WO2024008097A1 - Composé pour la dégradation ciblée de protéine cdk et son utilisation - Google Patents

Composé pour la dégradation ciblée de protéine cdk et son utilisation Download PDF

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WO2024008097A1
WO2024008097A1 PCT/CN2023/105759 CN2023105759W WO2024008097A1 WO 2024008097 A1 WO2024008097 A1 WO 2024008097A1 CN 2023105759 W CN2023105759 W CN 2023105759W WO 2024008097 A1 WO2024008097 A1 WO 2024008097A1
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substituted
unsubstituted
group
compound
alkyl
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Chinese (zh)
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李洪林
赵振江
钱旭红
陈卓
贺欢
刘琪
王洁
陈露
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华东理工大学
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    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems

Definitions

  • the present invention relates to the field of medicinal chemistry.
  • the present invention relates to compounds that target the degradation of CDK proteins, such as CDK4/6 and/or CDK9 proteins, their preparation methods and their use in the treatment of CDK protein-mediated diseases.
  • CDK4/6 and/or CDK9 play important roles in the formation and development of various cancers. Therefore, CDK4/6 and/or CDK9 targets have become important targets for targeted cancer therapy, especially for breast cancer, lung cancer, prostate cancer and other diseases. Targeting CDK4/6 and/or CDK9 kinases is very effective. therapeutic potential.
  • PROTACs utilize a bifunctional small molecule.
  • PROTACs can bind to target proteins and E3 at the same time in cells, ubiquitinating target proteins that cannot originally bind to E3, and then being recognized and degraded by the proteasome. Since the first PROTAC molecule was reported, many E3 ligases, such as von Hippel-Lindau (VHL), CRBN (cereblon), Mourine Double Mininute 2 (MDM2) and inhibitor of apoptosis protein 1 (cIAP1), have been used Different proteins for designing molecules that target PROTAC.
  • VHL von Hippel-Lindau
  • CRBN cereblon
  • MDM2 Mourine Double Mininute 2
  • cIAP1 inhibitor of apoptosis protein 1
  • PROTAC molecules can almost completely eliminate the function of target proteins.
  • PROTAC molecules usually do not need to bind firmly to the target molecule to achieve protein degradation, therefore, the occurrence of drug-induced resistance mutations can be effectively avoided.
  • PROTAC drugs targeting multiple targets have entered clinical trials.
  • the purpose of the present invention is to provide compounds capable of targeted degradation of CDK4/6 and/or CDK9 proteins, as well as preparation methods and applications thereof.
  • the compound of the present invention not only has excellent CDK4/6 and/or CDK9 protein degradation and anti-tumor activity, but also has little toxic and side effects on the human body, so it can be used to prepare anti-tumor drugs.
  • Another object of the present invention is to provide pharmaceutical compositions containing the above compounds.
  • Another object of the present invention is to provide the use of the above compounds in the preparation of drugs for treating diseases mediated by CDK4/6 and/or CDK9 proteins.
  • the present invention provides compounds represented by formula (I), or isomers, pharmaceutically acceptable salts, hydrated substance, solvate or prodrug:
  • R 1 is selected from the following group: unsubstituted or substituted (preferably halogen substituted) C 1 -C 10 linear or branched alkyl, unsubstituted or substituted (preferably halogen substituted) C 3 - C 8 cycloalkyl, unsubstituted or substituted C 3 -C 8 heterocyclyl, unsubstituted or substituted C 5 -C 10 aryl, unsubstituted or substituted C 5 -C 10 aromatic heterocyclyl;
  • R 2 is selected from the group consisting of hydrogen, acetyl, cyano, unsubstituted or substituted C 1 -C 10 alkyl, unsubstituted or substituted C 3 -C 8 cycloalkyl, unsubstituted or substituted C 3 - C 8 heterocyclyl, unsubstituted or substituted C 5 -C 10 aryl, unsubstituted or substituted C 5 -C 10 aromatic heterocyclyl, unsubstituted or substituted C 1 -C 10 alkyl acyl, unsubstituted or substituted amide group;
  • R 3 is selected from the following group: C 1 -C 8 alkyl or C 1 -C 8 aminoalkyl substituted primary amino or secondary amino group, C 3 -C 6 cycloalkyl substituted primary amino group, N is unsubstituted or Piperazinyl substituted with C 1 -C 6 alkyl;
  • X is substituted or unsubstituted CH or N;
  • n is an integer of 0-12, preferably 1-8, more preferably 1-6, most preferably 1-3;
  • n is an integer of 0-6, preferably 1-4;
  • Y is carbonyl or substituted or unsubstituted CH 2 .
  • the E3 ubiquitin ligase ligand is lenalidomide or pomalidomide.
  • the compound is a compound represented by formula (II):
  • R 1 , R 2 , R 3 , X, Linker, m and n are as described in claim 1;
  • Y is carbonyl or substituted or unsubstituted CH 2 .
  • R1 is selected from unsubstituted or substituted (preferably halogen substituted) methyl, ethyl, tert-butyl, isopropyl or cyclopentyl, or unsubstituted or on a heteroatom C 3 -C 8 heterocyclyl with C 1 -C 6 substituents.
  • R 2 is an acetyl group, a substituted or unsubstituted C 5 -C 10 aromatic heterocyclyl group, a substituted or unsubstituted amide group;
  • X is CH or N.
  • R 2 is an acetyl group, a furan ring, an amide group or a cyano group.
  • R 3 is a secondary amino group substituted by C 1 -C 8 alkyl group or a piperazinyl group that is unsubstituted on N or substituted by C 1 -C 3 alkyl group.
  • the pharmaceutically acceptable salts include potassium salts, sodium salts, hydrochloride salts, formate salts, trifluoroacetate salts, phosphate salts and sulfate salts.
  • the invention provides a compound, or an isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, selected from the group consisting of:
  • R 1 is unsubstituted or substituted (preferably halogen substituted) C 3 -C 8 cycloalkyl (preferably C 4 -C 6 cycloalkyl);
  • R 2 is hydrogen
  • R 3 is a piperazinyl group that is unsubstituted or substituted with C 1 -C 6 alkyl on N;
  • X is substituted or unsubstituted CH
  • n is an integer from 1 to 3;
  • n is an integer from 1 to 4.
  • Y is carbonyl group
  • the invention provides a compound, or an isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, selected from the group consisting of:
  • the present invention provides a pharmaceutical composition, which is characterized in that it contains the compound described in the first aspect or its isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug, and a pharmaceutical acceptable carrier or excipient.
  • the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders.
  • the present invention provides the compounds described in the first aspect, or isomers, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof for use in the preparation of drugs for treating CDK protein kinase-mediated diseases or Use in the preparation of food or health products.
  • the CDK protein kinase is CDK4/6 and/or CDK9, that is, the cell cycle-dependent kinase CDK4/6 and/or CDK9.
  • the CDK protein kinase-mediated disease is cancer.
  • the cancer is selected from the group consisting of bladder cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, epidermal cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer , cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer, skin cancer, lymphoid hematopoietic cell tumors, myeloid hematopoietic cell tumors, thyroid follicular cancer, tumors originating from stromal cells, tumors of the central or peripheral nervous system , melanoma, glioma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthomas, follicular thyroid carcinoma, Kaposi's sarcoma, renal cell carcinoma, intrauterine Membranous carcinoma, head and neck squamous cell carcinoma, acute myeloid leukemia, or other cancers regulated by CDK isoform
  • the lymphoid hematopoietic cell tumor is selected from the group consisting of leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, multiple myeloma, Hodgkin lymphoma tumour, non-Hodgkin's lymphoma, pilocytic lymphoma, or Burkitt's lymphoma.
  • FIG 1 shows the degradation of CDK4/6 protein by compounds 7a-7f
  • Figure 2 shows the experimental results of the selectivity of PROTACs in degrading CDKs
  • FIG. 3 shows the experimental results of the degradation mechanism of PROTACs
  • FIG. 4 shows the experimental results of the degradation mechanism of PROTACs.
  • PROTAC molecules After extensive and in-depth research, the inventor discovered a batch of PROTAC molecules with completely new structures. These compounds can degrade CDK proteins, and the DC 50 value of the CDK kinase degradation activity reaches the nM level. On this basis, the present invention was completed.
  • alkyl refers to a linear or branched saturated hydrocarbon group.
  • an alkyl group can have 1 to 10 carbon atoms (eg, 1 to 8 carbon atoms).
  • alkyl groups include methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, sec-butyl, tert-butyl group), pentyl group (for example, n-pentyl group, isopentyl group, neopentyl group), hexyl group (for example, n-hexyl group and its isomers), etc.
  • Lower alkyl groups generally have up to 4 carbon atoms.
  • Examples of lower alkyl groups include methyl, ethyl, endo (eg n-propyl and isopropyl) and butyl groups (eg n-butyl, isobutyl, sec-butyl, tert-butyl).
  • one alkyl group or two or more alkyl groups can form a bridged alkyl group; i.e., where the alkyl group is connected through another group (shown particularly in cyclic groups group), which are bridged by alkyl chains to form a ring, that is, a bridged fused ring is formed.
  • cycloalkyl refers to a non-aromatic carbocyclic group, including cyclic alkyl, alkenyl and alkynyl groups.
  • Cycloalkyl groups may be monocyclic (eg, cyclohexyl) or polycyclic (eg, containing fused, bridged, and/or spiro ring systems), in which the carbon atoms are located inside or outside the ring system.
  • a cycloalkyl group as a whole can have 3 to 14 ring atoms (e.g., 3 to 8 carbon atoms for a monocyclic cycloalkyl group and 7 to 14 carbon atoms for a polycyclic cycloalkyl group) .
  • the cycloalkyl group can be covalently attached to the defined chemical structure at any suitable ring position.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, Bornyl, Norpinyl, Norcaryl, adamantyl and spiro[4.5]decyl, and their homologues, isomers, etc.
  • heterocyclyl includes but is not limited to C 3 -C 8 heterocyclyl containing 1-3 heteroatoms selected from O, S or N, such as 5-membered or 6-membered heterocyclic groups, including But not limited to furyl, thienyl, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, ? Phylline etc.
  • aryl refers to a monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms, such as 5 to 10 carbon atoms, including phenyl, naphthyl, phenanthryl, anthracenyl, Indenyl, nyl, tetrahydronaphthyl, indenyl, etc.
  • the aryl group may be optionally substituted with 1-5 (e.g., 1, 2, 3, 4 or 5) substituents selected from: halogen, C 1-4 aldehyde, C 1-6 alkyl, cyano group, nitro, amino, amide, hydroxyl, hydroxymethyl, halogen-substituted alkyl (such as trifluoromethyl), halogen-substituted alkoxy (such as trifluoromethoxy), carboxyl, C 1-4 Alkoxy group, ethoxyformyl group, N(CH 3 ) and C 1-4 acyl group, etc., heterocyclyl group or heteroaryl group, etc.
  • 1-5 e.g., 1, 2, 3, 4 or 5
  • substituents selected from: halogen, C 1-4 aldehyde, C 1-6 alkyl, cyano group, nitro, amino, amide, hydroxyl, hydroxymethyl, halogen-substituted alkyl (such as trifluoromethyl
  • aromatic heterocyclyl means containing 5-14, such as 5-10 ring atoms, and 6, 10 or 14 electrons are shared on the ring system. And the ring atoms contained are carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur.
  • Useful aromatic heterocyclic groups include piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, including but not limited to Yu pyrimidinyl and so on.
  • the aromatic heterocyclyl group may be optionally substituted with 1-5 (eg, 1, 2, 3, 4 or 5) substituents selected from: halogen, C 1-4 aldehyde group, C 1-6 straight chain or branched alkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, halogen-substituted alkyl (such as trifluoromethyl), halogen-substituted alkoxy (such as trifluoromethoxy), carboxyl, C 1-4 alkoxy, ethoxyformyl, N(CH 3 ) and C 1-4 acyl.
  • 1-5 eg, 1, 2, 3, 4 or 5
  • substituents selected from: halogen, C 1-4 aldehyde group, C 1-6 straight chain or branched alkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, halogen-substituted alkyl (such as trifluoromethyl), halogen-substituted alkoxy (such
  • acylamino refers to a group with the structural formula "-R'-NH-C(O)-R", where R' can be selected from hydrogen or alkyl, and R can be selected from alkyl or alkenyl. radical, alkynyl group, alkyl group substituted by NR c R d , alkenyl group substituted by NR c R d and NR c R d substituted alkynyl group, alkyl group substituted by halogen, alkenyl group substituted by cyano group , where R c and R d can be selected from alkyl and alkenyl.
  • acyl refers to the group represented by -CHO.
  • alkyloyl or aryloyl refers to a group formed by an alkyl or aryl group attached to a CHO through which the group is attached to the remainder of the compound.
  • alkoxy refers to an oxy group substituted by an alkyl group.
  • Preferred alkoxy groups are those having 1 to 6 carbon atoms in length, more preferably those having 1 to 3 carbon atoms in length. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, etc.
  • Alkoxy groups may be substituted by one or more substituents, for example by halogen or haloalkyl.
  • the alkoxy group may be an alkyl group substituted by 1 to 4 fluorine atoms, or the alkyl group may be an alkyl group substituted by a fluoroalkyl group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • substituents selected from the following: halogen, C 1-4 aldehyde group, C 1-6 linear or branched alkyl group, cyano group, nitro group, amino group, hydroxyl group, hydroxymethyl group, halogen-substituted alkyl group (such as trifluoromethyl), halogen-substituted alkyl group Oxy (eg trifluoromethoxy), carboxyl, C 1-4 alkoxy, ethoxyformyl, N(CH 3 ) and C 1-4 acyl.
  • substituents selected from the following: halogen, C 1-4 aldehyde group, C 1-6 linear or branched alkyl group, cyano group, nitro group, amino group, hydroxyl group, hydroxymethyl group, halogen-substituted alkyl group (such as trifluoromethyl), halogen-substituted alkyl group Oxy (eg trifluoromethoxy), carboxyl, C 1-4 alkoxy,
  • CDK CDK protein
  • CDK kinase CDK protein kinase
  • CDK protein kinase CDK protein kinase
  • the cell cycle refers to the entire process that a cell goes through from the completion of one division to the end of the next division. It is the basic process of cell life transmission.
  • the cell cycle is mainly divided into 4 phases: G phase (First gap), S phase (Synthesis), G2 phase (Second gap), and M phase (Mitosis).
  • the G1 phase mainly prepares for the synthesis of DNA, and cells mainly synthesize RNA and ribosomes; the S phase mainly synthesizes DNA and enzymes related to DNA replication, and also synthesizes histones; the G2 phase is the preparation period for mitosis, the late stage of DNA synthesis, and a large number of Synthesis of proteins such as RNA and tubulin; M phase is the cell division phase, which is divided into pro, middle, post and telophase. After a cell cycle, the cell will divide into two, and the mother cell will pass the genetic material to the daughter cells, laying the foundation for subsequent cell differentiation and individual growth and development.
  • the cell cycle is a continuous and strictly controlled process, which is regulated by the following three types of proteins: cyclin, cyclin-dependent kinase (CDK), and cyclin-dependent kinase inhibitor.
  • CKI kinase inhibitor
  • Abnormal cell cycle is a prerequisite for tumor occurrence, which is mainly manifested by abnormal expression of enzymes and proteins related to regulating the cell cycle, leading to cell cycle disorder and malignant cell proliferation.
  • cell cycle phase Research on enzymes and proteins provides a theoretical basis for tumor treatment.
  • Cyclin-dependent kinase which belongs to the serine/threonine protein kinase family, is a key kinase involved in cell cycle regulation. Different CDKs play different roles in different stages of cells. More than 20 different CDK subtypes have been reported, which can be divided into two main categories according to their different functions. One type is involved in cell cycle regulation, mainly including CDK1, CDK2, CDK4, CDK6, etc.; the other type is involved in transcriptional regulation, mainly including CDK7, CDK8, CDK9, CDK10, CDK11, etc., of course there are also other functions, such as CDK3 , CDK5.
  • CDK monomers are inactive, and different CDKs need to be combined with the corresponding Cyclin to function.
  • 12 Cyclins (A-L) corresponding to CDKs have been identified.
  • CDK can be activated by phosphorylation by CAK, a CDK-activating kinase.
  • the activation of CDK is a complex process involving multiple enzymes and multi-step phosphorylation.
  • CAK makes the T-loop of CDK (such as T161 of CDK1, T160 of CDK2 ) occurs activating phosphorylation.
  • CDK nucleotide binding pocket (such as T14 of CDK1 and T15 of CDK2) can be phosphorylated by Wee1, preventing ATP binding and thus inactivating. These inhibitory phosphorylation can be bispecific. Dephosphorylation occurs under the action of phosphatase CDC25, thereby making CDK active again.
  • CDK activation is also regulated by inhibition, activation and inhibitory phosphorylation of endogenous inhibitors.
  • CDK endogenous inhibitors include two major families, INK4 and CIP/KIP. They bind to CDK monomers or directly bind to the phosphorylation activation site of the CDK-Cyclin complex to limit its conformational changes and inhibit CDK kinases. active.
  • CDK4/6 cell cycle-dependent kinase 4/6
  • CDK4/6 is an important regulatory factor in the G1 phase of the cell cycle and can specifically bind to Cyclin D to form a complex.
  • CDK4 is a protein kinase encoded by the CDK4 gene located on chromosome 12 in human cells. It is highly similar in structure to other CDKs and has a typical bilobed structure. CDKs are the engines of the cell cycle. In human cells, CDK4 and its highly homologous CDK6 play a key role in regulating the cell cycle.
  • CDK4/6 is a common downstream target of multiple cell signaling pathways, and many cancer-related signaling pathways lead to specific activation of CDK4/6.
  • retinoblastoma protein (Rb) binds to the transcription factor E2F and inhibits its activity, inhibits proliferation, and keeps cells in the G0 phase.
  • the PI3K/Akt/mTOR signaling pathway Under the stimulation of external mitotic signals, the PI3K/Akt/mTOR signaling pathway will be activated, and CDK4/6 will combine with Cyclin D to form a CDK4/6-Cyclin D complex.
  • This complex can catalyze the activation of Rb protein and phosphorylate it.
  • the phosphorylated Rb protein releases the transcription factor E2F.
  • E2F induces Cyclin E to bind to CDK2 and form a CDK2-Cyclin E complex.
  • This complex phosphorylates the Rb protein, thereby fully releasing the E2F transcription factor and advancing the cell cycle from the G1 phase. Enters S phase and participates in the process of DNA replication.
  • CDK9 combines with cell cyclins to form a subunit of positive transcription elongation factor b (P-TEFb), which specifically regulates gene transcription elongation and mRNA maturation.
  • P-TEFb positive transcription elongation factor b
  • CDK9 and cyclin complexes phosphorylate the C-terminal domain of RNA polymerase II (RNAPII). This stimulates and initiates transcriptional prolongation of the pause period.
  • RNAPII RNA polymerase II
  • Dysregulation of CDK9-related signaling systems is prominent in multiple cancer cells, including solid tumors and hematological malignancies.
  • Increasing evidence suggests that inhibition of CDK9 leads to selective reductions in protein levels of oncogenes (e.g., c-Myc) and anti-apoptotic proteins (e.g., Mcl-1), which play key roles in cancer cell growth and survival.
  • oncogenes e.g., c-Myc
  • Mcl-1 anti-apoptotic proteins
  • the homeostasis of normal cells benefits from the balance of positive and negative regulatory mechanisms of the cell cycle, and the regulation of the cell cycle Disorder is the fundamental reason for the uncontrolled growth of tumor cells.
  • the disruption of the intracellular molecular regulatory network and the instability of the genome lead to disordered cell cycle regulation and become a key factor in tumor formation.
  • Molecular analyzes of human tumors have shown that genes expressing cell cycle regulatory molecules are frequently mutated in human tumors. Cell cycle abnormalities are a hallmark of tumor formation and progression.
  • CDKs are rarely mutated in human cancers, except for CDK4, which is miscoded in a small family of melanomas, most tumors have mutations or abnormalities in the upstream regulatory proteins or downstream substrate proteins of CDKs. Therefore, CDKs are considered to be a better target for cancer treatment.
  • PROTAC ubiquitin ligase ligands
  • E3 ubiquitin ligase ligands such as lenalidomide or pomalidomide
  • Linkers to construct A series of PROTAC molecules.
  • the inventors conducted structural confirmation and molecular-level degradation activity testing on the constructed PROTAC molecules, and finally obtained a batch of compounds that can effectively degrade CDK kinase.
  • the present invention provides compounds represented by formula (I), or isomers, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:
  • R 1 , R 2 , R 3 , X, Linker, m and n are as described above.
  • the compound of the present invention can be a compound represented by formula (II), or an isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof:
  • Y can be carbonyl or substituted or unsubstituted CH 2 .
  • the compound of the present invention is a compound selected from the following group, or an isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof:
  • the compounds of the present invention should also include all pharmaceutically acceptable isotopically labeled compounds in which one or more atoms are replaced by atoms with the same atomic number, but with an atomic mass or mass number different from that normally found in nature. The atomic masses or mass numbers are different.
  • Isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen, such as 2 H and 3 H, isotopes of carbon, such as 11 C, 13 C and 14 C, isotopes of nitrogen, such as 13 N and 15 N, oxygen Isotopes such as " 15O , 17O and 18O ".
  • substitution with heavier isotopes such as deuterium or 2H may provide certain therapeutic advantages, with better metabolic stability, e.g., increased or reduced dosage requirements, and may therefore be preferred in certain circumstances. .
  • the invention provides a pharmaceutical composition.
  • the composition contains a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • Examples of pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, inorganic and organic acid salts, such as hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate , fumarates, mandelates, and oxalates; as well as inorganic and inorganic compounds formed with bases such as sodium hydroxyl, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methylglucamine.
  • inorganic and organic acid salts such as hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate , fumarates, mandelates, and oxalates
  • bases such as sodium hydroxyl, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methylglucamine.
  • TriS tris(hydroxymethyl)aminomethane
  • N-methylglucamine N-methylglucamine
  • compositions of the present invention may be formulated into formulations suitable for various routes of administration, including but not limited to parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial
  • parenteral subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial
  • the amount administered is that amount effective to ameliorate or eliminate one or more conditions.
  • an effective amount is an amount sufficient to ameliorate or in some way alleviate the symptoms associated with the disease.
  • Such amounts may be administered as a single dose or may be administered in accordance with an effective treatment regimen.
  • Doses may be administered to cure a disease, but they are usually administered to ameliorate the symptoms of the disease. Repeated dosing is generally required to achieve the desired improvement in symptoms.
  • the dosage of the drug will be determined based on the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.
  • the pharmaceutical preparations of the present invention can be administered to any mammal as long as they can obtain the therapeutic effects of the compounds of the present invention.
  • the most important of these mammals is humans.
  • diseases mediated by CDK protein kinases are various cancers.
  • the cancers include, but are not limited to: esophageal cancer, renal cell carcinoma, pancreatic cancer, colon cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, endometrial cancer, head and neck squamous cell carcinoma, acute myeloid leukemia, and Solid tumors. Or cancers in which other CDK subtypes are involved in regulation.
  • the pharmaceutical preparations of the invention can be produced in a known manner. For example, manufactured by traditional mixing, granulating, tableting, dissolving, or freeze-drying processes.
  • the solid excipients and the active compound can be combined and the mixture selectively milled. After adding appropriate amounts of auxiliaries if desired or necessary, the granule mixture is processed to obtain tablets or dragee cores.
  • Suitable excipients are in particular fillers, for example sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or dicalcium phosphate; and binders, for example starch pastes, including corn starch. , wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone.
  • sugars such as lactose or sucrose, mannitol or sorbitol
  • cellulose preparations or calcium phosphates such as tricalcium phosphate or dicalcium phosphate
  • binders for example starch pastes, including corn starch. , wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone
  • disintegrants can be added, such as the starches mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate.
  • Auxiliaries are in particular flow regulators and lubricants, for example silica, talc, stearates, such as magnesium calcium stearate, stearic acid or polyethylene glycol.
  • the tablet cores can be provided with a suitable coating to resist gastric juices. For this purpose, concentrated sugar solutions can be applied.
  • This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solution and suitable organic solvents or solvent mixtures.
  • suitable cellulose solutions may be used, such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate.
  • Dyestuffs or pigments may be added to the coating of the tablet or dragee core. For example, for identification or for characterizing combinations of active ingredient doses.
  • the present invention further provides a method for treating CDK protein kinase-mediated diseases, which method includes administering the compounds or pharmaceutical compositions of the present invention to a subject in need.
  • Administration methods include, but are not limited to, various administration methods well known in the art, and can be determined based on the actual condition of the patient. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal, or topical routes of administration.
  • the present invention also includes the use of the compounds of the present invention in the preparation of medicaments for preventing or treating CDK-mediated diseases or inhibiting CDK activity.
  • the disease mediated by CDK protein kinase is cancer.
  • the cancer is selected from the following group: bladder cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, epidermal cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, Cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer, skin cancer, lymphoid hematopoietic cell tumors, myeloid hematopoietic cell tumors, thyroid follicular cancer, mesenchymal cell tumors, central or peripheral nervous system tumors, Melanoma, glioma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthomas, follicular thyroid carcinoma, Kaposi's sarcoma, renal cell carcinoma, endometrium cancer, head and neck squamous cell carcinoma, acute myeloid leukemia, or other cancers regulated by CDK isoforms.
  • the lymphoid hematopoietic cell tumor is selected from the group consisting of leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, multiple myeloma, and Hodgkin lymphoma. , non-Hodgkin's lymphoma, pilocytic lymphoma, or Burkitt's lymphoma.
  • the compound provided by the present invention is a PROTAC molecule with a completely new structure
  • the compounds provided by the invention have excellent degradation activity against CDK protein kinase
  • the compounds provided by the present invention lay the foundation for the development of drugs that can target CDK degradation, have great industrialization and commercialization prospects and market value, and have significant economic benefits.
  • Jurkat cells were selected as the cell line (this cell line highly expresses CDK4/6 protein).
  • This cell line highly expresses CDK4/6 protein.
  • a 96-well plate 8000 cells/well were used. The initial concentration of the drug was 10 ⁇ M, and the drug was diluted 7 times in a three-fold gradient. The final drug concentration was 4.15 nM. eight drugs action concentration.
  • the drug is added for 72 hours. After 72 hours of action, 10 ⁇ L of CCK8 solution is added to each well. After incubation for 3-4 hours, the OD value of the cells is read with a microplate reader. Calculate the cell survival rate. Use Graphpad to fit. It can be seen from the figure that the compound exhibits degradation activity against CDK4/6 at a concentration of 1 ⁇ M.
  • the degradation activity of the compounds on CDK4/6 protein is shown in Table 3 and Figure 1.
  • CDK1/2/4/6 mainly It plays a role in regulating the cell cycle
  • CDK7/8/9 plays a role in transcription. Therefore, we conducted degradation selectivity experiments on some common CDKs in the CDK family (such as CDK1, CDK2, CDK5, CDK7, CDK8, and CDK9). , the experimental results are shown in Figure 2. The experimental results show that PROTAC molecules have a relatively obvious degradation effect on the degradation of CDK4/6/9, so PROTAC molecules have good selectivity for CDK4/6/9.
  • the PROTAC molecule is composed of three parts: a target protein ligand that can specifically bind to the target protein, a ligand that can bind to E3 ubiquitin ligase, and a linker that can connect the two parts. Since the ligands for the PROTAC molecules 7f and 7k designed in this chapter to recruit E3 ubiquitin ligase are Pomalidomide, after adding Pomalidomide to the degradation system, due to ligand competition, it is added to the degradation system. Pomalidomide will have a competitive inhibitory effect with the Pomalidomide ligand in the PROTAC molecule. The results are shown in Figure 3. After adding a sufficient amount of Pomalidomide to the degradation system, the degradation effect of PROTAC molecules on CDK4/6 is obviously inhibited. Therefore, It can be proven that our PROTAC molecules exert degradation effects by recruiting E3 ubiquitin ligases.
  • MG132 is a proteasome inhibitor. Its function is to bind to the proteasome and thereby inhibit the proteasome from degrading proteins. Therefore, if MG132 is added to the degradation system and the proteasome in the cell is bound by MG132, the proteasome will If it is inhibited, it will not be able to exert its degradation effect.
  • the experimental results are shown in Figure 4. After adding a sufficient amount of MG132 to the degradation system, the degradation effect of PROTAC molecules on CDK4/6 was obviously reversed. In the group where MG132 was not added, the degradation effect of PROTAC molecules on CDK4/6 was still the same. There is a better degradation effect. Therefore, the experimental results can prove that PROTAC molecules degrade the target protein through the ubiquitin-proteasome pathway.

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Abstract

L'invention concerne un composé représenté par la formule (I) ou un isomère, un sel pharmaceutiquement acceptable, un hydrate, un solvate ou un promédicament de celui-ci. Le composé est une molécule PROTAC ayant une excellente activité de dégradation sur une protéine kinase CDK, constitue une base pour développer un médicament capable de dégradation ciblée de CDK, et présente ainsi de grandes perspectives d'industrialisation et de commercialisation.
PCT/CN2023/105759 2022-07-04 2023-07-04 Composé pour la dégradation ciblée de protéine cdk et son utilisation WO2024008097A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106008511A (zh) * 2012-05-14 2016-10-12 华东理工大学 蝶啶酮衍生物及其作为egfr、blk、flt3抑制剂的应用
CN110357885A (zh) * 2019-07-24 2019-10-22 江南大学 一种蝶啶类化合物及其在药学上的应用
CN111892578A (zh) * 2020-08-03 2020-11-06 沈阳药科大学 一种靶向降解黏着斑激酶的化合物及应用
WO2021083949A1 (fr) * 2019-10-29 2021-05-06 F. Hoffmann-La Roche Ag Composés bifonctionnels pour le traitement du cancer
WO2021113557A1 (fr) * 2019-12-04 2021-06-10 Nurix Therapeutics, Inc. Composés bifonctionnels pour la dégradation de la btk par l'intermédiaire de la voie de l'ubiquitine-protéosome
WO2022068849A1 (fr) * 2020-09-30 2022-04-07 Beigene, Ltd. Composés bifonctionnels pour la dégradation de l'egfr et procédés d'utilisation associés
WO2022068933A1 (fr) * 2020-09-30 2022-04-07 Cullgen (Shanghai) , Inc. Composés et méthodes de traitement de maladies

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106008511A (zh) * 2012-05-14 2016-10-12 华东理工大学 蝶啶酮衍生物及其作为egfr、blk、flt3抑制剂的应用
CN110357885A (zh) * 2019-07-24 2019-10-22 江南大学 一种蝶啶类化合物及其在药学上的应用
WO2021083949A1 (fr) * 2019-10-29 2021-05-06 F. Hoffmann-La Roche Ag Composés bifonctionnels pour le traitement du cancer
WO2021113557A1 (fr) * 2019-12-04 2021-06-10 Nurix Therapeutics, Inc. Composés bifonctionnels pour la dégradation de la btk par l'intermédiaire de la voie de l'ubiquitine-protéosome
CN111892578A (zh) * 2020-08-03 2020-11-06 沈阳药科大学 一种靶向降解黏着斑激酶的化合物及应用
WO2022068849A1 (fr) * 2020-09-30 2022-04-07 Beigene, Ltd. Composés bifonctionnels pour la dégradation de l'egfr et procédés d'utilisation associés
WO2022068933A1 (fr) * 2020-09-30 2022-04-07 Cullgen (Shanghai) , Inc. Composés et méthodes de traitement de maladies

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