Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein:

X is N or CH;

L is O or NR 2a ;

(a) wherein when L is O, then:

Y is CH;

R 1 is —C(═O)NR 3 R 4 , —CH 2 CH 2 OH, —CH 2 NR 3 R 4 , or an oxetane ring, wherein the oxetane ring is optionally substituted with R 5 ;

R 2 is CF 3 ;

R 3 is —[CH(R 6a )] n —OR 6b , cyclopropyl, cyclobutyl, tetrahydro-2H-pyran ring, tetrahydrofuran ring, or oxetane ring, wherein said cyclopropyl, cyclobutyl, tetrahydro-2H-pyran ring, tetrahydrofuran ring, and oxetane ring are each optionally substituted with 1 or 2 groups independently selected from CN, OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and propoxy;

R 4 is H, CH 3 , or —[CH(R 6a )] n —OR 6b ;

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

each R 3a is independently CN, OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, or —CH 2 —OH;

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

R 5 is OH or NH 2 ;

R 6a and R 6b are each independently H or CH 3 ; and

each n is independently 2 or 3;

provided that when X is N, then NR 3 R 4 is not NHCH 2 CH 2 —OH, NHCH 2 CH 2 CH 2 —OH,

or alternatively,

(b) wherein when L is NR 2a , then:

Y is CH or N;

R 1 is 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) 2 R b , —S(═O) 2 NR e R f , —C(═O)R b , —C(═O)OR a , —C(═O)NR e R f , —OC(═O)R b , —OC(═O)NR e R f , —NR e R f , —NR c C(═O)R d , —NR c C(═O)OR d , —NR c S(═O) 2 R d , or —NR c S(═O) 2 NR e R 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;

R 2 is H, halo, cyano, nitro, C 1-4 alkyl, or C 1-4 haloalkyl;

R 2a is H or CH 3 ;

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 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; 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 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; 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 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 heterocycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-7 heteroaryl, C 1-7 heteroaryl-C 1-3 -alkyl, —OR a1 , —SR a1 , —S(═O)R b1 , —S(═O) 2 R b1 , —S(═O) 2 NR e1 R f1 , —C(═O)R b1 , —C(═O)OR a1 , —C(═O)NR e1 R f1 , —OC(═O)R b1 , —OC(═O)NR e1 R f1 , —NR e1 R f1 , —NR c1 C(═O)R d1 , —NR c1 C(═O)OR d1 , —NR c1 S(═O) 2 R d1 , and —NR c1 S(═O) 2 NR e1 R 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 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; and

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, hydroxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, cyano-C 1-4 alkyl, 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.

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

or a pharmaceutically acceptable salt thereof.

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

R 1 is —C(═O)NR 3 R 4 , —CH 2 CH 2 OH, —CH 2 NR 3 R 4 , or an oxetane ring, wherein the oxetane ring is optionally substituted with R 5 ;

R 3 is —CH 2 CH 2 —OR 6b , —CH(CH 3 )CH 2 —OR 6b , —CH 2 CH(CH 3 )—OR 6b , cyclopropyl, cyclobutyl, tetrahydro-2H-pyran ring, tetrahydrofuran ring, or oxetane ring, wherein said cyclopropyl, cyclobutyl, tetrahydro-2H-pyran ring, tetrahydrofuran ring, and oxetane ring are each optionally substituted with 1 or 2 groups independently selected from CH 3 , CN, OH, and OCH 3 ;

R 4 is H, CH 3 , —CH 2 CH 2 —OR 6b , —CH(CH 3 )CH 2 —OR 6b , or —CH 2 CH(CH 3 )—OR 6b ;

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

each R 3a is independently CN, OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, or —CH 2 —OH;

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

R 5 is OH or NH 2 ; and

R 6b is independently H or CH 3 .

4. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein each R 3a is independently CH 3 , CN, OH, OCH 3 , or —CH 2 —OH; or alternatively, two R 3a groups, taken together with the carbon atom to which they are both attached, form an oxetane ring.

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

L is O;

X is N or CH;

R 1 is an oxetane ring, wherein the oxetane ring is optionally substituted with R 5 ;

R 2 is CF 3 ; and

R 5 is OH or NH 2 .

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof, wherein:

R 3 is —CH 2 CH 2 —OR 6b , —CH(CH 3 )CH 2 —OR 6b , —CH 2 CH(CH 3 )—OR 6b , cyclopropyl, cyclobutyl, tetrahydro-2H-pyran ring, tetrahydrofuran ring, or oxetane ring, wherein said cyclopropyl, cyclobutyl, tetrahydro-2H-pyran ring, tetrahydrofuran ring, and oxetane ring are each optionally substituted with 1 or 2 groups independently selected from CH 3 , CN, OH, and OCH 3 ;

R 4 is H, CH 3 , —CH 2 CH 2 —OR 6b , —CH(CH 3 )CH 2 —OR 6b , or —CH 2 CH(CH 3 )—OR 6b ;

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

each R 3a is independently CH 3 , CN, OH, OCH 3 , or —CH 2 —OH;

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

R 5 is OH or NH 2 ; and

R 6b is independently H or CH 3 ;

provided that NR 3 R 4 is not NHCH 2 CH 2 —OH,

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

or a pharmaceutically acceptable salt thereof, wherein:

R 3 is —CH 2 CH 2 —OR 6b , —CH(CH 3 )CH 2 —OR 6b , or —CH 2 CH(CH 3 )—OR 6b ;

R 4 is H, CH 3 , —CH 2 CH 2 —OR 6b , —CH(CH 3 )CH 2 —OR 6b , or —CH 2 CH(CH 3 )—OR 6b ; and

R 6b is independently H or CH 3 ;

provided that NR 3 R 4 is not NHCH 2 CH 2 —OH.

9. A compound of claim 2 having Formula IIa,

or a pharmaceutically acceptable salt thereof, wherein:

R 3 is cyclopropyl, cyclobutyl, tetrahydro-2H-pyran ring, tetrahydrofuran ring, or oxetane ring, wherein said cyclopropyl, cyclobutyl, tetrahydro-2H-pyran ring, tetrahydrofuran ring, and oxetane ring are each optionally substituted with 1 or 2 groups independently selected from CH 3 , CN, OH, and OCH 3 ; and

R 4 is H.

10. A compound of claim 2 having Formula IIa,

or a pharmaceutically acceptable salt thereof, wherein:

R 3 and R 4 , taken together with the nitrogen atom to which they are attached, form an azetidinyl group, which is optionally substituted with 1 or 2 independently selected R 3a groups;

each R 3a is independently CH 3 , CN, OH, OCH 3 , or —CH 2 —OH;

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

provided that NR 3 R 4 is not

11. A compound of claim 2 having Formula IIa,

or a pharmaceutically acceptable salt thereof, wherein:

R 3 and R 4 , taken together with the nitrogen atom to which they are attached, form a 1H-pyrazolyl, a 1H-imidazolyl, a 1H-1,3,4-triazolyl, or a 1H-1,2,4-triazolyl group.

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

or a pharmaceutically acceptable salt thereof.

13. A compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is C 1-3 alkyl substituted by —OR a1 , —NR e1 R f1 , or C 2-7 heterocycloalkyl;

R a1 is H or C 1-4 alkyl;

R e1 is H or C 1-4 alkyl; wherein C 1-4 alkyl is substituted by 1 or 2 independently selected R h groups;

R f1 is H, C 1-4 alkyl, cyclopropyl, cyclobutyl, or cyclohexyl; wherein C 1-4 alkyl, cyclopropyl, cyclobutyl, or cyclohexyl are each substituted by 1 or 2 independently selected R h groups; and

each R h is independently selected from hydroxy, halo, cyano, C 1-4 alkyl, and C 1-4 alkoxy.

14. A compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 2 is CF 3 .

15. A compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein Y is N.

16. A compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein Y is CH.

17. A compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein X is N.

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

X is N or CH;

L is NR 2a ;

Y is CH or N;

R 1 is C 1-3 alkyl substituted by —OR a1 , —NR e1 R f1 , or C 2-7 heterocycloalkyl;

R 2 is CF 3 ;

R 2a is H or CH 3 ;

R a1 is H or C 1-4 alkyl;

R e1 is H or C 1-4 alkyl; wherein C 1-4 alkyl is substituted by 1 or 2 independently selected R h groups;

R f1 is H, C 1-4 alkyl, cyclopropyl, cyclobutyl, or cyclohexyl; wherein C 1-4 alkyl, cyclopropyl, cyclobutyl, or cyclohexyl are each substituted by 1 or 2 independently selected R h groups; and

each R h is independently selected from hydroxy, halo, cyano, C 1-4 alkyl, and C 1-4 alkoxy.

19. The compound of claim 1 , selected from:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

or a pharmaceutically acceptable salt of any of the aforementioned.

20. A compound of claim 1 , which is trans-3-(4-{[4-({[(1S)-2-hydroxy-1-methylethyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile, or a pharmaceutically acceptable salt thereof.

21. A compound of claim 1 , which is {trans-3-(4-{[4-({[(2R)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile, or a pharmaceutically acceptable salt thereof.

22. A compound of claim 1 , which is {trans-3-(4-{[4-({[(2S)-2-hydroxypropyl]amino}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile, or a pharmaceutically acceptable salt thereof.

23. A compound of claim 1 , which is {trans-3-(4-{[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile, or a pharmaceutically acceptable salt thereof.

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

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

26. A method according to claim 25 , wherein said compound, or pharmaceutically acceptable salt thereof, is selective for JAK1 over JAK2.

27. A method of treating a disease selected from myelofibrosis, polycythemia vera (PV), essential thrombocythemia (ET), post polycythemia vera myelofibrosis (Post-PV MF), post polycythemia vera myelofibrosis (Post-ET MF), multiple myeloma, pancreatic cancer, breast cancer, lung cancer, colorectal cancer, rheumatoid arthritis, psoriasis, lymphoma, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), cachexia, and Castleman's disease 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.

28. A method according to claim 27 , wherein said disease is rheumatoid arthritis.

29. A method according to claim 27 , wherein said disease is myelofibrosis.

30. A method according to claim 29 wherein said myelofibrosis is primary myelofibrosis (PMF).

31. A method according to claim 27 , wherein said disease is post polycythemia vera myelofibrosis (Post-PV MF).

32. A method according to claim 27 , wherein said disease is post polycythemia vera myelofibrosis (Post-ET MF).

33. A method according to claim 27 , wherein said disease is polycythemia vera (PV).

34. A method according to claim 27 , wherein said disease is essential thrombocythemia (ET).

35. A method according to claim 27 , wherein said disease is multiple myeloma.

36. A method according to claim 27 , wherein said disease is pancreatic cancer.

37. A method according to claim 27 , wherein said disease is breast cancer.

38. A method according to claim 27 , wherein said disease is lung cancer.

39. A method according to claim 27 , wherein said disease is colorectal cancer.

40. A method according to claim 27 , wherein said disease is psoriasis.

41. A method according to claim 27 , wherein said disease is lymphoma.

42. A method according to claim 27 , wherein said disease is leukemia.

43. A method according to claim 27 , wherein said disease is acute myelogenous leukemia.

44. A method according to claim 27 , wherein said disease is acute lymphoblastic leukemia.

45. A method according to claim 27 , wherein said disease is chronic myelogenous leukemia (CML).

46. A method according to claim 27 , wherein said disease is chronic myelomonocytic leukemia (CMML).

47. A method according to claim 27 , wherein said disease is Castleman's disease.

48. A method according to claim 27 , wherein said disease is cachexia, wherein said cachexia results from or is associated with cancer.