HETEROCYCLIC-SUBSTITUTED PYRROLOPYRIDINES AND PYRROLOPYRIMIDINES AS JAK INHIBITORS

• US 20120149682A1
• Filed: 11/18/2011
• Published: 06/14/2012
• Est. Priority Date: 11/19/2010
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Holdings Corporation And Incyte Corporation
• Inventors: Rodgers, James D., Zhu, Wenyu, Glenn, Joseph
• Granted Patent: US 9,034,884 B2
• Time in Patent Office: Days
• US Class Current: 514/210.21
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 19/04 for non-specific disorders of the connective tissue
• 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 37/06 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 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• 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: 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: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention provides heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines of Formula I:

wherein X, Y, Z, L, A, R⁵, n, m, and r are defined above, 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. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is O.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is cyano.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, and R⁴ are each H.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R⁵ is fluorine.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein r is 1.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring;

each of which is optionally substituted with 1, 2, 3, 4, or 5 independently selected R⁷ substituents.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R⁷ is independently selected from halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, —

C(═

O)R^b, and —

C(═

O)NR^eR^f;

wherein said C_1-6 alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R^g groups.

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

X is N;

Z is N;

L is O;

R¹, R², and R³ are each H;

each R⁵ is fluorine;

A is C_3-10 cycloalkyl, C_2-10heterocycloalkyl, C_6-10 aryl, or C_1-10 heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 independently selected R⁷ substituents;

each R⁷ is independently selected from halo, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_3-10 cycloalkyl-C_1-4-alkyl, C_2-10 heterocycloalkyl, C_2-10 heterocycloalkyl-C_1-4-alkyl, —

OR^a, —

SR^a, —

S(═

O)₂R^b, —

S(═

O)₂NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^a, —

C(═

O)NR^eR^f, —

OC(═

O)NR^eR^f, —

NR^eR^f, —

NR^cC(═

O)R^d, —

NR^cC(═

O)OR^d, —

NR^cC(═

O)NR^d, —

NR^cS(═

O)₂R^d, and —

NR^cS(═

O)₂NR^eR^f;

wherein said C_1-6 alkyl, C_3-10 cycloalkyl, C_3-10 cycloalkyl-C_1-4-alkyl, C_2-10 heterocycloalkyl, C_2-10 heterocycloalkyl-C_1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^g groups;

each R^g is independently selected from halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, C_2-7 heterocycloalkyl, —

OR^a1, —

S(═

O)₂R^b1, —

S(═

O)₂NR^e1R^f1, —

C(═

O)R^b1, —

C(═

O)OR^a1, —

C(═

O)NR^e1R^f1, —

OC(═

O)R^b1, —

OC(═

O)NR^e1R^f1, —

NR^c1C(═

O)OR^d1, —

NR^c1C(═

O)NR^d1, —

NR^c1S(═

O)₂R^d1, and —

NR^c1S(═

O)₂NR^e1R^f1;

wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R^h groups;

each R^a, R^c, R^d, and R^e is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^g groups;

each R^b is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl;

wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl are optionally substituted by 1, 2, 3, or 4 independently selected R^g groups;

each R^f is independently selected from H and C_1-6 alkyl;

each R^a1, R^c1, R^d1 and R^e1 is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl;

wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^h groups; and

each R^b1 is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl;

wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl optionally substituted by 1, 2, 3, or 4 independently selected R^h groups;

each Rⁿ is independently selected from H and C_1-6 alkyl;

m is 1;

n is 0, 1, or 2; and

r is 1.

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

X is N;

Z is N;

L is O;

R¹, R², and R³ are each H;

each R⁵ is fluorine;

A is C_6-10 aryl or C_1-10 heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 independently selected R⁷ substituents;

each R⁷ is independently selected from halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, —

S(═

O)₂R^b, —

S(═

O)₂NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^a, and —

C(═

O)NR^eR^f;

wherein said C_1-6 alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R^g groups;

each R^g is independently selected from halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, C_2-7 heterocycloalkyl, —

C(═

O)NR^e1R^f1, and —

NR^e1R^f1;

wherein said C_1-6 alkyl and C_2-7 heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R^h groups;

each R^a and R^e is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl;

wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl are optionally substituted by 1, 2, 3, or 4 independently selected R^g groups;

each R^b is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl;

wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl are optionally substituted by 1, 2, 3, or 4 independently selected R^g groups;

each R^f is independently selected from H and C_1-6 alkyl;

each R^e1 is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^h groups;

each R^f1 is independently selected from H and C_1-6 alkyl;

m is 1;

n is 0, 1, or 2; and

r is 1.

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

X is N;

Z is N;

L is O;

Y is cyano;

R¹, R², and R³ are each H;

each R⁵ is fluorine;

A is C_6-10 aryl, optionally substituted with 1, 2, 3, 4, or 5 independently selected R⁷ substituents;

each R⁷ is independently selected from halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, —

C(═

O)R^b, and —

C(═

O)NR^eR^f;

wherein said C_1-6 alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R^g groups;

each R^g is independently selected from halo, cyano, C_1-6 alkyl, C_2-7 heterocycloalkyl, —

C(═

O)NR^e1R^f1, and —

NR^e1R^f1;

wherein said C_1-6 alkyl and C_2-7 heterocycloalkyl is optionally substituted with 1 or 2 independently selected R^h groups;

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

each R^e is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^g groups;

each R^f is independently selected from H and C_1-6 alkyl;

each R^b is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl;

wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl are optionally substituted by 1, 2, 3, or 4 independently selected R^g groups;

each R^e1 is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^h groups;

each R^f is independently selected from H and C_1-6 alkyl;

m is 1;

n is 0 or 1; and

r is 1.

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

X is N;

Z is N;

L is O;

Y is cyano;

R¹, R², and R³ are each H;

each R⁵ is fluorine;

A is phenyl, optionally substituted with 1, 2, 3, 4, or 5 independently selected R⁷ substituents;

each R⁷ is independently selected from halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, —

C(═

O)R^b, and —

C(═

O)NR^eR^f;

wherein said C_1-6 alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R^g groups;

each R^g is independently selected from halo, cyano, C_1-6 alkyl, C_2-7 heterocycloalkyl, —

C(═

O)NR^e1R^f1, and —

NR^e1R^f1;

wherein said C_1-6 alkyl and C_2-7 heterocycloalkyl is optionally substituted with 1 or 2 independently selected R^h groups;

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

each R^e is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^g groups;

each R^f is independently selected from H and C_1-6 alkyl;

each R^b is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl;

wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl are optionally substituted by 1, 2, 3, or 4 independently selected R^g groups;

each R^e1 is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl, wherein said C_1-6 alkyl, C_3-7 cycloalkyl, and C_2-7 heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^h groups;

each R^f1 is independently selected from H and C_1-6 alkyl;

m is 1;

n is 0 or 1; and

r is 1.

34. The compound of claim 1, wherein said compound is a compound of Formula II:

35. The compound of claim 1, wherein said compound is a compound of Formula III:

36. A compound of claim 1, selected from:

4-[4-(3,5-difluorophenoxy)piperidin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(3-chloro-5-fluorophenoxy)piperidin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-{4-[3-fluoro-5-(trifluoromethyl)phenoxy]piperidin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-4-[4-(3,4,5-trifluorophenoxy)piperidin-1-yl]butanenitrile;

3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-4-[4-(2,3,5-trifluorophenoxy)piperidin-1-yl]butanenitrile;

3-[(1-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperidin-4-yl)oxy]-5-fluorobenzonitrile;

3-[(1-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperidin-4-yl)oxy]-5-fluoro-N-methylbenzamide;

3-[(1-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperidin-4-yl)oxy]-5-fluoro-N,N-dimethylbenzamide;

3-[(1-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperidin-4-yl)oxy]-N-ethyl-5-fluorobenzamide;

3-[(1-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperidin-4-yl)oxy]-N-cyclopropyl-5-fluorobenzamide;

3-[(1-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperidin-4-yl)oxy]-5-fluoro-N-isopropylbenzamide;

N-(2-cyanoethyl)-3-[(1-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperidin-4-yl)oxy]-5-fluorobenzamide;

4-{4-[3-fluoro-5-(pyrrolidin-1-ylcarbonyl)phenoxy]piperidin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

N-(3-amino-3-oxopropyl)-3-[(1-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperidin-4-yl)oxy]-5-fluorobenzamide;

N-(tert-butyl)-3-[(1-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperidin-4-yl)oxy]-5-fluorobenzamide;

3-[(1-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperidin-4-yl)oxy]-5-fluoro-N-(2-morpholin-4-ylethyl)benzamide;

4-{4-[3-fluoro-5-(piperidin-1-ylcarbonyl)phenoxy]piperidin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-{4-[3-fluoro-5-(morpholin-4-ylcarbonyl)phenoxy]piperidin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-(4-{3-[(3,3-difluoropyrrolidin-1-yl)carbonyl]-5-fluorophenoxy}piperidin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-(4-{3-[(dimethylamino)methyl]-5-fluorophenoxy}piperidin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(3-{[cyclopropyl(methyl)amino]methyl}-5-fluorophenoxy)piperidin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-{4-[3-(azetidin-1-ylmethyl)-5-fluorophenoxy]piperidin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-(4-{3-[(cyclobutylamino)methyl]-5-fluorophenoxy}piperidin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-{4-[3-fluoro-5-(pyrrolidin-1-ylmethyl)phenoxy]piperidin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-{4-[3-fluoro-5-(piperidin-1-ylmethyl)phenoxy]piperidin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-1-pyrazol-1-yl]butanenitrile;

4-{4-[3-fluoro-5-(morpholin-4-ylmethyl)phenoxy]piperidin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-(4-{3-[(3,3-difluoropyrrolidin-1-yl)methyl]-5-fluorophenoxy}piperidin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(3-fluoro-5-{[2-methylpyrrolidin-1-yl]methyl}phenoxy)piperidin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(3-fluoro-5-{[(2-methoxyethyl)amino]methyl}phenoxy)piperidin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

3-[(1-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-fluoropiperidin-4-yl)oxy]-5-fluorobenzonitrile; and

4-[3-fluoro-4-(3-fluoro-5-{[2-methylpyrrolidin-1-yl]methyl}phenoxy)piperidin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

or a pharmaceutically salt of any of the aforementioned.

37. A compound of claim 1, selected from:

4-[4-(3-fluoro-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}phenoxy)piperidin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(3-fluoro-5-{[(2S)-2-methylpyrrolidin-1-yl]methyl}phenoxy)piperidin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[3-fluoro-4-(3-fluoro-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}phenoxy)piperidin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile; and

4-[3-fluoro-4-(3-fluoro-5-{[(2S)-2-methylpyrrolidin-1-yl]methyl}phenoxy)piperidin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

or a pharmaceutically salt of any of the aforementioned.

38. The compound according to claim 1, wherein the compound is the (R)-enantiomer, or a pharmaceutically acceptable salt thereof.

39. The compound according to claim 1, wherein the compound is the (S)-enantiomer, or a pharmaceutically acceptable salt thereof.

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

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

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

43. 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.

44. A method according to claim 43, 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.

45. A method according to claim 43, wherein said autoimmune disease is rheumatoid arthritis.

46. A method according to claim 43, wherein said autoimmune disease is a skin disorder.

47. A method according to claim 46, 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 43, wherein said cancer is a solid tumor.

49. A method according to claim 43, 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.

50. A method according to claim 43, wherein said cancer is lymphoma, leukemia, or multiple myeloma.

51. A method according to claim 43, 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).

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

53. A method according to claim 43, wherein said myeloproliferative disorder is primary myelofibrosis (PMF).

54. A method according to claim 43, 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.

8. (canceled)

10-11. -11. (canceled)

14-15. -15. (canceled)

17-19. -19. (canceled)

21-26. -26. (canceled)

29-30. -30. (canceled)

32. (canceled)