Compositions and methods for inhibition of the jak pathway

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), SO2 or NR1;
• each R1 independently is, for each occurrence, H, optionally substituted C1-6alkyl, C(O)—C1-6alkyl, CO2—C1-6alkyl or R50;
• each R50 is —C(R9)2-A-R10, where A is O or S;
• each R9 is independently for each occurrence H, optionally substituted C1-6alkyl, optionally substituted C6-10aryl or optionally substituted C7-16arylalkyl;
• or alternatively, two R9, together with the carbon to which they are attached, form an optionally substituted C3-8cycloalkyl group or an optionally substituted 3-8 membered heteroalicyclyl;
• R10 is Ra or —P(O)(OR11)2;
• each R11 is independently for each occurrence Ra or a monovalent cationic group;
• or two R11, together with the atoms to which they are attached, form a 4-8 membered cyclic phosphate group, or two R11 together represent a divalent cationic group;
• ring A is bicyclic;
• each R2 independently is, for each occurrence, H, Re, Rb, Re substituted with one or more of the same or different Ra and/or Rb, —ORe substituted with one or more of the same or different Ra and/or Rb, —SRe substituted with one or more of the same or different Ra and/or Rb, —C(O)Re substituted with one or more of the same or different Ra and/or Rb, —N(Ra)Re where Re is substituted with one or more of the same or different Ra and/or Rb, —S(O)2Re substituted with one or more of the same or different Ra and/or Rb, —N(Ra)—S(O)2Re where Re is substituted with one or more of the same or different Ra and/or Rb, —B(ORa)2, —B(N(Rc)2)2, —(C(Ra)2)m—Rb, —O—(C(Ra)2)m—Rb, —S—(C(Ra)2)m—Rb, —O—(C(Rb)2)m—Ra, —N(Ra)— (C(Ra)2)m—Rb, —O—(CH2)m—CH((CH2)mRb)Rb, —C(O)N(Ra)—(C(Ra)2)m—Rb, —O—(C(Ra)2)m—C(O)N(Ra)—(C(Ra)2)m—Rb, —N((C(Ra)2)mRb)2, —S—(C(Ra)2)m—C(O)N(Ra)—(C(Ra)2)m—Rb, —N(Ra)—C(O)—N(Ra)—(C(Ra)2)m—Rb, —N(Ra)—C(O)—(C(Ra)2)m—C(Ra)(Rb)2 or —N(Ra)—(C(Ra)2)m—C(O)—N(Ra)—(C(Ra)2)m—Rb;
• each Ra independently is, for each occurrence, H, deuterium, C1-6alkyl, C3-8cycloalkyl, C4-11cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
• each Rb independently is, for each occurrence, ═O, —ORa, —O—(C(Ra)2)m—ORa, haloC1-3alkyloxy, ═S, —SRa, ═NRa, ═NORa, —N(Rc)2, halo, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Ra, —S(O)2Ra, —SO3Ra, —S(O)N(Rc)2, —S(O)2N(Rc)2, —OS(O)Ra, —OS(O)2Ra, —OSO3Ra, —OS(O)2N(Rc)2, —C(O)Ra, —CO2Ra, —C(O)N(Rc)2, —C(NRa)—N(Rc)2, —C(NOH)—Ra, —C(NOH)—N(Rc)2, —OC(O)Ra, —OC(O)ORa, —OC(O)N(Rc)2, —OC(NH)—N(Rc)2, —OC(NRa)—N(Rc)2, —N(Ra)—S(O)2H, —[N(Ra)C(O)]nRa, —[N(Ra)C(O)]nORa, —[N(Ra)C(O)]nN(Rc)2 or —[N(Ra)C(NRa)]n—N(Rc)2;
• each Rc independently is, for each occurrence, Ra, or, alternatively, two Rc 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 Ra and/or Rd groups;
• each Rd is ═O, —ORa, haloC1-3alkyloxy, C1-6alkyl, ═S, —SRa, ═NRa, ═NORa, —N(Ra)2, halo, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Ra, —S(O2)Ra, —SO3Ra, —S(O)N(Ra)2, —S(O)2N(Ra)2, —OS(O)Ra, —OS(O)2Ra, —OSO3Ra, —OS(O)2N(Ra)2, —C(O)Ra, —CO2Ra, —C(O)N(Ra)2, —C(NRa)N(Ra)2, —C(NOH)Ra, —C(NOH)N(Ra)2, —OCO2Ra, —OC(O)N(Ra)2, —OC(NRa)N(Ra)2, —[N(Ra)C(O)]nRa, —(C(Ra)2)n—ORa, —N(Ra)—S(O)2Ra, —C(O)—C1-6haloalkyl, —S(O)2C1-6haloalkyl, —OC(O)Ra, —O(C(Ra)2)m—ORa, —S(C(Ra)2)m—ORa, —N(Ra)C1-6haloalkyl, —P(O)(ORa)2, —N(Ra)—(C(Ra)2)m—ORa, —[N(Ra)C(O)]nORa, —[N(Ra)C(O)]nN(Ra)2, —[N(Ra)C(NRa)]nN(Ra)2 or —N(Ra)C(O)C1-6haloalkyl;
• or two Rd, 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 Ra;
• each Re independently is, for each occurrence, C1-6alkyl, C3-8cycloalkyl, C4-11 cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 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 R2 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 Ra and/or Rb;
• Z1 and Z2 are each independently CH, CR2 or N;
• R3 is H, optionally substituted C1-6alkyl or R50;
• R4 is H, optionally substituted C1-6alkyl or R50;
• and
• R5 is halo, —CN, optionally substituted C1-6alkyl, alkynyl, hydroxy, optionally substituted C1-6alkoxy, nitro, —N(Ra)2, —C(O)N(Ra)2, —CO2Ra or —C(O)Ra.

A method, comprising administering a compound of formula I, or a salt thereof, or a composition compromising the compound or salt thereof,

• in an effective amount, wherein:
• X and Y are each independently O, S, S(O), SO2 or NR1;
• each R1 independently is, for each occurrence, H, optionally substituted C1-6alkyl, C(O)—C1-6alkyl, CO2—C1-6alkyl or R50;
• each R50 is —C(R9)2—O—R10 or —C(R9)2—S—R10;
• each R9 is independently for each occurrence H, optionally substituted C1-6alkyl, optionally substituted C6-10aryl or optionally substituted C7-16arylalkyl;
• or alternatively, two R9, together with the carbon to which they are attached, form an optionally substituted C3-8cycloalkyl group or an optionally substituted 3-8 membered heteroalicyclyl;
• R10 is Ra or —P(O)(OR11)2;
• each R11 is independently for each occurrence Ra or a monovalent cationic group;
• or two R11, together with the atoms to which they are attached, form a 4-8 membered cyclic phosphate group, or two R11 together represent a divalent cationic group;
• ring A is bicyclic;
• each R2 independently is, for each occurrence, H, Re, Rb, Re substituted with one or more of the same or different Ra and/or Rb, —OR′ substituted with one or more of the same or different Ra and/or Rb, —SRe substituted with one or more of the same or different Ra and/or Rb, —C(O)Re substituted with one or more of the same or different Ra and/or Rb, —N(Ra)Re where Re is substituted with one or more of the same or different Ra and/or Rb, —S(O)2Re substituted with one or more of the same or different Ra and/or Rb, —N(Ra)—S(O)2Re where Re is substituted with one or more of the same or different Ra and/or Rb, —B(ORa)2, —B(N(Rc)2)2, —(C(Ra)2)m—Rb, —O—(C(Ra)2)m—Rb, —S—(C(Ra)2)m—Rb, —O—(C(Rb)2)m—Ra, —N(Ra)—(C(Ra)2)m—Rb, —O—(CH2)m—CH((CH2)mRb)Rb, —C(O)N(Ra)—(C(Ra)2)m—Rb, —O—(C(Ra)2)m—C(O)N(Ra)—(C(Ra)2)m—Rb, —N((C(Ra)2)mRb)2, —S—(C(Ra)2)m—C(O)N(Ra)—(C(Ra)2)m—Rb, —N(Ra)—C(O)—N(Ra)—(C(Ra)2)m—Rb, —N(Ra)—C(O)—(C(Ra)2)m—C(Ra)(Rb)2 or —N(Ra)—(C(Ra)2)m—C(O)—N(Ra)—(C(Ra)2)m—Rb;
• each Ra independently is, for each occurrence, H, deuterium, C1-6alkyl, C3-8cycloalkyl, C4-11cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
• each Rb independently is, for each occurrence, ═O, —ORa, —O—(C(Ra)2)m—ORa, haloC1-3alkyloxy, ═S, —SRa, ═NRa, ═NORa, —N(Rc)2, halo, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Ra, —S(O)2Ra, —SO3Ra, —S(O)N(Rc)2, —S(O)2N(Rc)2, —OS(O)Ra, —OS(O)2Ra, —OSO3Ra, —OS(O)2N(Rc)2, —C(O)Ra, —CO2Ra, —C(O)N(Rc)2, —C(NRa)—N(Rc)2, —C(NOH)—Ra, —C(NOH)—N(Rc)2, —OC(O)Ra, —OC(O)ORa, —OC(O)N(Rc)2, —OC(NH)—N(Rc)2, —OC(NRa)—N(Rc)2, —N(Ra)—S(O)2H, —[N(Ra)C(O)]nRa, —[N(Ra)C(O)]nORa, —[N(Ra)C(O)]nN(Rc)2 or —[N(Ra)C(NRa)]n—N(Rc)2;
• each Rc independently is, for each occurrence, Ra, or, alternatively, two Rc 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 Ra and/or Rd groups;
• each Rd is ═O, —ORa, haloC1-3alkyloxy, ═S, —SRa, ═NRa, ═NORa, —N(Ra)2, halo, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Ra, —S(O2)Ra, —SO3Ra, —S(O)N(Ra)2, —S(O)2N(Ra)2, —OS(O)Ra, —OS(O)2Ra, —OSO3Ra, —OS(O)2N(Ra)2, —C(O)Ra, —CO2Ra, —C(O)N(Ra)2, —C(NRa)N(Ra)2, —C(NOH)Ra, —C(NOH)N(Ra)2, —OCO2Ra, —OC(O)N(Ra)2, —OC(NRa)N(Ra)2, —[N(Ra)C(O)]nRa, —(C(Ra)2)n—ORa, —N(Ra)—S(O)2Ra, —C(O)—C1-6haloalkyl, —S(O)2C1-6haloalkyl, —OC(O)Ra, —O(C(Ra)2)m—ORa, —S(C(Ra)2)m—ORa, —N(Ra)C1-6haloalkyl, —P(O)(ORa)2, —N(Ra)—(C(Ra)2)m—ORa, —[N(Ra)C(O)]nORa, —[N(Ra)C(O)]nN(Ra)2, —[N(Ra)C(NRa)]nN(Ra)2 or —N(Ra)C(O)C1-6haloalkyl;
• two Rd, 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 Ra;
• each Re independently is, for each occurrence, C1-6alkyl, C3-8cycloalkyl, C4-11 cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 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 R2 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 Ra and/or Rb;
• Z1 and Z2 are each independently CH, CR2 or N;
• R3 is H, optionally substituted C1-6alkyl or R50;
• R4 is H, optionally substituted C1-6alkyl or R50;
• and
• R5 is halo, —CN, optionally substituted C1-6alkyl, alkynyl, hydroxy, optionally substituted C1-6alkoxy, nitro, —N(Ra)2, —C(O)N(Ra)2, —CO2Ra or —C(O)Ra.