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;
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 Re 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, 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 of claim 1 , or a salt thereof, wherein the A ring is bicyclic aryl or bicyclic heteroaryl.
3. The compound of claim 1 , or a salt thereof, having a formula IA3
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.
4. The compound of claim 1 , or a salt thereof, having a formula II
wherein:
ring B, together with the two phenyl ring atoms to which it is attached, forms a 5-, 6- or 7-membered ring, optionally comprising 1, 2 or 3 heteroatoms independently selected from N(R c ), O and S;
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 0 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.
5. The compound of claim 4 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.
6. The compound of claim 1 , or a salt thereof, having a formula IIa
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.
7. The compound of claim 1 , or a salt thereof, having a formula IIb
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.
8. The compound of claim 1 , or a salt thereof, having a formula IIc
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.
9. The compound of claim 1 , or a salt thereof, having a formula IId
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 compound of claim 1 , or a salt thereof, having a formula IIe
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.
11. A pharmaceutical composition, comprising a compound, or a salt thereof, having a formula I
wherein:
X and Y each independently is O, S, S(O), SO 2 or NR 1 ;
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;
ring A is bicyclic;
each R 2 independently is, 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 independently is, 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 independently is, 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 independently is, 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 independently is, for each occurrence, 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;
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 .
12. The pharmaceutical composition of claim 11 wherein the compound, or a salt thereof, has a formula IA3
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.
13. The pharmaceutical composition of claim 11 wherein the compound, or a salt thereof, has a
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.
14. The composition according to claim 11 further comprising an excipient, a second therapeutic, or combinations thereof.