Compositions and methods for inhibition of the JAK pathway
Disclosed are compounds of formula I, compositions containing them, and methods of use for the compounds and compositions in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK 2 and JAK3, are therapeutically useful. Also disclosed are methods of making the compounds.
1. A compound of formula IA:
or salt thereof, wherein:
R 1 is H, optionally substituted C 1-6 alkyl, C(O)—C 1-6 alkyl, CO 2 —C 1-6 alkyl or R 50 ;
each R 50 is —C(R 9 ) 2 -A-R 10 , where A is O or S; each R 9 is independently for each occurrence H, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl or optionally substituted C 7-16 arylalkyl; or alternatively, two R 9 , together with the carbon to which they are attached, form an optionally substituted C 3-8 cycloalkyl group or an optionally substituted 3-8 membered heteroalicyclyl; R 10 is R a , —P(O)(OR 11 ) 2 , —P(O)(OR 11 )N(R 12 ) 2 or —P(O)(N(R 12 ) 2 ) 2 ; each R 11 is independently for each occurrence R a or a monovalent cationic group; or two R 11 , together with the atoms to which they are attached, form a 4-8 membered cyclic phosphate group; each R 12 is independently for each occurrence R c or —C 1-3 alkyl-N(R c ) 2 ; or two R 12 , each on separate nitrogens of —P(O)(N(R 12 ) 2 ) 2 , together with the atoms to which they are attached, form a 4-8 membered cyclic phosphonic acid bisamide group; or one R 12 along with R 11 , of the group —P(O)(OR 11 )N(R 12 ) 2 , together with the atoms to which they are attached, form a 4-8 membered cyclic phosphonamidate group;
each of R 2a−2e is independently for each occurrence H, R e , R b , R e substituted with one or more of the same or different R a and/or R b , —OR e substituted with one or more of the same or different R a and/or R b , —SR e substituted with one or more of the same or different R a and/or R b , —C(O)R e substituted with one or more of the same or different R a and/or R b , —N(R a )R e where R e is substituted with one or more of the same or different R a and/or R b , —S(O) 2 R e substituted with one or more of the same or different R a and/or R b , —N(R a )—S(O) 2 R e where R e is substituted with one or more of the same or different R a and/or R b , —B(OR a ) 2 , —B(N(R c ) 2 ) 2 , —(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —R b , —S—(C(R a ) 2 ) m —R b , —O—(C(R b ) 2 ) m —R a , —N(R a )—(C(R a ) 2 ) m —R b , —O—(CH 2 ) m —CH((CH 2 ) m R b )R b , —C(O)N(R a )—(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N((C(R a ) 2 ) m R b ) 2 , —S—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—(C(R a ) 2 ) m —C(R a )(R b ) 2 or —N(R a )—(C(R a ) 2 ) m —C(O)—N(R a )—(C(R a ) 2 ) m —R b ;
each R a is independently for each occurrence H, deuterium, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
each R b is independently for each occurrence ═O, —OR a , —O—(C(R a ) 2 ) m —OR a , haloC 1-3 alkyloxy, ═S, —SR a , ═NR a , ═NOR a , —N(R c ) 2 , halo, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O) 2 R a , —SO 3 R a , —S(O)N(R c ) 2 , —S(O) 2 N(R c ) 2 , —OS(O)R a , —OS(O) 2 R a , —OSO 3 R a , —OS(O) 2 N(R c ) 2 , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —C(NR a )—N(R c ) 2 , —C(NOH)—R a , —C(NOH)—N(R c ) 2 , —OC(O)R a , —OC(O)OR a , —OC(O)N(R c ) 2 , —OC(NH)—N(R c ) 2 , —OC(NR a )—N(R c ) 2 , —N(R a )—S(O) 2 H, —[N(R a )C(O)] n R a , —[N(R a )C(O)] n OR a , —[N(R a )C(O)] n N(R c ) 2 or —[N(R a )C(NR a )] n —N(R c ) 2 ;
each R c is independently for each occurrence R a , or, alternatively, two R c are taken together with the nitrogen atom to which they are bonded to form a 3 to 10-membered heteroalicyclyl or a 5-10 membered heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which is optionally substituted with one or more of the same or different R a and/or R d groups;
each R d is ═O, —OR a , haloC 1-3 alkyloxy, C 1-6 alkyl, ═S, —SR a , ═NR a , ═NOR a , —N(R a ) 2 , halo, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O 2 )R a , —SO 3 R a , —S(O)N(R a ) 2 , —S(O) 2 N(R a ) 2 , —OS(O)R a , —OS(O) 2 R a , —OSO 3 R a , —OS(O) 2 N(R a ) 2 , —C(O)R a , —CO 2 R a , —C(O)N(R a ) 2 , —C(NR a )N(R a ) 2 , —C(NOH)R a , —C(NOH)N(R a ) 2 ,—OCO 2 R a , —OC(O)N(R a ) 2 , —OC(NR a )N(R a ) 2 , —[N(R a )C(O)] n R a , —(C(R a ) 2 ) n —OR a , —N(R a )—S(O) 2 R a , —C(O)—C 1-6 haloalkyl, —S(O) 2 C 1-6 haloalkyl, —OC(O)R a , —O(C(R a ) 2 ) m —OR a , —S(C(R a ) 2 ) m —OR a , —N(R a )C 1-6 haloalkyl, —P(O)(OR a ) 2 , —N(R a )—(C(R a ) 2 ) m —OR a , —[N(R a )C(O)] n OR a , —[N(R a )C(O)] n N(R a ) 2 , —[N(R a )C(NR a )] n N(R a ) 2 or —N(R a )C(O)C 1-6 haloalkyl; or
two R d , taken together with the atom or atoms to which they are attached, combine to form a 3-10 membered partially or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a ;
each R e is independently for each occurrence C 1-6 alkyl, C 3-8 cycloalkyl, C4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
each m is 1, 2 or 3;
each n is 0, 1, 2 or 3;
R 4 is H or optionally substituted C 1-6 alkyl; and
R 5 is H, halo, —CN, optionally substituted C 1-6 alkyl, nitro, —N(R a ) 2 , —C(O)N(R a ) 2 , —CO 2 R a or —C(O)R a ;
provided that at least one of R 5 , R 2a , R 2b , R 2c and R 2d is —(C(R a ) 2 ) m —R b .
2. The compound of claim 1 , wherein at least one of R 2a , R 2b , R 2c and R 2d is —(C(R a ) 2 ) m —R b .
3. The compound of claim 1 , wherein at least one of R 2a , R 2b , R 2c and R 2d is —(CH 2 ) 1-2 —OH.
4. The compound of claim 1 , wherein at least one of R 2a , R 2b , R 2c and R 2d is —CH 2 OH.
5. The compound of claim 1 , wherein R 5 is optionally substituted C 1-6 alkyl.
6. The compound of claim 5 , wherein R 5 is —(C(R a ) 2 ) m —R b .
7. The compound of claim 6 , wherein R 5 is —CH 2 OH.
8. The compound of claim 1 , wherein R 2a is —OCH 3 , R 2b is —CH 2 OH, R 2c is —CH 3 , and R 5 is —CH 3 .
9. The compound of claim 1 , wherein R 2a is —CH 3 , R 2b is —CH 2 OH, R 2c is —CH 3 , and R 5 is —CH 3 .
10. The compound of claim 1 , wherein R 2a is —CH 3 , R 2b is —CH 2 OH, R 2c is —OCH 3 , and R 5 is —CH 3 .
11. The compound of claim 1 , wherein R 2a is —CH 3 , R 2b is F, R 2c is —CH 2 OH, and R 5 is —CH 3 .
12. The compound of claim 1 , wherein R 2a is —CH 3 , R 2b is —CH 3 , R 2c is —CH 2 OH, and R 5 is —CH 3 .
13. The compound of claim 1 , wherein R 2a is —CH 3 , R 2b is —CH 3 , R 2c is —CH 3 , and R 5 is —CH 2 OH.
14. The compound of claim 1 , wherein R 2a is —CH 3 , R 2b is F, R 2c is —CH 3 , and R 5 is —CH 2 OH.
15. The compound of claim 1 , wherein R 2a is —CH 3 , R 2b is —CH 3 , R 2c is —OCH 3 , and R 5 is —CH 2 OH.
16. A pharmaceutical composition comprising the compound according to claim 1 .
17. A method of inhibiting an activity of a JAK kinase, comprising contacting the JAK kinase with an amount of the compound of claim 1 or a pharmaceutical composition thereof, effective to inhibit an activity of the JAK kinase.