| CPC C07D 307/81 (2013.01) [C07D 213/74 (2013.01); C07D 277/64 (2013.01); C07D 405/10 (2013.01); C07D 409/10 (2013.01); C07D 417/10 (2013.01); C07D 491/048 (2013.01); C07F 5/025 (2013.01)] | 19 Claims |
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1. A method for treating cancer in a mammal, comprising administering a compound of formula (X), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal,
 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
X1 is C—R5, wherein the R5 of X1 is taken together with R3, and the atoms to which they are attached, to form a 5-membered heterocyclyl or a 5-membered heteroaryl, wherein the 5-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more D;
X2 is N or C—R5, wherein each R5 is independently selected from the group consisting of H, cyano, halo, C(O)NH2, N(Re)(Rf), C3-10cycloalkyl, C1-6alkoxy, C6-20aryl, S(O)2—C1-6alkyl, and C1-6alkyl, wherein the C1-6alkyl of R5 is optionally substituted with hydroxyl or N(Re)(Rf);
X3 is N or C—H;
R1 is:
(i) a 3-5 membered saturated heterocyclyl comprising at least one annular oxygen atom, wherein the 3-5 membered saturated heterocyclyl is optionally substituted with one or more C1-6alkyl, or
(ii) N(Re)(Rf), or
(iii)
 wherein Ra, Rb, and Rc are each independently selected from the group consisting of H, halo, cyano, hydroxyl, B(OH)2, C(O)—OH, C(O)—N(Re)(Rf), C(O)—C1-6alkoxy, C(O)—C1-6alkyl, C1-6alkyl, C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, C5-13spirocyclyl, and 5-20 membered heteroaryl, wherein the C1-6alkyl is further optionally substituted with hydroxyl, or
(iv)
 wherein Rd is selected from the group consisting of H, halo, cyano, hydroxyl, B(OH)2, C(O)—OH, C(O)—N(Re)(Rf), C(O)—C1-6alkoxy, C(O)—C1-6alkyl, C1-6alkyl, C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, C5-13spirocyclyl, and 5-20 membered heteroaryl, wherein the C1-6alkyl is further optionally substituted with hydroxyl;
L is absent or is selected from the group consisting of —O—, *—CH2—O—**, *—O—CH2—**, —CH═CH—, and —C≡C—, wherein ** indicates the attachment point to the R2 moiety and * indicates the attachment point to the remainder of the molecule;
R2 is C1-12alkyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, C5-13spirocyclyl, C6-20aryl, or 5-20 membered heteroaryl,
wherein the C1-12alkyl, C3-10cycloalkyl, 3-10 membered saturated heterocyclyl, C5-13spirocyclyl, C6-20aryl, or 5-20 membered heteroaryl of R2 is independently optionally substituted with one or more substituents selected from the group consisting of cyano, halo, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, NO2, N(Re)(Rf), O(Re), and S(Rg)5,
provided that, when R2 is C1-12alkyl, wherein the C1-12alkyl of R2 is independently optionally substituted with one or more substituents selected from the group consisting of cyano, halo, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, NO2, N(Re)(Rf), O(Re), and S(Rg)5 then L is —CH═CH— or —C≡C—;
R4 is H or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with hydroxyl;
Re and Rf are, independently of each other and independently at each occurrence, selected from the group consisting of H, cyano, hydroxyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C3-10cycloalkyl, C1-6alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C5-13spirocyclyl, C6-20aryl, and 3-20 membered heteroaryl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C1-6alkyl-C3-10cycloalkyl, 3-10 membered heterocyclyl, C5-13spirocyclyl, C6-20aryl, and 3-20 membered heteroaryl of Re and Rf are each independently optionally substituted with one or more substituents selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, oxo, cyano, halo, NO2, and hydroxyl; and
Rg is halo, wherein the cancer is selected from: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.
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