WO2023051302A1 - Composé hétérocyclique ayant une activité inhibitrice de kinase cycline-dépendante, son procédé de préparation et son utilisation médicale - Google Patents

Composé hétérocyclique ayant une activité inhibitrice de kinase cycline-dépendante, son procédé de préparation et son utilisation médicale Download PDF

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WO2023051302A1
WO2023051302A1 PCT/CN2022/119618 CN2022119618W WO2023051302A1 WO 2023051302 A1 WO2023051302 A1 WO 2023051302A1 CN 2022119618 W CN2022119618 W CN 2022119618W WO 2023051302 A1 WO2023051302 A1 WO 2023051302A1
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alkyl
cycloalkyl
group
alkoxy
aryl
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闫旭
陈振华
刘国标
谷晓成
尚飞
杜佩金
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National Institutes of Pharmaceutical R&D Co Ltd
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National Institutes of Pharmaceutical R&D Co Ltd
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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
    • A61K31/505—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a pyrimidopyridine compound, a preparation method thereof, a pharmaceutical composition containing the same, and its use as a cyclin-dependent kinase (CDK) inhibitor in the treatment of abnormal cell growth such as cancer use in medicines.
  • the compounds of the present invention can inhibit the cyclin-dependent kinases CDK2/cyclin E1 (CCNE1), CDK6/cyclin D1, CDK4/cyclin D3, and therefore can be used for the treatment of cancer, such as HR+/HER2- metastatic breast cancer, ovarian cancer, etc.
  • CDKs Cyclin-dependent kinases
  • CDKs belong to the serine/threonine protein kinase family and are key proteins in the regulation of the cell cycle.
  • CDKs mainly include CDK1-15, etc., which play a role by combining with the corresponding cell cycle protein (cyclin) to form a stable form of CDK/cyclin complex.
  • cyclin cell cycle protein
  • cells contain endogenous CDK and CDK/cyclin complex inhibitor (CKI), which together constitute the regulatory network of the cell cycle and are strictly controlled during cell division.
  • CKI CDK/cyclin complex inhibitor
  • CDK4 and CDK6 are very similar, and they can combine with the three subtypes of cyclin D (cyclinD1/D2/D3) to form a complex, which makes the retinoblastoma protein (Retinoblastoma protein, Rb) Phosphorylation of a series of substrates drives cell cycle progression.
  • the phosphorylated Rb protein releases the transcription factor E2F bound to it, etc.
  • E2F activates and transcribes a series of genes, making the cell enter the S phase and start DNA replication (Kato et al., Genes Dev, 1993, 7(3), 331-342; Dyson et al., Genes Dev, 1998, 12(15), 2245-2262).
  • the activity of CDK4/6 is also negatively regulated by the INK4 family (including p16 INK4A , p15 INK4B , p18 INK4C , p19 INK4D ).
  • INK4 can competitively bind with CDK and inhibit cyclin D-CDK4/6 Complex formation (Baker et al., Genes & Cancer, 2012, 3(11-12), 658-669).
  • CyclinD-CDK4/6-p16-Rb pathway has been found in most human cancers, which can promote the rapid development of G1 phase and lead to abnormal cell proliferation.
  • the main reasons include overexpression of cyclin D1 caused by gene rearrangement or gene amplification (Bergsagel et al., Blood, 2005, 106(1), 296-303); p16INK4a gene deletion, point mutation, or DNA methylation lead to p16INK4a inactivation (Ruas et al., Biochim Biophys Acta, 1998, 1378(2), F115-177); CDK4/6 gene amplification or point mutation (Hamilton et al., Cancer Treatment Reviews, 2016, 45, 129-138). Targeted intervention based on the abnormality of this pathway makes CDK4/6 one of the popular anti-tumor targets.
  • Flavopiridol the first-generation broad-spectrum CDK inhibitor
  • Flavopiridol can inhibit CDK1/2/4/6/7/9 at the same time, but due to its severe side effects, it may cause adverse reactions such as fatigue, diarrhea, and bone marrow suppression, and finally failed Can be successfully applied clinically (Senderowicz et al., Journal of Clinical Oncology, 1998, 16(9), 2986-2999).
  • Palbociclib, Ribociclib and Abemaciclib have been approved by the FDA for the first-line or second-line treatment of advanced breast cancer, and one drug, Lerociclib, is in clinical development.
  • Palbociclib is the first CDK4/6 inhibitor approved by the FDA. It is an oral pyridine compound that inhibits the proliferation of ER+ breast cancer cells by reducing the phosphorylation of Rb protein, preventing the cell cycle from G1 phase to S phase.
  • Palbociclib combined with letrozole or Fulvestrant can significantly prolong the progression-free survival of patients with reliable safety (Cristofanilli et al., Lancet Oncol, 2016, 17(4), 425- 439; Richard et al., Lancet Oncology, 2015; Finn et al., N Engl J Med, 2016, 375(20), 1925-1936; Nicholas et al., N Engl J Med, 2015, 373(3), 209-219 ).
  • Ribociclib (Kisqali, LEE011) and Abemaciclib (Verzenio, LY2835219) are oral reversible CDK4/6 inhibitors, which can cause G1 phase arrest by inhibiting Rb phosphorylation.
  • the IC 50 values of ribociclib for CDK4/6 inhibition are 10nM and 39nM, respectively, while the sensitivity to other CDK family members is low (the IC 50 values of CDK1 and CDK2 are both greater than 50mM) (Sherr et al., Cancer Discovery, 2016, 6( 4), 353-367). After 1-4 hours of oral administration, the Cmax value can be reached in the plasma; after 8 days of continuous administration, the stable state of blood is reached.
  • the binding rate of ribociclib to human plasma protein is 70%, and it can be decomposed by CPY3A4 (a weak inhibitor) in vivo, and the main products are N-hydroxy and N-demethyl derivatives.
  • Abemaciclib is more selective for CDK4/6 kinases with IC 50 values of 2 nM and 5 nM, respectively, while for CDK1 and CDK2 inhibition with IC 50 values >500 nM.
  • Abemaciclib is a phenylpyrimidine compound that is structurally related to palbociclib and ribociclib.
  • Abemaciclib exhibited a broader inhibitory effect and was able to inhibit Dyrk, PIM, HIPK and CAMK kinase families (Ki ⁇ 10nM) simultaneously (Chen et al., Molecular Cancer Therapeutics, 2016, 15(10), 2273-2281).
  • the in vivo pharmacokinetic data show that it reaches the peak within 4-24 hours after oral administration, and reaches a steady state after 5 days of continuous administration.
  • the binding rate of Abemaciclib to human plasma protein is about 96%, and it can be decomposed by CPY3A4 in vivo, and the main decomposition product is N-deethyl derivative.
  • the introduction of deuterium atoms makes the compound have stronger metabolic stability, and the metabolic stability is improved by 11-45%, which is manifested as a higher half-life.
  • the drug is approved in combination with Fluvestrant for the treatment of ER+/HER2- advanced or metastatic breast cancer.
  • Abemaciclib combined with gemcitabine also showed synergistic antitumor activity, and also had inhibitory effects on various types of tumors, including mantle cell lymphoma (MCL), colorectal cancer, lung cancer, glial Blastoma and acute myeloid leukemia (AML).
  • MCL mantle cell lymphoma
  • AML acute myeloid leukemia
  • CDK4/6 inhibitors combined with endocrine therapy can bring significant clinical benefits to certain types of breast cancer patients, some patients are still ineffective (10-20%), and 70-80% of tumor patients are treated after 12 -Drug resistance will develop after 36 months (Tripathy et al., Lancet Oncol, 2018, 19(7), 904-915).
  • CDK4/6 therapy resistance includes Rb loss, CCND1 overexpression, p16 amplification, overactivation of the CCNE1-CDK2 complex (eg, CCNE1 is high in breast and ovarian cancer cell line models CDK2 expression), CDK2 bypass activation, CDK4/6 activity increase, CDK7 overexpression, etc., all of which may be related to CDK4/6 treatment resistance (Taylor Harding et al., Oncotarget, 2014, 6(2), 696-714; Herrera-Abreu et al., Cancer Res, 2016, 76(8), 2301-2313).
  • Cyclin E (cyclin E) is a protein encoded by CCNE1, which begins to express in the middle of G1, and gradually degrades and disappears after the expression level reaches the peak in G1-S phase.
  • Cyclin E binds to CDK2 to form a complex, and phosphorylates the downstream substrates Rb, CDC6, NPAT and P107 to make the cell enter the S phase of DNA synthesis; Cyclin E plays a role in maintaining chromosome stability and regulating the cell spindle and centrosome cycle Important role; Cyclin E is highly expressed in a variety of malignant tumors, and CCNE1 gene amplification or overexpression is also related to poor prognosis of a variety of tumors, such as endometrioma, gastric cancer, ovarian cancer (George et al., Clinical cancer research, 2017, 23(7), 1862-1874; Nakayama et al., Cancer, 2010, 116(11), 2621-2634; KENTARO et al., Int J Oncol, 2015, 48(2), 506-516; Ooi et al., Human Pathology, 2016, S0046817716303082) etc.
  • CDK2 plays a key role in cell cycle regulation by interacting with chaperone proteins and phosphorylation activation, and participates in a series of biological processes, such as DNA damage, intracellular transport, protein degradation, signal transduction, DNA and RNA metabolism and translation et al. (Tadesse et al., Drug Discovery Today, 2020, 25(2), 406-413). CDK2 is underexpressed in most normal tissues (McCurdy et al., Oncogene, 2016). In dividing cells, CDK2 is a key cell cycle regulator, which is activated from the late G1 phase and continues to express throughout the S phase.
  • CDK2 binds CCNE1 or E2 and Cyclin A2, is activated by phosphorylation of cyclin complexes (CDK7, MAT1, cyclin H), and can be negatively regulated by CDC25A dephosphorylation.
  • CDK2-cyclinE and CDK4/6-cyclin-D co-phosphorylate Rb, causing Rb to release E2F and initiate the transcription of cell cycle regulatory genes.
  • CDK2 also regulates the phosphorylation of other proteins, linking them to the cell cycle. For example, phosphorylation of Smad3 by CDK2-cyclin-E limits its transcriptional activity, ultimately slowing cell cycle progression (Matsuura et al., Nature, 2004, 430(6996), 226-231).
  • CDK2 also phosphorylates prereplication complex proteins, which are required to initiate DNA synthesis.
  • CDC6 which is an essential protein for loading minichromosome maintenance (MCM) protein onto DNA and MCM helicase protein, and initiating DNA replication
  • CDK2 also plays an important role in regulating centrosome duplication by targeting phosphorylated centrosome proteins such as nucleophospholipid (Npm) and cp110, releasing centrioles and then maintaining centriole duplication (Adon et al., Molecular & Cellular Biology, 2010, 30 (3), 694-710; Hu et al., Cancer Research, 2015, 75(10), 2029-2038).
  • the protein structure of CDK2 is similar to that of most protein kinases, and it is folded in a "double leaf shape".
  • the smaller N-terminal region is mainly composed of ⁇ -sheets, including 5 long antiparallel ⁇ -strands and a C-helix.
  • the C-alpha helix contains the sequence PSTAIRE and is required for cyclin binding.
  • T-loop binds to the Ser/Thr (phosphorylated receptor) region of the substrate, activates phosphorylation, and plays a role in cell cycle regulation.
  • the N-terminal and C-terminal are composed of a flexible hinge region (residues 81(Glu)-84 (His)) connection, this region forms a deep cleft, the ATP binding site (Pavletich et al., Journal of Molecular Biology, 1999, 287(5), 821-828; Malumbres et al., Chemical Reviews, 2014, 15( 6), 122; Honda et al., Embo Journal, 2005, 24(3)).
  • CDK2 activation and inhibition are regulated by several mechanisms: In the absence of mitogen signaling, CDK2 is inactive. In the late G1 phase, CDK2 activity begins to increase, which is due to, first, E2F-mediated transcription of the CCNE gene, and its protein product binds and activates CDK2; full activation of the CDK2-cyclin E or A complex requires phosphorylation of Thr160 by CAK Furthermore, Wee1 and Myt1 kinases can inhibit the phosphorylation of Thr14 and Tyr15 respectively, and the dephosphorylation of these residues by the CDC25 protein phosphatase family can reactivate CDK2; in addition, the CDK inhibitory protein family Cip and Kip , can bind to CDK2 to inactivate it, and cyclins E and A can be degraded by ubiquitin ligase-mediated ubiquitination (Solomon et al., Journal of Medicinal Chemistry, 2018).
  • CDK2 can also bind cyclin A, participate in the progression of the entire S phase, and regulate DNA damage repair. Following DNA damage, the DNA damage response (DDR) arrests cells at the G1/S junction to repair damaged DNA and maintain genomic fidelity in daughter cells.
  • DDR DNA damage response
  • accumulation of p53 leads to upregulation of p21Cip1/Waf1 transcription, followed by cell cycle arrest through repression of cyclin-D1-CDK4/6 and cyclinE-CDK2 (Shieh et al., Genes & Development, 2000, 14(3), 289-300).
  • the second mechanism is to target CDC25A for degradation.
  • WEE1 prevents cells from entering S phase by continuously inhibiting the phosphorylation of CDK2 protein Thr14 and Tyr15 (Mailand et al., Science, 2000, 288(5470), 1425-1429).
  • the target protein of CDK2, FOXO1 plays an important role in dsDNA breakage triggering DNA damage, thereby inducing apoptosis.
  • CDK2 no longer phosphorylates FOXO1, allowing FOXO1 to exert transcriptional activity, and promotes cell apoptosis by up-regulating the expression of various pro-apoptotic proteins (FasL, TRAIL, and Bim) (Huang et al. People, Science, 2006, 314(5797), 294-297; Huang et al., Cell Cycle, 2007, 6(8), 902-906).
  • CDK4/6 inhibitors have become the first-line treatment for specific types of breast cancer, some types of breast cancer are naturally insensitive to CDK4/6 inhibitors, such as triple-negative breast cancer (TNBC).
  • TNBC triple-negative breast cancer
  • drug resistance to CDK4/6 was also found in ER+Her2- breast cancer.
  • Cyclin E is highly expressed in a variety of malignant tumors, including tumors insensitive to CDK4/6 inhibitors (TNBC) and ovarian cancer; the complex formed by CDK2 and CyclinE also plays an important role in CDK4/6 drug resistance ;Targeting CDK2 can delay the treatment resistance produced by CDK4/6 inhibitor molecules, and further exert curative effect on drug-resistant patients; while in the compounds targeting CDK2/4/6 to overcome CDK4/6 drug resistance, no effect has been seen Of the approved drugs, only Pfizer's PF-06873600 has entered clinical phase II research. Therefore, it is an urgent problem to develop CDK2/4/6 inhibitors with high selectivity and low drug toxicity to overcome CDK4/6 drug resistance.
  • CDK cyclin-dependent kinase
  • the object of the present invention is to provide a compound represented by general formula (I) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • Ring A is selected from heterocyclyl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy , Cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups;
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, Substituted by one or more groups of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • R is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl One or more groups of radical, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,
  • R and R together with their attached nitrogen and sulfur atoms form a heterocyclyl or heteroaryl, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxygen
  • halogen amino, nitro, cyano
  • oxygen One or more of substituent, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group substitution;
  • Each R is independently selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, the alkyl, Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, One or more groups of alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,
  • R is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O) Ra , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m R a , -S(O) m NR a R b and -NHS(O) m R a , the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano One or more groups of radical, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycl
  • R is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, acyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m R a , -S(O) m NR a R b and -NHS(O) m R a , the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro One or more of cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy
  • R a and R b are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl, wherein the alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further selected from the group consisting of halogen, amino, nitro, One or more of cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group replacement;
  • R a and R b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, One or more of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted;
  • n 0, 1, 2;
  • p 0, 1, 2, 3 or 4.
  • Ring A is selected from 3 to 12 membered monocyclic heterocyclic groups, spiro heterocyclic groups, condensed heterocyclic groups or bridged heterocyclic groups, preferably 5 to 7 membered monocyclic heterocyclic groups, 7 to 10 membered spiro heterocyclic groups, 7 to 10-membered fused heterocyclic group and 7 to 10-membered bridged heterocyclic group, more preferably pyrrolidinyl, piperidinyl, piperazinyl, said heterocyclic group is optionally further selected from halogen, amino, nitro, cyano radical, hydroxyl, mercapto, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 6 ring
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer Isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (II) or stereoisomers, tautomers, and mesomers thereof body, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • ring B, R 1 , R 2 , R 3 , R 4 , R 5 , and p are as defined in general formula (I).
  • Ring B is selected from C 3 -C 7 cycloalkyl, 4 to 7 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, more preferably
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (III) or stereoisomers, tautomers, meso body, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , and p are as defined in general formula (I).
  • Each R 3 is independently selected from halogen, amino, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, 4 to 7 membered Heterocyclyl, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, 4 to 7 membered heterocyclyl are optionally further selected from halogen, amino, nitr One or more of group, cyano group, hydroxyl group, mercapto group, carboxyl group, ester group, oxo group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group Substituted by a group; preferably halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6
  • p 0, 1, 2 or 3; preferably 1 or 2.
  • the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomers and tautomers according to the present invention mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 5-7 membered heterocyclyl, C 6 -C 10 Aryl and 5 to 10 membered heteroaryl, preferably C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl; preferably C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 5 to 7 membered heterocyclyl;
  • the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl are optionally further selected from halogen, amino, nitro, cyano, Hydroxy, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C Substituted by one or more groups of 6 cycloalkyl, 5 to 7 membered heterocyclyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy;
  • the 5 to 7 membered heterocyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, Oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 5 to 7 membered Substitution by one or more groups of heterocyclic group, C 1 -C 6 haloalkyl group, C 1 -C 6 alkoxy group, C 6 -C 10 aryl group, 5-10 membered heteroaryl group.
  • R 2 is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 5 to 7 membered heterocyclyl, C 6 - C 10 aryl and 5 to 10 membered heteroaryl, preferably hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl; preferably hydrogen and C 1 -C 6 alkyl;
  • the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl are optionally further selected from halogen, amino, nitro, cyano, Hydroxy, mercapto, carboxyl, ester, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C Substituted by one or more groups of 6 cycloalkyl, 5 to 7 membered heterocyclyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy;
  • the 5 to 7 membered heterocyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, Oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 5 to 7 membered Substitution by one or more groups of heterocyclic group, C 1 -C 6 haloalkyl group, C 1 -C 6 alkoxy group, C 6 -C 10 aryl group, 5-10 membered heteroaryl group.
  • R 4 is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 Haloalkoxy, preferably hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably R 4 is hydrogen or C 1 -C 6 alkyl.
  • R is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 Haloalkoxy, -C(O) Ra , preferably hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy , -C(O)R a ;
  • R a is selected from C 1 -C 6 alkyl groups.
  • Typical compounds of the invention include, but are not limited to, the following compounds:
  • the present invention further provides a compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer,
  • compound Ij and compound Ia undergo a dehydration reaction to obtain a compound of general formula (I);
  • the base is preferably triethylamine;
  • the catalyst is preferably triphenylphosphine dichloride;
  • Ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , and p are as defined in general formula (I).
  • the present invention further provides a compound represented by general formula (II) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer,
  • the base is preferably triethylamine
  • the catalyst is preferably triphenylphosphine dichloride
  • Ring B, R 1 , R 2 , R 3 , R 4 , R 5 , and p are as defined in general formula (II).
  • the present invention further provides a compound represented by general formula (III) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer,
  • the base is preferably triethylamine
  • the catalyst is preferably triphenylphosphine dichloride
  • R 1 , R 2 , R 3 , R 4 , R 5 , and p are as defined in general formula (III).
  • the present invention also provides a pharmaceutical composition, which comprises the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomer, tautomer body, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition which comprises the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomer, tautomer body, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the object of the present invention is also to provide the compound represented by general formula (I), general formula (II) or general formula (III) according to the present invention or its stereoisomer, tautomer, meso body, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of a cyclin-dependent kinase (CDK) inhibitory use in pharmaceuticals.
  • CDK cyclin-dependent kinase
  • the object of the present invention is also to provide the compound represented by general formula (I), general formula (II) or general formula (III) according to the present invention or its stereoisomer, tautomer, meso body, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it in the preparation of inhibiting cancer cell proliferation, inhibiting cancer cell invasion, or Use in drugs for inducing cancer cell apoptosis.
  • general formula (I), general formula (II) or general formula (III) according to the present invention or its stereoisomer, tautomer, meso body, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it in the preparation of inhibiting cancer cell proliferation, inhibiting cancer cell invasion, or Use in drugs for inducing cancer cell apoptosis.
  • the object of the present invention is also to provide the compound represented by general formula (I), general formula (II) or general formula (III) according to the present invention or its stereoisomer, tautomer, meso body, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation for prevention and/or treatment and cell cycle
  • a pharmaceutical composition comprising it in the preparation for prevention and/or treatment and cell cycle
  • Use in medicine for diseases associated with protein-dependent kinase activity such as cancer, especially in association with cyclin-dependent kinases CDK2/cyclin E1 (CCNE1), CDK6/cyclin D1, CDK4/ Cancers, more particularly breast cancers such as HR+/HER2- metastatic breast or ovarian cancers, characterized by amplification or overexpression of cyclin D3.
  • the present invention also relates to compounds represented by general formula (I), general formula (II) or general formula (III) or stereoisomers, tautomers, mesomers, exo Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as CDK inhibitors.
  • the present invention also relates to compounds represented by general formula (I), general formula (II) or general formula (III) or stereoisomers, tautomers, mesomers, exo Racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for inhibiting cancer cell proliferation, inhibiting cancer cell invasion, or inducing Cancer cell apoptosis.
  • the present invention also relates to compounds represented by general formula (I), general formula (II) or general formula (III) or stereoisomers, tautomers, mesomers, exo Racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising them, for use in the prevention and/or treatment of cyclin- Diseases associated with dependent kinase activity, such as cancer, in particular with amplification of the cyclin-dependent kinases CDK2/cyclin E1 (CCNE1), CDK6/cyclin D1, CDK4/cyclin D3 or cancers characterized by overexpression, more particularly breast cancer such as HR+/HER2- metastatic breast or ovarian cancer.
  • cyclin- Diseases associated with dependent kinase activity such as cancer
  • CCNE1 cyclin-dependent kinases
  • CDK2/cyclin E1 CCNE1
  • CDK6/cyclin D1, CDK4/cyclin D3 cancers
  • the present invention also relates to a method for inhibiting CDK, which comprises administering an effective amount of the compound represented by general formula (I), general formula (II) or general formula (III) according to the present invention to a subject in need
  • a method for inhibiting CDK which comprises administering an effective amount of the compound represented by general formula (I), general formula (II) or general formula (III) according to the present invention to a subject in need
  • the present invention also relates to a method for inhibiting cancer cell proliferation, inhibiting cancer cell invasion, or inducing cancer cell apoptosis, which comprises administering an effective amount of the general formula (I) and general formula (I) according to the present invention to a subject in need
  • the present invention also relates to a method for preventing and/or treating diseases related to cyclin-dependent kinase activity, which comprises administering to a subject in need an effective amount of the general formula (I) according to the present invention , the compound represented by general formula (II) or general formula (III) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, the disease such as cancer, especially with cyclin-dependent kinase CDK2/cyclin E1 (CCNE1), CDK6/cell Cancers characterized by amplification or overexpression of cyclin Dl, CDK4/cyclin D3, more particularly breast cancer such as HR+/HER2- metastatic breast or ovarian cancer.
  • the disease such as cancer, especially with cyclin-dependent kinase CDK2/cyclin E1 (CCNE1), CDK6/cell Cancers
  • Alkyl means a saturated monovalent aliphatic hydrocarbon group, which includes straight and branched chain groups having the indicated number of carbon atoms.
  • the alkyl group usually contains 1-20 carbon atoms (C 1 -C 20 alkyl), preferably 1 to 12 carbon atoms (C 1 -C 12 alkyl), more preferably 1 to 8 carbon atoms (C 1 -C 8 alkyl) or 1 to 6 carbon atoms (C 1 -C 6 alkyl”) or 1 to 4 carbon atoms (C 1 -C 4 alkyl).
  • alkyl examples include methyl, ethyl Base, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1, 2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2- Ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methyl Hexyl, 4-methylhexyl, 5-methylhexyl
  • Alkyl can be substituted or unsubstituted, when When substituted, the substituents may be substituted at any available point of attachment.
  • Optionally substituted alkyl groups described herein may be substituted with one or more substituents, which are independently selected unless otherwise stated. To the extent such substitution is chemically significant, the total number of substituents can be equal to the total number of hydrogen atoms on the alkyl group.
  • Optionally substituted alkyl typically contains 1 to 6 optional substituents, sometimes 1 to 5 optional substituents, preferably 1 to 4 optional substituents, or more preferably 1 to 3 optional substituents Substituents.
  • an alkyl group may be substituted by one or more (up to the total number of hydrogen atoms present on the alkyl group) halo groups.
  • C 1 -C 4 alkyl includes haloalkyl, especially fluoroalkyl having 1 to 4 carbon atoms, such as trifluoromethyl or difluoroethyl (ie CF 3 and —CH 2 CHF 2 ).
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- -butenyl etc.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, eg ethynyl, propynyl, butynyl and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contain 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclyls include:
  • fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene base and naphthyl. Phenyl is more preferred.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred examples are imidazolyl, furyl, thienyl, thiazolyl, pyryl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl
  • Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O-(alkyl) and -O-(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • haloalkyl refers to an alkyl group substituted with one or more halo, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • mercapto refers to -SH.
  • ester group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
  • Cancer refers to any malignant and/or invasive growth or tumor (caused by abnormal cell growth). Cancers include solid tumors named for the type of cells that form them, cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Cancers of the blood include, but are not limited to, leukemias, lymphomas, and myelomas. Cancer also includes primary cancer that started in a specific part of the body, metastatic cancer that has spread from where it started to other parts of the body, recurrence from the original primary cancer after remission, and second primary cancer (This is a new primary cancer in a person with a history of previous cancer of a different type than the new primary cancer).
  • the cancer may be selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, and gastric cancer.
  • the cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
  • Stereoisomers described herein may include cis and trans isomers, optical isomers such as (R) and (S) enantiomers of the compounds of the invention (including compounds exhibiting more than one isomeric type) Isomers, diastereoisomers, geometric isomers, rotamers, atropisomers, conformers and tautomers; and mixtures thereof (such as racemates and asymmetric enantiomer pair).
  • optical isomers such as (R) and (S) enantiomers of the compounds of the invention (including compounds exhibiting more than one isomeric type) Isomers, diastereoisomers, geometric isomers, rotamers, atropisomers, conformers and tautomers; and mixtures thereof (such as racemates and asymmetric enantiomer pair).
  • the compounds of the present invention may exhibit tautomerism and structural isomerism.
  • compounds may exist in several tautomeric forms, including enol and imine forms and keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of the present invention.
  • Tautomers exist as a mixture of tautomeric sets in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the provided compounds.
  • enantiomeric purity of the compounds described herein can be described in terms of enantiomeric excess (ee), which means that a sample contains one enantiomer in a greater amount than the other Degree.
  • ee enantiomeric excess
  • the ee of a racemic mixture is 0%, while the ee of a single, completely pure enantiomer is 100%.
  • diastereomeric purity can be described in terms of diastereomeric excess (de).
  • the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable base addition salt or acid addition salt with a base or an acid.
  • the base includes inorganic bases and organic bases.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc.
  • Acceptable inorganic bases include aluminum hydroxide, hydroxide Calcium, Potassium Hydroxide, Sodium Carbonate and Sodium Hydroxide etc.
  • the acid includes inorganic acid and organic acid, acceptable inorganic acid includes hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and the like.
  • Acceptable organic acids include acetic acid, trifluoroacetic acid, formic acid, ascorbic acid, and the like.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir.
  • Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • Hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in which the active ingredient is admixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil may also be used.
  • Soft gelatin capsules provide an oral formulation.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which may be natural
  • the resulting phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanylethyleneoxycetate Heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorb
  • Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners.
  • preservatives such as ethyl or n-propylparaben
  • coloring agents such as ethyl or n-propylparaben
  • flavoring agents such as sucrose, saccharin, or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives for admixture. Suitable dispersing or wetting agents and suspending agents are mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide Products such as polyethylene oxide sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • the pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then treated in a mixture of water and glycerol to form a microemulsion.
  • the injectable solution or microemulsion can be injected into the patient's bloodstream by local bolus injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
  • the pharmaceutical composition of the present invention may be in the form of sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are prepared as injectables.
  • the compounds of this invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's body weight, the patient's health status, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc.
  • the optimal treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
  • the present invention can contain the compound represented by the general formula (I), and its pharmaceutically acceptable salt, hydrate or solvate as the active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared into clinically acceptable dosage forms.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like.
  • the compound of the present invention can be used as the only active ingredient, and can also be used in combination with other drugs for treating diseases related to tyrosine kinase activity. Combination therapy is achieved by the simultaneous, separate or sequential administration of the individual therapeutic components.
  • the present invention adopts the following synthetic scheme to prepare the compound of general formula (I) of the present invention.
  • the present invention adopts the following Scheme 1 to prepare the compound represented by the general formula (I) of the present invention.
  • Step 1 In a polar aprotic solvent (such as dichloromethane), in the presence of a suitable base (such as triethylamine), the sulfonyl chloride compound is reacted to obtain the sulfonamide compound Ia;
  • a polar aprotic solvent such as dichloromethane
  • a suitable base such as triethylamine
  • Step 2 In a suitable solvent, in the presence of a suitable reducing agent, 4-chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester undergoes a reduction reaction to obtain Compound Ib;
  • the solvent is such as tetrahydrofuran, the The reducing agent such as diisobutylaluminum hydride;
  • Step 3 In a suitable solvent, in the presence of a suitable base, compound Ib reacts with compound Ic to obtain compound Id;
  • the solvent is for example isopropanol
  • the base is for example diisopropylethylamine
  • the reaction temperature can be Between room temperature and 80°C;
  • Step 4 In a suitable solvent, in the presence of a suitable oxidizing agent, compound Id undergoes an oxidation reaction to obtain compound Ie; the solvent such as ethyl acetate, the oxidizing agent such as manganese dioxide, the reaction temperature can be at 50°C to 80°C between;
  • Step 5 In a suitable solvent, in the presence of a suitable catalyst, compound Ie undergoes an Aldol cyclization reaction (see VanderWel et al., J.Med.Chezn.2005, 4S, 2371) to obtain compound If; the solvent such as Tetrahydrofuran, the catalyst such as LHMDS, the reaction temperature can be between -20°C and room temperature, and the reaction is carried out under nitrogen atmosphere;
  • Step 6 In a suitable solvent, in the presence of a suitable oxidizing agent, compound If is oxidized to obtain compound Ig; the solvent is especially a mixed solvent, such as a mixed solvent of 2-methyltetrahydrofuran and water, and the oxidizing agent includes but Not limited to potassium hydrogen persulfate, m-chloroperoxybenzoic acid, etc. Excessive oxidizing agents help the reaction to proceed completely, and the reaction temperature can be between 10°C and 80°C;
  • Step 7 In a suitable solvent, in the presence of a suitable base, compound Ig reacts with compound Ih to obtain compound Ii;
  • the solvent such as isopropanol, 2-methyltetrahydrofuran, the base such as diisopropylethyl Amines, the reaction temperature can be between room temperature and 80°C;
  • Step 8 In a suitable solvent, in the presence of a suitable acid, compound Ii is deprotected to obtain compound Ij; the solvent is such as dioxane, the acid is such as hydrochloric acid, and the reaction temperature is typically at room temperature; further The compound is freed by a base such as sodium hydroxide, potassium hydroxide;
  • Step 9 In a suitable solvent, in the presence of a suitable base and a catalyst, compound Ij and compound Ia undergo a dehydration reaction to obtain a compound of general formula (I);
  • the solvent is, for example, dichloromethane
  • the base such as triethylamine
  • the catalyst such as triphenylphosphine dichloride
  • the reaction is typically carried out under a nitrogen atmosphere
  • the reaction temperature is typically 0°C to room temperature;
  • ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , and p are as defined in general formula (I).
  • the present invention adopts the following scheme 2 to prepare the compound of general formula (II) of the present invention.
  • Step 1 In a polar aprotic solvent (such as dichloromethane), in the presence of a suitable base (such as triethylamine), the sulfonyl chloride compound is reacted to obtain the sulfonamide compound Ia;
  • a polar aprotic solvent such as dichloromethane
  • a suitable base such as triethylamine
  • Step 2 In a suitable solvent, in the presence of a suitable reducing agent, 4-chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester undergoes a reduction reaction to obtain Compound Ib;
  • the solvent is such as tetrahydrofuran, the The reducing agent such as diisobutylaluminum hydride;
  • Step 3 In a suitable solvent, in the presence of a suitable base, compound Ib reacts with compound Ic to obtain compound Id;
  • the solvent is for example isopropanol
  • the base is for example diisopropylethylamine
  • the reaction temperature can be Between room temperature and 80°C;
  • Step 4 In a suitable solvent, in the presence of a suitable oxidizing agent, compound Id undergoes an oxidation reaction to obtain compound Ie; the solvent such as ethyl acetate, the oxidizing agent such as manganese dioxide, the reaction temperature can be at 50°C to 80°C between;
  • Step 5 In a suitable solvent, in the presence of a suitable catalyst, compound Ie undergoes an Aldol cyclization reaction (see VanderWel et al., J.Med.Chezn.2005, 4S, 2371) to obtain compound If; the solvent such as Tetrahydrofuran, the catalyst such as LHMDS, the reaction temperature can be between -20°C and room temperature, and the reaction is carried out under nitrogen atmosphere;
  • Step 6 In a suitable solvent, in the presence of a suitable oxidizing agent, compound If is oxidized to obtain compound Ig; the solvent is especially a mixed solvent, such as a mixed solvent of 2-methyltetrahydrofuran and water, and the oxidizing agent includes but Not limited to potassium hydrogen persulfate, m-chloroperoxybenzoic acid, etc. Excessive oxidizing agents help the reaction to proceed completely, and the reaction temperature can be between 10°C and 80°C;
  • Step 7 In a suitable solvent, in the presence of a suitable base, compound Ig reacts with compound IIh to obtain compound IIi; Amines, the reaction temperature can be between room temperature and 80°C;
  • Step 8 In a suitable solvent, in the presence of a suitable acid, compound IIi is deprotected to obtain compound IIj; the solvent is such as dioxane, the acid is such as hydrochloric acid, and the reaction temperature is typically at room temperature; further The compound is freed by a base such as sodium hydroxide, potassium hydroxide;
  • Step 9 In a suitable solvent, in the presence of a suitable base and a catalyst, compound IIj and compound Ia undergo a dehydration reaction to obtain a compound of general formula (II);
  • the solvent is, for example, dichloromethane
  • the base such as triethylamine
  • the catalyst such as triphenylphosphine dichloride
  • the reaction is typically carried out under a nitrogen atmosphere
  • the reaction temperature is typically 0°C to room temperature;
  • ring B, R 1 , R 2 , R 3 , R 4 , R 5 , and p are as defined in general formula (II).
  • the present invention adopts the following scheme 3 to prepare the compound of general formula (III) of the present invention.
  • Step 1 In a polar aprotic solvent (such as dichloromethane), in the presence of a suitable base (such as triethylamine), the sulfonyl chloride compound is reacted to obtain the sulfonamide compound Ia;
  • a polar aprotic solvent such as dichloromethane
  • a suitable base such as triethylamine
  • Step 2 In a suitable solvent, in the presence of a suitable reducing agent, 4-chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester undergoes a reduction reaction to obtain Compound Ib;
  • the solvent is such as tetrahydrofuran, the The reducing agent such as diisobutylaluminum hydride;
  • Step 3 In a suitable solvent, in the presence of a suitable base, compound Ib reacts with compound IIIc to obtain compound IIId;
  • the solvent is for example isopropanol
  • the base is for example diisopropylethylamine
  • the reaction temperature can be Between room temperature and 80°C;
  • Step 4 In a suitable solvent, in the presence of a suitable oxidizing agent, compound IIId is oxidized to obtain compound IIIe; the solvent is, for example, ethyl acetate, and the oxidizing agent is, for example, manganese dioxide.
  • the reaction temperature can be between 50°C and 80°C between;
  • Step 5 In a suitable solvent, in the presence of a suitable catalyst, compound IIIe undergoes an Aldol cyclization reaction (see VanderWel et al., J.Med.Chezn.2005, 4S, 2371) to obtain compound IIIf;
  • the solvent such as Tetrahydrofuran, the catalyst such as LHMDS, the reaction temperature can be between -20°C and room temperature, and the reaction is carried out under nitrogen atmosphere;
  • Step 6 In a suitable solvent, in the presence of a suitable oxidizing agent, compound IIIf undergoes an oxidation reaction to obtain compound IIIg;
  • the solvent is particularly a mixed solvent, such as a mixed solvent of 2-methyltetrahydrofuran and water, and the oxidizing agent includes but Not limited to potassium hydrogen persulfate, m-chloroperoxybenzoic acid, etc. Excessive oxidizing agents help the reaction to proceed completely, and the reaction temperature can be between 10°C and 80°C;
  • Step 7 In a suitable solvent, in the presence of a suitable base, compound IIIg reacts with compound IIh to obtain compound IIIi;
  • the solvent such as isopropanol, 2-methyltetrahydrofuran, the base such as diisopropyl Amines
  • the reaction temperature can be between room temperature and 80°C;
  • Step 8 In a suitable solvent, in the presence of a suitable acid, compound IIIi is deprotected to obtain compound IIIj; the solvent is such as dioxane, the acid is such as hydrochloric acid, and the reaction temperature is typically at room temperature; further The compound is freed by a base such as sodium hydroxide, potassium hydroxide;
  • Step 9 In a suitable solvent, in the presence of a suitable base and a catalyst, compound IIIj and compound Ia undergo a dehydration reaction to obtain a compound of general formula (III);
  • the solvent is, for example, dichloromethane
  • the base such as triethylamine
  • the catalyst such as triphenylphosphine dichloride
  • the reaction is typically carried out under a nitrogen atmosphere
  • the reaction temperature is typically 0°C to room temperature
  • R 1 , R 2 , R 3 , R 4 , R 5 , and p are as defined in general formula (III).
  • the compounds of the present invention are prepared utilizing convenient starting materials and general preparative procedures.
  • the present invention gives typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But unless otherwise specified, other reaction conditions can also be adopted. Optimum conditions may vary with specific reactants or solvents used, but in general, reaction optimization steps and conditions can be identified.
  • protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions.
  • Suitable protecting groups for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art.
  • Protecting Groups in Organic Preparations by T.W. Greene and G.M. Wuts (3rd Edition, Wiley, New York, 1999 and citations in the book) describes in detail the protection or deprotection of a large number of protecting groups.
  • the separation and purification of compounds and intermediates takes appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer plate chromatography, preparative high-performance liquid chromatography or a combination of the above methods.
  • For its specific usage method please refer to the examples described in the present invention.
  • other similar separation and purification means can also be used. They can be characterized using conventional methods, including physical constants and spectral data.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined by LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector).
  • the lc6000 high performance liquid chromatograph (manufacturer: Innovation Tongheng) was used for the preparative liquid chromatography.
  • Chromatographic column is DaisogelC18 10 ⁇ m 100A (30mm ⁇ 250mm), mobile phase: acetonitrile/water.
  • the thin-layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate.
  • the specification of the silica gel plate used for thin-layer chromatography (TLC) is 0.20mm-0.25mm, and the specification used for the preparation of thin-layer chromatography separation and purification products is 0.5mm.
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Biide and other companies.
  • the reactions can all be carried out under a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Reaction solvent organic solvent or inert solvent are respectively expressed as that the solvent used does not participate in the reaction under the described reaction conditions, including such as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, Dichloromethane, ether, methanol, nitrogen-methylpyrrolidinone (NMP), pyridine, etc.
  • the solution refers to an aqueous solution.
  • the chemical reactions described in the present invention are generally carried out under normal pressure.
  • the reaction temperature is between -78°C and 200°C.
  • the reaction time and conditions are, for example, between -78°C and 200°C under one atmospheric pressure, and the reaction is completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin layer chromatography (TLC), and the system of developing agent used in the reaction has: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, C: acetone, The volume ratio of the solvent is adjusted according to the polarity of the compound.
  • TLC thin layer chromatography
  • the eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography include: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, the volume ratio of solvent is according to the compound It can be adjusted according to the polarity, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid.
  • Boc tert-butoxycarbonyl
  • DIPEA Diisopropylethylamine
  • EDTA ethylenediaminetetraacetic acid
  • IC 50 the concentration that inhibits 50% of the activity
  • LHMDS lithium hexamethyldisilazane salt (lithium bis(trimethylsilyl)amide)
  • mCPBA m-chloroperoxybenzoic acid
  • NBS N-bromosuccinimide
  • NCS N-chlorosuccinimide
  • NIS N-iodosuccinimide
  • PE petroleum ether
  • TBS tert-butyldimethylsilyl
  • TBHP tert-butyl hydroperoxide
  • Step 2 Preparation of ( ⁇ )-(1R*,2R*)-2-(benzylamino)-1-methylcyclopent-1-ol (( ⁇ )1b)
  • the acidic aqueous layer was cooled in an ice-water bath, and the pH was adjusted to 10 using 5N aqueous sodium hydroxide solution.
  • the resulting biphasic mixture was extracted with ethyl acetate (1200 mL ⁇ 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil. Concentrate under reduced pressure at 80° C. for 5 h, cool down to room temperature, disperse in petroleum ether, and filter to obtain 85.0 g of the title product as a brown solid.
  • the reaction mixture remained clear for about 1 min and then started to precipitate. After 5 min, a thick white suspension formed but did not interfere with stirring. Stirring was continued at 80 °C for 4 h, then heating was stopped and the mixture was continued to stir while gradually cooling to room temperature overnight. The mother liquor was collected by filtration and concentrated to give 45 g of a brown solid. Suspend the brown solid in water (250 mL) and ethyl acetate (500 mL) in a 1 L separatory funnel. Aqueous hydrochloric acid (4M, 150 mL, 600 mmol) was added and the mixture was stirred for about 30 seconds. A clear biphasic mixture is obtained.
  • Step 7 Preparation of 4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (1 g)
  • Step 8 8-((1R,2R)-2-Hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one ( 1h)
  • Step 9 8-((1R,2R)-2-Hydroxy-2-methylcyclopentyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one Preparation of (1i)
  • Step 10 4-((8-((1R,2R)-2-Hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine Preparation of -2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1j)
  • Step 11 8-((1R,2R)-2-Hydroxy-2-methylcyclopentyl)-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidine-7(8H ) - Preparation of ketone (1k)
  • Step 13 2-((1-(Cyclopropanesulfonylimino)piperidin-4-yl)amino)-8-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)pyridine
  • Step 1 2-((1-(Cyclopropanesulfonylimino)piperidin-4-yl)amino)-6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2 Preparation of -methylcyclopentyl)pyrido[2,3-d]pyrimidin-7(8H)-one (2)
  • Step 7 8-Cyclopentyl-2-(((1-(cyclopropanesulfonylimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (3)
  • Step 2 8-((1R,2R)-2-Hydroxy-2-methylcyclopentyl)-2-(((1-(N-methylcyclopropanesulfonylimino)piperidin-4-yl )amino)pyrido[2,3-d]pyrimidin-7(8H)-one (4) preparation
  • Example 5 6-(difluoromethyl)-8-(((1R,2R)-2-hydroxyl-2-methylcyclopentyl)-2-(((1-(N-methylcyclopropane Preparation of sulfonylimino))piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (5)
  • Example 7 8-cyclopentyl-2-(((1-(prop-2-ylsulfonylimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7( Preparation of 8H)-ketone (7)
  • Example 13 8-cyclopentyl-2-(((1-(S-methylsulfonylimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7(8H )-The preparation of ketone (13)
  • the preparation method is the same as that of Example 3, except that N-(tert-butyldimethylsilyl)cyclopropane in step 7 is replaced by N-(tert-butyldimethylsilyl)methanesulfonamide (11a) Sulfonamide (11), yielding the title compound.
  • Example 15 6-(Difluoromethyl)-2-(((1-(N,S-dimethylsulfonylimino)piperidin-4-yl)amino)-8-((1R,2R Preparation of )-2-hydroxy-2-methylcyclopentyl)pyrido[2,3-d]pyrimidin-7(8H)-one (15)
  • Example 22 8-(2-Methylcyclopentyl)-2-((1-(S-methylsulfonylimino)piperidin-4-yl)amino)pyrido[2,3-d] Preparation of pyrimidin-7(8H)-one (22-P1 and 22-P2)
  • Preparative liquid chromatography chromatographic column: Daisogei 30mm ⁇ 250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%.
  • Preparative liquid chromatography chromatographic column: Daisogei 30mm ⁇ 250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%.
  • the preparation method is the same as that of Example 3, except that 2,2-dimethylcyclopentylamine is used instead of cyclopentylamine and N-(tert-butyldimethylsilyl)methanesulfonamide (11a) is used instead of N-( tert-Butyldimethylsilyl)cyclopropanesulfonamide (1l) to give the title compound.
  • Example 28 6-Acetyl-8-cyclopentyl-2-(((1-(S-methylsulfonylimino)piperidin-4-yl)amino)pyrido[2,3-d] Preparation of pyrimidin-7(8H)-one (28)
  • Step 1 4-((6-iodo-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1- Preparation of tert-butyl carboxylate (28a)
  • Step 2 4-(((8-cyclopentyl-6-(1-ethoxyvinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2- base)amino)piperidine-1-carboxylate tert-butyl ester (28b)
  • Step 3 Preparation of 6-acetyl-8-cyclopentyl-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (28c)
  • Step 1 4-((6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino) Preparation of tert-butyl piperidine-1-carboxylate (29a)
  • tert-butyl 4-aminopiperidine-1-carboxylate (2.52g, 12.0mmol) and toluene (10mL) were added to the reaction flask.
  • Silyl)amide lithium (1M in THF, 12mL, 12.0mmol
  • stirred reaction for 20 minutes added compound 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3- d] Pyrimidin-7(8H)-one (1.03g, 3.00mmol) (commercial reagent CAS: 1016636-76-2), stirred overnight. It was concentrated under reduced pressure, and EtOAc (20 mL ⁇ 3) and water (10 mL) were added to the residue.
  • the preparation method was the same as that of Example 3, except that N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (1l) was replaced by isothiazolidine 1,1-dioxide to prepare compound 30.
  • Compound 31 was prepared in the same manner as in Example 22, except that ethyl propionate was used instead of ethyl acetate.
  • Example 33 6-(Difluoromethyl)-8-(2-methylcyclopentyl)-2-(((1-(S-methylsulfonylimino)piperidin-4-yl)amino Preparation of ]pyrido[2,3-d]pyrimidin-7(8H)-one (33-P1 and 33-P2)
  • Step 1 6-(Difluoromethyl)-8-(2-methylcyclopentyl)-2-(((1-(methylsulfonylimino)piperidin-4-yl)amino]pyridine
  • Step 1 6-(Difluoromethyl)-8-(2-methylcyclopentyl)-2-(((1-(methylsulfonylimino)piperidin-4-yl)amino]pyridine
  • Preparative liquid chromatography chromatographic column: Daisogei 30mm ⁇ 250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%.
  • Preparative liquid chromatography chromatographic column: Daisogei 30mm ⁇ 250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%.
  • Example 34 6-Acetyl-5-methyl-8-(2-methylcyclopentyl)-2-(((1-(S-methylsulfonylimino)piperidinyl-4-yl )amino)pyrido[2,3-d]pyrimidin-7(8H)-one (34) preparation
  • Step 1 4-(((5-Methyl-8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl )amino)piperidine-1-carboxylate tert-butyl ester (34c)
  • Example 28 The remaining steps are the same as in Example 28, except that 4-(((5-methyl-8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3 -d]pyrimidin-2-yl)amino)tert-butyl-1-carboxylate tert-butyl ester (34c) instead of 4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[ 2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester (3e) to give compound 34.
  • Example 36 8-cyclopentyl-2-(((1-(thiophene-2-sulfonylimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7(8H )-The preparation of ketone (36)
  • Compound 37 was prepared in the same manner as in Example 22, except that ethyl acetate was replaced with ethyl 2-fluoroacetate.
  • Step 1 4-(((6-Chloro-8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl) Preparation of tert-butyl amino)piperidine-1-carboxylate (38a)
  • Step 1 4-(((6-Bromo-8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl) Preparation of tert-butyl amino)piperidine-1-carboxylate (39a)
  • Step 2 4-((8-(2-methylcyclopentyl)-7-oxo-6-(prop-1-en-2-yl)-7,8-dihydropyrido[2,3 -d] Preparation of pyrimidin-2-yl)amino)piperidine-1-carboxylate tert-butyl ester (39b)
  • Step 3 4-(((6-isopropyl-8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2- base)amino)piperidine-1-carboxylate tert-butyl ester (39c)
  • Example 40 8-cyclobutyl-2-(((1-(S-methylsulfonylimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7(8H )-The preparation of ketone (40)
  • the preparation method is the same as in Example 3, except that cyclopentylamine is replaced by 3,3-difluorocyclopentylamine hydrochloride and N-(tert-butyldimethylsilyl)methanesulfonamide (11a) is replaced by N -(tert-Butyldimethylsilyl)cyclopropanesulfonamide (11), compound 47 was obtained.
  • N-benzyl-3-methylcyclopentane-1-amine (25.0 g, crude product) and isopropanol (200 mL) were added to the reaction flask, and palladium hydroxide on carbon (3.00 g ). The hydrogen gas was replaced, and the reaction was carried out overnight at 45°C. After the reaction was completed, it was filtered, and the temperature of the filtrate was lowered to 5° C., and dioxane hydrochloride solution (4.0 M, 50 mL) was added dropwise, and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain 17.9 g of crude reddish-brown solid, which was directly used in the next step.
  • the preparation method is the same as that of Example 3, except that cyclopentylamine is replaced by cyclohexylamine and N-(tert-butyldimethylsilyl) methanesulfonamide (11a) is replaced by N-(tert-butyldimethylsilyl) Silyl)cyclopropanesulfonamide (1l), to obtain compound 50.
  • Example 51 6-(Difluoromethyl)-2-((1-(S-methylsulfonylimino)piperidin-4-yl)amino)-8-(spiro[2.4]hept-4- base) pyrido[2,3-d]pyrimidin-7-(8H)-one (51)
  • Test Example 1 Inhibitory activity of compounds of the present invention on CDK2/4/6
  • ADP-Glo Kinase Assay Kit (Promega, Cat. No. V9102) was used to detect the inhibitory activity of the test compound on CDK2/CyclinE1 kinase.
  • the kinase phosphorylates the substrate and consumes ATP at the same time, and the remaining ATP can be converted into light by Ultra-Glo TM luciferase.
  • the luminescent signal is positively correlated with the kinase activity, and the value of this luminescent signal can be detected. Reflects kinase activity.
  • the compound to be tested was dissolved in DMSO (Sigma, product number D8418), and then diluted to a concentration of 200 nM, and the initial concentration of the test was set at 100 nM, with 3-fold dilution and 10 gradients.
  • Add 2.5 ⁇ l of a mixture of Histone H1 protein (SignalChem, Cat. No.
  • X is the logarithmic value of the compound concentration
  • Y is the percentage of inhibition
  • Bottom is the minimum percentage of inhibition
  • Top is the maximum percentage of inhibition
  • HillSlope is the slope of the curve.
  • ADP-Glo Kinase Assay Kit (Promega, Cat. No. V9102) was used to detect the inhibitory activity of the test compound on CDK6/CyclinD1 kinase.
  • the compound to be tested was dissolved in DMSO (Sigma, Cat. No. D8418), and the initial concentration of the test was set to 1000 nM, with 3-fold dilution and 10 gradients.
  • X is the logarithmic value of the compound concentration
  • Y is the percentage of inhibition
  • Bottom is the minimum percentage of inhibition
  • Top is the maximum percentage of inhibition
  • HillSlope is the slope of the curve.
  • ADP-Glo Kinase Assay Kit (Promega, Cat. No. V9102) was used to detect the inhibitory activity of the test compound on CDK4/CyclinD3 kinase.
  • the compound to be tested was dissolved in DMSO (Sigma, Cat. No. D8418), and the initial concentration of the test was set to 1000 nM, with 3-fold dilution and 10 gradients.
  • X is the logarithmic value of the compound concentration
  • Y is the percentage of inhibition
  • Bottom is the minimum percentage of inhibition
  • Top is the maximum percentage of inhibition
  • HillSlope is the slope of the curve.
  • IC 50 values of the compounds of the present invention for the inhibition of CDK2, CDK6 and CDK4 kinases are shown in Table 1 below.
  • Table 1 The compounds of the present invention inhibit the IC50 values of CDK2, CDK6 and CDK4 kinases
  • Test Example 2 The level of cytological inhibition of CDK2/4/6 pathway by the compound of the present invention
  • OVCAR3 and HCC1806 cell lines (both purchased from Nanjing Kebai Biotechnology Co., Ltd., ATCC numbers are HTB- 161TM and CRL-2335 TM ) were cultured in RPMI1640 (Gibco, C11875500BT), adding 10% FBS (Gbico, 10099141) and double antibodies (1% penicillin and streptomycin, Gibco, 15140-122).
  • 5,000 OVCAR3 or HCC1806 cells were seeded in a white transparent bottom 96-well (Nunc, 249944)/384-well plate (Corning, 3570), and placed in a 5% incubator at 37°C overnight. The next day, add the compound to be tested, dissolve the compound with DMSO, and dilute it.
  • the initial concentration of the test starts from 10 mM, and it is diluted 3 times. Set up 10 concentration gradients, and each gradient has 3 replicate wells. Place the cell plate in an incubator at 37°C, 5% CO 2 for 7 days. Using the CELL Titer-GLO luminescence method, the total ATP content was detected to determine the level of cell proliferation.
  • the cells in the 384-well plate were taken out and equilibrated at room temperature for 30 minutes; 30 ⁇ L of CTG (CTG, Promega, Cat. No. G7572) was added to each well, shaken and mixed, and incubated at room temperature for 10 minutes; the fluorescence value was read with a multi-functional microplate reader (Biotek, model Cytation 3).
  • GraphPad Prism 6.0 software analyzed the Log value of the compound response at different concentrations to determine the IC 50 of proliferation inhibition.
  • MCF7 cells Human breast cancer cells (MCF7 cells) (purchased from ATCC, No. HTB-22) were cultured in EMEM medium (ATCC, 30-2003), adding 10% FBS (Gbico, 10099141). After the cells grow to a confluence of 70-80%, the cells are digested to prepare a cell suspension. Cells were seeded in a 384-well plate (Corning, 3570), 500 cells/well, and placed in a 5% incubator at 37°C overnight. The next day, the compound to be tested was added, and the compound was dissolved in DMSO, diluted, and the initial concentration of the test was 10 mM, diluted 3 times, and 10 concentration gradients were set, with 3 replicate wells for each gradient.
  • IC 50 values of the compounds of the present invention for the inhibition of OVCAR3, HCC1806 and MCF-7 cells are shown in Table 2 below.
  • Test example 3 mouse pharmacokinetic experiment of the compound of the present invention
  • the experimental animals were male ICR mice aged 7-8 weeks, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and raised in an SPF environment with a temperature of 20-26°C, a daily temperature difference of no more than 4°C, and a relative humidity of 40-70°C. %RH, 12h/12h alternate lighting every day.
  • the experimental animals went through an adaptation period of 3-5 days, and the animals administered orally were fasted overnight (>12h) one day before the experiment, without water.
  • the vehicles of the intravenous group and the intragastric administration group were both 3% DMSO+97% (20% HP- ⁇ -CD solution).
  • the compound solution preparation process is as follows: first dissolve the compound in DMSO and make a 10 mg/mL stock solution; take 100 ⁇ L of the stock solution, dilute it to 5 mL with 20% HP- ⁇ -CD, and obtain a concentration of 0.2 mg/mL Dosing solution: Take 100 ⁇ L of the stock solution, add solvent to make up to 5 mL, vortex to disperse evenly, and obtain a solution for gavage administration with a compound concentration of 1 mg/mL.
  • Body weight was weighed before administration, and 0.1mL blood samples were collected through the ophthalmic venous plexus and added to heparin sodium anticoagulant tubes to prevent coagulation.
  • Each test compound was administered intravenously to 6 rats, and 6 rats were given oral administration, and food was given 2 hours after administration.
  • the time points of sample collection are: gavage group: 5min, 15min, 30min, 1h, 2h, 4h before administration and after administration; intravenous group: 5min, 15min, 30min, 1h, 2h, 4h before administration and after administration .
  • Animal blood collection was divided into two parts, and cross-time point blood collection was adopted, and a maximum of 5 blood collection points were set for one mouse.
  • F% (AUC po x dose iv )/(AUC iv x dose po ) x 100%.
  • mice The pharmacokinetic parameters of the compounds of the present invention on mice are shown in Table 3 below.

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Abstract

L'invention concerne un composé hétérocyclique ayant une activité inhibitrice de kinase cycline-dépendante, son procédé de préparation et son utilisation médicale. Plus précisément, la présente invention concerne un composé tel que représenté dans la formule générale (I), son procédé de préparation, une composition pharmaceutique le contenant, et son utilisation en tant qu'inhibiteur de kinase cycline-dépendante (CDK) dans la prévention et/ou le traitement d'une croissance cellulaire anormale, telle que le cancer. La définition de chaque groupe dans la formule générale (I) est la même que celle dans la description.
PCT/CN2022/119618 2021-09-29 2022-09-19 Composé hétérocyclique ayant une activité inhibitrice de kinase cycline-dépendante, son procédé de préparation et son utilisation médicale Ceased WO2023051302A1 (fr)

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US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
WO2025180470A1 (fr) * 2024-02-29 2025-09-04 江苏亚虹医药科技股份有限公司 Inhibiteur de la kinase dépendante de la cycline et son utilisation médicale
WO2026024674A1 (fr) 2024-07-22 2026-01-29 Genesis Therapeutics, Inc. Méthodes de traitement de cancers associés à skp2

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CN109803968A (zh) * 2016-08-15 2019-05-24 辉瑞公司 吡啶并嘧啶酮cdk2/4/6抑制剂
WO2021003314A1 (fr) * 2019-07-02 2021-01-07 Nuvation Bio Inc. Composés hétérocycliques en tant qu'inhibiteurs de kinase
WO2021170076A1 (fr) * 2020-02-28 2021-09-02 Fochon Pharmaceuticals, Ltd. Composés en tant qu'inhibiteurs de cdk2/4/6
WO2021254384A1 (fr) * 2020-06-17 2021-12-23 微境生物医药科技(上海)有限公司 Nouveau dérivé de pyrido[2,3-d]pyrimidine-7(8h)-one

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JP7112755B2 (ja) * 2017-01-23 2022-08-04 シャンハイ ロングウッド バイオファーマシューティカルズ カンパニー リミテッド Ｊａｋ酵素阻害剤及びその製造方法と用途
WO2022152259A1 (fr) * 2021-01-15 2022-07-21 江苏先声药业有限公司 Inhibiteur de cdk2/4/6, son procédé de préparation et son application

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CN109803968A (zh) * 2016-08-15 2019-05-24 辉瑞公司 吡啶并嘧啶酮cdk2/4/6抑制剂
WO2021003314A1 (fr) * 2019-07-02 2021-01-07 Nuvation Bio Inc. Composés hétérocycliques en tant qu'inhibiteurs de kinase
WO2021170076A1 (fr) * 2020-02-28 2021-09-02 Fochon Pharmaceuticals, Ltd. Composés en tant qu'inhibiteurs de cdk2/4/6
WO2021254384A1 (fr) * 2020-06-17 2021-12-23 微境生物医药科技(上海)有限公司 Nouveau dérivé de pyrido[2,3-d]pyrimidine-7(8h)-one

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
WO2025180470A1 (fr) * 2024-02-29 2025-09-04 江苏亚虹医药科技股份有限公司 Inhibiteur de la kinase dépendante de la cycline et son utilisation médicale
WO2026024674A1 (fr) 2024-07-22 2026-01-29 Genesis Therapeutics, Inc. Méthodes de traitement de cancers associés à skp2

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