Pyrimidine-2-amine compounds and their use as inhibitors of JAK kinases

1. A method for inhibiting JAK2 activity in a mammal, wherein the method comprises administering to the mammal a effective amount of a compound of formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:

n is 0, 1 or 2;

m is 0, 1 or 2;

Y is selected from the group consisting of ═C(R 6 )— and ═N—;

R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, —R 8 —C(O)OR 6 , —R 9 —N(R 6 )R 7 and —R 9 —OR 6 ;

each R 2 , when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and —OR 6 ;

each R 3 , when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R 4 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, —R 8 —OR 6a , —R 8 —S(O) p R 6a (where p is 0, 1 or 2), —R 8 —C(O)R 6a , —R 8 —C(O)OR 6a , —R 8 —C(O)N(R 6a )R 7a , —R 8 —N(R 6a )R 7a , —R—N(R 6a )—R 9 —N(R 6a )R 7a , —R 8 —N(R 6a )—R 9 —OR 7a , —R 8 —N(R 6a )C(O)R 7a , —R 8 —N(R 6a )S(O) 2 R 7a , —R 8 —N(R 6a )C(O)—R 8 —N(R 6a )R 7a , and —R 8 —N(R 6a )—R 9 —N(R 6a )S(O) 2 R 7a , where each R 6a and R 7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted aralkyl, and where the N-heterocyclyl, the N-heteroaryl and the aryl are each independently optionally substituted by one or more substituents selected from the group consisting of —C(O)R 6 , —R 8 —N(R 6 )R 7 , —R 8 —C(O)N(R 6 )R 7 , alkyl, halo and optionally substituted aryl;

R 5 is an N-heterocyclyl, wherein a nitrogen atom in the N-heterocyclyl is optionally substituted by a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 8 —OR 6 , —R 8 —C(O)R 6 , —R 8 —C(O)OR 6 , —R 9 —N(R 6 )R 7 , —R 8 —C(O)N(R 6 )R 7 , —R 8 —C(N═R 6 )N(R 6 )R 7 , —R 8 —S(O) 2 N(R 6 )R 7 , and —R 8 —S(O) t R 6 (where t is 1 or 2); and a carbon atom in the N-heterocyclyl is optionally substituted by a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 8 —OR 6 , —R 8 —C(O)R 6 , —R 8 —C(O)OR 6 , —R 9 —N(R 6 )R 7 , —R 8 —C(O)N(R 6 )R 7 , —R 8 —S(O) 2 N(R 6 )R 7 , and —R 8 —S(O) p R 6 (where p is 0, 1 or 2);

each R 6 and each R 7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, and optionally substituted heteroarylalkynyl; or any R 6 and R 7 , together with the common nitrogen to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R 8 is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; and

each R 9 is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain;

provided at least one of R 5 and a substituent on R 4 is a bridged N-heterocyclyl;

as an isolated stereoisomer or a mixture thereof;

or the method comprises administering to the mammal a composition comprising a pharmaceutically acceptable excipient and a effective amount of a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, as defined above.

2. The method of claim 1 wherein the compound of formula (Ia) is a Compound of formula (Ia-1)

3. The method of claim 2 wherein the compound is selected from the group consisting of:

wherein:

each R 2a is independently selected from hydrogen, alkyl, halo, cyano and —OR;

each 5a is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 8 —OR 6 , —R 8 —C(O)R 6 , —R 8 —C(O)OR 6 , —R 9 —N(R 6 )R 7 , —R 8 —C(O)N(R 6 )R 7 , —R 8 —C(N═R 6 )N(R 6 )R 7 , —R 8 —S(O) 2 N(R 6 )R 7 , and —R 8 —S(O) t R 6 (where t is 1 or 2).

4. The method of claim 3 wherein:

each n is 0 or 1;

each R 4 is independently selected from the group consisting of phenyl, benzimidazolyl, benzo[b] [1,4]oxazinyl, benzo[b]azepinyl, 2,3,4,5-tetrahydro-1H-benzo[b]azepinyl, 3,4-dihydro-2H-benzo [b][1,4]thiazinyl, 3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl, 6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl, 7,8,9,9a-tetrahydro-5H-pyrido [2,3 -e]pyrrolo [1,2-a] [1,4]diazepin- 10(11H)-onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl, each optionally substituted by one or more substituents independently selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, —R 8 —OR 6a , —R 8 —S(O) p R 6a (where p is 0, 1 or 2), —R 8 —C(O)R 6a , —R 8 —C(O)OR 6a ,—R 8 —C(O)N(R 6a )R 7a , —R 8 —N(R 6a )R 7a , —R 8 —N(R 6a )-R 9 —N(R 6a )R 7a , —R 8 —N(R 6a )—R 9 —OR 7a , —R 8 —N(R 6a )C(O)R 7a , —R 8 —N(R 6a )S(O) 2 R 7a , —R 8 —N(R 6a )C(O)—R 8 —N(R 6a )R 7a , and —R 8 —N(R 6a )—R 9 —N(R 6a )S(O) 2 R 7a , where the N-heterocyclyl, the N-heteroaryl and the aryl are each independently optionally substituted by one or more substituents selected from the group consisting of —C(O)R 6 , —R 8 —N(R 6 )R 7 , —R 8 —C(O)N(R 6 )R 7 , alkyl, halo and optionally substituted aryl;

each R ha and R 7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl;

each R 8 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and

each R 9 is an optionally substituted straight or branched alkylene chain.

5. The method of claim 4 wherein the compound is a compound of formula (Ia- 1 a).

6. The method of claim 4 wherein the compound is a compound of formula (Ia-1b).

7. The method of claim 4 wherein the compound is a compound of formula (Ia-1c).

8. The method of claim 4 wherein the compound is a compound of formula (Ia-1d).

9. The method of claim 4 wherein the compound is a compound of formula (Ia-1e).

10. The method of claim 4 wherein the compound is a compound of formula (Ia- 1f).

11. The method of claim 4 wherein the compound is a compound of formula (Ia-1g).

12. The method of claim 4 wherein the compound is a compound of formula (Ia-1h).

13. The method of claim 4 wherein the compound is a compound of formula (Ia-1i).

14. The method of claim 4 wherein the compound is a compound of formula (Ia-1j).

15. The method of claim 4 wherein the compound is a compound of formula (Ia-1k).

16. The method of claim 4 wherein the compound is a compound of formula (Ia-11).

17. The method of claim 2 wherein:

n is 0 or 1;

m is 0 or 1;

R 1 is selected from the group consisting of hydrogen or alkyl;

R 2 is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and —OR 6 ;

R 3 is independently selected from the group consisting of alkyl, halo and haloalkyl;

R 4 is heteroaryl optionally substituted by a bridged N-heterocyclyl, where the bridged N-heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and optionally substituted aryl;

R 5 is a non-bridged N-heterocyclyl, wherein a nitrogen atom in the non-bridged N-heterocyclyl is optionally substituted by a substituent selected from the group consisting of alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R 8 —C(O)R 6 , —R 8 —C(O)OR 6 , —R 9 —N(R 6 )R 7 , —R 8 —C(O)N(R 6 )R 7 , —R 8 —S(O) 2 N(R 6 )R 7 , and —R 8 —S(O) t R 6 (where t is 1 or 2); and wherein a carbon atom in the non-bridged N-heterocyclyl is optionally substituted by a substituent selected from the group consisting of alkyl, halo, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R 8 —OR 6 , —R 8 —C(O)R 6 , —R 8 —C(O)OR 6 , —R 9 —N(R 6 )R 7 , —R 8 —C(O)N(R 6 )R 7 , —R 8 —S(O) 2 N(R 6 )R 7 , and —R 8 —S(O) p R 6 (where p is 0, 1 or 2);

each R 6 and each R 7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; or any R 6 and R 7 , together with the common nitrogen to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

each R 8 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and

each R 9 is an optionally substituted straight or branched alkylene chain.

18. The method of claim 1 wherein the compound of formula (Ia) is a compound of formula (Ia-2):

19. The method of claim 18 wherein the compound is selected from the group consisting of:

wherein:

each 5a is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 8 —OR 6 , —R 8 —C(O)R 6 , —R 8 —C(O)OR 6 , —R 9 —N(R 6 )R 7 , —R 8 —C(O)N(R 6 )R 7 , —R 8 —C(N=R 6 )N(R 6 )R 7 , —R 8 —S(O) 2 N(R 6 )R 7 , and —R 8 —S(O) t R 6 (where t is 1 or 2).

20. The method of claim 19 wherein:

each n is 0 or 1;

each m is 0 or 1;

each R 4 is independently selected from the group consisting of phenyl, benzimidazolyl, benzo[b][1,4]oxazinyl, benzo [b]azepinyl, 2,3,4,5-tetrahydro-1H-benzo[b]azepinyl, 3,4-dihydro-2H-benzo [b][1,4]thiazinyl, 3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, imidazo[1,2-a]pyridinyl, 6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indolyl, 7,8,9,9a-tetrahydro-5H-pyrido [2,3-e]pyrrolo [1,2-a][1,4]diazepin-10(11H)-onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, and thiazolyl, each optionally substituted by one or more substituents independently selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, —R 8 —OR 6a , —R 8 —S(O) p R 6a (where p is 0, 1 or 2), —R 8 —C(O)R 6a , —R 8 —C(O)OR 6a ,—R 8 —C(O)N(R 6a )R 7a , —R 8 —N(R 6a )R 7a , —R 8 —N(R 6a )-R 9 —N(R 6a )R 7a , —R 8 —N(R 6a )—R 9 —OR 7a , —R 8 —N(R 6a )C(O)R 7a , —R 8 —N(R 6a )S(O) 2 R 7a , —R 8 —N(R 6a )C(O)—R 8 —N(R 6a )R 7a , and —R 8 —N(R 6a )—R 9 —N(R 6a )S(O) 2 R 7a , where the N-heterocyclyl, the N-heteroaryl and the aryl are each independently optionally substituted by one or more substituents selected from the group consisting of —C(O)R 6 , —R 8 —N(R 6 )R 7 , —R 8 —C(O)N(R 6 )R 7 , alkyl, halo and optionally substituted aryl;

each R ha and R 7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl;

each R 8 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and

each R 9 is an optionally substituted straight or branched alkylene chain.

21. The method of claim 20 wherein the compound is a compound of formula (Ia-2a).

22. The method of claim 1 wherein the compound is 4-(6-(morpholin-4-yl)pyridin-3-yl)—N—(3-methyl-4-1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrimidin-2-amine, or a pharmaceutically acceptable salt thereof.