HETEROCYCLIC COMPOUNDS AND THEIR USES

摘要

Substituted bicyclic heteroaryls and compositions containing them, for the treatment of general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, including but not restricted to autoimmune diseases such as systemic lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia, allergic conditions including all forms of hypersensitivity, The present invention also enables methods for treating cancers that are mediated, dependent on or associated with p110δ activity, including but not restricted to leukemias, such as Acute Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell Acute Lymphoblastic leukaemia (T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (NHL) B-cell lymphoma and solid tumors, such as breast cancer.

主权项

1. A compound having the structure: or any pharmaceutically-acceptable salt thereof, wherein:
n is 0, 1, 2 or 3;R1 is a direct-bonded, partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic or 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but containing no more than one O or S atom, substituted by 0, 1, 2 or 3 substituents independently selected from halo, C1-6alk, C1-4haloalk, cyano, nitro, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Ra, —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2Ra, —OC2-6 alkNRaRa, —OC2-6 alkORa, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)Ra, —S(═O)2N(Ra)C(═O)ORa, (═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)Ra, —N(Ra)C(═O)ORa, —N(Ra) C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Ra, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa and —NRaC2-6alkORa, wherein the available carbon atoms of the ring are additionally substituted by 0, 1 or 2 oxo or thioxo groups, and wherein the ring is additionally substituted by 0 or 1 directly bonded, SO2 linked, C(═O) linked or CH2 linked group selected from phenyl, pyridyl, pyrimidyl, morpholino, piperadinyl, piperadinyl, cyclopentyl, cyclohexyl all of which are further substituted by 0, 1, 2 or 3 independent Rb groups;
R2 is selected from H, halo, C1-6alk, C1-4haloalk cyano, and nitro;R3 is selected from H, halo, nitro, cyano, C1-4alk, OC1-4alk, OC1-4haloalk, NHC1-4alk, N(C1-4alk)C1-4alk and C1-4haloalk;R4 is, independently, in each instance, halo, nitro, cyano, C1-4alk, OC1-4alk, OC1-4haloalk, NHC1-4alk, N(C1-4alk)C1-4alk, C1-4haloalk or an unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but containing no more than one O or S, the ring being substituted by 0, 1, 2 or 3 substituents selected from halo, C1-4alk, C1-3haloalk, —OC1-4alk, —NH2, —NHC1-4alk, and —N(C1-4alk)C1-4alk;R5 is, independently, in each instance, H, halo, C1-6alk, C1-4haloalk, or C1-6alk substituted by 1, 2 or 3 substituents selected from halo, cyano, OH, OC1-4alk, C1-4alk, C1-3haloalk, OC1-4alk, NH2, NHC1-4alk and N(C1-4alk)C1-4alk; or both R5 groups together form a C3-6spiroalk substituted by 0, 1, 2 or 3 substituents selected from halo, cyano, OH, OC1-4alk, C1-4alk, C1-3haloalk, OC1-4alk, NH2, NHC1-4alk and N(C1-4alk)C1-4alk;R6 is NHR9;R9 is H, C1-6alk or C1-4haloalk;R10 is in each instance H, halo, C1-3alk, C1-3haloalk or cyano;R11 is selected from H, halo, C1-6alk, C1-4haloalk cyano, nitro, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Ra, —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2Ra, —OC2-6alkNRaRa, —OC2-6alkORa, —SRa, —S(═O)Ra, —S(═O)2Rb, —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)Ra, (═O)2N(Ra)C(═O)ORa, —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)Ra, —N(Ra)C(═O)ORa, —N(Ra) C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Ra, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa, —NRaC2-6alkORa, —NRaC2-6alkCO2Ra, —NRaC2-6alkSO2Rb, —CH2C(═O)Ra, —CH2C(═O)ORa, —CH2C(═O)NRaRa, —CH2C(═NRa)NRaRa, —CH2ORa, —CH2O C(═O)Ra, —CH2OC(═O)NRaRa, —CH2OC(═O)N(Ra)S(═O)2Ra, —CH2OC2-6alkNRaRa, —CH2OC2-6alkORa, —CH2SRa, —CH2S(═O)Ra, —CH2S(═O)2Rb, —CH2S(═O)2NRaRa, —CH2S(═O)2N(Ra)C(═O)Ra, —CH2S(═O)2N(Ra)C(═O)ORa, —CH2S(═O)2N(Ra)C(═O) NRaRa, —CH2NRaRa, —CH2N(Ra)C(═O)Ra, —CH2N(Ra)C(═O)ORa, —CH2N(Ra)C(═O) NRaRa, —CH2N(Ra)C(═NRa)NRaRa, —CH2N(Ra)S(═O)2Ra, —CH2N(Ra)S(═O)2NRaRa, —CH2NRaC2-6alkNRaRa, —CH2NRaC2-6alkORa, —CH2NRaC2-6alkCO2Ra, —CH2NRaC2-6alkSO2Rb, —CH2Rc, —C(═O)Rc and —C(═O)N(Ra)Rc;
Ra is independently, at each instance, H or Rb;Rb is independently, at each instance, phenyl, benzyl or C1-6alk, the phenyl, benzyl and C1-6alk being substituted by 0, 1, 2 or 3 substituents selected from halo, C1-3haloalk, —OH, —OC1-4alk, —NH2, —NHC1-4alk and —N(C1-4alk)C1-4alk; andRc is a saturated or partially-saturated 4-, 5- or 6-membered ring containing 1, 2 or 3 heteroatoms selected from N, O and S, the ring being substituted by 0, 1, 2 or 3 substituents selected from halo, C1-4alk, C1-3haloalk, —OC1-4alk, —NH2, —NHC1-4alk and —N(C1-4alk)C1-4alk.