Pyrazolopyrimidine JAK inhibitor compounds and methods

1. A compound of Formula Ia:

or an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H;

R 2 is —OR 4 , —NR 3 R 4 , —NR 3 NR 12 R 4 , —NR 3 S(O)R 4 or —NR 3 S(O) 2 R 4 ;

R 3 is H or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, wherein said alkyl, alkenyl and alkynyl are optionally substituted by oxo, F, OR a or NR a R b ;

R 4 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —(C 0 -C 5 alkyl)(C 1 -C 9 heterocyclyl), —(C 0 -C 5 alkyl)(C 3 -C 6 cycloalkyl), —(C 0 -C 5 alkyl)(C 1 -C 9 heteroaryl), —(C 0 -C 5 alkyl)(C 6 -C 10 aryl), wherein said alkyl, alkenyl and alkynyl are optionally substituted by R 8 , and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by R 9 ; or

R 3 and R 4 are taken together with the nitrogen to which they are attached to form a C 1 -C 9 heterocyclyl optionally substituted by R 13 ;

Z is —NR 5 R 6 ;

R 5 is H or C 1 -C 3 alkyl;

R 6 is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, —(C 0 -C 5 alkyl)(C 1 -C 9 heterocyclyl), —(C 0 -C 5 alkyl)(C 3 -C 8 cycloalkyl), —(C 0 -C 5 alkyl)(C 1 -C 9 heteroaryl), —(C 0 -C 5 alkyl)(C 6 -C 9 aryl), wherein said alkyl, alkenyl and alkynyl are optionally substituted by R 10 , and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by R 11 ;

R 7 is H, halo, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl or —O(C 1 -C 3 alkyl);

R 8 is independently oxo, halo, OR a or NR a R b ;

R 9 is independently oxo, —CN, —CF 3 , halo, —C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , —(C 0 -C 5 alkyl)NR a R b , —(C 0 -C 5 alkyl)OR a , —(C 0 -C 5 alkyl)SR a , —O[C(R a ) 2 ] 1-3 O—, C 1 -C 3 alkyl optionally substituted by oxo or F, —(C 0 -C 5 alkyl)(C 3 -C 6 cycloalkyl) optionally substituted by oxo or F, —(C 0 -C 5 alkyl)C 1 -C 9 heterocyclyl optionally substituted by halo, oxo, C 1 -C 3 alkyl or C(O)C 1 -C 3 alkyl, —(C 0 -C 5 alkyl)C 6 aryl optionally substituted by halo or C 1 -C 3 alkyl —O(C 1 -C 3 alkyl), or —(C 0 -C 5 alkyl)C 1 -C 9 heteroaryl optionally substituted by halo or C 1 -C 3 alkyl;

R 10 is independently oxo, halo, OR a or NR a R b ;

R 11 is independently oxo, —CN, —CF 3 , halo, —O[C(R a ) 2 ] 1-3 O—, —C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , —(C 0 -C 5 alkyl)NR a R b , —(C 0 -C 5 alkyl)OR a , C 1 -C 6 alkyl optionally substituted by oxo or F, —(C 0 -C 5 alkyl)C 1 -C 9 heterocyclyl optionally substituted by halo, oxo, C 1 -C 3 alkyl or C(O)C 1 -C 3 alkyl, —(C 0 -C 5 alkyl)C 1 -C 9 heteroaryl optionally substituted by halo or C 1 -C 3 alkyl, —(C 0 -C 5 alkyl)phenyl optionally substituted by C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, C 3 -C 6 cycloalkyl, —CF 3 , halo, —CN, —OR a or —NR a R b , or —(C 0 -C 5 alkyl)C 3 -C 6 cycloalkyl optionally substituted by oxo, —NR c R d , C 1 -C 3 alkyl or F;

R 12 is H or C 1 -C 3 alkyl;

R 13 is oxo, halo, C 1 -C 3 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OR a , C 6 aryl, C 3 -C 6 cycloalkyl, C 1 -C 5 heteroaryl or C 4 -C 5 heterocyclyl; wherein said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by C 1 -C 4 alkyl, —(C 0 -C 3 alkyl)OR c , oxo, halo or NR c R d ;

R a and R b are independently H, —CF 3 , —CHF 2 , —CH 2 F, C 1 -C 6 alkyl, C 6 aryl, C 3 -C 6 cycloalkyl or C 4 -C 5 heterocyclyl; wherein said alkyl, aryl and cycloalkyl are optionally substituted by C 1 -C 4 alkyl, —(C 0 -C 3 alkyl)OR c , oxo, halo, NR c R d or C 4 -C 5 heterocyclyl; or

R a and R b together with the atom to which they are attached form a C 1 -C 5 heterocyclyl optionally substituted by oxo, F, C 1 -C 3 alkyl, —C(O)C 1 -C 6 alkyl or —C(O)OR a ; and

R c and R d are independently H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or phenyl, wherein said alkyl, cycloalkyl and phenyl are optionally substituted by halo, CH 3 OH, NH 2 , C(O)O(C 1 -C 6 alkyl) or C(O)NH(C 1 -C 6 alkyl).

2. A compound of claim 1 , selected from Formula I:

or an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H;

R 2 is —OR 4 or —NR 3 R 4 ;

R 3 is H or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, wherein said alkyl, alkenyl and alkynyl are optionally substituted by oxo, F, OR a or NR a R b ;

R 4 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —(C 0 -C 5 alkyl)(C 1 -C 9 heterocyclyl), —(C 0 -C 5 alkyl)(C 3 -C 6 cycloalkyl), —(C 0 -C 5 alkyl)(C 1 -C 9 heteroaryl), —(C 0 -C 5 alkyl)(C 6 -C 9 aryl), wherein said alkyl, alkenyl and alkynyl are optionally substituted by oxo, F, OR a or NR a R b , and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by

oxo, —CN, —CF 3 , halo, —C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , —(C 0 -C 5 alkyl)NR a R b , —(C 0 -C 5 alkyl)OR a , —O[C(R a ) 2 ] 1-3 O—

C 1 -C 3 alkyl optionally substituted by oxo or F,

—(C 0 -C 5 alkyl)C 1 -C 9 heterocyclyl optionally substituted by halo, oxo, C 1 -C 3 alkyl or C(O)C 1 -C 3 alkyl, or

—(C 0 -C 5 alkyl)C 1 -C 9 heteroaryl optionally substituted by halo or C 1 -C 3 alkyl; or

R 3 and R 4 are taken together with the nitrogen to which they are attached to form a C 1 -C 5 heterocyclyl optionally substituted by oxo, F, C 1 -C 3 alkyl, —C(O)C 1 -C 6 alkyl or —C(O)OR a ;

Z is —NR 5 R 6 ;

R 5 is H or C 1 -C 3 alkyl;

R 6 is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, —(C 0 -C 5 alkyl)(C 1 -C 9 heterocyclyl), —(C 0 -C 5 alkyl)(C 3 -C 8 cycloalkyl), —(C 0 -C 5 alkyl)(C 1 -C 9 heteroaryl), —(C 0 -C 5 alkyl)(C 6 -C 9 aryl), wherein said alkyl, alkenyl and alkynyl are optionally substituted by oxo, F, OR a or NR a R b , and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by

oxo, —CN, —CF 3 , halo, —O[C(R a ) 2 ] 1-3 O—, —C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , —(C 0 -C 5 alkyl)NR a R b , —(C 0 -C 5 alkyl)OR a ,

C 1 -C 6 alkyl optionally substituted by oxo or F,

—(C 0 -C 5 alkyl)C 1 -C 9 heterocyclyl optionally substituted by halo, oxo, C 1 -C 3 alkyl or C(O)C 1 -C 3 alkyl,

—(C 0 -C 5 alkyl)C 1 -C 9 heteroaryl optionally substituted by halo or C 1 -C 3 alkyl,

—(C 0 -C 5 alkyl)phenyl optionally substituted by C 1 -C 3 alkyl, —CF 3 , halo, —CN, —OR a or —NR a R b , or

—(C 0 -C 5 alkyl)C 3 -C 6 cycloalkyl optionally substituted by oxo, —NR c R d , C 1 -C 3 alkyl or F;

R a and R b are independently H, —CF 3 , —CHF 2 , —CH 2 F, C 1 -C 6 alkyl, C 6 aryl, C 3 -C 6 cycloalkyl or C 4 -C 5 heterocyclyl; wherein said alkyl, aryl and cycloalkyl are optionally substituted by C 1 -C 4 alkyl, —(C 0 -C 3 alkyl)OR c , oxo, halo, NR c R d or C 4 -C 5 heterocyclyl; or

R a and R b together with the atom to which they are attached form a C 1 -C 5 heterocyclyl optionally substituted by oxo, F, C 1 -C 3 alkyl, —C(O)C 1 -C 6 alkyl or —C(O)OR a ; and

R c and R d are independently H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or phenyl, wherein said alkyl, cycloalkyl and phenyl are optionally substituted by halo, CH 3 OH, NH 2 , C(O)O(C 1 -C 6 alkyl) or C(O)NH(C 1 -C 6 alkyl).

3. The compound of claim 1 , wherein R 2 is —NHR 4 .

4. The compound of claim 3 , wherein R 2 is —NH 2 .

5. The compound of claim 3 , wherein R 4 is C 1 -C 6 alkyl, —(C 0 -C 5 alkyl)(C 1 -C 9 heterocyclyl), —(C 0 -C 5 alkyl)(C 3 -C 6 cycloalkyl), —(C 0 -C 5 alkyl)(C 1 -C 9 heteroaryl), —(C 0 -C 5 alkyl)(C 6 -C 10 aryl), wherein said alkyl is optionally substituted by R 8 , and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by R 9 .

6. The compound of claim 1 , wherein R 3 and R 4 are taken together with the nitrogen to which they are attached to form a C 1 -C 9 heterocyclyl optionally substituted by R 13 .

7. The compound of claim 1 , wherein R 2 is —NHS(O) 2 R 4 .

8. The compound of claim 7 , wherein R 4 is —(C 6 -C 10 aryl) optionally substituted by R 9 .

9. The compound of claim 1 , wherein R 6 is C 1 -C 10 alkyl, —(C 0 -C 5 alkyl)(C 1 -C 9 heterocyclyl), —(C 0 -C 5 alkyl)(C 3 -C 8 cycloalkyl), —(C 0 -C 5 alkyl)(C 1 -C 9 heteroaryl), —(C 0 -C 5 alkyl)(C 6 -C 9 aryl), wherein said alkyl is optionally substituted by R 10 , and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by R 11 .

10. The compound of claim 1 , wherein R 7 is H; R 2 is —NR 3 S(O) 2 R 4 ; R 3 is H; and R 4 is phenyl optionally substituted by 1-3 substituents selected from C 1 -C 3 alkyl, —CF 3 and halo; Z is —NR 5 R 6 ; R 5 is H; and R 6 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and wherein R 6 is optionally substituted by 1 to 3 substituents selected from oxo, halo and C 1 -C 6 alkyl.

11. The compound of claim 1 , wherein R 7 is H; R 2 is —NR 3 R 4 ; R 3 is H; R 5 is H; R 6 is pyrazolyl substituted by phenyl and further optionally substituted by methyl, and wherein said phenyl is optionally substituted by one or two substituents selected from methyl, halo, methoxy, cyano, trifluoromethyl, hydroxy and trifluoromethoxy.

12. The compound of claim 1 , wherein R 4 is phenyl, —(CH 2 )phenyl, —(CH 2 CH 2 )phenyl, —CH(CH 3 )phenyl, —CH(CH 2 CH 3 )phenyl, —(R) —CH(CH 3 )phenyl, —(S)—CH(CH 3 )phenyl, —(R)—CH(CH 2 CH 3 )phenyl, —(S)—CH(CH 2 CH 3 )phenyl or —C(CH 3 ) 2 -phenyl, wherein said phenyl is optionally substituted by R 9 .

13. The compound of claim 1 , wherein R 9 is independently selected from methyl, ethyl, i-propyl, cyclopropyl, F, Cl, —OCH 2 O—, —OCH 2 CH 2 O—, —OCH 2 CH 2 CH 2 O—, —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 NMe 2 , —O(CH 2 ) 1-3 (C 4 -C 5 heterocyclyl), C 3 -C 5 heteroaryl, —(CH 2 ) 0-3 C 3 -C 5 heterocyclyl optionally substituted by C 1 -C 3 alkyl or halo, —OH, —OCH 3 , —OCH 2 CH 3 , —SH, —SCH 3 , —SCH 2 CH 3 , —N(CH 3 ) 2 —N(CH 2 CH 3 ) 2 , —CN, —CF 3 , —OCF 3 , —OCHF 2 and C(O)O(C 1 -C 3 alkyl).

14. The compound of claim 1 , wherein R 4 is selected from: H, methyl, ethyl, i-propyl, —CH 2 CH 2 OH,

wherein the wavy lines represent the point of attachment of R 4 .

15. The compound of claim 1 , wherein R 6 is

—(C 0 -C 1 alkyl)(C 6 -C 8 cycloalkyl) optionally substituted by oxo, —CN, —CF 3 , halo, —C(O)C 1 -C 6 alkyl, —C(O)OR a , —C(O)NR a R b , —(C 0 -C 5 alkyl)NR a R b , —(C 0 -C 5 alkyl)OR a or C 1 -C 6 alkyl optionally substituted by oxo or F,

—(C 0 -C 2 alkyl)C 4 -C 5 heterocyclyl optionally substituted by halo, oxo, C 1 -C 3 alkyl or C(O)C 1 -C 3 alkyl,

—(C 0 -C 2 alkyl)C 3 -C 5 heteroaryl optionally substituted by halo, C 1 -C 3 alkyl or phenyl, wherein said phenyl is optionally substituted by C 1 -C 3 alkyl, —CF 3 , halo, —CN, —OR a or —NR a R b ,

—(C 0 -C 2 alkyl)phenyl optionally substituted by halo, —CN, —OR a or —NR a R b , or

—(C 0 -C 2 alkyl)C 6 -C 7 cycloalkyl optionally substituted by oxo, C 1 -C 3 alkyl or F.

16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

17. A method of manufacturing a compound of claim 1 , comprising contacting a compound of formula i:

wherein R is independently halogen, with a compound of formula NHR 3 R 4 , under conditions sufficient to form the compound of claim 1 .

18. The method of claim 17 , wherein R is Cl.