Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidines derivatives as JAK inhibitors

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein:

X is N;

Y is H, cyano, halo, C 1-3 alkyl, or C 1-3 haloalkyl;

Z is CR 4 ;

W is N;

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 , R 3 , and R 4 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) 2 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-C3-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 Z is CH.

3. The compound of claim 1 , 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 3 , 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 Y is cyano.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 are each H.

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

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

9. 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.

10. 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 , or —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.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R g is independently selected from C 2-7 heterocycloalkyl, —OR a1 , 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.

12. 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.

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

R 1 , R 2 , and R 3 are each H;

Y is cyano;

L is C(R 6 ) 2 , C(═O), C(═O)N(R′), S(═O) 2 , or S(═O) 2 N(R 7 );

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, —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, and 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 b1 is independently selected from 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;

each R b1 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

n is 0; and

m is 1.

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

R 1 , R 2 , and R 3 are each H;

Y is cyano;

L is C(R 6 ) 2 , C(═O), C(═O)O, C(═O)N(R′), S(═O) 2 , or S(═O) 2 N(R 7 ); or

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 , or —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 , 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.

15. The compound of claim 1 , selected from:

{cis-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;

{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; and

{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;

or a pharmaceutically acceptable salt of any of the aforementioned.

16. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cyclobutyl ring in Formula I is the cis form.

17. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cyclobutyl ring in Formula I is the trans form.

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

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

20. The method according to claim 19 , wherein said compound, or pharmaceutically acceptable salt thereof, is selective for JAK1 over JAK2.