Pyridinone-based epigenetic modifiers and uses thereof

Patent metadata

Field	Value
Publication number	US-11840533-B2
Application number	US-202217663499-A
Country	US
Kind code	B2
Filing date	May 16, 2022
Priority date	Dec 1, 2017
Publication date	Dec 12, 2023
Grant date	Dec 12, 2023

Abstract

Described herein are pyridinone-based compounds, derivatives thereof, and pharmaceutical formulations thereof. In some aspects, the pyridinone-based compounds, derivatives thereof, and/or pharmaceutical formulations thereof can be administered to a subject in need thereof. In some aspects, pyridinone-based compounds, derivatives thereof, and/or pharmaceutical formulations thereof can modulate an activity and/or a function of a BRD protein and/or BET protein.

First claim

The invention claimed is:

1. A method of treating cancer in a subject in need thereof,
the method comprising administering a compound according to Formula XXVI to the subject

wherein R 12 is a C 1 -C 3 alkyl, a C 1 -C 3 haloalkyl, propylenyl, —CH 2 (CO)CH═CH 2 , oxiran-2-ylmethyl, or CH 2 (CO)CH 2 Cl,
wherein R 11 is a nitrogen-containing bicyclic or tricyclic heteroaryl, an aryl, or a biaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: —N(R a )S(O) 2 R b , —S(O) 2 NR a R b , —C(O)NR a R b , —N(R a )C(O)R b , —NR a R b , —(C 1 -C 6 alkylenyl)R c , —(C 1 -C 3 cycloalkylenyl)R c , an aryl, a heteroaryl, and —(C 1 -C 6 alkylenyl)R c R c , —H, a halogen, —CN, a propylenyl, a C 1 -C 3 alkyl, a C 1 -C 3 haloalkyl, —OR 70 , —NR 70 R 70 , —C(O)OR 70 , —C(O)NR 70 R 70 , —S(O) 2 R 70 , —S(O) 2 NR 70 R 70 , —CH 2 (CO)CH═CH 2 , oxiran-2-ylmethyl, and CH 2 (CO)CH 2 Cl, and R 70 ,
wherein X is optionally present, and when present, is selected from —O—, —C(O)—, —N(R 77 )—, and —CH(R 70 )—,
R 77 is selected from the group consisting of: —H, a halogen, —CN, a C 1 -C 3 haloalkyl, —OR 70 , —NR 70 R 70 , —C(O)OR 70 , —C(O)NR 70 R 70 , —S(O) 2 R 70 , and —S(O) 2 NR 70 R 70 ,
wherein R 70 , at each occurrence, are each independently selected from the group consisting of: a C 1 -C 6 alkyl, a C 2 -C 6 alkenyl, a C 2 —C alkynyl, a halogen, a C 1 -C 6 haloalkyl, —CN, NO 2 , —OR e , —S(O) 2 NR e R f , —C(O)R e , —C(O)NR e R f , —NR e R f , —N(R e )C(O)R f , a —(C 1 -C 6 alkylenyl)-OR e , a —(C 1 -C 6 alkylenyl)-C(O)NR e R f , a —(C 1 -C 6 alkylenyl)-NR e R f , and a —(C 1 -C 6 alkylenyl)-N(R e )C(O)R f ,
wherein R a and R b , at each occurrence, are independently selected from the group consisting of: H, a C 1 -C 6 alkenyl, a C 1 -C 6 alkynyl, a C 1 -C 6 haloalkyl, R c , and a C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of: —OR e , —NR e R f , —C(O)OR e , —C(O)NR e R f , —S(O) 2 R e , —S(O) 2 NR e R f , and R c ,
wherein R c and R c′ , at each occurrence, are each independently selected from the group consisting of: an aryl, a heteroaryl, a heterocycle, a cycloalkyl, and a cycloalkenyl, and wherein each R c group is optionally substituted with 1, 2, 3, 4, or 5 R d groups, wherein R d , at each occurrence, are each independently selected from the group consisting of: a C 1 -C 6 alkyl, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl, a halogen, a C 1 -C 6 haloalkyl, —CN, NO 2 , —OR e , —S(O) 2 NR e R f , —C(O)R e , —C(O)NR e R f , —NR e R f , —N(R e )C(O)R f , a —(C 1 -C 6 alkylenyl)-OR e , a —(C 1 -C 6 alkylenyl)-C(O)NR e R f , a —(C 1 -C 6 alkylenyl)-NR e R f , and a —(C 1 -C 6 alkylenyl)-N(R e )C(O)R f ,
and wherein R e and R f , at each occurrence, are each independently selected from the group consisting of: H, a C 1 -C 6 alkyl, a C 1 -C 6 cycloalkyl, a aryl, a heteroaryl and a C 1 -C 6 haloalkyl, and
wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, Kaposi Sarcoma, AIDS-related lymphoma, primary central nervous system (CNS) lymphoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/Rhabdoid tumors, basal cell carcinoma of the skin, bile duct cancer, bladder cancer, bone cancer, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, cardiac tumors, germ cell tumors, embryonal tumors, cervical cancer, cholangiocarcinoma, chordroma, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative neoplasms, colorectal cancer, craniopharyngioma, cutaneous T-Cell lymphoma, ductal carcinoma in situ, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fallopian tube cancer, gallbladder cancer, kidney cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors, central nervous system germ cell tumors, extracranial germ cell tumors, extragonadal germ cell tumors, ovarian germ cell tumors, ovarian cancer, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, head and neck cancers, hepatocellular (liver) cancer, Langerhans cell histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, islet cell tumors, pancreatic neuroendocrine tumors, kidney (renal cell) cancer, laryngeal cancer, leukemia, lip cancer, oral cancer, lung cancer (non-small cell and small cell), lymphoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell neck cancer, midline tract carcinoma, multiple endocrine neoplasia syndromes, multiple myeloma, plasma cell neoplasms, mycosis fungoides, myelodyspastic syndromes, myelodysplastic/myeloproliferative neoplasms, chronic myelogenous leukemia, nasal cancer, sinus cancer, non-Hodgkin lymphoma, pancreatic cancer, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, peritoneal cancer, prostate cancer, rectal cancer, Rhabdomyosarcoma, salivary gland cancer, uterine sarcoma, Sezary syndrome, skin cancer, small intestine cancer, large intestine cancer (colon cancer), soft tissue sarcoma, T-cell lymphoma, throat cancer, oropharyngeal cancer, nasopharyngeal cancer, hypoharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, urethral cancer, uterine cancer, vaginal cancer, cervical cancer, vascular tumors and cancer, vulvar cancer, and Wilms Tumor.

2. The method of claim 1 , wherein the cancer is breast cancer, prostate cancer, pancreatic cancer, melanoma, or leukemia.

3. The method of claim 1 , wherein the compound has the structure according to Formula XXV

wherein R 1 is

wherein R 2 is

wherein R 3 is H, CH 3 , or CH 2 CH 3 , and
wherein X 1 , X 2 , and X 3 , are each independently selected from the group consisting of: C or N.

4. The method of claim 1 , wherein the compound has the structure according to Formula I

wherein R 12 is a C 1 -C 3 alkyl, a C 1 -C 3 haloalkyl, propylenyl, —CH 2 (CO)CH═CH 2 , oxiran-2-ylmethyl, or CH 2 (CO)CH 2 C 1 ,
wherein R 11 is a nitrogen-containing bicyclic or tricyclic heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: —N(R a )S(O) 2 R b , —S(O) 2 NR a R b , —C(O)NR a R b —N(R a )C(O)R b —NR a R b , —(C 1 -C 6 alkylenyl)R c , —(C 1 -C 3 cycloalkylenyl)R c , an aryl, a heteroaryl, and —(C 1 -C 6 alkylenyl)R c R c′ ,
wherein R a and R b , at each occurrence, are each independently selected from the group consisting of: H, a C 1 -C 6 alkenyl, a C 1 -C 6 alkynyl, a C 1 -C 6 haloalkyl, R c , and a C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of: —OR e , —NR e R f , —C(O)OR e , —C(O)NR e R f , —S(O) 2 R e , —S(O) 2 NR e R f , and R c ,
wherein R c and R c′ , at each occurrence, are each independently selected from the group consisting of: an aryl, a heteroaryl, a heterocycle, a cycloalkyl, and a cy

Assignees

• Univ Illinois

Inventors

• Thatcher Gregory R
• Xiong Rui
• Zhao Jiong
• Li Yangfeng

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title