Compositions and methods for inhibition of the JAK pathway

A compound of formula IA:

• or salt thereof, wherein:
• R1 is 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, —P(O)(OR11)2, —P(O)(OR11)N(R12)2 or —P(O)(N(R12)2)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;
• each R12 is independently for each occurrence Rc or —C1-3alkyl-N(Rc)2;
• or two R12, each on separate nitrogens of —P(O)(N(R12)2)2, together with the atoms to which they are attached, form a 4-8 membered cyclic phosphonic acid bisamide group;
• or one R12 along with R11, of the group —P(O)(OR11)N(R12)2, together with the atoms to which they are attached, form a 4-8 membered cyclic phosphonamidate group;
• R2a, R2b and R2c are each independently CH3, —OCH3, or F;
• R2d is H or F;
• R2e is 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 is independently 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 is independently 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 is independently 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 is independently 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;
• each m is 1, 2 or 3;
• each n is 0, 1, 2 or 3;
• R4 is H or optionally substituted C1-6alkyl;
• and
• R5 is H, halo, —CN, optionally substituted C1-6alkyl, nitro, —N(Ra)2, —C(O)N(Ra)2, —CO2Ra or —C(O)Ra.