PIPERIDINYLCYCLOBUTYL SUBSTITUTED PYRROLOPYRIDINE AND PYRROLOPYRIMIDINE DERIVATIVES AS JAK INHIBITORS

• US 20140005166A1
• Filed: 05/17/2013
• Published: 01/02/2014
• Est. Priority Date: 05/18/2012
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: RODGERS, JAMES D., Shepard, Stacey, Zhu, Wenyu, Shao, Lixin, Glenn, Joseph
• Granted Patent: US 9,193,733 B2
• Time in Patent Office: Days
• US Class Current: 514/210.21
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/107 with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Abstract

The present invention provides piperidinylcyclobutyl substituted pyrrolopyrimidines and pyrrolopyridines of Formula I, as defined herein, as well as their compositions and methods of use, that modulate the activity of Janus kinases (JAKs) and are useful in the treatment of diseases related to the activity of JAKs including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.

Claims

1. A compound of Formula I:

2. A compound of claim 1, having Formula II:

5. A compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —

C(═

O)NR³R⁴, —

CH₂CH₂OH, —

CH₂NR³R⁴, or an oxetane ring, wherein the oxetane ring is optionally substituted with R⁵;

R³ is —

CH₂CH₂—

OR^6b, —

CH(CH₃)CH₂—

OR^6b, —

CH₂CH(CH₃)—

OR^6b, cyclopropyl, cyclobutyl, tetrahydro-2H-pyran ring, tetrahydrofuran ring, or oxetane ring, wherein said cyclopropyl, cyclobutyl, tetrahydro-2H-pyran ring, tetrahydrofuran ring, and oxetane ring are each optionally substituted with 1 or 2 groups independently selected from CH₃, CN, OH, and OCH₃;

R⁴ is H, CH₃, —

CH₂CH₂—

OR^6b, —

CH(CH₃)CH₂—

OR^6b, or —

CH₂CH(CH₃)—

OR^6b;

or alternatively, R³ and R⁴, taken together with the nitrogen atom to which they are attached, form an azetidinyl, 1H-pyrazolyl, a 1H-imidazolyl, a 1H-1,3,4-triazolyl, or a 1H-1,2,4-triazolyl group, wherein said azetidinyl group is optionally substituted with 1 or 2 independently selected R^3a groups;

each R^3a is independently CN, OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, or —

CH₂—

OH;

or alternatively, two R^3a groups, taken together with the carbon atom to which they are both attached, form an oxetane ring;

R⁵ is OH or NH₂; and

R^6b is independently H or CH₃.

6. A compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein each R^3a is independently CH₃, CN, OH, OCH₃, or —

CH₂—

OH;

or alternatively, two R^3a groups, taken together with the carbon atom to which they are both attached, form an oxetane ring.

7. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

L is O;

X is N or CH;

R¹ is an oxetane ring, wherein the oxetane ring is optionally substituted with R⁵;

R² is CF₃; and

R⁵ is OH or NH₂.

8. A compound of claim 2, having Formula IIa:

9. A compound of claim 2, having Formula IIa,

10. A compound of claim 2, having Formula IIa,

11. A compound of claim 2 having Formula IIa,

12. A compound of claim 2 having Formula IIa,

13. A compound of claim 2 having Formula IIa,

14. A compound of claim 1, having Formula III:

21. A compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C_1-3 alkyl substituted by —

OR^a1, —

NR^e1R^f1, or C_2-7 heterocycloalkyl;

R^a1 is H or C_1-4 alkyl;

R^e1 is H or C_1-4 alkyl;

wherein C_1-4 alkyl is substituted by 1 or 2 independently selected R^h groups;

R^f1 is H, C_1-4 alkyl, cyclopropyl, cyclobutyl, or cyclohexyl;

wherein C_1-4 alkyl, cyclopropyl, cyclobutyl, or cyclohexyl are each substituted by 1 or 2 independently selected R^h groups; and

each R^h is independently selected from hydroxy, halo, cyano, C_1-4 alkyl, and C_1-4 alkoxy.

22. A compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R² is CF₃.

23. A compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein Y is N.

24. A compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

25. A compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein X is N.

27. A compound of claim 1, or a pharmaceutically acceptable salt thereof;

wherein;

X is N or CH;

L is NR^2a;

Y is CH or N;

R¹ is C_1-3 alkyl substituted by —

OR^a1, —

NR^e1R^f1, or C_2-7 heterocycloalkyl;

R² is CF₃;

R^2a is H or CH₃;

R^a1 is H or C_1-4 alkyl;

R^e1 is H or C_1-4 alkyl;

wherein C_1-4 alkyl is substituted by 1 or 2 independently selected R^h groups;

R^f1 is H, C_1-4 alkyl, cyclopropyl, cyclobutyl, or cyclohexyl;

wherein C_1-4 alkyl, cyclopropyl, cyclobutyl, or cyclohexyl are each substituted by 1 or 2 independently selected R^h groups; and

each R^h is independently selected from hydroxy, halo, cyano, C_1-4 alkyl, and C_1-4 alkoxy.

28. The compound of claim 1, selected from:

{trans-3-(4-{[4-({[(1S)-2-hydroxy-1-methylethyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-({[(1R)-2-hydroxy-1-methylethyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(2-methoxyethyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

1-{[2-[(1-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperidin-4-yl)oxy]-6-(trifluoromethyl)pyridin-4-yl]methyl}azetidine-3-carbonitrile;

[trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[4-[(tetrahydro-2H-pyran-4-ylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)cyclobutyl]acetonitrile;

{trans-3-(4-{[4-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

[trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[4-{[(3S)-tetrahydrofuran-3-ylamino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)cyclobutyl]acetonitrile;

[trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[4-{[(3R)-tetrahydrofuran-3-ylamino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)cyclobutyl]acetonitrile;

{trans-3-(4-{[4-{[(3-methyloxetan-3-yl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(1-methylcyclopropyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-[(oxetan-3-ylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(trans-3-hydroxycyclobutyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-[(3,3-dimethylazetidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-({[(2R)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-({[(2S)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[bis(2-hydroxyethyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(2-hydroxyethyl)(methyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(cis-3-hydroxycyclobutyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(2-hydroxyethyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-(1H-imidazol-1-ylmethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

[trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[4-(1H-1,2,4-triazol-1-ylmethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)cyclobutyl]acetonitrile;

[trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[4-(4H-1,2,4-triazol-4-ylmethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)cyclobutyl]acetonitrile;

{trans-3-(4-{[4-(1H-pyrazol-1-ylmethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-[(3,3-dimethylazetidin-1-yl)carbonyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[6-[(ethylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[6-{[(2-hydroxyethyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[6-{[(trans-3-hydroxycyclobutyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(2-hydroxyethyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(trans-3-hydroxycyclobutyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-[(3,3-dimethylazetidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-[(3,3-difluoropyrrolidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[cyclopropyl(methyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{cis-3-(4-{[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

and {trans-3-(4-{[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-(azetidin-1-ylmethyl)-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-(morpholin-4-ylmethyl)-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-[(3-hydroxyazetidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(2-hydroxyethyl)(methyl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-(methoxymethyl)-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-{4-[[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl](methyl)amino]piperidin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-{4-[[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl](methyl)amino]piperidin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[4-(3-hydroxyoxetan-3-yl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile; and

{trans-3-(4-{[4-(3-aminooxetan-3-yl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

or a pharmaceutically acceptable salt of any of the aforementioned.

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

32. A method of inhibiting an activity of JAK1 comprising contacting JAK1 with a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

33. A method according to claim 32, wherein said compound, or pharmaceutically acceptable salt thereof, is selective for JAK1 over JAK2.

34. A method of treating an autoimmune disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bone resorption disease, or organ transplant rejection in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

35. A method according to claim 34, wherein said autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn'"'"'s disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder.

36. A method according to claim 34, wherein said autoimmune disease is rheumatoid arthritis.

38. A method according to claim 34, wherein said skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.

40. A method according to claim 34, wherein said cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi'"'"'s sarcoma, Castleman'"'"'s disease or pancreatic cancer.

41. A method according to claim 34, wherein said cancer is lymphoma, leukemia, or multiple myeloma.

42. A method according to claim 34, wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).

43. A method according to claim 34, wherein said myeloproliferative disorder is myelofibrosis.

44. A method according to claim 34 wherein said myeloproliferative disorder is primary myelofibrosis (PMF).

45. A method according to claim 34, wherein said bone resorption disease is osteoporosis, osteoarthritis, bone resorption associated with hormonal imbalance, bone resorption associated with hormonal therapy, bone resorption associated with autoimmune disease, or bone resorption associated with cancer.

3-4. -4. (canceled)

15-20. -20. (canceled)

26. (canceled)

29-30. -30. (canceled)

37. (canceled)

39. (canceled)