Heterocyclic compounds and uses thereof
AssigneePlexxikon Inc.
InventorsJiazhong Zhang, John Buell, Katrina Chan, Prabha N. Ibrahim, Jack Lin, Phuongly Pham, Songyuan Shi, Wayne Spevak, Guoxian Wu, Jeffrey Wu
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Abstract
Heterocyclic compounds of formula (I), methods for their preparation, pharmaceutical compositions containing such a compound and their therapeutic uses.
Claims17
A method for treating a subject suffering or at risk of a disease or condition mediated by a bromodomain, said method comprising administering to the subject in need thereof an effective amount of a compound of formula (Va),
- wherein the disease or condition is lung cancer, breast cancer, colon carcinomas, midline carcinomas, acral lentiginous melanoma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, bone cancer, Burkitt's lymphoma, cutaneous T-cell lymphoma, colorectal cancer, diffuse large B-cell lymphoma, enteropathy-associated T-cell lymphoma, follicular lymphoma, gastrointestinal cancer, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant peripheral nerve sheath tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, medullary carcinoma of the breast, medulloblastoma, melanoma, merkel cell cancer, mesothelioma, multiple myeloma, neuroblastoma, neurofibroma, nodular melanoma, osteosarcoma, ovarian cancer, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, prostate cancer, pancreatic cancer, skin cancer, T-cell lymphoma, uveal melanoma, ulcerative colitis, chronic obstructive pulmonary disease (COPD), atherosclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, or osteoarthritis,
- wherein the compound of formula (Va) has the following structure:
- or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof,
- wherein:
- R2 is H;
- R4 is H;
- R6 is H;
- R7 is H, —OH, C1-6 alkyl, deuterated C1-6 alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
- R1 is heteroaryl optionally substituted with from 1-3 Rj groups;
- each Rj is independently halogen, —CN, —OH, —NH2, —NO2, —C(O)OH, —C(S)OH, —C(O)NH2, —C(S)NH2, —S(O)2NH2, —NHC(O)NH2, —NHC(S)NH2, —NHS(O)2NH2, —C(NH)NH2, —CH═C(Rk)(Rk), —ORk, —SRk, —OC(O)Rk, —OC(S)Rk, —P(═O)HRk, —P(═O)RkRk, —PH(═O)ORk, —P(═O)(ORk)2, —OP(═O)(ORk)2, —C(O)H, —O(CO)ORk, —C(O)Rk, —C(S)Rk, —C(O)ORk,—C(S)ORk, —S(O)Rk, —S(O)2Rk, —C(O)NHRk, —C(S)NHRk, —C(O)NRkRk, —C(S)NRkRk, —S(O)2NHRk, —S(O)2NRkRk, —C(NH)NHRk, —C(NH)NRkRk, —NHC(O)Rk, —NHC(S)Rk, —NRkC(O)Rk, —NRkC(S)Rk, —NHS(O)2Rk, —NRkS(O)2Rk, —NHC(O)NHRk, —NHC(S)NHRk, —NRkC(O)NH2, —NRkC(S)NH2, —NRkC(O)NHRk, —NRkC(S)NHRk, —NHC(O)NRkRk, —NHC(S)NRkRk, —NRkC(O)NRkRk, —NRkC(S)NRkRk, —NHS(O)2NHRk, —NRkS(O)2NH2, —NRkS(O)2NHRk, —NHS(O)2NRkRk, —NRkS(O)2NRkRk, —NHRk, or —NRkRk;
- each Rk is independently H, C1-6alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, or cycloalkylalkyl;
- or
- two Rk groups when attached to the same carbon or nitrogen atom are taken together to form a 3- to 6-membered carbocyclic ring or 3- to 8-membered heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N, and S, wherein the nitrogen or sulfur ring atoms are optionally oxidized;
- R3 is H, halogen, —CN, optionally substituted C1-6alkyl, optionally substituted deuterated C1-6alkyl, optionally substituted aryl, optionally substituted aryl-C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-C1-4alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl-C1-4alkyl, optionally substituted heterocycloalkyl, or optionally substituted heterocycloalkyl-C1-4alkyl;
- and
- R5 is
- optionally substituted with from 1 to 2 R11 groups independently selected from D, halogen, C1-6alkyl, deuterated C1-6alkyl, C1-4haloalkyl, C1-4haloalkoxy, and —CN;
- wherein the wavy line indicates the point of attachment to the rest of molecule.
The method according to any of the preceding claims, wherein the disease or condition mediated by a bromodomain is ulcerative colitis, chronic obstructive pulmonary disease (COPD), atherosclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, non-small cell lung cancer, small cell lung cancer, ovarian cancer, melanoma, midline carcinomas, acute myeloid leukemia, breast cancer, lymphoma, or neuroblastoma.
Dependencies are inferred from the claim text.