Aminopyrimidine kinase inhibitors

摘要

Disclosed are compounds, pharmaceutical compositions containing those compounds, and uses of the compounds and compositions as modulators of casein kinase 1 (e.g., CK1γ), casein kinase 2 (CK2), Pim1, Pim2, Pim3, the TGFβ pathway, the Wnt pathway, the JAK/STAT pathway, and/or the mTOR pathway. Uses are also disclosed for the treatment or prevention of a range of therapeutic indications due at least in part to aberrant physiological activity of casein kinase 1 (e.g., CK1γ), casein kinase 2 (CK2), Pim1, Pim2, Pim3, the TGFβ pathway, the Wnt pathway, the JAK/STAT pathway, and/or the mTOR pathway.

主权项

1. A method of treating cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula 1:or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:
W and X are independently oxygen or sulfur; Z1, Z2 and Z3 are independently C—R20 or N, provided that at least one of Z1 and Z2 is N; R1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —COR6, —C(O)OR6, —SO2(R6), —C(O)N(R6)(R7), —SO2N(R6)(R7), and —[C(R4)2]p—R5; R2 and R3 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R4)2]p—R5, —COR6, —C(O)OR6, —SO2(R6), —C(O)N(R6)(R7), —SO2N(R6)(R7), —P(O)(OR6)(OR7); or R2 and R3 are joined together to form an optionally substituted heterocyclic ring; R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, hydroxy, alkoxy, hydroxyalkyl, and alkoxyalkyl; R5 is selected from the group consisting of aryl, heteroaryl, heterocyclyl, —N(R8)(R9), —N(R8)COR9, —N(R8)C(O)OR9, —N(R8)SO2(R9), —CON(R8)(R9), —OC(O) N(R8)—(R9), —SO2N(R8)(R9), —OC(O)OR8, —COOR9, —C(O)N(OH)(R8), —OS(O)2OR8, —S(O)2OR8, —S(O)2R8, —OR8, —COR8, —OP(O)(OR8)(OR8), —P(O)(OR8)(OR8) and —N(R8)P(O)(OR9)(OR9); R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R7 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R6 and R7 are joined together to form a heterocyclic ring; R8 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; R9 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl; or R8 and R9 are joined together to form a heterocyclic ring; R20 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, halo, haloalkyl, trifluoromethyl, fluoroalkyl, perfluoroalkyl, thio, cyano, hydroxy, methoxy, alkoxy, phenoxy, aryloxy, heteroaryloxy, carboxyl, alkoxycarbonyl, acyl, nitro, amino, alkylamino, arylamino, heteroarylamino, amido, acylamino, sulfate, sulfonate, sulfonyl, sulfoxido, sulfonamido, sulfamoyl, —[C(R4)2]p—R5, NR14R15, OR16, O—[C(R4)2]p—R5, NR14—[C(R4)2]p—R5 and SR16; R14 and R15 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R4)2]p—R5, —COR6, —C(O)OR6, —SO2(R6), —C(O)N(R6)(R7), —SO2N(R6)(R7), and —P(O)(OR6)(OR7); or R14 and R15 are joined together to form an optionally substituted heterocyclic ring; R16 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, —[C(R4)2]p—R5, —COR6, and —C(O)N(R6)(R7); and p is 1, 2, 3, 4, 5, or 6; wherein any one of the aforementioned alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, and heterocyclylalkyl may be optionally substituted; and wherein the cancer is selected from the group consisting of:
adrenocortical carcinoma; anal cancer; basal cell carcinoma; bladder cancer; breast cancer; bronchial adenomas/carcinoids; cervical cancer; colon cancer; colorectal cancer; endometrial cancer; esophageal cancer; extrahepatic bile duct cancer; gallbladder cancer; gastric (stomach) cancer; gastrointestinal carcinoid tumor; gestational trophoblastic tumor; head and neck cancer, hepatocellular (liver) cancer; hypopharyngeal cancer; kidney (renal cell) cancer; laryngeal cancer; lip and oral cavity cancer; metastatic squamous neck cancer with occult primary; multiple endocrine neoplasia syndrome; nasal cavity and paranasal sinus cancer; nasopharyngeal cancer; Non-Small Cell Lung cancer; oral cancer; oropharyngeal cancer; pancreatic cancer; parathyroid cancer; penile cancer; pituitary tumor; prostate cancer; rectal cancer; salivary gland cancer; skin carcinoma, Merkel Cell; small cell lung cancer; small intestine cancer; squamous cell carcinoma; thymoma; thymoma and thymic carcinoma; thyroid cancer; transitional cell cancer of the renal pelvis and ureter; urethral cancer; uterine cancer, endometrial; vaginal cancer; vulvar cancer; Wilms' Tumor;acute lymphoblastic leukemia; acute myeloid leukemia; AIDS-related lymphoma; Burkitt's lymphoma; chronic lymphocytic leukemia; chronic myelogenous leukemia; chronic myeloproliferative disorders; cutaneous T-cell lymphoma; hairy cell leukemia; hematologic (blood) cancer; Hodgkin's lymphoma; multiple myeloma/plasma cell neoplasm' mycosis fungoides; myelodysplastic syndromes; myelodysplastic/myeloproliferative diseases; multiple myeloma; Non-Hodgkin's lymphoma; primary central nervous system lymphoma; Sezary Syndrome; Waldenstrom's Macroglobulinemia;Ewing's sarcoma; Kaposi's Sarcoma; osteosarcoma/malignant fibrous histiocytoma of bone; soft tissue sarcoma; uterine sarcoma;extracranial germ cell tumor; extragonadal germ cell tumor; ovarian cancer; ovarian epithelial cancer; ovarian germ cell tumor; and testicular cancer.