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.
1. A compound of formula I, or salt thereof,
wherein:
X and Y are each independently O, S, S(O), SO 2 or NR 1 ;
each R 1 is independently for each occurrence 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 or —P(O)(OR 11 ) 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, or two R 11 together represent a divalent cationic group;
ring A is bicyclic aryl ring system, or ring A is
where the R b substituent for
is OH, C 1-6 alkyl, —CO 2 C 1-6 alkyl, —C(O)C 1-6 alkyl or —S(O) 2 C 1-6 alkyl;
each R 2 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 , ═N2, —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 scycloalkyl, 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;
p is 0, 1, 2, 3 or 4;
each m is 1, 2 or 3;
each n is 0, 1, 2 or 3;
two R 2 groups, taken together with the atom or atoms to which they are attached, combine to form a 4-10 membered partially or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a and/or R b ;
Z 1 and Z 2 are each independently CH, CR 2 or N;
R 3 is H, optionally substituted C 1-6 alkyl or R 50 ;
R 4 is H, optionally substituted C 1-6 alkyl or R 50 ; and
R 5 is halo, —CN, optionally substituted C 1-6 alkyl, alkynyl, hydroxy, optionally substituted C 1-6 alkoxy, nitro, —N(R a ) 2 , —C(O)N(R a ) 2 , —CO 2 R a or —C(O)R a .
2. The compound according to claim 1 wherein X is selected from O, S, S(O), or SO 2 .
3. The method according to claim 1 wherein R 5 is halo, —CN,
optionally substituted C 1-6 alkyl, alkynyl, hydroxy, optionally substituted C 1-6 alkoxy, —N(R a ) 2 , —C(O)N(R a ) 2 , —CO 2 R a or —C(O)R a .
4. A method, comprising:
providing a compound according to claim 1 ; and
administering the compound to a subject to treat a bowel disorder.
5. The method of claim 4 , wherein the compound has a formula IA3
or a salt thereof, wherein R b is OH, C 1-6 alkyl, —CO 2 C 1-6 alkyl, —C(O)C 1-6 alkyl or —S(O) 2 C 1-6 alkyl.
6. The method of claim 4 , wherein the compound has a formula II
or a salt thereof, wherein:
ring B, together with the two phenyl ring atoms to which it is attached, forms a 5-, 6- or 7-membered bicyclic aryl ring system, optionally comprising 1, 2 or 3 heteroatoms independently selected from N(R c ) and O, or forms
where the R b substituent is OH, C 1-6 alkyl, —CO 2 C 1-6 alkyl, —C(O)C 1-6 alkyl or —S(O) 2 C 1-6 alkyl;
each R 1 independently is, for each occurrence, 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 scycloalkyl group or an optionally substituted 3-8 membered heteroalicyclyl; R 10 is R a or —P(O)(OR 11 ) 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, or two R 11 together represent a divalent cationic group
R 5 is halo, —CN, optionally substituted C 1-6 alkyl, alkynyl, hydroxy, optionally substituted C 1-6 alkoxy, nitro, —N(R a ) 2 , —C(O)N(R a ) 2 , —CO 2 R a or —C(O)R a
each R a independently is C 1-6 alkyl;
each R b independently is, for each occurrence, ═O, —OR a , haloC 1-3 alkyloxy, —SR a , —N(R c ) 2 , halo, —CF 3 , —CN, —S(O) 2 N(R c ) 2 , —S(O) 2 R a , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —N(R a )—S(O) 2 H, or —C(R a ) 2 —N(R c ) 2 ; and
Z 1 is CH, CR 2 , C-halo or, C-optionally substituted C 1-6 alkyl, or N.
7. The method of claim 6 , wherein the B ring is cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane, morpholine, piperidine, dioxane, oxathiazinane, piperazine, cycloheptane, cycloheptene, azepane, tetrahydroazepine, diazepane, cyclooctane, cyclooctene, azocane, hexahydroazocine, diazocane or hexahydrodiazocine.
8. The method of claim 4 , wherein the compound has a formula IIa
or a salt thereof, wherein:
each R 1 independently is, for each occurrence, 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 or —P(O)(OR 11 ) 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, or two R 11 together represent a divalent cationic group
R 5 is halo, —CN, optionally substituted C 1-6 alkyl, alkynyl, hydroxy, optionally substituted C 1-6 alkoxy, nitro, —N(R a ) 2 , —C(O)N(R a ) 2 , —CO 2 R a or —C(O)R a
each R a independently is C 1-6 alkyl;
each R b independently is, for each occurrence, ═O, —OR a , haloC 1-3 alkyloxy, —SR a , —N(R c ) 2 , halo, —CF 3 , —CN, —S(O) 2 N(R c ) 2 , —S(O) 2 R a , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —N(R a )—S(O) 2 H, or —C(R a ) 2 —N(R c ) 2 ; and
Z 1 is CH, CR 2 , C-halo or C-optionally substituted C 1-6 alkyl, or N.
9. The method of claim 4 , wherein the compound has a formula IIb
or a salt thereof, wherein:
each R 1 independently is, for each occurrence, 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 or —P(O)(OR 11 ) 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, or two R 11 together represent a divalent cationic group
R 5 is halo, —CN, optionally substituted C 1-6 alkyl, alkynyl, hydroxy, optionally substituted C 1-6 alkoxy, nitro, —N(R a ) 2 , —C(O)N(R a ) 2 , —CO 2 R a or —C(O)R a
each R a independently is C 1-6 alkyl;
each R b independently is, for each occurrence, ═O, —OR a , haloC 1-3 alkyloxy, —SR a , —N(R C ) 2 , halo, —CF 3 , —CN, —S(O) 2 N(R c ) 2 , —S(O) 2 R a , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —N(R a )—S(O) 2 H, or —C(R a ) 2 —N(R c ) 2 ; and
Z 1 is CH, CR 2 , C-halo or C-optionally substituted C 1-6 alkyl, or N.
10. The method of claim 4 , wherein the compound has a formula IIc
or a salt thereof, wherein:
each R 1 independently is, for each occurrence, 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 or —P(O)(OR 11 ) 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, or two R 11 together represent a divalent cationic group
R 5 is halo, —CN, optionally substituted C 1-6 alkyl, alkynyl, hydroxy, optionally substituted C 1-6 alkoxy, nitro, —N(R a ) 2 , —C(O)N(R a ) 2 , —CO 2 R a or —C(O)R a
each R a independently is C 1-6 alkyl;
each R b is independently is, for each occurrence, ═O, —OR a , haloC 1-3 alkyloxy, —SR a , —N(R c ) 2 , halo, —CF 3 , —CN, —S(O) 2 N(R c ) 2 , —S(O) 2 R a , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —N(R a )—S(O) 2 H, or —C(R a ) 2 —N(R c ) 2 ; and
Z 1 is CH, CR 2 , C-halo or C-optionally substituted C 1-6 alkyl, or N.
11. The method of claim 4 , wherein the compound has a formula IId
or a salt thereof, wherein:
each R 1 independently is, for each occurrence, H, optionally substituted C 1-6 alkyl, C(O)—C 1-6 alkyl, C02-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 scycloalkyl group or an optionally substituted 3-8 membered heteroalicyclyl; R 10 is R a or —P(O)(OR 11 ) 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, or two R 11 together represent a divalent cationic group
R 5 is halo, —CN, optionally substituted C 1-6 alkyl, alkynyl, hydroxy, optionally substituted C 1-6 alkoxy, nitro, —N(R a ) 2 , —C(O)N(R a ) 2 , —CO 2 R a or —C(O)R a
each R a independently is C 1-6 alkyl;
each R b independently is, for each occurrence, ═O, —OR a , haloC 1-3 alkyloxy, —SR a , —N(R c ) 2 , halo, —CF 3 , —CN, —S(O) 2 N(R c ) 2 , —S(O) 2 R a , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —N(R a )—S(O) 2 H, or —C(R a ) 2 —N(R c ) 2 ; and
Z 1 is CH, CR 2 , C-halo or C-optionally substituted C 1-6 alkyl, or N.
12. The method of claim 4 , wherein the compound has a formula IIe
or a salt thereof, wherein:
each R 1 independently is, for each occurrence, 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 or —P(O)(OR 11 ) 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, or two R 11 together represent a divalent cationic group
R 5 is halo, —CN, optionally substituted C 1-6 alkyl, alkynyl, hydroxy, optionally substituted C 1-6 alkoxy, nitro, —N(R a ) 2 , —C(O)N(R a ) 2 , —CO 2 R a or —C(O)R a
each R a independently is C 1-6 alkyl;
each R b independently is, for each occurrence, ═O, —OR a , haloC 1-3 alkyloxy, —SR a , —N(R c ) 2 halo, —CF 3 , —CN, —S(O) 2 N(R c ) 2 , —S(O) 2 R a , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —N(R a )—S(O) 2 H, or —C(R a ) 2 —N(R c ) 2 ; and
Z 1 is CH, CR 2 , C-halo or C-optionally substituted C 1-6 alkyl, or N.
13. The method according to claim 4 wherein the bowel disorder is irritable bowel syndrome.
14. The compound according to claim 4 wherein X is O, S, S(O), or SO 2 .
15. The method according to claim 4 wherein R 5 is halo, —CN, optionally substituted C 1-6 alkyl, alkynyl, hydroxy, optionally substituted C 1-6 alkoxy, —N(R a ) 2 , —C(O)N(R a ) 2 , —CO 2 R a or —C(O)R a .