Cyclohexyl Azetidine Derivatives as JAK Inhibitors

• US 20130045963A1
• Filed: 08/17/2012
• Published: 02/21/2013
• Est. Priority Date: 08/18/2011
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Rodgers, James D., Arvanitis, Argyrios G.
• Granted Patent: US 9,359,358 B2
• Time in Patent Office: Days
• US Class Current: 514/210.18
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 19/10 for osteoporosis
• 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 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 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 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 473/04 two oxygen atoms
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention provides cyclohexyl azetidine derivatives, as well as their compositions and methods of use, that modulate the activity of Janus kinase (JAK) and are useful in the treatment of diseases related to the activity of JAK including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.

Claims

1. A compound of Formula I:

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴, and R⁵ are each independently selected from H, —

CF₃, —

CH₂R^x, and —

C(CH₃)₂R^x.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein each R^x group is independently selected from OR^a1 and NR^e1R^f1.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R^a1, R^c1, R^d1, R^e1, and R^f1 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Cy², and —

C_1-3 alkylene-Cy²;

wherein said C_1-6 alkyl is optionally substituted by 1, 2, or 3 independently selected R^k groups;

or

each R^e1 and R^f1, together with the nitrogen atom to which they are attached, forms a 4-6 membered monocyclic heterocycloalkyl ring;

which is optionally substituted with 1, 2, or 3 independently selected R^m groups.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein each Cy² is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-2-yl, and 1H-imidazol-4-yl, which are each optionally substituted by 1, 2, or 3 independently selected R^m groups.

8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein each R^m is independently selected from halo, hydroxy, C_1-4 alkoxy, hydroxyl-C_1-4 alkyl, and C_1-4 alkoxy-C_1-4 alkyl.

9. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein each R^k is independently selected from hydroxy, C_1-4 alkoxy, hydroxyl-C_1-4 alkyl, and C_1-4 alkoxy-C_1-4 alkyl.

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the 6-membered aromatic ring formed by carbon atom, X, Y, W, Z, and V is selected from:

26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

X is N;

Y is CR²;

W is CR³ or N;

Z is CR⁴;

V is CR⁵;

R², R³, R⁴, and R⁵ are each independently selected from H, halo, CN, C_1-6 alkyl, C_1-6 haloalkyl, Cy, OR^a, C(═

O)OR^a, and C(═

O)NR^eR^f;

wherein said C_1-6 alkyl is optionally substituted by 1, 2, or 3 independently selected R^x groups;

each Cy is independently selected from 3-6-membered monocyclic cycloalkyl optionally substituted by 1, 2, or 3 independently selected R^g groups;

each R^a, R^e, and R^f is, independently, H or C_1-6 alkyl;

wherein said C_1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R^h groups;

or

each R^e and R^f, together with the nitrogen atom to which they are attached, form a 4-6 membered monocyclic heterocycloalkyl ring;

each R^g is independently selected from hydroxy and hydroxyl-C_1-4 alkyl;

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

each R^x group is independently selected from OR^a1 and NR^e1R^f1;

each R^a1, R^e1, and R^f1 is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, Cy², and —

C_1-3 alkylene-Cy²;

wherein said C_1-6 alkyl is optionally substituted by 1, 2, or 3 independently selected R^k groups;

or

each R^e1 and R^f1, together with the nitrogen atom to which they are attached, forms a 4-6 membered monocyclic heterocycloalkyl ring;

which is optionally substituted with 1, 2, or 3 independently selected R^m groups;

each Cy² is independently selected from 3-6-membered monocyclic cycloalkyl, 4-6 membered monocyclic heterocycloalkyl, and 5-6 membered monocyclic heteroaryl, which are each optionally substituted by 1, 2, or 3 independently selected R^m groups;

each R^k is independently selected from hydroxy, C_1-4 alkoxy, hydroxyl-C_1-4 alkyl, and C_1-4 alkoxy-C_1-4 alkyl; and

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

27. The compound of claim 1, having Formula II:

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein:

R² is C_1-3haloalkyl;

R⁴ is selected from —

CH₂OH, —

C(CH₃)₂OH, and —

CH₂NR^e1R^f1;

R^e1 is H or C_1-4 alkyl;

R^f1 is H, C_1-6alkyl, C_1-6 haloalkyl, Cy², or —

C_1-2 alkylene-Cy²;

wherein said C_1-6 alkyl is optionally substituted with 1 or 2 groups selected from —

OH and —

OCH₃;

or R^e1 and R^f1 together with the nitrogen atom to which they are attached form a 4-6-membered monocyclic heterocycloalkyl ring, which is optionally substituted by one —

F, —

OH, or —

CH₂OH group; and

Cy² is cyclopropyl, cyclobutyl, 5-membered monocyclic heterocycloalkyl, or 5-membered monocyclic heteroaryl;

each of which is optionally substituted by a —

CH₂OH group.

29. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein:

R² is C_1-3 haloalkyl;

R⁴ is selected from —

CH₂OH, —

C(CH₃)₂OH, and —

CH₂NR^e1R^f1 wherein

R^e1 is H, methyl or ethyl; and

R^f1 is H, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, tert-butyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-hydroxy-1-methylethyl, 2-methoxy-1-methylethyl, 2-hydroxy-2-methylethyl, 2-hydroxy-2,2-dimethylethyl, 2,3-dihydroxypropyl, cyclopropylmethyl, (1-(hydroxymethyl)cyclopropyl)methyl, 2-(hydroxymethyl)tetrahydrofuran-2-yl, or 1H-imidazol-4-ylethyl;

or

R^e1 and R^f1, together with the nitrogen atom to which they are attached, form a group selected from azetidinyl, 3-hydroxy-azetidinyl, 3-fluoro-azetidinyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, 3-fluoropyrrolidinyl, 2-(hydroxymethyl)pyrrolidinyl, and piperidinyl.

30. The compound of claim 1, having Formula III:

31. The compound of claim 1, having Formula IV:

32. The compound of claim 1, having Formula V:

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein:

R⁴ is selected from —

CH₂OH, —

C(CH₃)₂OH, —

CH₂NR^e1R^f1 and C(═

O)NR^eR^f;

R^e1 is H, methyl or ethyl;

R^f1 is H, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-methylethyl, or cyclopropylmethyl;

or

R^e1 and R^e1, together with the nitrogen atom to which they are attached, form a group selected from azetidinyl, 3-hydroxy-azetidinyl, 3-fluoro-azetidinyl, 3-cyano-azetidinyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, 3-fluoropyrrolidinyl, 2-(hydroxymethyl)pyrrolidinyl, piperidinyl, 4-hydroxypiperidinyl, 3-methyloxetan-3-yl, pyrazolyl, and imidazolyl;

R^e is H or methyl; and

R^f is H, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, or cyclobutyl;

or

R^e and R^f, together with the nitrogen atom to which they are attached, form a group selected from azetidinyl, 3-hydroxy-azetidinyl, 3-fluoro-azetidinyl, 3-cyano-azetidinyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, 3-fluoropyrrolidinyl, 2-(hydroxymethyl)pyrrolidinyl, and piperidinyl.

34. The compound of claim 1, having Formula III-A:

35. The compound of claim 34, wherein R^a1 is H, methyl or ethyl.

37. A compound of claim 1, selected from:

{1-(cis-4-{[6-[(dimethylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,1-pyrazol-1-yl]azetidin-3-yl)acetonitrile;

{1-(cis-4-{[6-(aminomethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-[(methylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-1 [6-[(ethylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-[(isopropylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-[(cyclopropylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-{[ethyl(methyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-{[(cyclopropylmethyl)amino]methyl}-2-(tri fluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,1-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-([6-[(cyclobutylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-{[(2-hydroxyethyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-{[(2-hydroxyethyl)(methyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-{[ethyl(2-hydroxyethyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(cis-4-{[6-{[(2,2,2-trifluoroethyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)azetidin-3-yl]acetonitrile;

{1-(cis-4-{[6-{[(2-fluoroethyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

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

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

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

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

{1-(cis-4-{[6-{[(2-hydroxy-2-methylpropyl)amino]triethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-{[(3-hydroxypropyl)amino]methyl-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-[(2-methoxyethyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-(azetidin-1-ylmethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-[(3-hydroxyazetidin-1-yl)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl)acetonitrile;

{1-(cis-4-{[6-1 [(3S)-3-hydroxypyrrolidin-1-yl]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(cis-4-{[6-({[(2S)-tetrahydrofuran-2-ylmethyl]amino}methyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)azetidin-3-yl]acetonitrile;

{1-(cis-4-{[6-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

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

{1-(cis-4-{[6-1 [(3S)-3-fluoropyrrolidin-1-yl]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl)acetonitrile;

{1-(cis-4-{[6-[(propylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-{[(2,3-dihydroxypropyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-[(butylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-[(isobutylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-{[butyl(methyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3 [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-[(3-fluoroazetidin-1-yl)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-[({[1-(hydroxymethyl)cyclopropyl]methyl}amino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

2-(1-(cis-4-((6-(((2-(1H-imidazol-4-yl)ethyl)amino)methyl)-2-(trifluoromethyl)pyrimidin-4-yl)oxy}cyclohexyl)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile;

{1-(cis-4-{[6-{[(3-methoxypropyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-{[(2-methoxy-1-methylethyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-{[(2-methoxyethyl)(methyl)amino]methyl-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-(1-hydroxy-1-methylethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; and

{1-(cis-4-{[6-[(tert-butylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1, selected from:

6-[(cis-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-N-ethyl-2-(trifluoromethyl)pyrimidine-4-carboxamide;

{1-(cis-4-{[6-(pyrrolidin-1-ylcarbonyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-{[(2-hydroxy-1,1-dimethylethyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-{[(1-methylcyclopropyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

6-[(cis-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-2-(trifluoromethyl)pyrimidine-4-carbonitrile;

{1-(cis-4-{[6-(2-hydroxyethoxy)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-(1,2-dihydroxy-1-methylethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-(1-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-(2-hydroxy-1-methylethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-(1-fluoro-1-methylethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-[1-(hydroxymethyl)cyclopropyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[6-(2-hydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

6-[(cis-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-N,N-dimethyl-2-(trifluoromethyl)pyrimidine-4-carboxamide;

6-[(cis-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-N-ethyl-N-methyl-2-(trifluoromethyl)pyrimidine-4-carboxamide;

6-[(cis-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-N-(2-methoxyethyl)-2-(trifluoromethyl)pyrimidine-4-carboxamide;

{1-(cis-4-{[6-(2-fluoroethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl)acetonitrile;

{1-(cis-4-{[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-[(methylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-[(dimethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

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

{1-(cis-4-{[4-{[(2-hydroxy-1,1-dimethylethyl)amino]methyl-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl)acetonitrile;

{1-(cis-4-{[4-[(cyclopropylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

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

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

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

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

{1-(cis-4-{[4-[(cyclobutylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

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

{1-(cis-4-{[4-[(3-hydroxyazetidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

2-[(cis-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-N-methyl-6-(trifluoromethyl)isonicotinamide;

2-[(cis-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-N,N-dimethyl-6-(trifluoromethyl)isonicotinamide;

2-[(cis-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-N-(2-hydroxyethyl)-N-methyl-6-(trifluoromethyl)isonicotinamide;

2-[(cis-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-N-isopropyl-6-(trifluoromethyl)isonicotinamide;

2-[(cis-4-(3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-N-[(1S)-2-hydroxy-1-methylethyl]-6-(trifluoromethyl)isonicotinamide;

2-[(cis-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-N-[(1R)-2-hydroxy-1-methylethyl]-6-(trifluoromethyl)isonicotinamide;

2-[(cis-4-(3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-N-cyclopropyl-6-(trifluoromethyl)isonicotinamide;

2-[(cis-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-N-cyclopropyl-N-methyl-6-(trifluoromethyl)isonicotinamide;

N-(sec-butyl)-2-[(cis-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-6-(trifluoromethyl)isonicotinamide;

{1-(cis-4-{[4-[(3-hydroxyazetidin-1-yl)carbonyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

2-[(cis-4-(3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-N-cyclobutyl-6-(trifluoromethyl)isonicotinamide;

1-[2-[(cis-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-6-(trifluoromethyl)isonicotinoyl]azetidine-3-carbonitrile;

{1-(cis-4-{[4-(morpholin-4-ylmethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-([4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

{1-(cis-4-{[4-[(4-hydroxypiperidin-1-yl)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

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

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

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

or a pharmaceutically acceptable salt thereof.

39. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

41. A method according to claim 40, wherein said compound, or pharmaceutically acceptable salt thereof, is selective for JAK1 over JAK2.

42. 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.

43. A method according to claim 42, 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.

44. A method according to claim 42, wherein said autoimmune disease is rheumatoid arthritis.

45. A method according to claim 42, wherein said autoimmune disease is a skin disorder.

46. A method according to claim 45, wherein said skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.

48. A method according to claim 42, 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.

49. A method according to claim 42, wherein said cancer is lymphoma, leukemia, or multiple myeloma.

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

51. A method according to claim 42, wherein said myeloproliferative disorder is myelofibrosis.

52. A method according to claim 42, wherein said myeloproliferative disorder is primary myelofibrosis (PMF).

53. A method according to claim. 42, wherein said myeloproliferative disorder is post polycythemia vera myelofibrosis (Post-PV MF).

54. A method according to claim 42, wherein said myeloproliferative disorder is post-essential thrombocythemia myelofibrosis (Post-ET MF).

55. A method according to claim 42, 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.

2-3. -3. (canceled)

10-21. -21. (canceled)

23-25. -25. (canceled)

36. (canceled)

47. (canceled)