 , CN, C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, C 1 -C 12 alkoxyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -C 12 aryl, 5-12 membered heteroaryl, —(CR 6 R 7 ) n —OR c , —(CR 6 R 7 ) n —NR a R b , —C(═O)R 5 , —OC(═O)R 5 , —O(CR 6 R 7 ) n —R 5 , —N(R c )C(═O)R 5 , —(CR 6 R 7 ) n C(═O)OR c , —(CR 6 R 7 ) n C(═O)NR a R b , —C(═NR c )NR a R b , —N(R c )C(═O)NR a R b , —N(R c )S(═O) m R 5 or —S(═O) 2 NR a R b , wherein R 1 is optionally substituted by 1, 2, 3, 4 or 5 R 8 groups;

each R 2 is independently H, F, Cl, Br, I, NO 2 , N 3 , CN, OH, NH 2 , —C(═O)CH 2 CN, C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, C 1 -C 12 alkoxy, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, —(CR 6 R 7 ) n OR c , —(CR 6 R 7 ) n —NR a R b , —C(═O)R 5 , —S(═O) 2 R 5 , —OC(═O)R 5 , —O(CR 6 R 7 ) n —R 5 , —O(CR 6 R 7 ) n —OR c , —N(R c )C(═O)R 5 , —(CR 6 R 7 ) n C(═O)OR c , —(CR 6 R 7 ) n C(═O)NR a R b , —C(═NR c )NR a R b , —N(R c )C(═O)NR a R b , —N(R c )S(═O) m R 5 or —S(═O) 2 NR a R b , or two adjacent R 2 taken together with the atoms to which they are attached form a C 3 -C 12 cycloalkyl or 3-12 membered heterocycloalkyl group, wherein each of the above substituents is optionally independently substituted by 1, 2, 3, 4 or 5 R 8 groups;

each R 3 and R 4 is independently H, F, Cl, Br, I, NO 2 , N 3 , CN, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, —(C 1 -C 4 alkylene)-(C 3 -C 12 cycloalkyl), C 6 -C 12 aryl, 3-12 membered heterocyclyl, —(C 1 -C 4 alkylene)-(3-12 membered heterocyclyl), 5-12 membered heteroaryl, —(CR 6 R 7 ) n OR c , —(CR 6 R 7 ) n NR a R b , —C(═O)R 5 , —OC(═O)R 5 , —O(CR 6 R 7 ) n —R 5 , —N(R c )C(═O)R 5 , —(CR 6 R 7 ) n C(═O)OR c , —(CR 6 R 7 ) n C(═O)NR a R b , —C(═NR c )NR a R b , —N(R c )C(═O)NR a R b , —N(R c )S(═O) m R 5 or —S(═O) 2 NR a R b , wherein each R 3 and R 4 is optionally independently substituted by 1, 2, 3, 4 or 5 R 8 groups;

each R 5 is independently H, C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, wherein each R 5 is optionally independently substituted by 1, 2, 3, 4 or 5 R 8 groups;

each R 6 and R 7 is independently H, F, Cl, Br, I, NO 2 , N 3 , CN, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, or R 6 and R 7 taken together with the carbon atom to which they are attached form a C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl group, wherein each of the above substituents is optionally independently substituted by 1, 2, 3, 4 or 5 R 8 groups;

each R 8 is independently F, Cl, Br, I, CN, NO 2 , N 3 , C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, NH 2 , —NH(C 1 -C 12 alkyl), —NH(CH 2 ) n —(C 3 -C 12 cycloalkyl), —NH(CH 2 ) n —(C 6 -C 12 aryl), —NH(CH 2 ) n -(3-12 membered heterocyclyl), —NH(CH 2 ) n -(5-12 membered heteroaryl), —N(C 1 -C 12 alkyl) 2 , —N[(CH 2 ) n —(C 3 -C 12 cycloalkyl)] 2 , —N[(CH 2 ) n —(C 6 -C 12 aryl)] 2 , —N[(CH 2 ) n -(3-12 membered heterocyclyl)] 2 , —N[(CH 2 ) n -(5-12 membered heteroaryl)] 2 , OH, —O(C 1 -C 12 alkyl), —O(CH 2 ) n —(C 3 -C 12 cycloalkyl), —O(CH 2 ) n —(C 6 -C 12 aryl), —O(CH 2 ) n -(3-12 membered heterocyclyl) or —O(CH 2 ) n -(5-12 membered heteroaryl);

each R a , R b and R c is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, —(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl), 3-6 membered heterocyclyl, —(C 1 -C 4 alkylene)-(3-6 membered heterocyclyl), C 6 -C 10 aryl, —(C 1 -C 4 alkylene)-(C 6 -C 10 aryl), 5-10 membered heteroaryl or —(C 1 -C 4 alkylene)-(5-10 membered heteroaryl), or R a and R b taken together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl group, wherein each of the above substituents is optionally independently substituted by 1, 2, 3 or 4 substitutents independently selected from F, Cl, Br, CN, N 3 , OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylamino;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3 or 4.

2. The compound of claim 1 , wherein Z is C 8 -C 11 spiro bicycloalkyl, C 8 -C 10 fused bicycloalkyl, 8-11 membered spiro heterobicyclyl or 8-10 membered fused heterobicycloalkyl, wherein Z is optionally substituted by 1, 2, 3 or 4 R 2 groups.

3. The compound of claim 1 , wherein Z 1 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl, wherein Z 1 is optionally substituted by 1, 2 or 3 R 3 groups.

4. The compound of claim 1 , wherein R 1 is H, F, Cl, CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, —(CR 6 R 7 ) n —OR c , —(CR 6 R 7 ) n —NR a R b , —C(═O)R 5 , —(CR 6 R 7 ) n C(═O)NR a R b or —S(═O) 2 NR a R b , wherein R 1 is optionally substituted by 1, 2 or 3 R 8 groups.

5. The compound of claim 1 , wherein each R 2 is independently H, F, Cl, CN, N 3 , NO 2 , OH, NH 2 , —C(═O)CH 2 CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, phenyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, —(CR 6 R 7 ) n —OR c , —(CR 6 R 7 ) n —NR a R b , —C(═O)R 5 , —S(═O) 2 R 5 , —O(CR 6 R 7 ) n —R 5 , —O(CR 6 R 7 ) n —OR c , —N(R c )C(═O)R 5 , —(CR 6 R 7 ) n C(═O)NR a R b , —N(R c )C(═O)NR a R b , —N(R c )S(═O) m R 5 or —S(═O) 2 NR a R b , or two adjacent R 2 taken together with the atoms to which they are attached form a C 3 -C 6 cycloalkyl, or 3-6 membered heterocycloalkyl group, wherein each of the above substituents is optionally independently substituted by 1, 2 or 3 R 8 groups.

6. The compound of claim 1 , wherein each R 3 and R 4 is independently H, F, Cl, Br, I, NO 2 , N 3 , CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, —(C 1 -C 2 alkylene)-(C 3 -C 6 cycloalkyl), phenyl, 3-6 membered heterocyclyl, —(C 1 -C 2 alkylene)-(3-6 membered heterocyclyl), 5-6 membered heteroaryl, —(CR 6 R 7 ) n —OR c , —(CR 6 R 7 ) n —NR a R b , —C(═O)R 5 , —OC(═O)R 5 , —O(CR 6 R 7 ) n —R 5 , —N(R c )C(═O)R 5 , —(CR 6 R 7 ) n C(═O)OR c , —(CR 6 R 7 ) n C(═O)NR a R b , —N(R c )S(═O) m R 5 or —S(═O) 2 NR a R b , wherein each R 3 and R 4 is optionally independently substituted by 1, 2 or 3 R 8 groups.

7. The compound of claim 1 , wherein each R 5 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, phenyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each R 5 is optionally independently substituted by 1, 2 or 3 R 8 groups.

8. The compound of claim 1 , wherein each R 6 and R 7 is independently H, F, Cl, Br, I, CN, N 3 , NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, phenyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl, or R 6 and R 7 taken together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl, phenyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl group, wherein each of the above substituents is optionally independently substituted by 1, 2 or 3 R 8 groups.

9. The compound of claim 1 , wherein each R 8 is independently F, Cl, CN, N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, phenyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, NH 2 , —NH(C 1 -C 6 alkyl), —NH(CH 2 ) n —(C 3 -C 6 cycloalkyl), —NH(CH 2 ) n -phenyl, —NH(CH 2 ) n -(3-6 membered heterocyclyl), —NH(CH 2 ) n -(5-6 membered heteroaryl), —N(C 1 -C 4 alkyl) 2 , —N[(CH 2 ) n —(C 3 -C 6 cycloalkyl)] 2 , —N[(CH 2 ) n -phenyl] 2 , —N[(CH 2 ) n -(3-6 membered heterocyclyl)] 2 , —N[(CH 2 ) n -(5-6 membered heteroaryl)] 2 , OH, —O(C 1 -C 6 alkyl), —O(CH 2 ) n —(C 3 -C 6 cycloalkyl), —O(CH 2 ) n -phenyl, —O(CH 2 ) n -(3-6 membered heterocyclyl) or —O(CH 2 ) n -(5-6 membered heteroaryl).

10. The compound of claim 1 , wherein each R a , R b and R c is independently H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, —(C 1 -C 2 alkylene)-(C 3 -C 6 cycloalkyl), 3-6 membered heterocyclyl, —(C 1 -C 2 alkylene)-(3-6 membered heterocyclyl), phenyl, —(C 1 -C 2 alkylene)-phenyl, 5-6 membered heteroaryl or —(C 1 -C 2 alkylene)-(5-6 membered heteroaryl), or R a and R b taken together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl group, wherein each of the above substituents is optionally independently substituted by 1, 2 or 3 substitutents independently selected from F, Cl, CN, N 3 , OH, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 alkylamino.

11. The compound of claim 1 , wherein Z is:

or a stereoisomer thereof, wherein each X, X′, X 2 and X 3 is independently CH 2 , NH or O, with the proviso that when X 2 is O, X 3 is not O; and wherein Z is optionally substituted by 1, 2 or 3 R 2 groups.

12. The compound of claim 1 , wherein A is:

wherein A is optionally substituted by 1, 2 or 3 R 4 groups.

13. The compound of claim 1 , wherein Z 1 is H, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

14. The compound of claim 1 , wherein R 1 is H, F, Cl, CN, N 3 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, —(CR 6 R 7 ) n —OR c , —(CR 6 R 7 ) n —NR a R b , —C(═O)R 5 , —(CR 6 R 7 ) n C(═O)NR a R b or —S(═O) 2 NR a R b , wherein R 1 is optionally substituted by 1, 2 or 3 R 8 groups.

15. The compound of claim 1 , wherein each R 2 is independently H, F, Cl, CN, N 3 , NO 2 , OH, NH 2 , —C(═O)CH 2 CN, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, phenyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, —(CR 6 R 7 ) n —OR c , —(CR 6 R 7 ) n —NR a R b , —C(═O)R 5 , —S(═O) 2 R 5 , —O(CR 6 R 7 ) n —R 5 , —O(CR 6 R 7 ) n —OR c , —N(R c )C(═O)R 5 , —(CR 6 R 7 ) n C(═O)NR a R b , —N(R c )S(═O) m R 5 or —S(═O) 2 NR a R b , wherein each R 2 is optionally independently substituted by 1, 2 or 3 R 8 groups.

16. The compound of claim 1 , wherein each R 5 is independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, phenyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each R 5 is optionally independently substituted by 1, 2 or 3 R 8 groups.

17. The compound of claim 1 having one of the following structures:

or a stereoisomer, a tautomer, an N-oxide, a solvate, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof.

19. The pharmaceutical composition of claim 18 further comprising a therapeutic agent selected from the group consisting of chemotherapeutic agents, anti-proliferative agents, phosphodiesterase 4 (PDE4) inhibitors, β 2 -adrenoreceptor agonists, corticosteroids, non-steroidal GR agonists, anticholinergic agents, antihistamines, anti-inflammatory agents, immunosuppressants, immunomodulators, agents for treating atherosclerosis, agents for treating pulmonary fibrosis and combinations thereof.

20. A method of treating a disease in a patient comprising administering to the patient a compound of claim 1 or a stereoisomer, a tautomer, an N-oxide, a solvate, or pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of transplantation rejection, cancer, chronic obstructive pulmonary disease (COPD), asthma, systemic lupus erythematosis, cutaneous lupus erythematosis, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, type I diabetes mellitus, allergic airway disease, sinusitis, eczema, hives, food allergies, allergies to insect venom, inflammatory bowel syndrome, Crohn's disease, rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.

21. The method of claim 20 , wherein the cancer is selected from the group consisting of polycythemia vera, essential thrombocytosis, myelofibrosis, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), and acute lymphocytic leukemia (ALL).

22. The method of claim 20 , wherein the transplantation rejection is organ transplant rejection, tissue transplant rejection or cell transplant rejection.

23. A method of treating a disease in a patient comprising administering to the patient the pharmaceutical composition of claim 18 or a stereoisomer, a tautomer, an N-oxide, a solvate, or pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of transplantation rejection, cancer, chronic obstructive pulmonary disease (COPD), asthma, systemic lupus erythematosis, cutaneous lupus erythematosis, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, type I diabetes mellitus, allergic airway disease, sinusitis, eczema, hives, food allergies, allergies to insect venom, inflammatory bowel syndrome, Crohn's disease, rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.

24. A method of inhibiting the activity of a protein kinase selected from the group consisting of JAK kinase, FLT3 kinase, Aurora kinase or a combination thereof comprising contacting the kinase with a compound of claim 1 or a stereoisomer, a tautomer, an N-oxide, a solvate, or pharmaceutically acceptable salt thereof.

25. A method of inhibiting the activity of a protein kinase selected from the group consisting of JAK kinase, FLT3 kinase, Aurora kinase or a combination thereof comprising contacting the kinase with the pharmaceutical composition of claim 18 .

26. The method of claim 23 , wherein the cancer is selected from the group consisting of polycythemia vera, essential thrombocytosis, myelofibrosis, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), and acute lymphocytic leukemia (ALL).

27. The method of claim 23 , wherein the transplantation rejection is organ transplant rejection, tissue-transplant rejection or cell-transplant rejection.