CYCLOBUTYL SUBSTITUTED PYRROLOPYRIDINE AND PYRROLOPYRIMIDINES DERIVATIVES AS JAK INHIBITORS

• US 20150087632A1
• Filed: 12/01/2014
• Published: 03/26/2015
• Est. Priority Date: 11/19/2010
• Status: Abandoned Application

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation
• Inventors: Rodgers, James D., Shepard, Stacey, Zhu, Wenyu, Shao, Lixin, Glenn, Joseph
• Application Number:
  US14/556,775
• Publication Number:
  US 20150087632A1
• Time in Patent Office: Days
• US Class Current: 514/210.21
• CPC Class Codes: A01N 43/90 having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 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 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/08 Antiseborrheics
• 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 27/04 Artificial tears; Irrigation solutions
• 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 3/04 Anorexiants; Antiobesity agents
• 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 35/04 : specific for metastasis
• 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 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/12 : for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• 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 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 cyclobutyl substituted pyrrolopyrimidines and pyrrolopyridines of Formula I:

wherein X, Y, Z, L, A, R⁵, n and m 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 CH or N;

Y is H, cyano, halo, C_1-3 alkyl, or C_1-3 haloalkyl;

Z is CR⁴ or N;

W is CH or N;

when W is CH, then L is O, S, C(R⁶)₂, C(═

O), C(═

O)N(R⁷), C(═

O)O, C(═

O)C(R⁶)₂, S(═

O), S(═

O)₂, S(═

O)N(R⁷), or S(═

O)₂N(R⁷);

or

when W is N, then L is C(R⁶)₂, C(═

O), C(═

O)O, C(═

O)N(R⁷), C(═

O)C(R⁶)₂, S(═

O), S(═

O)₂, S(═

O)N(R⁷), or S(═

O)₂N(R⁷);

R¹, R², R³, and R⁴ are each independently H, hydroxy, halo, C_1-3 alkyl, or C_1-3 haloalkyl;

each R⁵ is independently hydroxy, C_1-4 alkoxy, fluorine, C_1-4 alkyl, hydroxy-C_1-4-alkyl, C_1-4 alkoxy-C_1-4-alkyl, or C_1-4 fluoroalkyl;

each R⁶ is, independently, H or C_1-4 alkyl;

or

two R⁶ groups, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring;

R⁷ is H or C_1-4 alkyl;

A is C_1-6 alkyl, C_3-10 cycloalkyl, C_2-10 heterocycloalkyl, C_6-10 aryl, or C_1-10 heteroaryl;

wherein said C_1-6 alkyl, C_3-10 cycloalkyl, C_2-10 heterocycloalkyl, C_6-10 aryl, and C_1-10 heteroaryl are each optionally substituted with p independently selected R⁸ substituents;

wherein p is 1, 2, 3, 4, or 5;

each R⁸ is independently selected from halo, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_3-10 cycloalkyl-C_1-4-alkyl, C_2-10 heterocycloalkyl, C_2-10 heterocycloalkyl-C_1-4-alkyl, C_6-10 aryl, C_6-10 aryl-C_1-4-alkyl, C_1-10 heteroaryl, C_1-10 heteroaryl-C_1-4-alkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, —

S(═

O)₂NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^a, —

C(═

O)NR^eR^f, —

OC(═

O)R^b, —

OC(═

O)NR^eR^f, —

NR^eR^f, —

NR^cC(═

O)R^d, —

NR^cC(═

O)OR^d, —

NR^cS(═

O)₂R^d, and —

NR^cS(═

O)₂NR^eR^f;

wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_3-10 cycloalkyl-C_1-4-alkyl, C_2-10 heterocycloalkyl, C_2-10 heterocycloalkyl-C_1-4-alkyl, C_6-10 aryl, C_6-10 aryl-C_1-4-alkyl, C_1-10 heteroaryl, and C_1-10 heteroaryl-C_1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^g groups;

each R^a, R^c, R^d, R^e, and R^f is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_3-10 cycloalkyl-C_1-4-alkyl, C_2-10 heterocycloalkyl, C_2-10 hetero cycloalkyl-C_1-4-alkyl, C_6-10 aryl, C_6-10 aryl-C_1-4-alkyl, C_1-10 heteroaryl, and C_1-10 heteroaryl-C_1-4-alkyl;

wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_3-10 cycloalkyl-C_1-4-alkyl, C_2-10 heterocycloalkyl, C_2-10 heterocycloalkyl-C_1-4-alkyl, C_6-10 aryl, C_6-10 aryl-C_1-4-alkyl, C_1-10 heteroaryl, and C_1-10 heteroaryl-C_1-4-alkyl 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_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_3-10 cycloalkyl-C_1-4-alkyl, C_2-10 heterocycloalkyl, C_2-10 hetero cycloalkyl-C_1-4-alkyl, C_6-10 aryl, C_6-10 aryl-C_1-4-alkyl, C_1-10 heteroaryl, and C_1-10 heteroaryl-C_1-4-alkyl;

wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_3-10 cycloalkyl-C_1-4-4-alkyl, C_2-10 heterocycloalkyl, C_2-10 heterocycloalkyl-C_1-4-alkyl, C_6-10 aryl, C_6-10 aryl-C_1-4-alkyl, C_1-10 heteroaryl, and C_1-10 heteroaryl-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, nitro, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-3-alkyl, C_2-7 heterocycloalkyl, C_2-7 hetero cycloalkyl-C_1-3-alkyl, phenyl, phenyl-C_1-3-alkyl, C_1-7 hetero aryl, C_1-7 heteroaryl-C_1-3-alkyl, —

OR^a1, —

SR^a1, —

S(═

O)R^b1, —

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^e1R^f1, —

NR^c1C(═

O)R^d1, —

NR^c1C(═

O)OR^d1, —

NR^c1S(═

O)₂R^d1, and —

NR^c1S(═

O)₂NR^e1R^f1;

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

each R^a1, R^c1, R^d1, R^e1, and R^f1 is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-3-alkyl, C_2-7 heterocycloalkyl, C_2-7 heterocycloalkyl-C_1-3-alkyl, phenyl, phenyl-C_1-3-alkyl, C_1-7 heteroaryl, and C_1-7 heteroaryl-C_1-3-alkyl;

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

each R^b1 is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-3-alkyl, C_2-7 heterocycloalkyl, C_2-7 heterocycloalkyl-C_1-3-alkyl, phenyl, phenyl-C_1-3-alkyl, C_1-7 heteroaryl, and C_1-7 heteroaryl-C_1-3-alkyl;

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

each R^h is independently selected from cyano, halo, hydroxy, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, amino, C_1-4 alkylamino, di-C_1-4-alkylamino, thio, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, carbamyl, C_1-6 alkylcarbamyl, di(C_1-6 alkyl)carbamyl, carboxy, C_1-6 alkylcarbonyl, C_1-6 alkoxycarbonyl, C_1-6 alkylcarbonylamino, C_1-6 alkylsulfonylamino, aminosulfonyl, C_1-6 alkylaminosulfonyl, di(C_1-6 alkyl)aminosulfonyl, aminosulfonylamino, C_1-6 alkylaminosulfonylamino, di(C_1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C_1-6 alkylaminocarbonylamino, and di(C_1-6 alkyl)aminocarbonylamino;

m is 0, 1, or 2; and

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

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

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

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

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein L is O.

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

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

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

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

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is H, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, 1,2-dimethylpropyl, 1-(tert-butyl)methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, a tetrahydropyran ring, a pyrrolidine ring, a piperidine ring, a pyridine ring, a pyrimidine ring, a thiazole ring, or a pyrazine ring;

each of which is optionally substituted with p independently selected R⁸ substituents;

provided when L is O, S, C(═

O), C(═

O)O, S(═

O), or S(═

O)₂, then A is not H.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R⁸ is independently selected from halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, C_2-7 heterocycloalkyl, —

OR^a, —

C(═

O)OR^a, or —

NR^eR^f;

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

wherein each R^a, R^e, and R^f is independently selected from H, C_1-6 alkyl, and C_1-6 haloalkyl.

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

X is N;

Z is N;

R¹, R², and R³ are each H;

Y is cyano;

W is N and L is C(R⁶)₂, C(═

O), C(═

O)O, C(═

O)N(R⁷), S(═

O)₂, or S(═

O)₂N(R⁷);

or

W is CH and L is O;

R⁶ is H;

R⁷ is H or methyl;

A is methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, 1,2-dimethylpropyl, 1-(tert-butyl)methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, a tetrahydropyran ring, a pyrrolidine ring, a piperidine ring, a pyridine ring, a pyrimidine ring, a thiazole ring, or a pyrazine ring;

each of which is optionally substituted with p independently selected R⁸ substituents;

each R⁸ is independently selected from halo, cyano, C_1-6 alkyl, C_1-6haloalkyl, C_3-7 cycloalkyl, C_2-7 heterocycloalkyl, —

OR^a, —

C(═

O)OR^a, or —

NR^eR^f;

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

wherein each R^a, R^e, and R^f is independently selected from H, C_1-6 alkyl, and C_1-6haloalkyl;

each R^g is independently selected from C_2-7 heterocycloalkyl, —

OR^a1, —

NR^e1R^f1;

wherein said C_2-7 heterocycloalkyl is optionally substituted by 1 or 2 R^h groups independently selected from fluoro, OH, C_1-3 alkyl, C_1-3 alkoxy, and hydroxy-C_1-4 alkyl; and

wherein each R^a1, R^e1 and R^f1 are independently selected from H, C_3-7 cycloalkyl, and C_1-6 alkyl;

p is 1, 2, or 3;

m is 1; and

n is 0.

27. The compound according to claim 1, wherein said compound has Formula IV:

28. The compound according to claim 1, wherein said compound has Formula V:

29. The compound according to claim 1, selected from:

3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)methyl]-5-fluorobenzonitrile;

3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile;

4-{3-(cyano methyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine-1-carboxamide;

{3-(4-{[(2S)-2-methylpyrrolidin-1-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-(4-{[(2S)-2-ethylpyrrolidin-1-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-{4-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

[1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile;

{3-[4-(3,5-difluorobenzoyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-{4-[(2-chloro-5-fluoropyridin-3-yl)carbonyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-{4-[(5-fluoropyridin-3-yl)carbonyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-{4-[2-(difluoromethyl)-3-fluoroisonicotinoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)carbonyl]-5-fluorobenzonitrile;

[1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile;

[1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[6-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile;

{3-[4-(3,4-difluorobenzoyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-[4-(2-chloro-3,6-difluoro benzyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-{4-[3-fluoro-5-(trifluoromethyl)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-{4-[2-fluoro-4-(trifluoromethyl)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-[4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

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

{3-(4-{[6-(difluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-{4-[2-fluoro-3-(trifluoromethyl)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-{4-[(5-fluoropyridin-3-yl)methyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-{4-[(2-isopropylpyrimidin-4-yl)carbonyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-[4-(piperidin-1-ylcarbonyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-{4-[4-fluoro-3-(trifluoromethoxy)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-(4-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-{4-[4-chlorobenzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-{4-[2-fluoro-4-(trifluoromethyl)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N,N-dimethylpiperazine-1-carbo xamide;

{3-(4-{3-[(dimethylamino)methyl]-5-fluorobenzoyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-(4-{3-[(dimethylamino)methyl]-5-fluorobenzyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-[4-(ethylsulfonyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{3-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N,N-dimethylpiperazine-1-sulfonamide;

4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-ethyl-N-methylpiperazine-1-carboxamide;

{3-{4-[3-[(dimethylamino)methyl]-5-(trifluoromethyl)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

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

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

[1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile-d1; and

or a pharmaceutically acceptable salt of any of the aforementioned.

30. The compound of claim 1, selected from:

3-[(4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)carbonyl]-5-[(dimethylamino)methyl]benzonitrile;

3-[(4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1yl]cyclobutyl}piperazin-1-yl)methyl]-5-[(dimethylamino)methyl]benzonitrile;

3-[(4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)methyl]-5-[(dimethylamino)methyl]benzonitrile;

{trans-3-{4-[3-[(dimethylamino)methyl]-5-(trifluoromethyl)benzyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{cis-3-{4-[3-[(dimethylamino)methyl]-5-(trifluoromethyl)benzyl]piperazin-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]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

6-[(4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)carbonyl]-2-(trifluoromethyl)pyrimidine-4-carboxylic acid;

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

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

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

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

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

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

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

{trans-3-(4-{[6-[(tert-butylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{[6-(1-hydroxy-1-methylethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

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

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

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

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

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

{cis-3-(4-{[6-[1-(dimethylamino)cyclobutyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

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

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

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

{trans-3-(4-{[6-(1-methoxy-1-methylethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

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

2-[(4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)carbonyl]-6-(trifluoromethyl)isonicotinonitrile;

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

{trans-3-(4-{[4-(4,5-dihydro-1H-imidazol-2-yl)-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{trans-3-(4-{3-(difluoromethyl)-5-[(dimethylamino)methyl]benzoyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

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

{trans-3-(4-{[6-(1-hydroxy-1-methylethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperazin-1-yl)-1-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-isopropyl-N-methylpiperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-methyl-N-propylpiperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-ethylpiperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[3-(dimethylamino)propyl]-N-methylpiperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclopropyl-N-methylpiperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-methyl-N-(2,2,2-trifluoro ethyppiperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-isopropylpiperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-(trans-4-hydroxycyclo hexyl)piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(3R)-tetrahydro furan-3-yl]piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-(2-hydroxycyclopentyl)piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S,2R)-2-hydroxycyclopentyl]piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclopentylpiperazine-1-carboxamide;

{trans-3-(4-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-(cyclopropylmethyl)piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1R)-1,2-dimethylpropyl]piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-1,2-dimethylpropyl]piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-1-cyclopropylethyl]piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1R)-1-cyclopropylethyl]piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclopropylpiperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclobutylpiperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-(2,2-dimethylpropyl)piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-isobutylpiperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1R)-1-methylpropyl]piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-1-methylpropyl]piperazine-1-carboxamide;

4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclobutylpiperazine-1-carboxamide;

4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1R)-1-methylpropyl]piperazine-1-carboxamide;

4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-1-methylpropyl]ppiperazine-1-carboxamide;

4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclopropylpiperazine-1-carboxamide;

4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-isopropylpiperazine-1-carboxamide;

4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-cyclopentylpiperazine-1-carbo xamide;

4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1R)-1,2-dimethylpropyl]ppiperazine-1-carbo xamide;

4-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-1,2-dimethylpropyl]piperazine-1-carbo xamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-methylpiperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1R)-2,2,2-trifluoro-1-methylethyl]piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl]piperazine-1-carboxamide;

4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(1S)-1-(trifluoromethyl)propyl]piperazine-1-carboxamide;

[trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile;

[trans-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(4-{[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]carbonyl}piperazin-1-yl)cyclobutyl]acetonitrile;

N′

-cyano-4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N,N-dimethylpiperazine-1-carboximidamide;

{trans-3-[4-(methylsulfonyl)piperazin-1-yl]-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

isopropyl 4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazine-1-carboxylate;

{cis-3-(4-{[4-(methoxymethyl)-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-(methoxymethyl)-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-(hydroxymethyl)-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;

{cis-3-(4-{[4-(hydroxymethyl)-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-hydroxy-1-methylethyl)-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-[(tert-butylamino)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;

{cis-3-(4-{[4-[(tert-butylamino)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-(aminomethyl)-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-[(dimethylamino)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-[(ethylamino)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-[(methylamino)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;

2-[(1-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperidin-4-yl)oxy]-6-(trifluoromethyl)isonicotinonitrile;

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)isonicotinonitrile;

{cis-3-{4-[3-[(dimethylamino)methyl]-5-(trifluoromethyl)benzoyl]piperazin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

3-[(4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)carbonyl]-5-[(dimethylamino)methyl]benzonitrile;

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

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

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

3-[(1-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperidin-4-yl)oxy]-5-[(dimethylamino)methyl]benzonitrile;

{cis-3-{4-[3-[(dimethylamino)methyl]-5-(trifluoromethyl)phenoxy]piperidin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{cis-3-{4-[3-[(diethylamino)methyl]-5-(trifluoromethyl)phenoxy]piperidin-1-yl}-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

{cis-3-(4-{3-(difluoromethyl)-5-[(dimethylamino)methyl]phenoxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

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

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

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

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

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

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

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

4-{trans-3-(cyano methyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]piperazine-1-carbo xamide;

{trans-3-(4-{[4-{[(2-hydroxy-1,1-dimethylethyl)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)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-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-(azetidin-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-hydroxyazetidin-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-(pyrrolidin-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-(morpholin-4-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-difluoropyrrolidin-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-{[(2S)-2-(hydroxymethyl)pyrrolidin-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-(hydroxymethyl)pyrro lidin-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-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile;

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

{cis-3-(4-{[4-[(2-oxo-1,3-oxazolidin-3-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; and

{trans-3-(4-{[4-[(2-oxo-1,3-oxazolidin-3-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;

or a pharmaceutically acceptable salt of any of the aforementioned.

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

35. A method according to claim 34, wherein said compound, or pharmaceutically acceptable salt thereof, is selective for JAK1 over JAK2.

36. 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.

37. A method according to claim 36, wherein said autoimmune disease is a skin disorder, psoriasis, 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.

42. A method according to claim 36, wherein said cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi'"'"'s sarcoma, Castleman'"'"'s disease, pancreatic cancer, lymphoma, leukemia, or multiple myeloma.

44. A method according to claim 36, 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), myelofibrosis, primary myelofibrosis (PMF), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).

47. A method according to claim 36, 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.

5-8. -8. (canceled)

16. (canceled)

18-25. -25. (canceled)

31-33. -33. (canceled)

38-41. -41. (canceled)

43. (canceled)

45-46. -46. (canceled)