Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors
The present invention provides cyclobutyl substituted pyrrolopyrimidines and pyrrolopyridines of Formula I: wherein X, Y, Z, L, A, R 5 , 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.
1. A compound of Formula I:
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 N;
W is CH or N;
when W is CH, then L is O, S, C(R 6 ) 2 , C(═O), C(═O)N(R 7 ), C(═O)O, C(═O)C(R 6 ) 2 , S(═O), S(═O) 2 , S(═O)N(R 7 ), S(═O) 2 N(R 7 ), or C(═NR 7a )N(R 7 ); or
when W is N, then L is C(R 6 ) 2 , C(═O), C(═O)O, C(═O)N(R 7 ), C(═O)C(R 6 ) 2 , S(═O), S(═O) 2 , S(═O)N(R 7 ), S(═O) 2 N(R 7 ), or C(═NR 7a )N(R 7 );
R 1 , R 2 and R 3 are each independently H, hydroxy, halo, C 1-3 alkyl, or C 1-3 haloalkyl;
each R 5 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 R 6 is, independently, H or C 1-4 alkyl; or
two R 6 groups, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring;
R 7 is H or C 1-4 alkyl;
R 7a is H, OH, CN, C 1-4 alkoxy, or C 1-4 alkyl;
or R 7 and R 7a , taken together with the C(═N)N moiety to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl ring or a 5- or 6-membered heteroaryl ring;
A is H, 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 R 8 substituents; wherein p is 1, 2, 3, 4, or 5; provided when L is O, S, C(═O), C(═O)O, S(═O), or S(═O) 2 , then A is not H;
each R 8 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) 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 , and —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;
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;
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;
m is 0, 1, or 2; and
n is 0, 1, 2, 3, or 4.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is N.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein L is C(R 6 ) 2 , C(═O), C(═O)O, C(═O)N(R 7 ), S(═O) 2 , S(═O) 2 N(R 7 ) or C(═NR 7a )N(R 7 ).
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H, R 7 is H or methyl, and R 7a is CN.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is CH.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein L is O.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is cyano.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and R 3 are each H.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1.
11. 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 R 8 substituents; provided when L is O, S, C(═O), C(═O)O, S(═O), or S(═O) 2 , then A is not H.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 8 is independently selected from halo, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —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 , and —NR c S(═O) 2 NR e R f ; wherein said C 1-6 alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R g groups.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 8 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 , and —NR e R 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.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein 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) 2 R b1 , —S(═O) 2 NR e1 R f1 , —C(═O)R b1 , —C(═O)OR a1 , and —NR e1 R f1 ; wherein said C 1-6 alkyl, C 3-7 cycloalkyl, C 2-7 heterocycloalkyl and are each optionally substituted by 1, 2, 3, or 4 independently selected R h groups.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R g is independently selected from C 2-7 heterocycloalkyl, —OR a and —NR e1 R 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.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R h is independently selected from fluoro, OH, C 1-3 alkyl, C 1-3 alkoxy, and hydroxy-C 1-4 alkyl.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is N;
Z is N;
R 1 , R 2 , and R 3 are each H;
Y is cyano;
W is N and L is C(R 6 ) 2 , C(═O), C(═O)N(R 7 ), S(═O) 2 , or S(═O) 2 N(R 7 ); or
W is CH and L is O;
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 R 8 substituents; wherein p is 1, 2, 3, 4, or 5;
each R 8 is independently selected from halo, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —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 , and —NR c S(═O) 2 NR e R 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 3-7 cycloalkyl, C 2-7 heterocycloalkyl, —S(═O) 2 R b1 , —S(═O) 2 NR e1 R f1 , —C(═O)R b1 , —C(═O)OR a1 , and —NR e1 R f1 ; wherein said C 1-6 alkyl, C 3-7 cycloalkyl, C 2-7 heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R h groups;
each R a , R c , R d , R e , and R f is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
each R b is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;
each R a1 , R c1 , R d1 , R e1 , and R f1 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
each R b1 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;
n is 0; and
m is 1.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is N;
Z is N;
R 1 , R 2 , and R 3 are each H;
Y is cyano;
W is N and L is C(R 6 ) 2 , C(═O), C(═O)N(R 7 ), S(═O) 2 , or S(═O) 2 N(R 7 ); or
W is CH and L is O;
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 R 8 substituents; wherein p is 1, 2, 3, 4, or 5;
each R 8 is independently selected from halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —OR a and —NR e R 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 C 2-7 heterocycloalkyl and —NR e1 R f1 ; wherein said C 2-7 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 independently selected R h groups;
each R h is independently selected from C 1-4 alkyl;
each R a , R e , and R f is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
each R a1 , R e1 , and R f1 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
n is 0; and
m is 1.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is N;
Z is N;
R 1 , R 2 , and R 3 are each H;
Y is cyano;
W is N and L is C(R 6 ) 2 , C(═O), C(═O)N(R 7 ), S(═O) 2 , or S(═O) 2 N(R 7 );
R 6 is H;
R 7 is H or methyl;
A is methyl, ethyl, cyclopropyl, phenyl, 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 R 8 substituents; wherein p is 1, 2, or 3;
each R 8 is independently selected from halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —OR a and —NR e R 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 C 2-7 heterocycloalkyl and —NR e1 R f1 ; wherein said C 2-7 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 independently selected R h groups;
each R h is independently C 1-4 alkyl;
each R a , R e , and R f is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
each R a1 , R e1 , and R f1 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
n is 0; and
m is 1.
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is N;
Z is N;
R 1 , R 2 , and R 3 are each H;
Y is cyano;
W is CH and L is O;
R 6 is H;
R 7 is H or methyl;
A is phenyl, which is optionally substituted with p independently selected R 8 substituents; wherein p is 1, 2, or 3;
each R 8 is independently selected from halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —OR a and —NR e R f ; wherein said C 1-6 alkyl is optionally substituted by p independently selected R g groups;
each R g is independently selected from C 2-7 heterocycloalkyl and —NR e1 R f1 ; wherein said C 2-7 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 independently selected R h groups;
each R h is independently C 1-4 alkyl;
each R a , R e , and R f is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
each R a1 , R e1 , and R f1 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
n is 0; and
m is 1.
21. The compound accordingly to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is N;
Z is N;
R 1 , R 2 , and R 3 are each H;
Y is cyano;
W is N and L is C(R 6 ) 2 , C(═O), C(═O)O, C(═O)N(R 7 ), S(═O) 2 , S(═O) 2 N(R 7 ) or C(═NR 7a )N(R 7 ); or
W is CH and L is O;
R 6 is H;
R 7 is H or methyl;
R 7a is CN;
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; wherein said methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, 1,2-dimethylpropyl, 1-(tert-butyl)methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, a tetrahydropyran ring, pyrrolidine ring, piperidine ring, pyridine ring, pyrimidine ring, thiazole ring, and pyrazine ring are each optionally substituted with p independently selected R 8 substituents; provided when L is O, S, C(═O), C(═O)O, S(═O), or S(═O) 2 , then A is not H;
each R 8 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 , and —NR e R 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;
each R g is independently selected from C 2-7 heterocycloalkyl, —OR a and —NR e1 R 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.
22. The compound accordingly to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is N;
Z is N;
R 1 , R 2 , and R 3 are each H;
Y is cyano;
W is N and L is C(R 6 ) 2 , C(═O), C(═O)O, C(═O)N(R 7 ), S(═O) 2 , or S(═O) 2 N(R 7 ); or
W is CH and L is O;
R 6 is H;
R 7 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 R 8 substituents;
each R 8 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 , and —NR e R 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;
each R g is independently selected from C 2-7 heterocycloalkyl, —OR a1 , —NR e1 R 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.
23. The compound according to claim 1 , wherein said compound has Formula IV:
or a pharmaceutically acceptable salt thereof.
24. The compound according to claim 1 , wherein said compound has Formula V:
or a pharmaceutically acceptable salt thereof.
25. 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-(cyanomethyl)-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-difluorobenzyl)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-carboxamide;
{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-dl; and
or a pharmaceutically acceptable salt of any of the aforementioned.
26. 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-1-yl]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-(aminomethyl)-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-[(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-aminocyclobutyl)-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-aminocyclobutyl)-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;
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-trifluoroethyl)piperazine-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-hydroxycyclohexyl)piperazine-1-carboxamide;
4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}-N-[(3R)-tetrahydrofuran-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]piperazine-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-carboxamide;
4-{cis-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-{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-carboxamide;
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-(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-(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-(cyanomethyl)-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-carboxamide;
{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)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;
{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.
27. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cyclobutyl ring in Formula I is the cis form.
28. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cyclobutyl ring in Formula I is the trans form.
29. A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
30. The compound of claim 1 , which is [trans-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, or a pharmaceutically acceptable salt thereof.
31. The compound of claim 1 , which is {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, or a pharmaceutically acceptable salt thereof.
32. The compound of claim 1 , which is {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.
33. The compound of claim 1 , which is {trans-3-(4-{[4-{[(2R)-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.
34. A composition comprising a compound according to claim 30 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
35. A composition comprising a compound according to claim 31 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
36. A composition comprising a compound according to claim 32 and at least one pharmaceutically acceptable carrier.
37. A composition comprising a compound according to claim 33 and at least one pharmaceutically acceptable carrier.
38. 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 N;
W is CH or N;
when W is CH, then L is O, S, C(R 6 ) 2 , C(═O), C(═O)N(R 7 ), C(═O)O, C(═O)C(R 6 ) 2 , S(═O), S(═O) 2 , S(═O)N(R 7 ), or S(═O) 2 N(R 7 ); or
when W is N, then L is C(R 6 ) 2 , C(═O), C(═O)O, C(═O)N(R 7 ), C(═O)C(R 6 ) 2 , S(═O), S(═O) 2 , S(═O)N(R 7 ), or S(═O) 2 N(R 7 );
R 1 , R 2 and R 3 are each independently H, hydroxy, halo, C 1-3 alkyl, or C 1-3 haloalkyl;
each R 5 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 R 6 is, independently, H or C 1-4 alkyl; or
two R 6 groups, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring;
R 7 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 R 8 substituents; wherein p is 1, 2, 3, 4, or 5;
each R 8 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) 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 , and —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;
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;
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.
39. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N.