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EP-4737449-A1 - P53-Y220C SELECTIVE SMALL-MOLECULAR REACTIVATOR COMPOUND, PHARMACEUTICAL COMPOSITION AND USE THEREOF

EP4737449A1EP 4737449 A1EP4737449 A1EP 4737449A1EP-4737449-A1

Abstract

Provided in the present invention are compounds shown as formula (I) and racemates, stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, which have good p53-Y220C mutant activation effect, can be used for treating tumor diseases containing p53-Y220C mutant proteins, and can be used for preparing drugs for such disorders or diseases.

Inventors

  • GENG, Kaijun
  • LU, BIAO
  • YANG, FANGLONG
  • WANG, SIQIN
  • JIN, LEI

Assignees

  • Changchun Genescience Pharmaceutical Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240626

Claims (10)

  1. A compound shown as formula (I), and a racemate, a stereoisomer, a tautomer, an isotope-labeled counterpart, a nitrogen oxide, a solvate, a polymorph, a metabolite, an ester, a prodrug or a pharmaceutically acceptable salt thereof: wherein R 1 and R 2 are the same or different, and are independently selected from H, halogen, C 1-12 alkyl, or C 1-12 alkoxy; R 3 is selected from H, or C 1-12 alkyl; R 4 is selected from H, halogen, cyano, C 1-12 alkyl, C 2-12 alkoxy, C 2-12 alkenyl, C 1-12 alkynyl, C 3-12 cycloalkyl, halo-C 1-12 alkyl, halo-C 1-12 alkoxy, halo-C 3-12 cycloalkyl, cyano-C 1-12 alkyl, or cyano-C 1-12 alkoxy; W is selected from C 2-6 alkenylene, C 2-6 alkynylene, C 3-14 cycloalkylene, C 6-10 arylene, or 5-10 membered heteroarylene; ring A is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; R a is selected from H, CN, oxo (=O), halogen, OH, or the following groups unsubstituted or optionally substituted with one, two or more R a1 : C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)N(R a11 )(R a12 ), -N(R a13 )(R a14 ), -S(O) 2 -R a15 , -S(O)(=NR a16 )(R a17 ), or -P(O)(R a18 )(R a19 ); each R a1 is the same or different and is independently selected from H, OH, CN, halogen, or the following groups unsubstituted or optionally substituted with one, two or more R a2 : C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -NH 2 , or -S(O) 2 -C 1-12 alkyl; each R a2 is the same or different and is independently selected from H, OH, NH 2 , CN, halogen, C 1-6 alkyl, or C 1-6 alkoxy; R a11 , R a12 , R a13 , R a14 , R a15 , R a16 , R a17 , R a18 , and R a19 are the same or different and are independently selected from H, C 1-12 alkyl, C 3-7 cycloalkyl, or 3-8 membered heterocyclyl; m is selected from 0, 1, 2, 3, 4, or 5; Z is absent, or is selected from NH, S, O, C 1-6 alkylene, or C 1-6 alkylene-NH; ring E is selected from 3-14 membered heterocyclyl, or C 3-12 cycloalkyl; R e is selected from H, halogen, or the following groups unsubstituted or optionally substituted with one, two or more R e1 : C 1-12 alkyl, halo-C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 1-12 alkyl-NH-, or (C 1-12 alkyl) 2 -N-; each R e1 is the same or different and is independently selected from H, OH, NH 2 , CN, halogen, C 1-6 alkyl, or C 1-6 alkoxy; or, two R e attached to the same carbon atom together with the atoms to which they are respectively attached form a C 3-12 cycloalkane ring, or a 3-14 membered heterocycle; or, two R e attached to different carbon atoms together with the atoms to which they are respectively attached form a 3-14 membered heterocycle; p is selected from 0, 1, 2, 3, 4, or 5; X 1 , X 2 , and X 3 are the same or different, and are independently selected from CH or N, and at least two of X 1 , X 2 , and X 3 are CH; R x is selected from H, CN, halogen, C 1-12 alkyl, or C 1-12 alkoxy; n is selected from 0, 1, 2 or 3; Y is selected from C(O), C(O)NH, C(S), or SO 2 .
  2. The compound, and the racemate, stereoisomer, tautomer, isotope-labeled counterpart, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 , R 2 , and R 3 are the same or different and are independently selected from H, or C 1-6 alkyl; preferably, R 1 , R 2 , and R 3 are all H; preferably, R 4 is selected from C 1-6 alkyl, C 2-6 alkenyl, halo-C 1-6 alkyl, or cyano-C 1-6 alkyl; preferably, R 4 is selected from C 1-6 alkyl, halo-C 1-6 alkyl or cyano-C 1-6 alkyl; preferably, R 4 is selected from methyl, ethyl, propyl, isopropyl, vinyl, cyanomethyl, 2-fluoroethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl; preferably, R 4 is selected from methyl, ethyl, propyl, isopropyl, cyanomethyl, 2-fluoroethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl.
  3. The compound, and the racemate, stereoisomer, tautomer, isotope-labeled counterpart, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein W is selected from C 2-4 alkenylene, C 2-4 alkynylene, C 3-6 cycloalkylene, C 6-10 arylene, or 5-6 membered heteroarylene; preferably, W is selected from:
  4. The compound, and the racemate, stereoisomer, tautomer, isotope-labeled counterpart, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring A is selected from phenyl, 5-6 membered heteroaryl, 8-9 membered heteroaryl, 6-10 membered heterocyclyl, or C 3-6 membered cycloalkyl; preferably, ring A is selected from phenyl, 5-6 membered heteroaryl, 8-9 membered heteroaryl, 8-9 membered heterocyclyl, or C 3-6 membered cycloalkyl; preferably, ring A is selected from: preferably, R a is selected from H, CN, oxo (=O), halogen, OH, or the following groups unsubstituted or optionally substituted with one, two or more R a1 : C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -C(O)(NHC 1-6 alkyl), - S(O) 2 -C 1-6 alkyl, -S(O)(=NH)(C 1-6 alkyl), -S(O)(NC 1-6 alkyl)(C 1-6 alkyl), -P(O)(C 1-6 alkyl)(C 1-6 alkyl), or -NH 2 ; each R a1 is the same or different and is independently selected from H, OH, CN, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, cyano-C 1-6 alkyl, cyano-C 1-6 alkoxy, C 1-6 alkyl-NH-, (C 1-6 alkyl) 2 -N-, -S(O) 2 -C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, or hydroxy-C 1-6 alkyl; preferably, R a is selected from H, F, Cl, CN, oxo (=O), OH, or the following groups unsubstituted or optionally substituted with one, two or more R a1 : methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, isopropoxy, propoxy, phenyl, pyridyl, benzyl, piperidyl, -C(O)NHCH 3 , -S(O) 2 -CH 3 , -S(O)(=NH)(CH 3 ), -P(O)(CH 3 )(CH 3 ), or -NH 2 ; each R a1 is the same or different and is independently selected from H, CN, OH, F, Cl, methyl, ethyl, methoxy, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 OH, -CH 2 CN, -N(CH 3 ) 2 , -S(O) 2 -CH 3 , preferably, R a is selected from H, F, Cl, CN, oxo (=O), OH, NH 2 , methylamino, dimethylamino, methyl, ethyl, isopropyl, tert-butyl, -C(CH 3 ) 2 CH 2 CH 3 , -CH 2 C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, benzyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy, isopropyloxy, 2-hydroxyethyl, preferably, is selected from
  5. The compound, and the racemate, stereoisomer, tautomer, isotope-labeled counterpart, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein Z is absent, or is selected from NH, S, O, CH 2 , or CH 2 NH; preferably, ring E is selected from 5-9 membered heterocyclyl or C 5-6 cycloalkyl; preferably, ring E is selected from 6-9 membered heterocyclyl or C 5-6 cycloalkyl; preferably, ring E is selected from preferably, ring E is selected from preferably, R e is selected from H, halogen, or the following groups unsubstituted or optionally substituted with one, two or more R e1 : C 1-6 alkyl, halo-C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4-9 membered heterocyclyl, or (C 1-6 alkyl) 2 -N-; each R e1 is the same or different and is independently selected from OH, halogen, C 1-3 alkyl, or C 1-3 alkoxy; or two R e together with the atoms to which they are respectively attached form a C 3-6 cycloalkane ring; preferably, R e is selected from H, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, or (C 1-6 alkyl) 2 -N-; or, two R e together with the atoms to which they are respectively attached form a C 3-6 cycloalkane ring; preferably, R e is selected from H, F, Cl, methyl, deuterated methyl (CD 3 ), trifluoromethyl, ethyl, isopropyl, cyclopropyl, methoxy, dimethylamino, or, two R e attached to the same carbon atom together with the atoms to which they are respectively attached form a cyclopropane ring, or, two R e attached to different carbon atoms together with the atoms to which they are respectively attached form preferably, R e is selected from H, F, Cl, methyl, deuterated methyl (CD 3 ), trifluoromethyl, ethyl, isopropyl, cyclopropyl, methoxy, dimethylamino, or, two R e attached to the same carbon atom together with the atoms to which they are respectively attached form a cyclopropane ring, or or, two R e attached to different carbon atoms together with the atoms to which they are respectively attached form preferably, X 1 , X 2 , and X 3 are all CH, or one of X 1 , X 2 , and X 3 is N; preferably, R x is selected from H, CN, halogen, C 1-6 alkyl, or C 1-6 alkoxy; preferably, R x is selected from H, F, Cl, CN, methoxy, or methyl.
  6. The compound, and the racemate, stereoisomer, tautomer, isotope-labeled counterpart, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the compound shown as formula (I) has a structure shown below: wherein ring A, ring E, X 1 , X 2 , X 3 , Y, R 1 , R 2 , R 3 , R 4 , R a , R e , R x , m, n, and p are as defined in any one of claims 1 to 5; preferably, the compound shown as formula (I) has a structure shown below: or wherein ring A, ring E, X 1 , X 2 , X 3 , Y, R 1 , R 2 , R 3 , R 4 , R a , R e , R x , m, n, and p are as defined in any one of claims 1 to 5; preferably, the compound shown as formula (I) has a structure shown below: wherein R a , R x , m, and n are as defined in any one of claims 1 to 5; preferably, the compound shown as formula (I) has a structure shown below: wherein ring A, R a , R x , m, and n are as defined in any one of claims 1 to 5; preferably, the compound shown as formula (I) has a structure shown below: wherein R a and R e are as defined in any one of claims 1 to 5.
  7. The compound, and the racemate, stereoisomer, tautomer, isotope-labeled counterpart, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the compound shown as formula (I) is selected from the following structures:
  8. A method for preparing the compound, and the racemate, stereoisomer, tautomer, isotope-labeled counterpart, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, comprising the following step: allowing compound 1 to react with compound 2 to give the compound shown as formula (1); wherein ring A, ring E, X 1 , X 2 , X 3 , W, Y, Z, R 1 , R 2 , R 3 , R 4 , R a , R e , R x , m, n, and p are as defined in any one of claims 1 to 7.
  9. A pharmaceutical composition, comprising a therapeutically effective amount of at least one of the compound, and the racemate, stereoisomer, tautomer, isotope-labeled counterpart, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.
  10. Use of at least one of the compound, and the racemate, stereoisomer, tautomer, isotope-labeled counterpart, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 in the preparation of a drug; preferably, the use can be use in the preparation of drugs against tumors containing p53-Y220C mutant, such as in the preparation of p53-Y220C reactivator drugs; preferably, the tumor containing p53-Y220C mutant includes acute lymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumors such as cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive cell tumor, neuroectodermal tumor, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma, Burkitt's lymphoma, cancer of unknown primary, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, germ cell tumors, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gliomas, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell carcinoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, lip and oral cancer, liposarcoma, liver cancer, lung cancer such as non-small cell lung cancer and small cell lung cancer, lymphoma, leukemia, macroglobulinemia, malignant bone fibrous histiocytoma/osteosarcoma, medulloblastoma, melanoma, mesothelioma, metastatic squamous cell carcinoma with occult primary, oral cancer, multiple endocrine neoplasms syndrome, myelodysplastic syndrome, myeloid leukemia, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma/malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic islet cell carcinoma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germ cell tumor, pituitary adenoma, pleuropulmonary blastoma, plasmacytoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, transitional cell carcinoma of renal pelvis and ureter, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, sarcoma, skin cancer, cutaneous Merkel cell carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, T-cell lymphoma, laryngeal cancer, thymoma, thymic carcinoma, thyroid cancer, gestational trophoblastic tumor, cancer of unknown primary site, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and nephroblastoma.

Description

The present invention claims priority to prior applications including Patent Application No. 202310767412.7 filed with the China National Intellectual Property Administration on June 27, 2023, entitled "p53-Y220C Selective Small-Molecule Reactivator Compound, Pharmaceutical Composition and Use Thereof"; Patent Application No. 202310972386.1 filed with the China National Intellectual Property Administration on August 3, 2023, entitled "p53-Y220C Selective Small-Molecule Reactivator Compound, Pharmaceutical Composition and Use Thereof"; Patent Application No. 202311158861.8 filed with the China National Intellectual Property Administration on September 8, 2023, entitled "p53-Y220C Selective Small-Molecule Reactivator Compound, Pharmaceutical Composition and Use Thereof"; Patent Application No. 202311378644.X filed with the China National Intellectual Property Administration on October 23, 2023, entitled "p53-Y220C Selective Small-Molecule Reactivator Compound, Pharmaceutical Composition and Use Thereof"; Patent Application No. 202311566589.7 filed with the China National Intellectual Property Administration on November 22, 2023, entitled "p53-Y220C Selective Small-Molecule Reactivator Compound, Pharmaceutical Composition and Use Thereof"; and Patent Application No. 202410171815.X filed with the China National Intellectual Property Administration on February 6, 2024, entitled "p53-Y220C Selective Small-Molecule Reactivator Compound, Pharmaceutical Composition and Use Thereof". The above prior applications are incorporated herein by reference in their entirety. TECHNICAL FIELD The present invention belongs to the field of pharmaceutical compounds, and specifically, relates to p53-Y220C selective small-molecule reactivator compounds, pharmaceutical compositions and uses thereof. BACKGROUND Tumor is a set of related diseases characterized by uncontrolled proliferation of tumor cells that may metastasize throughout the body. Tumor cell proliferation is dependent on the proto-oncogene and the cancer suppressor gene, and gene mutation can lead to abnormal activation or activity inhibition of these two genes, which further promote uncontrolled cell division. As a well-known cancer suppressor gene, TP53 is known as the "Genome Guardian". TP53 is a member of the p53-like transcription factor family which includes three members, TP53, TP63 and TP73 genes encoding p53, p63 and p73 proteins, respectively. They have similar structures: their DNA binding domains are almost identical and can all bind to similar DNA-specific sequences, regulating the transcription of the same gene and some different genes; their C-terminal domains differ in size, sequence and function, regulating DNA binding and transcription and mediating protein interactions; their N-terminal sequences encode at least two different transcription activation domains. Similar to p53, p63 is also a key transcription factor that responds to DNA damage by inducing apoptosis, acts on the skull, face, limbs, and central nervous system, and participates in the generation and regeneration of squamous cell epithelium throughout the body. The production of ciliary epithelial cells requires p73, which acts on male germ cells, the immune system, the hearing system, the trachea, the lungs, the central nervous system, etc. The p53 cancer suppressor factor is mainly distributed in the nucleoplasm of cells. As a sensor of cell stress, it can respond to a variety of cell stresses, including ultraviolet radiation, hypoxia, oncogene activation and DNA damage. Upon activation, p53 binds to specific DNA sequences in the form of a tetramer, mediates downstream gene transcription, and inhibits cancer progression through a variety of mechanisms, such as regulation of cell cycle, apoptosis, aging, stem cell differentiation, metabolism (lowering glycosynthesis), ROS and mitochondria, and DNA damage repair. p53 can activate proteins involved in the above pathways, including, for example, Fas/Apol, KILLER/DR5, Bax, Puma, Noxa, Bid, caspase-3, caspase-6, caspase-7, caspase-8, caspase-9 and p21. In addition, p53 can also inhibit the transcription of a variety of genes, including c-MYC, Cyclin B, VEGF, RAD51 and hTERT. Due to its key role in tumor suppression, TP53 gene is the most frequently mutated gene in human cancers, with p53 mutations present in nearly 50% of malignant tumors. Contrary to the mutations of other cancer suppressor genes such as RB1, APC, PTEN, most TP53 mutations are missense mutations in up to 75% of cases. Most missense mutations are located in the DNA binding domain of p53, resulting in abnormal folding of the protein sequence required for DNA recognition and binding. p53 may be mutated in many amino acid sites, such as Vall43, Hisl68, Argl75, Tyr220, Gly245, Arg248, Arg299, Phe270, Arg273 and Arg282. Accordingly, p53 mutations that can abrogate wild-type p53 activity include, for example, R175H, Y220C, G245S, R248Q, R248W, R273H and R282H. These p53 mutations can