Substituted heterocycles as Janus kinase inhibitors

• US 8,513,270 B2
• Filed: 12/20/2007
• Issued: 08/20/2013
• Est. Priority Date: 12/22/2006
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Arvanitis, Argyrios G., Rodgers, James D., Storace, Louis, Folmer, Beverly
• Primary Examiner(s): Leeser, Erich A
• Application Number:
  US11/961,424
• Publication Number:
  US 20080188500A1
• Time in Patent Office: 2,070 Days
• Field of Search: 514/267, 544/250
• US Class Current: 514/267
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• 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 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 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: C07D 471/14 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/14 : Ortho-condensed systems

Abstract

The present invention provides substituted tricyclic heteroaryl compounds, including, for example, pyridoindoles, pyrimidinoindoles and triazinoindoles that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases such as immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.

Claims

1. A compound of Formula IIIG:

2. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R¹ is H, C_1-6 alkyl, or C(O)C_1-6 alkyl.

3. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R¹ is H.

4. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R² is H.

5. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R is selected from H, halo, CN, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, and OR^a1;

wherein said C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═

NRⁱ)NR^c1R^d1, NR^c1C(═

NRⁱ)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

6. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R is selected from halosulfanyl, NO₂, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═

NRⁱ)NR^c1R^d1, NR^c1C(═

NRⁱ)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

7. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R is selected from H, halo, CN, C_1-6 alkyl and OR^a1.

8. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Q¹ is CR^Q.

9. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Q² is CR^Q.

10. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Q³ is CR^Q.

11. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Q³ is N.

12. A compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R^Q is H.

13. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein W¹ is CR^W.

14. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein W¹ is N.

15. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein W² is CR^W.

16. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein W² is N.

17. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A¹ is CR^W.

18. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A¹ is N.

19. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A² is CR^W.

20. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A² is N.

21. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is a divalent moiety selected from C_1-6 allylene, (C_1-6 alkylene)_p-O—

(C_1-6 alkylene)_q, (C_1-6alkylene)_p-S—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-NR^c3—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-C(O)—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-OC(O)—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-C(O)NR^c3—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-OC(O)NR^c3—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-SO—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-SO₂—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-SONR^c3—

C_1-6 alkylene)_q, (C_1-6 alkylene)_p-SO₂NR^c3—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-NR^c3CONR^d3—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-NR^c3SONR^d3—

(C_1-6 alkylene)_q, and (C_1-6 alkylene)_p-NR^c3SO₂NR^d3—

(C_1-6 alkylene)_q, wherein the C_1-6 alkylene is optionally substituted by 1, 2, or 3 substituents independently selected from C_1-6 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 hydroxyalkyl, C_1-4 cyanoalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, CN, NO₂, SCN, OH, C_1-4 haloalkyl, halosulfanyl, C_1-4 alkoxy-C_1-4 alkyl, C_1-4alkoxy, C_1-4 haloalkoxy, amino, C_1-4 alkylamino, and C_2-8 dialkylamino.

22. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is a divalent moiety selected from (C_1-6 alkylene)_p-C(O)NR^c3—

(C_1-6 alkylene)_q and (C_1-6 alkylene)_p-NR^c3CONR^d3—

(C_1-6 alkylene)_q, wherein the C_1-6 alkylene is optionally substituted by 1, 2, or 3 substituents independently selected from C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 hydroxyalkyl, C_1-4 cyanoalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, CN, NO₂, SCN, OH, C_1-4 haloalkyl, halosulfanyl, C_1-4 alkoxy-C_1-4 alkyl, C_1-4alkoxy, C_1-4 haloalkoxy, amino, C_1-4 alkylamino, and C_2-8 dialkylamino.

23. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is a divalent moiety selected from (C_1-6 alkylene)_p-C(O)NR^c3—

(C_1-6 alkylene)_q and (C_1-6 alkylene)_p-NR^c3CONR^d3—

(C_1-6alkylene)_q.

24. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is a divalent moiety selected from C(O)NH, C(O)NH—

(C_1-6 alkylene) and NHCONH.

25. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is C(O)NH.

26. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is C(O)NH—

(C_1-6 alkylene).

27. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is NHCONH.

28. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula IIIJ:

29. The compound of claim 1, selected from:

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide;

3-(4-Methyl-1H-imidazol-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-(4-formyl-1H-imidazol-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-[4-(hydroxymethyl)-1H-imidazol-1-yl]-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-4-[(methylamino)methyl]-1H-imidazol-1-yl-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-3-(trifluoromethyl)benzamide;

4-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-3-(trifluoromethyl)benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-N′

-[3-(trifluoromethyl)phenyl]urea;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-N′

-[3-(trifluoromethyl)phenyl]urea;

4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

4-chloro-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

4-cyano-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

2-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide;

4-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide;

2-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-2,5-bis(trifluoromethyl)benzamide;

3-chloro-2-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)-benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3,5-bis(trifluoromethyl)benzamide;

4-methoxy-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide;

3-methoxy-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-2-(trifluoromethyl)benzamide;

N-[4-fluoro-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide;

N-[3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide;

3-chloro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(pentafluoro-λ

(6)-sulfanyl)-benzamide;

N-[4-chloro-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-4-(trifluoromethyl)pyridine-2-carboxamide;

3-(1H-imidazol-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)-benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(1H-1,2,4-triazol-1-yl)-5-(trifluoro-methyl)benzamide;

3-{4-[(dimethylamino)methyl]-1H-imidazol-1-yl}-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-{[3-(dimethylamino)propyl]amino}-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-{[3-(1H-imidazol-1-yl)-propyl]amino}-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-phenyl]-5-(trifluoromethyl)benzamide;

3-(dimethylamino)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)-benzamide;

3-{[2-(dimethylamino)ethyl]amino}-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

4-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-3-(trifluoromethyl)benzamide;

3-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-2,5-bis(trifluoromethyl)benzamide;

3-chloro-2-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-5-(trifluoromethyl)-benzamide;

4-methyl-3-(9H-pyrimido-[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

4-methyl-N-(3-methyl-phenyl)-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide;

4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethoxy)phenyl]benzamide;

N-(2,5-difluorobenzyl)-4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide;

4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)benzyl]benzamide;

4-methyl-N-(5-methyl-1,3-thiazol-2-yl)-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide;

4-chloro-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

4-methoxy-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-benzamide;

4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-(9H-pyrimido[4,5-b]-indol-7-yl)benzamide;

4-methyl-N-[(1R)-1-phenylethyl]-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide;

4-methyl-N-[(1S)-1-phenylethyl]-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide;

4-methyl-N-[3-(pentafluoro-λ

(6)-sulfanyl)phenyl]-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide;

4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[5-(trifluoromethyl)pyridin-3-yl]benzamide;

N-[3-(2-amino-9H-pyrimido[4,5-b]indol-7-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide;

N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-3-(trifluoromethyl)benzamide;

3-fluoro-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide;

3-(1H-imidazol-1-yl)-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide;

N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-3-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)benzamide;

3-(4-formyl-1H-imidazol-1-yl)-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide;

3-[4-(hydroxymethyl)-1H-imidazol-1-yl]-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide;

3-[2-(dimethylamino)ethyl]amino-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide;

3-[3-(dimethylamino)propyl]amino-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide; and

pharmaceutically acceptable salts thereof.

30. A composition comprising a compound according to claim 1, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

31. A method of treating myeloproliferative disorder in a patient, the method comprising, administering to said patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

32. The method of claim 31 wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).

33. A method of treating acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), or chronic myeloid leukemia (CML), in a patient, the method comprising, administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

34. A method of treating Type I diabetes in a patient, the method comprising, administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

35. A method of treating psoriasis in a patient, the method comprising, administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.