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WO2020207260A1 - Inhibiteur de cdk et son utilisation - Google Patents

Inhibiteur de cdk et son utilisation Download PDF

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Publication number
WO2020207260A1
WO2020207260A1 PCT/CN2020/081432 CN2020081432W WO2020207260A1 WO 2020207260 A1 WO2020207260 A1 WO 2020207260A1 CN 2020081432 W CN2020081432 W CN 2020081432W WO 2020207260 A1 WO2020207260 A1 WO 2020207260A1
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Prior art keywords
alkyl
heterocycloalkyl
cycloalkyl
halogen
group
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PCT/CN2020/081432
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English (en)
Chinese (zh)
Inventor
林星雨
陆婷婷
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Zhuhai Yufan Biotechnologies Co Ltd
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Zhuhai Yufan Biotechnologies Co Ltd
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Priority to CN202080000675.XA priority Critical patent/CN113661164B/zh
Publication of WO2020207260A1 publication Critical patent/WO2020207260A1/fr
Anticipated expiration legal-status Critical
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a cyclin-dependent kinase inhibitor and its application.
  • Cyclin-dependent kinases is a Ser/Thr kinase system corresponding to the cell cycle process. Cyclin-dependent protein kinases are a group of serine/threonine protein kinases. CDK drives the cell cycle by chemically acting on serine/threonine proteins. It acts in concert with cyclin and is an important factor in cell cycle regulation. CDK can combine with cyclin to form a heterodimer, where CDK is a catalytic subunit, and cyclin is a regulatory subunit. Different cyclin-CDK complexes can catalyze the phosphorylation of different substrates through CDK activity, and achieve different timing of the cell cycle. Phase advancement and transformation.
  • CDK cyclindependent kinase inhibitor
  • CDK 1-8 There are 8 types of CDK family, including CDK 1-8. Each CDK binds to different types of cyclin to form a complex, which regulates the process of cells transitioning from G1 phase to S phase or G2 phase to M phase and exiting M phase. Various CDKs are activated alternately along the cell cycle phase, phosphorylating the corresponding substrates, so that cell cycle events proceed in an orderly manner.
  • CDKs have three important functional domains.
  • the first functional domain is the binding site of ATP and the active part of the enzyme;
  • the second functional domain is the binding site of the regulatory subunit (Cyclin);
  • the third functional domain is the binding site of P13suc1 (P13suc1 can inhibit kinase activity and prevent cells Enter or exit phase M).
  • Various CDKs are activated at specific times in the cell cycle, and through phosphorylation of substrates, drive cells to complete the cell cycle.
  • Patent document CN200680047113.0 provides a novel imidazo[1,2-a]pyrazine compound as a cyclin-dependent kinase inhibitor, the general formula of the compound is
  • the compound or pharmaceutical composition can be used to treat, prevent, inhibit or alleviate one or more diseases related to CDKs.
  • Patent document CN200680025008.7 discloses a new class of compounds with the structure
  • the pharmaceutical composition containing the compound can be used to treat or prevent diseases or disorders related to abnormal or unregulated kinase activity, especially abnormal activation of CDKs, Aurora, Jak2, Rock, CAMKII, FLT3, Tie2, TrkB, FGFR3 and KDR kinase The method of the disease or disorder.
  • the present invention provides a novel compound and pharmaceutical composition to treat diseases and disorders related to CDK.
  • One object of the present invention is to provide a compound of general formula I and a preparation method thereof, which is a CDK kinase inhibitor; another object of the present invention is to provide a use of the compound.
  • the present invention provides a compound of general formula I:
  • A is selected from C or N
  • B is selected from C or N.
  • R 1 is selected from -H, halogen, -CN, -OC 0-10 alkyl, C 1-10 linear/branched alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl) , C 3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -OH, -NO 2 , carboxy and its substituents, -S (C 0-10 Alkyl) (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), -SO 2 N (C 0-10 alkyl) (C 0-10 alkyl) , S(O)k(C 0-10 alkyl),
  • R 3 does not exist.
  • R 3 is selected from -H, halogen, -NO 2 , -CN, C 1-5 straight chain/branched chain alkyl, -N (C 0 -10 alkyl) (C 0-10 alkyl), -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, -OC 0-10 alkyl, -OH, carboxyl and its substituents, -S (C 0-10 alkyl) (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0 -10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), -SO 2 N (C 0-10 alkyl) (C 0 -10 alkyl), S(O)k(C 0-10
  • R 4 is selected from -H, halogen, -NO 2 , -CN, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, -OC 0-10 alkyl, C 1-10 straight chain/branched chain Alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), C 3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl , -OH, -NO 2 , carboxyl and its substituents, -S (C 0-10 alkyl) (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl) ), -N (C 0-10 alkyl) CO (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl) ,
  • the dotted line represents a single bond (ie, R 6 and R 7 are connected through the single bond to form a ring with the carbon atom to which they are connected) or absent (ie, R 6 and R 7 are not connected).
  • R 5 , R 6 and R 7 are independently selected from -H, halogen, -NO 2 , -CN, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, -OC 0-10 alkyl, C 1-10 straight chain/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), C 3-10 cycloalkyl, -CO (C 0-10 alkyl),- CON (C 0-10 alkyl) (C 0-10 alkyl), -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -N heterocyclic aromatic, carboxyl and its substitution Group, -N (O) (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl) (C 0-10 alkyl) ), -N(C 0
  • the ring Ar is fused with the ring R g , and the fused bond is any bond on the ring Ar.
  • the ring Ar is selected from an aromatic five-membered heterocyclic group, an aromatic six-membered heterocyclic group or a phenyl group, and the aromatic five-membered heterocyclic group is selected from: imidazolyl, thiazolyl, oxazolyl, and pyrrolyl , Pyrazolyl, furyl or thienyl, the aromatic six-membered heterocyclic group is selected from: pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, optionally the aromatic five-membered heterocyclic group Group, aromatic six-membered heterocyclic group or phenyl group can be substituted by the following groups: halogen, -CN, -OCF 3 , C 1-10 linear/branched chain alkyl, -N(C 0- 10 alkyl) (C 0-10 alkyl), -SO 2 , -SO 2 N (C 0-10 alkyl) (C 0
  • ring Ar is pyrrolyl, such as
  • the ring R g is selected from C 3-8 saturated/unsaturated cycloalkyl or C 3-8 saturated/unsaturated heterocycloalkyl containing -O-, -N-, -S-, and optionally the C 3 -8 saturated/unsaturated cycloalkyl or C 3-8 saturated/unsaturated heterocycloalkyl containing -O-, -N-, -S- can be substituted by the following groups: halogen, -CN, -OCF 3 , C 1-10 linear/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -SO 2 , -SO 2 N (C 0-10 alkyl) ) (C 0-10 alkyl), -SO 2 N (C 0-10 alkyl) CON (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 , -N (C 0-10
  • the ring R g is R 8 is selected from O, S or NR 9 , R 9 is selected from -H, halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, -OC 0-10 alkyl, C 1 -10 straight chain/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), C 3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl , -S heterocycloalkyl.
  • R 1 is selected from -H, halogen, -CN, -OC 0-10 alkyl, C 1-10 linear/branched alkyl, more preferably, R 1 is selected from H, -CN, -CH 3. -CH 2 CH 3 .
  • B is N and R 3 is not present.
  • R 5 , R 6 and R 7 are independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OC 0-10 alkyl, C 1-10 linear/branched alkyl, -N (C 0 -10 alkyl) (C 0-10 alkyl), C 3-10 cycloalkyl, -CO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl) ), -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -N heterocyclic aryl, N, O substituted fused ring alkyl, N, O substituted spiro cycloalkyl, N, O substituted bridged cycloalkyl, wherein the H on the above group can be substituted by the following groups: halogen, -CN, -OH, -CON (C 0-10 alkyl) (C 0-10 alkyl
  • R 4 and R 5 are independently selected from -H, halogen, -CN, -CF 3 , -OC 0-10 alkyl, C 1-10 linear/branched alkyl; more preferably, R 4 And R 5 are independently selected from H, -CN, -CH 3 , and -CH 2 CH 3 .
  • R 7 is selected from -H, halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, -OC 0-10 alkyl, C 1-10 straight chain/branched chain alkane Group, -N(C 0-10 alkyl)(C 0-10 alkyl), C 3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl; More preferably, R 7 is selected from H, -CN, -CH 3 , and -CH 2 CH 3 .
  • R 14 , R 15 and R 16 are independently selected from -H, halogen, -NO 2 , -CN, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, -OC 0-10 alkyl, C 1-10 straight chain/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), C 3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkane Group, -S heterocycloalkyl, carboxy and its substituents, -CON (C 0-10 alkyl) (C 0-10 alkyl), -N (O) (C 0-10 alkyl) (C 0 -10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0- 10 alkyl), -SO
  • R 14 , R 15 and R 16 are independently selected from -H, halogen, -CN, -CF 3 , -OC 0-10 alkyl, and C 1-10 linear/branched alkyl.
  • R 14 , R 15 and R 16 are independently selected from H, -CN, -CH 3 , and -CH 2 CH 3 .
  • the ring Ar is selected from imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl or phenyl, optionally the imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl or benzene
  • the H on the group can be substituted by the following groups: halogen, -CN, -OCF 3 , C 1-10 linear/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl) , -SO 2 , -SO 2 N (C 0-10 alkyl) (C 0-10 alkyl), -SO 2 N (C 0-10 alkyl) CON (C 0-10 alkyl) (C 0 -10 alkyl), -N (C 0-10 alkyl) SO 2 , -N (C 0-10 alkyl) CON (C 0-10 alkyl) (C 0-10 al
  • the ring R g is selected from C 5-7 saturated/unsaturated cycloalkyl or C 5-7 saturated/unsaturated heterocycloalkyl containing -O-, -N-, optionally the C 5- 7 saturated/unsaturated cycloalkyl or C 5-7 saturated/unsaturated heterocycloalkyl containing -O-, -N- can be substituted by the following groups: halogen, -CN, -OCF 3 , C 1-10 straight chain/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -SO 2 , -SO 2 N (C 0-10 alkyl) (C 0- 10 alkyl), -SO 2 N (C 0-10 alkyl) CON (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 , -N (C 0-10 alkyl) CON (C 0-10 alkyl
  • R 8 is selected from O, ring R g is C 5-7 saturated/unsaturated cyclic ketone, C 5-7 saturated/unsaturated cyclic lactone, C 5-7 saturated/unsaturated cyclic lactam.
  • the condensed ring structure formed by ring Ar and ring R g is as follows:
  • R 11 , R 12 , R 13 , R 13 ' are independently selected from -H, halogen, -NO 2 , -CN, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, -OC 0-10 Alkyl, C 1-10 straight/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), C 3-10 cycloalkyl, -O heterocycloalkyl,- N heterocycloalkyl, -S heterocycloalkyl.
  • R 11 , R 12 , R 13 , and R 13 ′ are independently selected from -H, halogen, -NO 2 , -CN, -CF 3 , C 1-6 linear/branched chain alkyl, -N( C 0-10 alkyl) (C 0-10 alkyl), C 3-7 cycloalkyl.
  • R 11 , R 12 , R 13 , and R 13 ′ are independently selected from -H, halogen, -CN, and -CH 3 .
  • n is an integer between 0-6, such as 0, 1, 2, 3, 4, 5, and 6.
  • A is N and B is N.
  • R 2 is selected from -H, halogen, -CN, C 1-5 straight chain/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -CF 3 , wherein the above groups
  • the H on the group can be substituted by the following groups: halogen, -CN, -OH, C 1-10 linear/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -OC 0-10 alkyl, C 3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl.
  • the R 2 is selected from -H or F.
  • R 6 is selected from halogen, -OC 0-10 alkyl, C 1-6 linear/branched alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), C 3 -10 cycloalkyl, -CO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -O heterocycloalkyl, -N heterocycloalkyl, -N heterocyclic aromatic group, N, O substituted fused ring alkyl, N, O substituted spiro cycloalkyl, N, O substituted bridged cycloalkyl, wherein H on the above groups can be substituted by the following groups : -CN, -OH, -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), C 1-10 linear
  • R 6 is selected from
  • said R 6 is selected from:
  • R 10 is selected from halogen, -CN, -CF 3 , -OC 0-10 alkyl, C 1-10 linear/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl) ), C 3-10 cycloalkyl, -CO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -O heterocycloalkyl, -N hetero Cycloalkyl, -S heterocycloalkyl, -N heterocyclic aromatic group, wherein H on the above groups can be substituted by the following groups: halogen, -CN, -OH, -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), C 1-10 linear/branched chain alkane Group, -N (C 0-10 alkyl)
  • R 10 is selected from -OC 0-10 alkyl, C 1-10 linear/branched alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), C 3-10 Cycloalkyl, -CO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -O heterocycloalkyl, -N heterocycloalkyl, of which the above
  • the H on the group can be substituted by the following groups: halogen, -CN, -OH, -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), C 1-10 linear/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl) , -OC 0-10 alkyl, C 3-10 cycloalkyl, -
  • R 10 is selected from H, C 1-5 straight chain/branched chain alkyl, hydroxy substituted C 1-5 straight chain/branched chain alkyl,
  • the R 10 is selected from:
  • the general compounds of the present invention also include their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, and also includes pharmaceutics Acceptable excipients.
  • the auxiliary materials are selected from: carriers, diluents, binders, lubricants, wetting agents and the like.
  • the pharmaceutical composition contains a therapeutically effective amount of a compound of formula I.
  • the pharmaceutical composition can be used alone or in combination with other kinds of pharmaceutical preparations.
  • the other types of pharmaceutical preparations include: DNA mutual interference agents such as cisplatin or doxorubicin, paclitaxel, docetaxel or epsilon, tamoxifen, methotrexate, uracil mustard, nitrogen mustard, iso Cyclophosphamide, melphalan, chlorambucil, piperamide, triptamide, triethylene thiophosphoramide, busulfan, carmustine, lomustine, streptozocin, tar Carpazine, fluorouracil deoxynucleoside, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, racovanin, oxaliplatin, doxorubicin Star, trastuzumab, fulvestrant, exemestane, rituximab.
  • DNA mutual interference agents such as cisplatin or doxorubicin, paclitaxel, do
  • the pharmaceutical composition further includes antioxidants, buffers, bacteriostatic agents, etc., and solutes that make the preparation isotonic with the blood of the subject, as well as aqueous and non-aqueous sterile suspending agents, which may include suspending agents.
  • aqueous and non-aqueous sterile suspending agents which may include suspending agents.
  • the pharmaceutical composition is suitable for gastrointestinal administration or parenteral administration, such as administration by intravenous, intramuscular, intradermal and subcutaneous routes.
  • the pharmaceutical composition can be prepared into the following forms of pharmaceutical preparations: injections, syrups, elixirs, suspensions, powders, granules, tablets, capsules, lozenges, creams, ointments, lotions, gels , Emulsion, etc.
  • any commonly used carriers in the art can be used, such as: water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol and polyethylene sorbitan fat Acid esters and so on.
  • common dissolving agents and buffers can also be added.
  • the present invention provides a compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds in the preparation of inhibiting one or more cyclin-dependent kinases (CDK ) In the application of drugs.
  • CDK cyclin-dependent kinases
  • the present invention provides a compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds for preparing and treating one or more cyclin-dependent kinases (CDK) ) Application in medicine for related diseases.
  • CDK cyclin-dependent kinases
  • the cyclin-dependent kinase is CDK1-8, and more preferably, the cyclin-dependent kinase is CDK4, CDK6.
  • the disease related to cyclin-dependent kinase is a proliferative disease, selected from cancer, autoimmune disease, viral disease, fungal disease, neuropathy, arthritis, inflammation, neuronal disease, hair loss and cardiovascular disease disease.
  • the cancer includes, but is not limited to, malignant tumors, hematopoietic tumors of the lymphatic system, hematopoietic tumors of the bone marrow system, tumors of mesenchymal origin, tumors of the central and peripheral nervous system.
  • the malignant tumor is selected from: bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer), head and neck cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer , Stomach cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer.
  • the hematopoietic tumor of the lymphatic system is selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hair Cell lymphoma, mantle cell lymphoma, myeloma and Burkett's lymphoma.
  • the hematopoietic tumor of the bone marrow system is selected from the group consisting of acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia.
  • the tumor of mesenchymal origin is selected from: fibrosarcoma and rhabdomyosarcoma.
  • the tumors of the central and peripheral nervous system are selected from the group consisting of astrocytoma, fibroblastic neuroma, glioma and schwannoma.
  • the autoimmune disease is selected from: systemic lupus, lupus erythematosus, autoimmune-regulated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes.
  • the viral infection is selected from: herpes virus, pox virus, Epstein-Barr virus, Sindbis virus and adenovirus.
  • the neuropathy is selected from: Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and cerebellar decline.
  • the compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds can be used alone or in combination with other types of pharmaceutical preparations and/or treatments. Methods are used in combination.
  • the other types of pharmaceutical preparations include, but are not limited to: cell growth inhibitors, cytotoxic agents, tubulin interaction agents, hormone agents, antimetabolites, and antitumor agents, and the treatment methods include but are not limited to: hormone therapy , Immunotherapy, radiotherapy; preferably used in combination with hormone therapy and immunotherapy.
  • the cytotoxic agent is selected from: DNA mutual interference agents such as cisplatin or doxorubicin.
  • the tubulin interaction agent is selected from the group consisting of paclitaxel, docetaxel or epsilon.
  • the hormone agent is selected from: tamoxifen.
  • the antimetabolite is selected from: methotrexate.
  • the anti-tumor agent is selected from the group consisting of: uracil mustard, nitrogen mustard, ifosfamide, melphalan, chlorambucil, piperamide, trataamide, triethylene thiophosphoramide, and buxiao An, carmustine, lomustine, streptozocin, dacarbazine, fluorouracil, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, ol Saliplatin, racovanin, oxaliplatin, doxorubicin, trastuzumab, fulvestrant, exemestane, rituximab.
  • the present invention provides a compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds in the prevention and/or treatment of cancer, autoimmune diseases, and viral diseases. , Fungal diseases, neuropathy, arthritis, inflammation, neuronal diseases, hair loss and cardiovascular diseases.
  • the present invention provides a compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds for the preparation of prevention and/or treatment of cancer, autoimmune diseases, viruses Disease, fungal disease, neuropathy, arthritis, inflammation, neuronal disease, hair loss and cardiovascular disease drug application.
  • C 0-10 alkyl refers to H
  • C 0-10 alkyl includes H, C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 Alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl.
  • C 1-10 straight chain/branched chain alkyl in the present invention includes methyl, ethyl, C 3 straight chain/branched chain alkyl, C 4 straight chain/branched chain alkyl, C 5 straight chain /Branched chain alkyl, C 6 straight chain/branched chain alkyl, C 7 straight chain/branched chain alkyl, C 8 straight chain/branched chain alkyl, C 9 straight chain/branched chain alkyl, C 10 straight chain /Branched alkyl.
  • C 3-10 branched chain alkyl in the present invention includes isopropyl, isobutyl, tert-butyl and isopentyl.
  • C 3-10 cycloalkyl in the present invention includes C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl, C 8 cycloalkyl Group, C 9 cycloalkyl, C 10 cycloalkyl.
  • halogen in the present invention includes fluorine, chlorine, bromine and iodine.
  • heterocycloalkyl in the present invention refers to a non-aromatic saturated monocyclic or polycyclic ring system containing 3-10 ring atoms, preferably 5-10 ring atoms, wherein one or more of the ring atoms is not carbon Atoms, but for example nitrogen, oxygen or sulfur atoms.
  • Preferred heterocycloalkyl groups contain 5-6 ring atoms.
  • the prefix aza, oxa or thia before heterocycloalkyl means that at least one nitrogen, oxygen or sulfur atom is used as a ring atom.
  • heterocyclic aromatic group in the present invention refers to an aromatic monocyclic or polycyclic ring system containing 5-14 ring atoms, preferably 5-10 ring atoms, wherein one or more ring atoms are not carbon atoms, and It is, for example, a nitrogen, oxygen or sulfur atom.
  • Preferred heterocyclic aromatic groups contain 5-6 ring atoms.
  • heterocyclic aromatic groups include pyrazinyl, furyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolyl, pyrazolyl , Triazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, 2,3-diaza naphthyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl , Indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridyl, imidazo Pyridyl, isoquinolyl, 1,2,4-triazinyl, benzothiazoly
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  • CDK4/CycD3 recombinant human protease was purchased from Carna (Cat#04-105), ATP was purchased from Sigma (Cat#A7699-5G), staurosporine was purchased from MedChemExpress (Cat#HY-15141), HTRF Toolbox For Kinases CDK4 kit was purchased from Cisbio (Rbpeptide-biotin: Cat#64CUS000C01B; Anti-pRb(Ser780) EuK: Cat#64CUSKAY; Streptavidin-XL665: Cat#610SAXLB; 5X Enzymatic buffer: Cat#62EZBFDD; Detection buffer: #62SDBRDD).
  • the HTRF assay kit can be used to detect the phosphorylation of retinoblastoma gene product (Rb).
  • the experimental reaction was carried out in a 384-well plate (Greiner, Cat#784075), and the total reaction system was 20 ⁇ L.
  • the reaction system mainly includes 1 ⁇ kinase buffer, 50mM MgCl 2 , 1mM DTT, 1 ⁇ M RB protein and 70 ⁇ M ATP.
  • the compound C1 prepared in Example 1 and the compound C2 prepared in Example 2 were serially diluted with DMSO for 10 concentration points, and 50 nL was transferred to the experimental measurement plate. After adding 12nM CDK4/CycD3, the experimental reaction started.
  • Inhibition rate % (max-sample)/(max-min)*100.
  • min represents the ratio of signal value of 665/615 of the control well without enzyme
  • max represents the ratio of signal value of 665/615 of the DMSO control well .
  • CDK6/CycD3 recombinant human protease was purchased from Carna (Cat#04-107), ATP was purchased from Sigma (Cat#A7699-5G), staurosporine was purchased from MedChemExpress (Cat#HY-15141), HTRF Toolbox For Kinases CDK 4 kit was purchased from Cisbio (Rbpeptide-biotin: Cat#64CUS000C01B; Anti-pRb(Ser780)-EuK: Cat#64CUSKAY; Streptavidin-XL665: Cat#610SAXLB; 5X Enzymatic buffer: Cat#62EZBFDD; Detection buffer :Cat#62SDBRDD).
  • the HTRF assay kit can be used to detect the phosphorylation of retinoblastoma gene product (Rb).
  • the experimental reaction was carried out in a 384-well plate (Greiner, Cat#784075), and the total reaction system was 20 ⁇ L.
  • the reaction system mainly includes 1 ⁇ kinase buffer, 50mM MgCl 2 , 1mM DTT, 1 ⁇ M RB protein and 140 ⁇ M ATP.
  • the compound C1 prepared in Example 1 and the compound C2 prepared in Example 2 were serially diluted with DMSO for 10 concentration points, and 100 nL was transferred to the experimental measurement plate. After adding 12.5nM CDK6/CycD3, the experimental reaction started.
  • Inhibition rate % (max-sample)/(max-min)*100.
  • min represents the ratio of signal value of 665/615 of the control well without enzyme
  • max represents the ratio of signal value of 665/615 of the DMSO control well .

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Abstract

La présente invention concerne un composé de formule générale I, ou un sel pharmaceutiquement acceptable, un stéréoisomère, un ester, un promédicament, un solvate et un composé deutéré de celui-ci, une composition contenant le composé de formule générale I, et une utilisation du composé de formule générale I, ou du sel pharmaceutiquement acceptable, du stéréoisomère, de l'ester, du promédicament, du solvate, et du composé deutéré de celui-ci dans la préparation de médicaments pour le traitement d'une ou de plusieurs maladies liées à la kinase dépendante de la cycline. (I)
PCT/CN2020/081432 2019-04-08 2020-03-26 Inhibiteur de cdk et son utilisation Ceased WO2020207260A1 (fr)

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US11667651B2 (en) 2017-12-22 2023-06-06 Hibercell, Inc. Aminopyridine derivatives as phosphatidylinositol phosphate kinase inhibitors
WO2023150612A1 (fr) * 2022-02-03 2023-08-10 Prelude Therapeutics, Incorporated Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques
US12006332B2 (en) 2019-06-17 2024-06-11 Hibercell, Inc. Aminopyrimidine derivatives as phosphatidylinositol phosphate kinase inhibitors
WO2024125451A1 (fr) * 2022-12-11 2024-06-20 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Dérivés de pipérindine-ones, procédés de préparation et utilisations médicinales associés
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025217307A1 (fr) 2024-04-09 2025-10-16 Revolution Medicines, Inc. Procédés de prédiction de la réponse à un inhibiteur de ras(on) et polythérapies
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11667651B2 (en) 2017-12-22 2023-06-06 Hibercell, Inc. Aminopyridine derivatives as phosphatidylinositol phosphate kinase inhibitors
US12006332B2 (en) 2019-06-17 2024-06-11 Hibercell, Inc. Aminopyrimidine derivatives as phosphatidylinositol phosphate kinase inhibitors
WO2022133215A1 (fr) * 2020-12-18 2022-06-23 Prelude Therapeutics Incorporated Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques
CN116940563A (zh) * 2020-12-18 2023-10-24 普莱鲁德疗法有限公司 Cdk抑制剂及其作为药物的用途
WO2023150612A1 (fr) * 2022-02-03 2023-08-10 Prelude Therapeutics, Incorporated Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques
WO2024125451A1 (fr) * 2022-12-11 2024-06-20 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Dérivés de pipérindine-ones, procédés de préparation et utilisations médicinales associés
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025217307A1 (fr) 2024-04-09 2025-10-16 Revolution Medicines, Inc. Procédés de prédiction de la réponse à un inhibiteur de ras(on) et polythérapies
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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