WO2024046443A1 - Composés macrocycliques utilisés en tant qu'inhibiteurs sélectifs de cdk - Google Patents
Composés macrocycliques utilisés en tant qu'inhibiteurs sélectifs de cdk Download PDFInfo
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- WO2024046443A1 WO2024046443A1 PCT/CN2023/116366 CN2023116366W WO2024046443A1 WO 2024046443 A1 WO2024046443 A1 WO 2024046443A1 CN 2023116366 W CN2023116366 W CN 2023116366W WO 2024046443 A1 WO2024046443 A1 WO 2024046443A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
Definitions
- the present disclosure generally relates to macrocyclic compounds as selective CDK inhibitors, compositions comprising the same, and methods of using the same, for inhibiting cyclin-dependent kinases and/or for treating cancer described herein.
- Cyclin-dependent kinases are important cellular enzymes that perform essential functions in regulating eukaryotic cell division and proliferation.
- the cyclin-dependent kinase catalytic units are activated by regulatory subunits known as cyclins. At least sixteen mammalian cyclins have been identified (Johnson DG, Walker CL. Cyclins and Cell Cycle Checkpoints. Annu. Rev. Pharmacol. Toxicol. (1999) 39: 295-312) .
- Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6, and likely other heterodynes are important regulators of cell cycle progression.
- cyclin/CDK heterodynes Additional functions include regulation of transcription, DNA repair, differentiation and apoptosis (Morgan DO. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell. Dev. Biol. (1997) 13: 261-291) .
- CDK2 Overexpression of CDK2 is associated with abnormal regulation of cell-cycle.
- the cyclin E/CDK2 complex plays and important role in regulation of the G1/Stransition, histone biosynthesis and centrosome duplication. Progressive phosphorylation of Rb by cyclin D/CDK4/6 and cyclin E/CDK2 releases the G1 transcription factor, E2F, and promotes S-phase entry. Activation of cyclin A/CDK2 during early S-phase promotes phosphorylation of endogenous substrates that permit DNA replication and inactivation of E2F, for S-phase completion. (Asghar et al. The history and future of targeting cyclin-dependent kinases in cancer therapy, Nat. Rev. Drug. Discov. 2015; 14 (2) : 130-146) .
- CDK2 knock out mice are viable with minimum defects, suggesting CDK2 is not essential for normal cell proliferation (Berthet et al., CDK2 knock out mice are viable. Curr Biol. (2003) 13 (20) : 1775-85) .
- selective CDK2 inhibitors may minimize clinical toxicity while being active in treating patients with high tumor cyclin E1 and/or E2 expression.
- a series of multitarget inhibitor CDK inhibitors are disclosed in WO2018033815A1, US20200247784A1, WO2022135442A1 and WO2022135365A1.
- major companies have identified and discovered a series of inhibitors that selectively inhibit CDK2 for the treatment of cancer and other diseases, such as Seliciclib, Dinaciclib, PF-07104091.
- Seliciclib which inhibits CDK2, 7, and 9 is being investigated for treatment of advanced solid tumors in conjunction with chemotherapy.
- Dinaciclib is a potent multitarget inhibitor of CDK1, 2, 5, and 9, is currently in clinical development for breast and hematological cancers.
- CDK2 inhibitor PF-07104091 is identical to the chemical structure for example 13 in WO2020157652, is currently in clinical development. Despite significant efforts, there are no approved agents targeting CDK2. An unmet medical need therefore exists for effective and safe CDK inhibitors, especially the CDK inhibitors having selectivity for CDK2.
- A-L2 moiety (Formula I shown on “SUMMARY” section) is specifically composed and designed for that purpose.
- a compound of formula I or a pharmaceutically acceptable salt thereof can inhibit the activity of CDKs, including CDK2, thereby effecting biological functions.
- the invention provides compounds that are selective for CDK2.
- the disclosure also provides pharmaceutical compositions and medicaments, comprising the compounds or salts of the invention.
- a process for preparing a pharmaceutical composition comprising mixing pharmaceutically acceptable excipients with a therapeutically effective amount of a compound with formula I or a pharmaceutically acceptable salt thereof.
- a compound with formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in the prevention or treatment of cancer.
- a method of treating or preventing cancer comprising administering a therapeutically effective amount a compound with formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need.
- the disclosure also provides a use of a compound with formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the manufacture of a medicament for use in the treatment of cancer.
- the disclosure also provides a use of a compound with formulaIIas intermediate in the synthesis of a compound with formula I or a pharmaceutically acceptable salt thereof.
- the present invention provides compounds of formula I or a pharmaceutically acceptable salt thereof. Such compounds can inhibit the activity of CDKs, including CDK2. In some embodiments, the invention provides compounds that are selective for CDK2.
- L 1 is a saturated or unsaturated C 1-9 aliphatic chain optionally substituted with 1-9 R 1 , optionally 1-6 carbon atoms on the aliphatic chain are independently replaced with N, O, S;
- L 2 is absent or is independently selected from group consisting of OH, saturated or unsaturated C 1-5 aliphatic chain optionally substituted with 1-5 R 2 , optionally 1-3 carbon atoms on the aliphatic chain are independently replaced with N, O, S;
- Ring A is absent or is selected from group consisting of optionally substituted 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the 1-4 heteroatom is independently selected from N, O, S;
- the compound of formula I or a pharmaceutically acceptable salt wherein:
- L 1 is a saturated or unsaturated C 3-9 aliphatic chain optionally substituted with 1-6 R 1 , optionally 1-6 carbon atoms on the aliphatic chain are independently replaced with N, O, S;
- L 1 is selected from group consisting of optionally 1-6 R 1 substituted C 3-9 alkylene, C 3-9 heteroalkylene, C 3-9 alkenylene, C 3-9 heteroalkenylene, C 3-9 alkynylene, C 3-9 heteroalkynylene; wherein the 1-6 heteroatom is independently selected from N, O, S; more preferably, L 1 is selected from group consisting of optionally 1-4 R 1 substituted C 4-6 alkylene, C 4-6 heteroalkylene, C 4-6 alkenylene, C 4-6 heteroalkenylene, C 4-6 alkynylene, C 4-6 heteroalkynylene; wherein the 1-6 heteroatom is independently selected from N, O.
- the compound of formula I or a pharmaceutically acceptable salt wherein:
- the compound of formula I or a pharmaceutically acceptable salt wherein:
- the compound of formula I or a pharmaceutically acceptable salt wherein:
- Ring A is selected from group consisting of optionally substituted 6-10 membered aryl or 5-10 membered heteroaryl, wherein the 1-4 heteroatom is independently selected from N;
- the compound of formula I or a pharmaceutically acceptable salt, wherein the compound is selected from:
- the compounds disclosed herein may exist as tautomers and optical isomers (e.g., enantiomers, diastereomers, diastereomeric mixtures, racemic mixtures, and the like) .
- Compounds provided herein can also include all isotopes of atoms occurring in the intermediates or final compounds.
- Isotopes include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include tritium and deuterium.
- One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance.
- the compound includes at least one deuterium atom.
- one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium.
- the compound includes two or more deuterium atoms.
- the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms.
- Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N. Y., Appleton-Century-Crofts, 1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011) .
- Isotopically labeled compounds can be used in various studies such as NMR spectroscopy, metabolism experiments, and/or assays.
- any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
- a position is designated specifically as “H” or “hydrogen, ” the position is understood to have hydrogen at its natural abundance isotopic composition.
- a position is designated specifically as “D” or “deuterium” , the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45%incorporation of deuterium) .
- a pharmaceutical composition comprising a compound with formula I or a pharmaceutically acceptable salt thereof and pharmaceutical excipients.
- a process for preparing a pharmaceutical composition comprising mixing pharmaceutically acceptable excipients with a therapeutically effective amount of a compound with formula I or a pharmaceutically acceptable salt thereof.
- composition refers to a mixture of at least one compound useful within the disclosure with a pharmaceutically acceptable carrier.
- the pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
- the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function.
- a compound with formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in the prevention or treatment of cancer.
- a method of treating or preventing cancer comprising administering a therapeutically effective amount a compound with formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need.
- the disclosure also provides a use of a compound with formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the manufacture of a medicament for use in the treatment of cancer.
- the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma) , esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC) , liver cancer (including HCC) , pancreatic cancer, stomach (including gastric) cancer and/or thyroid cancer.
- lung cancer including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma
- esophageal cancer esophageal cancer
- head and neck cancer colorectal cancer
- kidney cancer including RCC
- liver cancer including HCC
- pancreatic cancer including gastric cancer and/or thyroid cancer.
- the breast cancer is selected from ER-positive/HR-positive, HER2-negative breast cancer, ER-positive/HR-positive, HER2-positive breast cancer, triple negative breast cancer (TNBC) , and inflammatory breast cancer.
- the breast cancer is selected from endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition.
- the cancer is advanced or metastatic cancer.
- the cancer is characterized by an amplification or overexpression of cyclin E1 and/or cyclin E2.
- the compound with formulaII is used as an intermediate in the synthesis of a compound with formula I or a pharmaceutically acceptable salt thereof.
- alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C 1 -C 6 alkyl means an alkyl having one to six carbon atoms) and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl, neopentyl, and hexyl. Other examples of C 1 -C 6 alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.
- aliphatic chain refers to organic chain containing at least two carbon atoms, which is including but not limited to alkylene, heteroalkylene, alkenylene, heteroalkenylene and heteroalkynylene.
- alkene refers to a monovalent group derived from a hydrocarbon moiety containing, in certain embodiments, from two to six, or two to eight carbon atoms having at least one carbon-carbon double bond.
- the alkenyl group may or may not be the point of attachment to another group.
- alkenyl includes, but is not limited to, ethenyl, 1-propenyl, 1-butenyl, heptenyl, octenyl and the like.
- aryl refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings.
- Aryl groups can include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members.
- Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group.
- Representative aryl groups include phenyl, naphthyl and biphenyl.
- Other aryl groups include benzyl, having a methylene linking group.
- aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl.
- Aryl groups can be substituted or unsubstituted.
- alkylene refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated (i.e., C 1-6 means one to six carbons) , and linking at least two other groups, i.e., a divalent hydrocarbon radical.
- the two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group.
- a straight chain alkylene can be the bivalent radical of - (CH 2 ) n-, where n is 1, 2, 3, 4, 5 or 6.
- Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.
- alkenylene refers to a bivalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing at least one double bond.
- C 3 -C 9 alkenylene refers to a bivalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from three to nine carbon atoms.
- Non-limiting examples of "C 3 -C 9 alkenylene” groups include prop-1-enylene (a C 3 alkenylene) , but-1-enylene (a C 4 alkenylene) , pent-1-enylene (a C 5 alkenylene) , pent-4-enylene (a C 5 alkenylene) , penta-1, 4-dienylene (a C 5 alkenylene) , hexa-1-enylene (a C 6 alkenylene) , hexa-2-enylene (a C 6 alkenylene) , hexa-3-enylene (a C 6 alkenylene) , hexa-1-, 4-dienylene (a C 6 alkenylene) , hexa-1-, 5-dienylene (a C 6 alkenylene) and hexa-2-, 4-dienylene (a C 6 alkenylene) .
- cycloalkylene refers to a cycloalkyl, as defined herein, having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent cycloalkyl.
- examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene and cyclohexylene.
- Cycloalkylenes of the present disclosure include monocyclic, bicylic and tricyclic ring structures.
- halo or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
- cycloalkyl means a non-aromatic carbocyclic system that is fully saturated having 1, 2 or 3 rings wherein such rings may be fused.
- fused means that a second ring is present (i.e., attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring.
- Cycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature with each individual ring within the bicycle varying from 3-8 atoms.
- cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [3.1.0] hexyl, spiro [3.3] heptanyl, and bicyclo [1.1.1] pentyl.
- haloalkyl refers to an alkyl group, as defined above, substituted with one or more halo substituents, wherein alkyl and halo are as defined herein.
- Haloalkyl includes, by way of example, chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, and the like.
- heterocyclyl or “heterocycloalkyl” means a non-aromatic carbocyclic system containing 1, 2, 3, 4 heteroatoms selected independently from N, O or S and having 1, 2 or 3 rings wherein such rings may be fused, wherein fused is defined above.
- Heterocyclyl also includes bicyclic structures that may be Bridged-ring or Spiro-ring in nature with each individual ring within the bicycle varying from 3-8 atoms, and containing 0, 1, 2, 3 or 4 N, atoms.
- heterocyclyl includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams) and also specifically includes, but is not limited to, epoxidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl) , pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2, 5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1, 3-oxazinanyl, 1, 3-thiazinanyl, 2-azabicyclo- [2.1.1] hexanyl, 5-azabicyclo [2.1.1] hexanyl, 6-azabicyclo [3.1.1] heptanyl, 2-azabic
- the 1, 2, 3 or 4 heteroatoms on ring A is N, specifically includes, but is not limited to, aziridinyl, azetidinyl, pyrrolidinyl, 2, 5-dihydro-1H-pyrrolyl, piperidinyl, piperazinyl, 2-azabicyclo- [2.1.1] hexanyl, 5-azabicyclo [2.1.1] hexanyl, 6-azabicyclo [3.1.1] heptanyl, 2-azabicyclo [2.2.1] -heptanyl, 3-azabicyclo [3.1.1] heptanyl, 2-azabicyclo [3.1.1] heptanyl, 3-azabicyclo [3.1.0] -hexanyl, 2-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [3.2.1] octanyl, 8-azabicyclo [3.2.1] octanyl, triazolyl, tetrazolyl.
- heteroaryl refers any mono-or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen (including quaternary nitrogens) .
- substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
- the term “optionally substituted” means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group (s) individually and independently selected from groups described herein.
- the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
- an element means one element or more than one element.
- use of the term “including” as well as other forms, such as “include, ” “includes, ” and “included, ” is not limiting.
- administration refers to the providing a therapeutic agent to a subject.
- Multiple techniques of administering a therapeutic agent exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
- treat, ” “treated, ” “treating, ” or “treatment” includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated.
- prevent means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.
- the term “patient, ” “individual, ” or “subject” refers to a human or a non-human mammal.
- Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline, and marine mammals.
- the patient, subject, or individual is human.
- the terms “effective amount, ” “pharmaceutically effective amount, ” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
- the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
- pharmaceutically acceptable salt refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
- pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as formate.
- Step 1 ethyl 1- (5- ( (tert-butoxycarbonyl) amino) pentyl) -1H-pyrazole-5-carboxylate
- Step3 ethyl 1- (5- ( ( ( ( (1R, 3S) -3- (3- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) pentyl) -1H-pyrazole-5-carboxylate
- Step4 ethyl 1- (5- ( ( ( ( ( (1R, 3S) -3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) pentyl) -1H-pyrazole-5-carboxylate
- Step5 1- (5- ( ( ( ( ( ( (1R, 3S) -3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) pentyl) -1H-pyrazole-5-carboxylic acid
- Step6 (1 1 S, 1 3 R, Z) -2 1 - (tert-butyl) -2 1 H, 5 1 H-13-oxa-3, 11-diaza-2 (5, 3) , 5 (5, 1) -dipyrazola-1 (1, 3) -cyclop entanacyclotridecaphane-4, 12-dione
- Step7 (1 1 S, 1 3 R, Z) -2 1 H, 5 1 H-13-oxa-3, 11-diaza-2 (5, 3) , 5 (5, 1) -dipyrazola-1 (1, 3) -cyclopentanacyclotridecaphane-4, 12-dione
- Step 1 ethyl 1- (6- (tert-butoxycarbonyl) amino) hexyl) -1H-pyrazole-5-carboxylate
- Step 2 ethyl 1- (6-aminohexyl) -1H-pyrazole-5-carboxylate
- Step 3 ethyl 1- (6- ( ( ( ( (1R, 3S) -3- (3- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) hexyl) -1H-pyrazole-5-carboxylate
- Step 4 ethyl 1- (6- ( ( ( ( (1R, 3S) -3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) hexyl) -1H-pyrazole-5-carboxylate
- Step 5 1- (6- ( ( ( ( ( ( (1R, 3S) -3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) hexyl) -1H-pyrazole-5-carboxylic acid
- Step 6 (11S, 13R, Z) -21- (tert-butyl) -21H, 51H-14-oxa-3, 12-diaza-2 (5, 3) , 5 (5, 1) -dipyrazola-1 (1, 3) -cyclopentanacyclotetradecaphane-4, 13-dione
- Step 7 (11S, 13R, Z) -21H, 51H-14-oxa-3, 12-diaza-2 (5, 3) , 5 (5, 1) -dipyrazola-1 (1, 3) -cyclopentanacyclotetradecaphane-4, 13-dione
- Step 1 ethyl 1- (2-azidoethyl) -1H-pyrazole-5-carboxylate
- Step 2 ethyl 1- (2- (5- (aminomethyl) -1H-1, 2, 3-triazol-1-yl) ethyl) -1H-pyrazole-5-carboxylate
- Step 3 ethyl 1- (2- (5- ( ( ( ( ( ( (1R, 3S) -3- (3- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) methyl) -1H-1, 2, 3-triazol-1-yl) ethyl) -1H-pyrazole-5-carboxylate
- Step 4 1- (2- (5- ( ( ( ( ( ( ( ( (1R, 3S) -3- (3- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) methyl) -1H-1, 2, 3-triazol-1-yl) ethyl) -1H-pyrazole-5-carboxylic acid
- Step 5 1- (2- (5- ( ( ( ( ( ( ( ( ( ( (1R, 3S) -3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) oxy) carb onyl) amino) methyl) -1H-1, 2, 3-triazol-1-yl) ethyl) -1H-pyrazole-5-carboxylic acid
- Step 6 (11S, 13R, Z) -21- (tert-butyl) -21H, 51H, 81H-12-oxa-3, 10-diaza-8 (1, 5) -triazola-2 (5, 3) , 5 (5, 1) -dipyrazola-1 (1, 3) -cyclopentanacyclododecaphane-4, 11-dione
- Step 7 (11S, 13R, Z) -21H, 51H, 81H-12-oxa-3, 10-diaza-8 (1, 5) -triazola-2 (5, 3) , 5 (5, 1) -dipyrazola-1(1, 3) -cyclopentanacyclododecaphane-4, 11-dione
- Step 1 ethyl 1- (2- (tert-butoxy) -2-oxoethyl) -1H-pyrazole-5-carboxylate
- Step 2 1- (2- (tert-butoxy) -2-oxoethyl) -1H-pyrazole-5-carboxylic acid
- Step 3 tert-butyl 2- (5- ( (1- (tert-butyl) -5- ( (1S, 3R) -3- ( (tert-butyldimethylsilyl) oxy) cyclopentyl) -1H-pyrazol-3-yl) carbamoyl) -1H-pyrazol-1-yl) acetate
- Step 4 tert-butyl 2- (5- ( (1- (tert-butyl) -5- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-3-yl) carbamoyl) -1H-pyrazol-1-yl) acetate
- Step5 tert-butyl 2- (5- ( (1- (tert-butyl) -5- ( (1S, 3R) -3- ( ( (4-nitrophenoxy) carbonyl) oxy) cyclopentyl) -1H-pyrazol-3-yl) carbamoyl) -1H-pyrazol-1-yl) acetate
- Step6 tert-butyl 2- (5- ( (1- (tert-butyl) -5- ( (1S, 3R) -3- ( ( (1-cyanocyclopropyl) carbamoyl) oxy) cyclopentyl) -1H-pyrazol-3-yl) carbamoyl) -1H-pyrazol-1-yl) acetate
- Step7 tert-butyl 2- (5- ( (5- ( (1S, 3R) -3- ( ( (1- (aminomethyl) cyclopropyl) carbamoyl) oxy) cyclopentyl) -1- (tert-butyl) -1H-pyrazol-3-yl) carbamoyl) -1H-pyrazol-1-yl) acetate
- Step8 2- (5- ( (5- ( (1S, 3R) -3- ( ( (1- (aminomethyl) cyclopropyl) carbamoyl) oxy) cyclopentyl) -1- (tert-butyl) -1H-pyrazol-3-yl) carbamoyl) -1H-pyrazol-1-yl) acetic acid
- Step9 (1'S, 3'R, Z) -1'- (tert-butyl) spiro [cyclopropane-1, 10'-13-oxa-3, 8, 11-triaza-2 (5, 3) , 5 (5, 1) - dipyrazola-1 (1, 3) -cyclopentanacyclotridecaphane] -4', 7', 12'-trione
- Step 1 methyl 3-bromo-1- (6- ( (tert-butoxycarbonyl) amino) hexyl) -1H-pyrazole-5-carboxylate
- Step 2 methyl 1- (6-aminohexyl) -3-bromo-1H-pyrazole-5-carboxylate
- Step 3 methyl 1- (6- ( ( ( ( (1R, 3S) -3- (3- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) hexyl) -3-bromo-1H-pyrazole-5-carboxylate
- Step 4 methyl 1- (6- ( ( ( ( (1R, 3S) -3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) hexyl) -3-bromo-1H-pyrazole-5-carboxylate
- Step 5 1- (6- ( ( ( ( ( (1R, 3S) -3- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) hexyl) -3-bromo-1H-pyrazole-5-carboxylic acid
- Step 6 (11S, 13R, Z) -53-bromo-21- (tert-butyl) -21H, 51H-14-oxa-3, 12-diaza-2 (5, 3) , 5 (5, 1) -dipyrazola-1 (1, 3) -cyclopentanacyclotetradecaphane-4, 13-dione
- Step 7 (11S, 13R, Z) -21- (tert-butyl) -53- ( (E) -styryl) -21H, 51H-14-oxa-3, 12-diaza-2 (5, 3) , 5 (5, 1) -dipyrazola-1 (1, 3) -cyclopentanacyclotetradecaphane-4, 13-dione
- Step 8 (11S, 13R, Z) -21- (tert-butyl) -53-phenethyl-21H, 51H-14-oxa-3, 12-diaza-2 (5, 3) , 5 (5, 1) -dipyrazola-1 (1, 3) -cyclopentanacyclotetradecaphane-4, 13-dione
- Step 9 (11S, 13R, Z) -53-phenethyl-21H, 51H-14-oxa-3, 12-diaza-2 (5, 3) , 5 (5, 1) -dipyrazola-1 (1, 3) -cyclopentanacyclotetradecaphane-4, 13-dione
- CDK1/Cyclin B1 assay The purpose of CDK1/Cyclin B1 assay is to evaluate the inhibition of small molecule inhibitors by using a luminescence-based ADP-Glo assay.
- CDK1/Cyclin B1 catalyzes the production of ADP from ATP with phosphoryl transferring to the substrate Histone H1 protein (SignalChem) .
- the ADP-Glo assay measures the amount of ADP to reflect the rate of kinase reaction. Wild-type CDK1 and wild-type Cyclin B1 enzyme complex was purchased from Proqinase.
- X log of inhibitor concentration
- Y %Inhibition
- CDK2/Cyclin E1 assay The purpose of CDK2/Cyclin E1 assay is to evaluate the inhibition of small molecule inhibitors by using a luminescence-based ADP-Glo assay.
- CDK2/Cyclin E1 catalyzes the production of ADP from ATP with phosphoryl transferring to the substrate Histone H1 protein (SignalChem) .
- the ADP-Glo assay measures the amount of ADP to reflect the rate of kinase reaction. Wild-type CDK2 and wild-type Cyclin E enzyme complex was purchased from Proqinase. Compounds dilutions were transferred into each well of 384-well assay plates (784075, Greiner) using Echo 550.2.5 ⁇ L 2 ⁇ enzyme was added into assay plate, room temperature for 10 mins.
- %Inhibition 100 - (Signalcmpd -SignalAve_PC) / (SignalAve_VC -SignalAve_PC) ⁇ 100.
- X log of inhibitor concentration
- Y %Inhibition
- the antiproliferation effect was assessed against the human ovarian adenocarcinoma cell lines based on DNA content measurement.
- the cell line NIH: OVCAR-3 (ATCC, HTB-161) were maintained in RPMI 1640 (Invitrogen, 11875-085) medium supplement with 20% (v/v) fetal bovine serum (BI, 04-002-1A) and 0.01 mg/mL insulin (Merck, 407709) .
- TOV-21G ATCC, CRL-11730
- Both cell lines were cultured according to the standard instruction of the American Type Culture Collection. The cell lines were authenticated by short tandem repeat profiling.
- Results of the CDK2 Biochemical Assay are presented in Table 2.
- Compounds having an IC 50 less than or equal to 50 nM are represented as "A” ; compounds having an IC 50 greater than 50 nM but less than or equal to 150 nM are represented as “B” ; compounds having an IC 50 greater than 150 nM but less than or equal to 300 nM are represented as "C” ; and compounds having an IC 50 greater than 300 nM are represented as "D” .
- Results of the CDK2 selectivity against CDK1 are presented in Table 2.
- Compounds having the selectivity less than or equal to 10-fold are represented as “D” ;
- Compounds having the selectivity greater than 100-fold are represented as "A” .
- Results of the Cell Assay are presented in Table 2.
- Compounds having an IC 50 less than or equal to 150 nM are represented as "A” ; compounds having an IC 50 greater than 150 nM hut less than or equal to 3 ⁇ M are represented as “B” ; compounds having an IC 50 greater than 3 ⁇ M but less than or equal to 30 ⁇ M are represented as "C” ; and compounds having an IC 50 greater than 30 ⁇ M are represented as "D” .
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Abstract
L'invention concerne des composés macrocycliques, des compositions pharmaceutiques et des procédés d'utilisation associés à des kinases dépendantes des cyclines (CDK). Les composés selon l'invention sont des inhibiteurs sélectifs de CDK2, qui peuvent être utilisés pour le traitement du cancer.
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PCT/CN2023/116366 WO2024046443A1 (fr) | 2022-09-01 | 2023-08-31 | Composés macrocycliques utilisés en tant qu'inhibiteurs sélectifs de cdk |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2020125513A1 (fr) * | 2018-12-19 | 2020-06-25 | 凯复制药有限公司 | Composé macrocyclique servant d'inhibiteur de cdk, son procédé de préparation et son utilisation en médecine |
US20210261530A1 (en) * | 2019-01-31 | 2021-08-26 | Pfizer Inc. | Cdk2 inhibitors |
CN113603708A (zh) * | 2021-07-27 | 2021-11-05 | 中国药科大学 | 一种具有大环骨架结构的新型cdk9抑制剂的制备及其应用 |
WO2022018667A1 (fr) * | 2020-07-24 | 2022-01-27 | Pfizer Inc. | Polythérapies utilisant des inhibiteurs de cdk2 et de cdc25a |
WO2022137106A1 (fr) * | 2020-12-24 | 2022-06-30 | Pfizer Inc. | Formes solides d'un inhibiteur de cdk2 |
WO2022174031A1 (fr) * | 2021-02-12 | 2022-08-18 | Relay Therapeutics, Inc. | Inhibiteurs de cdk et leurs procédés d'utilisation |
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2023
- 2023-08-31 WO PCT/CN2023/116366 patent/WO2024046443A1/fr unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2020125513A1 (fr) * | 2018-12-19 | 2020-06-25 | 凯复制药有限公司 | Composé macrocyclique servant d'inhibiteur de cdk, son procédé de préparation et son utilisation en médecine |
US20220017520A1 (en) * | 2018-12-19 | 2022-01-20 | Keythera (Suzhou) Pharmaceuticals Co. Ltd. | Macrocyclic compound as cdk inhibitor, preparation method therefor, and use thereof in medicine |
US20210261530A1 (en) * | 2019-01-31 | 2021-08-26 | Pfizer Inc. | Cdk2 inhibitors |
WO2022018667A1 (fr) * | 2020-07-24 | 2022-01-27 | Pfizer Inc. | Polythérapies utilisant des inhibiteurs de cdk2 et de cdc25a |
WO2022137106A1 (fr) * | 2020-12-24 | 2022-06-30 | Pfizer Inc. | Formes solides d'un inhibiteur de cdk2 |
WO2022174031A1 (fr) * | 2021-02-12 | 2022-08-18 | Relay Therapeutics, Inc. | Inhibiteurs de cdk et leurs procédés d'utilisation |
CN113603708A (zh) * | 2021-07-27 | 2021-11-05 | 中国药科大学 | 一种具有大环骨架结构的新型cdk9抑制剂的制备及其应用 |
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