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WO2024199524A1 - Composé en tant qu'inhibiteur de pkmyt1 - Google Patents

Composé en tant qu'inhibiteur de pkmyt1 Download PDF

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Publication number
WO2024199524A1
WO2024199524A1 PCT/CN2024/085203 CN2024085203W WO2024199524A1 WO 2024199524 A1 WO2024199524 A1 WO 2024199524A1 CN 2024085203 W CN2024085203 W CN 2024085203W WO 2024199524 A1 WO2024199524 A1 WO 2024199524A1
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WO
WIPO (PCT)
Prior art keywords
alkylene
alkyl
cycloalkyl
heterocyclyl
independently selected
Prior art date
Application number
PCT/CN2024/085203
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English (en)
Chinese (zh)
Inventor
刘扬
刘磊
刘爱国
赵春艳
于晓虹
Original Assignee
江苏星盛新辉医药有限公司
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Publication of WO2024199524A1 publication Critical patent/WO2024199524A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a class of compounds or pharmaceutically acceptable salts used as PKMYT1 inhibitors, preparation methods thereof, pharmaceutical compositions and use thereof in treating PKMYT1-related diseases.
  • PKMYT1 Protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1) belongs to the WEE family of serine/threonine kinases. PKMYT1 specifically regulates the activity of cyclin-dependent kinase 1 (CDK1) by phosphorylating CDK1, thereby regulating the transition from G2 to M phase of the cell cycle. PKMYT1 is not essential for checkpoint-triggered cell cycle arrest following DNA damage in normal cells. Depletion of PKMYT1 by siRNA alone does not affect long-term cell growth, but PKMYT1 plays a more important role in cells with genomic instability or in the presence of replication stress or other impaired cell cycle checkpoint regulation.
  • CDK1 cyclin-dependent kinase 1
  • CCNE1 gene amplification is a common tumor driver mutation that occurs in a variety of malignancies, including ovarian cancer, breast cancer, gastric cancer, and lung cancer.
  • Cyclin E1, encoded by CCNE1 binds to and activates CDK2, promoting the transition from the G1 phase to the S phase of the cell cycle.
  • Overexpression of Cyclin E impairs G1/S checkpoint regulation, causing cells to enter the S phase prematurely, increasing DNA replication pressure, and leading to genomic instability.
  • cells with CCNE1 amplification are more dependent on the regulation of other cell cycle checkpoints and the integrity of DNA repair mechanisms.
  • PKMYT1 kinase inhibition and CCNE1 amplification are synthetically lethal.
  • WEE1 which is in the same family as PKMYT1
  • PKMYT1 inhibitors and WEE1 inhibitors can target the DNA damage response (DDR) in cancer, inhibit the damage and repair of tumor cell DNA, and promote their apoptosis.
  • DDR DNA damage response
  • WEE1 inhibitors are being developed for the treatment of tumors. Studies have shown that compared with WEE1, PKMYT1 inhibition has less effect on normal cells, so PKMYT1 inhibitors have better safety. Finding PKMYT1 inhibitors is considered a promising approach to developing new anticancer agents.
  • Ring A is selected from a benzene ring, a C 5-6 hydrocarbon ring, a 5-6 membered heterocyclic ring and a 5-6 membered heteroaromatic ring;
  • E is selected from O and S;
  • R1 is selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, -C1-4 alkylene- C3- 10 Cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, CN, NO 2 , aryl, -C 1-4 alkylene-aryl, heteroaryl, -C 1-4 alkylene-heteroaryl, -NR A1 R B1 , -OR A1 , -SR A1 , -C( ⁇ O) R A1 , -C( ⁇ NR E1 ) R A1 , -C( ⁇ N-OR B1 ) R A1 , -C( ⁇ O)OR A1 , -OC( ⁇ O) R A1 , -C( ⁇ O)NR A1 R B1 , -NR A1 C( ⁇ O) R B1 , -C( ⁇ NR
  • R 3 together with the atoms to which they are attached form a C 3-10 monocyclic hydrocarbon ring or a 4-12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms or a 5-10 membered heteroaromatic ring or a benzene ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted by at least one substituent independently selected from RX3 ;
  • R 7 and R 8 together with the atoms to which they are attached form a C 5-6 hydrocarbon ring or a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur and nitrogen, and the ring is unsubstituted or substituted by at least one substituent independently selected from R X7 ;
  • each of RA1, RA2 , RA3 , RA4 , RA5 , RA6 , RA7 , RA8 , RB1 , RB2 , RB3 , RB4 , RB5 , RB6 , RB7 and RB8 is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, -C1-4 alkylene- C3-10 cycloalkyl, heterocyclyl, -C1-4 alkylene - heterocyclyl , aryl, -C1-4 alkylene-aryl, heteroaryl and -C1-4 alkylene-heteroaryl, wherein each of alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from RX ;
  • RA1 and RB1 or “RA2 and RB2 ” or “ RA3 and RB3 ” or “ RA4 and RB4 ” or “ RA5 and RB5 ” or “ RA6 and RB6 ” or “ RA7 and RB7 ” or “ RA8 and RB8 ” together with the atoms to which they are attached, form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from RX ;
  • Ra1 and Rb1 is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, -C1-4 alkylene- C3-10 cycloalkyl, heterocyclyl, -C1-4 alkylene-heterocyclyl, aryl, -C1-4 alkylene-aryl, heteroaryl and -C1-4 alkylene-heteroaryl, wherein each of alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and hetero Aryl is unsubstituted or substituted with at least one substituent independently selected from R Y ;
  • Ra1 and Rb1 together with the atoms or atoms to which they are attached together form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from RY ;
  • each R c1 and R d1 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, aryl, -C 1-4 alkylene-aryl, heteroaryl and -C 1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from RY ;
  • each R c1 and R d1 together with the single or multiple carbon atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with 1, 2 or 3 groups independently selected from RY ;
  • each R e1 is independently selected from hydrogen, C 1-10 alkyl, CN, NO 2 , —S( ⁇ O) r R a1 , —C( ⁇ O) R a1 , —C( ⁇ O) OR a1 , —C( ⁇ O) NR a1 R b1 , and —S( ⁇ O) r NR a1 R b1 , wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from RY ;
  • Each RY is independently selected from halogen, NO2 , -CN, C1-10 alkyl, -OH, -O( C1-10 alkyl), -O( C3-10 cycloalkyl), -O( C1-4 alkylene- C3-10 cycloalkyl), -O(heterocyclyl), -O( C1-4 alkylene-heterocyclyl), -SH, -S( C1-10 alkyl), -S( C3-10 cycloalkyl), -S(C1-4 alkylene- C3-10 cycloalkyl), -S(heterocyclyl), -S( C1-4 alkylene-heterocyclyl), -NH2 , -NH ( C1-10 alkyl), -N( C1-10 alkyl) 2 , -NH( C3-10 cycloalkyl), -NH( C1-4 alkylene- C3-10 cycloalkyl), -NH(heterocycly
  • g is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8;
  • Each r is independently selected from 1 and 2;
  • Each t is independently selected from 0, 1, 2, 3 and 4.
  • a pharmaceutical composition comprising a preventively or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • synthetic lethality refers to the situation where two or more individual genes simultaneously express abnormally, leading to cell death, while only one or a portion of the genes express abnormally, leading to cell death; wherein the abnormal expression includes mutation, overexpression or gene inhibition.
  • the two synthetic lethal genes are referred to as a synthetic lethal gene pair.
  • cyclin E1 refers to the G1/S specific cyclin E1 (gene name: CCNE1). Cells that overexpress cyclin E1 show higher cyclin E1 activity than cells that normally express cyclin E1. CCNE1-amplified cells are cells that have a higher CCNE1 gene copy number than normal cells. Cells that overexpress cyclin E1 can be CCNE1-amplified cells, for example, in one embodiment, cells that overexpress cyclin E1 have more than 2 copies of CCNE1 compared to diploid normal cells having 2 copies of CCNE1. In addition to directly detecting the copy number of the CCNE1 gene, cyclin E1 overexpression can also be determined by identifying the expression level of the gene product in the cell (e.g., mRNA transcription level or cyclin E1 protein level).
  • cancer overexpressing cyclin E1 and "CCNE1 amplified cancer” are used interchangeably.
  • CCNE1 amplified cancers include, but are not limited to, uterine sarcoma, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, liver cancer, and endometrial cancer.
  • FBXW7 refers to F-box/WD repeat-containing protein 7 (gene name: FBXW7).
  • An FBXW7 gene with an inactivating mutation refers to a mutant FBXW7 gene that cannot produce a normal functional FBXW7 protein or produces a reduced amount of FBXW7 protein in a cell.
  • FBXW7 mutation cancers include, but are not limited to, blood tumors, gliomas, liver cancer (e.g., hepatocellular carcinoma), uterine cancer (e.g., endometrial carcinoma), colorectal cancer (e.g., colorectal adenocarcinoma), breast cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), gastric cancer, esophageal cancer, esophageal junction adenocarcinoma, bladder cancer (e.g., urothelial bladder carcinoma), head and neck cancer (e.g., head and neck squamous cell carcinoma), cervical cancer (e.g., cervical squamous cell carcinoma), melanoma, ovarian cancer (e.g., high-grade serous ovarian cancer).
  • liver cancer e.g., hepatocellular carcinoma
  • uterine cancer e.g., endometrial carcinoma
  • colorectal cancer e.
  • p53 protein refers to tumor protein p53 (gene name: TP53).
  • a TP53 gene with an inactivating mutation refers to a mutant TP53 gene that cannot produce a functional p53 protein or produces a reduced amount of p53 protein in a cell.
  • C1 - C10 or " C1-10” encompasses a range of 1-10 carbon atoms and should be understood to also encompass any subranges and individual point values therein, such as C2-3 , C2-4 , C2-5 , C3-4 , C3-5 , C3-6 , C3-7 , C1-2 , C1-3, C1-4 , C1-5 , C1-6 , C1-7 , C1-8 , C1-9 , etc. , as well as C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , etc.
  • C3 - C10 or " C3-10” should also be understood in a similar manner, for example, it can include C3-4 , C3-5 , C3-6 , C3-7 , C3-8 , C4-5 , C4-6 , C4 - C7 , C5 -C6, etc., as well as C3 , C4, C5 , C6 , C7, C8, C9, C10 , etc.
  • the expression “3-14 yuan” should be understood to include any sub-ranges and each point value therein, such as 3-4, 3-5 , 3-6 , 3-7 , 3-8 , 4-5 , 4-6, 4-7, 5-6, 3, 4, 5, 6 or 7 yuan, etc.
  • p is an integer selected from 0 to 13
  • p is any integer from 0 to 13, for example, p may be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13.
  • Other similar expressions such as p1 and p2 should also be understood in a similar manner.
  • any variable e.g., R x
  • its definition is independent at each occurrence.
  • the expression "each R x is independently selected from” means that if multiple R x are contained, the options for each R x substituent are independent of each other at each occurrence.
  • Other variables or expressions such as R 3 should also be understood in a similar manner.
  • substituted and “substituted” refer to one or more (e.g., one, two, three or four) hydrogen atoms on the designated atom being replaced by a selection from the indicated group, provided that the normal atomic valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds. When a substituent is described as not present, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure can achieve a stable state of the compound.
  • the point of attachment of a substituent may be from any convenient position of the substituent.
  • a bond to a substituent is shown as passing through a bond connecting two atoms in a ring, then such a substituent may be bonded to any ring-forming atom in the substitutable ring.
  • halo or "halogen” or “halo” is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.
  • hydrocarbyl refers to a monovalent group derived from a hydrocarbon.
  • hydrocarbyl groups include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, and aryl.
  • alkyl refers to a saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond.
  • Alkyl includes straight chain alkyl and branched chain alkyl.
  • Alkyl can contain 1-10 carbon atoms, known as C 1-10 alkyl, such as C 1-6 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 3 alkyl, C 4 alkyl, C 3-6 alkyl.
  • Non-limiting examples of straight chain alkyl include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc.
  • Non-limiting examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbuty
  • a divalent group refers to a group obtained by removing a hydrogen atom from a carbon atom with free valence electrons of a corresponding monovalent group.
  • a divalent group has two attachment sites connected to the rest of the molecule, wherein the two attachment sites can be located on the same atom or two different atoms of the divalent group.
  • Alkylene or “alkylidene” refers to a saturated divalent hydrocarbon group.
  • Alkylene includes straight chain or branched chain alkylene. Examples of straight chain alkylene include, but are not limited to, methylene ( -CH2- ), -( CH2 ) 2- , -( CH2 ) 3- , - ( CH2) 4- , -( CH2 ) 5- , -( CH2 ) 6- , and the like.
  • branched alkylene groups include, but are not limited to, -CH( CH3 )-, -CH( C2H5 )-, -CH( CH3 ) -CH2- , -CH( C3H7 ) - , -CH ( C2H5 ) -CH2- , -C( CH3 ) 2 - CH2- , -(CH (CH3 ) ) 2- , -CH( CH3 )-(CH2) 2- , -CH2 - CH (CH3 ) -CH2- , -CH(C4H9)-, -C ( CH3 ) ( C3H7 )-, -C(C2H5) 2- , -CH( C3H7 ) -CH2- , -CH ( C2H5 ) -CH( CH3 )-, -CH( C2H5 )-( CH2 ) 2- , and -CH( CH3 ) -CH2- .
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group having at least one double bond consisting of carbon atoms and hydrogen atoms.
  • the alkenyl group may have 2-8 carbon atoms, i.e., " C2-8 alkenyl", such as C2-4 alkenyl, C3-4 alkenyl.
  • Non-limiting examples of alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, etc.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond.
  • the alkynyl group may have 2-8 carbon atoms, i.e., " C2-8 alkynyl", such as C2-4 alkynyl, C3-4 alkynyl.
  • Non-limiting examples of alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, etc.
  • alkoxy refers to an alkyl group as defined above that is connected to an oxygen atom by a single bond. The alkoxy group is connected to the rest of the molecule through the oxygen atom.
  • the alkoxy group can be represented as -O(alkyl).
  • C 1-8 alkoxy or “-O(C 1-8 alkyl)” refers to an alkoxy group containing 1 to 8 carbon atoms, wherein the alkyl portion can be a straight chain or branched structure.
  • Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentoxy, etc.
  • hydrocarbon ring and “cycloalkyl” refer to a saturated or unsaturated non-aromatic ring system consisting of carbon atoms and hydrogen atoms.
  • Hydrocarbon ring and “cycloalkyl” preferably contain 1 or 2 rings respectively.
  • the “hydrocarbon ring” and “cycloalkyl” can be a monocyclic, condensed polycyclic, bridged or spirocyclic structure.
  • Hydrocarbon ring” and “cycloalkyl” can have 3-10 carbon atoms respectively, i.e. "C 3-10 hydrocarbon ring” (e.g.
  • C 4 hydrocarbon ring, C 5 hydrocarbon ring, C 6 hydrocarbon ring, C 7 hydrocarbon ring) and "C 3-10 cycloalkyl” e.g. C 3-8 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl.
  • hydrocarbon rings include but are not limited to cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, etc.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[2.2.1]heptane and spiro[3.3]heptane, cyclopentenyl, cyclohexenyl, etc.
  • the C atoms in the cycloalkyl are optionally substituted with oxo.
  • the C atoms in the cycloalkyl are optionally substituted with imino.
  • the imino is substituted with -OR, wherein R is H or C 1-10 alkyl.
  • cyclic alkyl and “cycloalkyl” have the same meaning herein and are used interchangeably. Refers to a saturated cycloalkyl group. Cycloalkyl can have 3, 4, 5, 6, 7, 8, 9 or 10 ring carbon atoms (C 3-10 ). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In some embodiments, cycloalkyl is a C 3-7 monocyclic or bicyclic cycloalkyl, preferably a C 3-6 monocyclic cycloalkyl, particularly a cyclopropyl.
  • heterocycle and “heterocyclyl” each refer to a monocyclic or bicyclic ring system (3-14-membered, 7-14-membered, 3-8-membered, 3-7-membered, 4-6-membered, 5-6-membered) having, for example, 3-14 ring atoms (e.g., 7-14, 3-8, 3-7, 4-6, or 5-6 ring atoms), wherein at least one ring atom (e.g., 1, 2, or 3) is a heteroatom selected from oxygen, sulfur, nitrogen, and phosphorus, and the remaining ring atoms are C.
  • the ring system may be saturated (also understood as the corresponding "heterocycloalkane” or “heterocycloalkyl”) or unsaturated (i.e., having one or more double bonds and/or triple bonds in the ring).
  • “heterocycle” and “heterocyclyl” each may be benzo-fused.
  • “Heterocycle” and “heterocyclyl” each do not have aromaticity.
  • the C, N, S, and P atoms in “heterocycle” and “heterocyclyl” are optionally substituted with oxo.
  • the C, S and P atoms in "heterocycle” and “heterocyclyl” are optionally substituted by imino.
  • the imino is substituted by -OR, wherein R is H or C 1-10 alkyl.
  • the heterocyclic group can be, for example, a four-membered ring, such as azetidinyl, oxetanyl; or a five-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, oxopyrrolidinyl, 2-oxoimidazolidin-1-yl; or a six-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,1-dioxo-1,2-thiazin-2-yl or trithianyl; or a seven-membered ring, such as diazepine, Base ring.
  • a four-membered ring such as azetidinyl, oxet
  • the heterocyclic group may be bicyclic, without limitation, for example, a five-membered and a five-membered ring, such as octahydrocyclopenta[c]pyrrolyl; or a five-membered and a six-membered bicyclic ring, such as octahydropyrrolo[1,2-b]pyrazinyl.
  • the heterocycle may be unsaturated, i.e., it may contain one or more double bonds, without being limited thereto, for example, an unsaturated heterocycle containing a nitrogen atom may be a 1,6-dihydropyrimidine, a 1,2-dihydropyrimidine, a 1,4-dihydropyrimidine, a 1,6-dihydropyridine, a 1,2-dihydropyridine, a 1,4-dihydropyridine, a 2,3-dihydro-1H-pyrrole, a 3,4-dihydro-1H-pyrrole, a 2,5-dihydro-1H-pyrrolyl, a 4H-[1,3,4]thiadiazinyl, a 4,5-dihydrooxazolyl or a 4H-[1,4]thiazinyl ring, an unsaturated heterocycle containing an oxygen atom may be a 2H-pyran, a 4H-pyran, a 2,
  • Exemplary bicyclic heterocycles also include:
  • aryl refers to an aromatic ring group of an all-carbon monocyclic or fused polycyclic (such as a bicyclic) ring having a conjugated ⁇ electron system.
  • an aryl group may have 6-14 carbon atoms, preferably 6-10, more preferably 6 or 10.
  • Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9 or 10 ring atoms ("5-10 membered heteroaryl”), in particular 5 or 6 or 9 or 10 ring atoms, and including at least one (suitably 1 to 4, more suitably 1, 2 or 3) heteroatoms which may be identical or different, such as oxygen, nitrogen or sulfur. Furthermore, in each case “heteroaromatic ring” and “heteroaryl” may each be benzo-fused.
  • the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl,
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • the methods for preparing the pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.
  • the compounds of the present invention encompass pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites or prodrugs thereof.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present invention.
  • the compounds of the present invention may exist in E or Z configurations of carbon-carbon double bonds or carbon-nitrogen double bonds, wherein “E” represents the preferred substituents on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond according to the Cahn-Ingold-Prelog priority rules, and "Z” represents the preferred substituents on the same side of the carbon-carbon double bond or carbon-nitrogen double bond.
  • the compounds of the present invention may also exist in the form of mixtures of "E" and "Z" isomers.
  • Isomer forms also include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Purification and separation of such materials can be achieved by standard techniques known in the art.
  • the compounds of the present invention may contain a bond with hindered rotation, so that two separate torsional isomers can be separated. All possible torsional isomers are included within the scope of the present invention.
  • the separation method of torsional isomers can be a known method or a method described herein.
  • chiral chromatography is used to separate torsional isomers, for example, using supercritical CO2 and MeOH as mobile phases.
  • Optically pure enantiomers can be obtained by resolving racemic mixtures according to conventional methods, for example, by forming diastereomeric salts using optically active acids or bases, or by forming covalent diastereomers.
  • a mixture of diastereoisomers can be separated into single diastereomers based on their physical and/or chemical differences by methods known in the art (e.g., by chromatography or fractional crystallization). Then, the optically active enantiomer base or acid is released from the separated diastereomeric salts.
  • Another method for separating racemic enantiomers can use chiral chromatography (e.g., a chiral HPLC column), and the separated chiral isomers can be subjected to conventional derivatization treatment or non-derivatization before separation, depending on which method can achieve more effective separation of chiral isomers.
  • Enzymatic methods can also be used to separate derivatized or non-derivatized chiral isomers.
  • the present invention can be obtained by chiral synthesis using optically active raw materials. Optically pure compounds invented.
  • the compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol.
  • a solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol.
  • the amount of the solvent, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • the present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • the compounds of the invention may exist in isotopically labeled or enriched form, containing one or more atoms having a different atomic mass and mass number from the most common atomic mass in nature.
  • Isotopes may be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 I.
  • metabolites of the compounds of the present invention i.e., substances formed in vivo when the compounds of the present invention are administered.
  • Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymolysis, etc. of the administered compounds.
  • the present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity but are converted, for example by hydrolytic cleavage, into compounds of the invention having the desired activity when administered into or onto the body.
  • polymorph or “polymorph” refers to a single polymorph or a mixture of more than one polymorph in any proportion.
  • crystalline form or “crystal” refers to any solid material that exhibits a three-dimensional ordering, in contrast to amorphous solid material, which produces a characteristic X-ray powder diffraction pattern with well-defined peaks.
  • amorphous refers to any solid material that has no order in three dimensions.
  • pharmaceutically acceptable means that it is within the scope of normal medical judgment and will not cause undue toxicity, irritation, allergic response, or the like in contact with the tissues of patients.
  • pharmaceutically acceptable carrier refers to those substances that have no significant irritation to organisms and do not impair the biological activity and performance of the active compound.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.
  • active ingredient refers to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition.
  • the term "effective amount”, “therapeutically effective amount” or “prophylactically effective amount” refers to a sufficient amount of the drug or pharmaceutical agent that can achieve the desired effect with acceptable side effects.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the individual and on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.
  • subject includes humans or non-human animals.
  • exemplary human subjects include human subjects (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • the present invention provides a compound having the structure of formula (I):
  • Ring A is selected from a benzene ring, a C 5-6 hydrocarbon ring, a 5-6 membered heterocyclic ring and a 5-6 membered heteroaromatic ring;
  • E is selected from O and S;
  • R 3 together with the atoms to which they are attached form a C 3-10 monocyclic hydrocarbon ring or a 4-12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms or a 5-10 membered heteroaromatic ring or a benzene ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted by at least one substituent independently selected from RX3 ;
  • R 7 and R 8 together with the atoms to which they are attached form a C 5-6 hydrocarbon ring or a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur and nitrogen, and the ring is unsubstituted or substituted by at least one substituent independently selected from RX7 ;
  • each of RA1, RA2 , RA3 , RA4 , RA5 , RA6 , RA7 , RA8 , RB1 , RB2 , RB3 , RB4 , RB5 , RB6 , RB7 and RB8 is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, -C1-4 alkylene- C3-10 cycloalkyl, heterocyclyl, -C1-4 alkylene - heterocyclyl , aryl, -C1-4 alkylene-aryl, heteroaryl and -C1-4 alkylene-heteroaryl, wherein each of alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from RX ;
  • RA1 and RB1 or “RA2 and RB2 ” or “ RA3 and RB3 ” or “ RA4 and RB4 ” or “ RA5 and RB5 ” or “ RA6 and RB6 ” or “ RA7 and RB7 ” or “ RA8 and RB8 ” together with the atoms to which they are attached, form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from RX ;
  • each of Ra1 and Rb1 is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, -C1-4 alkylene- C3-10 cycloalkyl, heterocyclyl, -C1-4 alkylene-heterocyclyl, aryl, -C1-4 alkylene-aryl, heteroaryl and -C1-4 alkylene-heteroaryl, wherein each of alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from RY ;
  • Ra1 and Rb1 together with the atoms or atoms to which they are attached together form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from RY ;
  • each R c1 and R d1 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -C 1-4 alkylene-C 3-10 cycloalkyl, heterocyclyl, -C 1-4 alkylene-heterocyclyl, aryl, -C 1-4 alkylene-aryl, heteroaryl and -C 1-4 alkylene-heteroaryl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from RY ;
  • each R c1 and R d1 together with the single or multiple carbon atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring is unsubstituted or substituted with 1, 2 or 3 groups independently selected from RY ;
  • each R e1 is independently selected from hydrogen, C 1-10 alkyl, CN, NO 2 , —S( ⁇ O) r R a1 , —C( ⁇ O) R a1 , —C( ⁇ O) OR a1 , —C( ⁇ O) NR a1 R b1 , and —S( ⁇ O) r NR a1 R b1 , wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from RY ;
  • Each RY is independently selected from halogen, NO2 , -CN, C1-10 alkyl, -OH, -O( C1-10 alkyl), -O( C3-10 cycloalkyl), -O( C1-4 alkylene- C3-10 cycloalkyl), -O(heterocyclyl), -O( C1-4 alkylene-heterocyclyl), -SH, -S( C1-10 alkyl), -S( C3-10 cycloalkyl), -S(C1-4 alkylene- C3-10 cycloalkyl), -S(heterocyclyl), -S( C1-4 alkylene-heterocyclyl), -NH2 , -NH ( C1-10 alkyl), -N( C1-10 alkyl) 2 , -NH( C3-10 cycloalkyl), -NH( C1-4 alkylene- C3-10 cycloalkyl), -NH(heterocycly
  • g is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8;
  • Each r is independently selected from 1 and 2;
  • Each t is independently selected from 0, 1, 2, 3 and 4.
  • t is 0. In one embodiment, g is selected from 0, 1 and 2. In one embodiment, E is O. In one embodiment, E is S.
  • each of RA1 , RA2 , RA3 , RA4 , RA5 , RA6 , RA7 , RA8, RB1 , RB2 , RB3 , RB4 , RB5 , RB6 , RB7 and RB8 is independently selected from hydrogen and C1-10 alkyl , wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from RX .
  • it is selected from halogen, C 1-10 alkyl, CN, NO 2 , -(CR c1 R d1 ) t NR a1 R b1 , -(CR c1 R d1 ) t OR b1 , -(CR c1 R d1 ) t C( ⁇ O)R a1 , -(CR c1 R d1 ) t C( ⁇ O)OR b1 , -(CR c1 R d1 ) t OC( ⁇ O)R b1 , -(CR c1 R d1 ) t C( ⁇ O)NR a1 R b1 and -(CR c1 R d1 ) t NR a1 C( ⁇ O)R b1 , wherein each alkyl, alkylene, cycloalkyl and heterocyclyl is unsubstituted or substituted by at least one substituent independently selected from RY
  • each RX , RX1 , RX2 , RX4 , RX5 , RX6 , RX7 and RX8 is independently selected from halogen, C 1-10 alkyl, CN and NO 2 , wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from RY .
  • each R a1 and R b1 is independently selected from hydrogen and C 1-10 alkyl, wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from RY .
  • each R c1 and R d1 is independently selected from hydrogen, halogen and C 1-10 alkyl, wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from RY .
  • each RY is independently selected from halogen, NO2 , -CN, C1-10 alkyl, -OH, -O ( C1-10 alkyl), -NH2 , -NH( C1-10 alkyl) and -N( C1-10 alkyl) 2 , preferably selected from halogen, NO2 , -CN and C1-10 alkyl.
  • R 1 is selected from C 1-10 alkyl, -NR A1 R B1 , -OR A1 and -SR A1 , preferably selected from -NR A1 R B1 and -OR A1 , in particular -NR A1 R B1 .
  • each R B1 is independently selected from C 1-10 alkyl
  • each R A1 is hydrogen.
  • each R A1 and R B1 are hydrogen.
  • each R E1 is independently selected from hydrogen and C 1-10 alkyl.
  • R 1 is -NH 2.
  • R 1 is selected from -NR A1 R B1 and hydrogen, preferably selected from -NH 2 and hydrogen.
  • each RB2 is independently selected from C 1-10 alkyl
  • each RA2 is hydrogen.
  • each RA2 and RB2 are hydrogen.
  • each RE2 is independently selected from hydrogen and C 1-10 alkyl.
  • any two adjacent R3 together with the atoms to which they are attached form a C5-6 monocyclic hydrocarbon ring or a 5-6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms or a 5 membered heterocyclic ring containing 1, 2 or 3 heteroatoms or a 6 membered heteroaromatic ring containing 1 or 2 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, preferably selected from oxygen, sulfur and nitrogen; the ring is unsubstituted or substituted by at least one substituent independently selected from RX3 .
  • g is 1 or 2.
  • halogen is selected from F, Cl and Br.
  • each RB3 is independently selected from C1-10 alkyl
  • each RA3 is hydrogen.
  • each RA3 and RB3 are hydrogen.
  • each RE3 is independently selected from hydrogen and C1-10 alkyl.
  • g is 2, and two R3 are adjacent, and two R3 together with the atoms to which they are attached form cyclohexene or cyclohexane, wherein the cyclohexene or cyclohexane is unsubstituted or substituted by at least one substituent independently selected from RX3 .
  • each R 3 is independently selected from F, Cl, Br, CN, OH, methyl, ethyl, isopropyl, tert-butyl, cyclopropane, azetidinyl, cyclohexenyl, piperidinyl, morpholinyl, oxopiperazinyl, pyridinyl, thiazolyl, pyrazolyl, diethylamino, amino, vinyl, ethynyl, acetyl, carbamoyl, methoxy, ethoxy, methylthio, ethylthio, isopropylthio, methylsulfonyl and phenyl, wherein the methyl, ethyl, isopropyl, Tert-butyl, cyclopropane, azetidinyl, cyclohexenyl, piperidinyl, morpholinyl, oxopiperazinyl
  • each RX is independently selected from F, Cl, Br, CN, OH, C1-10 alkyl, -O( C1-10 alkyl) and heterocyclyl, wherein the C1-10 alkyl is unsubstituted or substituted with at least one substituent independently selected from halogen.
  • each R 3 is independently selected from F, Cl, Br, CN, OH, methyl, ethyl, isopropyl, tert-butyl, cyclopropane, diethylamino, amino, vinyl, ethynyl, acetyl, carbamoyl, methoxy, methylthio, ethylthio, isopropylthio, methylsulfonyl, phenyl,
  • R is methyl.
  • R is methyl or ethyl.
  • R is methyl or methylthio.
  • R is methylthio.
  • R is methyl or cyclopropane.
  • R is methyl or isopropyl. In one embodiment, R is methyl or Cl. In one embodiment, R is methyl or trifluoromethyl. In one embodiment, R is methyl or isopropyl. In one embodiment, R is isopropyl. In one embodiment, R is tert-butyl.
  • any two adjacent R 3 together with the atoms to which they are attached form a ring selected from the group consisting of cyclohexene, cyclohexane, dihydropyran, tetrahydropyran, cyclohexenone, cyclohexanone, dihydropyridone, piperidone, tetrahydropyridine, piperidine, cyclopentene, cyclopentane, dihydrothiophene, tetrahydrothiophene, pyridine and dihydropyridine, which ring is unsubstituted or substituted with at least one substituent independently selected from RX 3.
  • any two adjacent R 3 together with the atoms to which they are attached form a ring selected from the group consisting of:
  • the ring is unsubstituted or substituted with at least one substituent independently selected from RX3 ; wherein represents the site of attachment of R 3 to Ring A.
  • any two adjacent R 3 together with the atoms to which they are attached form The ring is unsubstituted or substituted with at least one substituent independently selected from RX3 ; wherein
  • RX3 is C1-10 alkyl, especially methyl.
  • RX3 is selected from -( CRc1Rd1 ) tNRa1Rb1 ; wherein Ra1 is selected from In one embodiment, any two adjacent R3 together with the atoms to which they are attached form a structure selected from the following:
  • R is selected from C 1-10 alkyl, preferably methyl or ethyl , wherein each alkyl is unsubstituted or substituted by at least one substituent independently selected from RX4. In one embodiment, R is selected from C 1-10 alkyl . In a particular embodiment, R is methyl. In one embodiment, R is selected from halogen , especially Cl .
  • R 5 is selected from hydrogen, halogen, C 1-10 alkyl, CN, NO 2 , -NR A5 R B5 and -OR A5 , in particular selected from hydrogen, halogen, C 1-10 alkyl, CN and NO 2 , wherein each alkyl group is unsubstituted or substituted with at least one substituent independently selected from RX5 .
  • R 5 is selected from halogen, in particular F.
  • R 5 is hydrogen.
  • R 6 is selected from hydrogen, halogen, C 1-10 alkyl, CN, NO 2 , -NR A6 RB6 and -OR A6 , wherein each alkyl group is unsubstituted or substituted by at least one substituent independently selected from RX6 .
  • R 6 is hydrogen.
  • R 6 is F.
  • R 7 is selected from halogen, C 1-10 alkyl, CN, NO 2 , -NR A7 RB7 and -OR A7 , wherein each alkyl group is unsubstituted or substituted by at least one substituent independently selected from RX7 .
  • R 7 is selected from -NR A7 RB7 and -OR A7 , preferably -OR A7 .
  • R 7 is -OH.
  • R 7 and R 8 together with the atoms to which they are attached form a C 5-6 hydrocarbon ring or a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur and nitrogen, and the ring is unsubstituted or substituted with at least one substituent independently selected from RX3 .
  • R 7 and R 8 together with the atoms to which they are attached form a C 5 hydrocarbon ring or a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, preferably a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur and nitrogen, and the ring is unsubstituted or substituted with at least one substituent independently selected from RX7 .
  • R7 and R8 together with the atoms to which they are attached form a pyrazole ring, an isothiazole ring, a thiazole ring, a dihydroisoxazole ring or a dihydrooxazole ring, preferably a pyrazole ring or an isothiazole ring, in particular a pyrazole ring; the ring is unsubstituted or substituted by at least one substituent independently selected from RX7 .
  • in formula (I) The structure is In one embodiment, in formula (I) The structure is selected from in particular In one embodiment, in formula (I) The structure is
  • R 7 and R 8 together with the atoms to which they are attached form a ring, and formula (I) has the structure of formula (I-1):
  • X 1 is selected from N(R 9a ), N, O, S, C(R 9a R 9a' ) and C(R 9a );
  • X 2 is selected from N(R 9b ), N, O, S, C(R 9b R 9b' ) and C(R 9b );
  • X 3 is selected from N(R 9c ), N, O, S, C(R 9c R 9c ') and C(R 9c );
  • R 9a , R 9a′ , R 9b , R 9b ′, R 9c and R 9c′ are each independently selected from hydrogen and R X ;
  • Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and E are as defined in formula (I).
  • X 1 is selected from S and N(R 9a ), preferably NH or N(CH 3 ), in particular NH.
  • X 2 is selected from N and O.
  • X 3 is selected from C(R 9c R 9c′ ) and C(R 9c ).
  • X 1 is N(R 9a ), preferably NH or N(CH 3 ), especially NH; and X 2 is N.
  • R 9c is selected from hydrogen and C 1-10 alkyl and R 9c′ , if applicable, is selected from hydrogen and C 1-10 alkyl; preferably, R 9c is hydrogen and R 9c′ , if applicable, is hydrogen.
  • ring A is selected from a benzene ring, a C5-6 hydrocarbon ring and a 5-6 membered heteroaromatic ring. In one embodiment, ring A is selected from thiophene, thiazole, pyrazole, imidazole, pyrrole, furan, a benzene ring, pyridine, cyclohexene and cyclopentene, which are substituted by g substituents independently selected from R 3 .
  • ring A is selected from a 5-membered heteroaromatic ring and cyclopentene, preferably selected from thiophene, thiazole, pyrazole, imidazole, pyrrole, furan and cyclopentene, which is substituted by g substituents independently selected from R 3.
  • ring A is thiophene, which is substituted by g substituents independently selected from R 3.
  • ring A is thiazole, which is substituted by g substituents independently selected from R 3.
  • ring A is pyrazole, which is substituted by g substituents independently selected from R 3.
  • ring A is imidazole, which is substituted by g substituents independently selected from R 3.
  • ring A is pyrrole, which is substituted by g substituents independently selected from R 3.
  • ring A is furan, which is substituted by g substituents independently selected from R 3 .
  • ring A is selected from a 5-membered heteroaromatic ring and cyclopentene, and formula (I) has the structure of formula (II) as follows:
  • a 1 is selected from N(R 3a ), N, O, S, C(R 3a R 3a' ) and C(R 3a );
  • a 2 is selected from N(R 3b ), N, O, S, C(R 3b R 3b' ) and C(R 3b );
  • a 3 is selected from N(R 3c ), N, O, S, C(R 3c R 3c′ ) and C(R 3c );
  • R 3a , R 3a′ , R 3b , R 3b′ , R 3c and R 3c′ are each independently selected from hydrogen and R 3 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and E are as defined in formula (I).
  • Ring A is selected from a 5-membered heteroaromatic ring.
  • ring A is selected from thiophene, thiazole and imidazole, wherein A2 is C( R3b ); A1 is selected from N( R3a ), N, S and C( R3a ) and A3 is selected from N( R3c ), N, S and C( R3c ). In one embodiment, ring A is thiophene, wherein A2 is C( R3b ); A1 is C( R3a ) and A3 is S, or A1 is S and A3 is C( R3c ). In one embodiment, ring A is thiazole, A2 is C( R3b ); A1 is N and A3 is S, or A1 is S and A3 is N.
  • ring A is imidazole, A2 is C( R3b ); A1 is N and A3 is N. In one embodiment, Ring A is cyclopentene, A1 is C( R3a ), A2 is C( R3b ), and A3 is C( R3c ).
  • R3a and R3c are each hydrogen.
  • Ring A is thiophene
  • R 3b is selected from halogen, C 1-10 alkyl and C 3-10 cycloalkyl
  • R 3a and R 3c are each independently selected from C 1-10 alkyl; wherein each alkyl, cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from RX3 .
  • Ring A is pyrazole, wherein A 2 is N; A 1 is N(R 3a ) and A 3 is C(R 3c ), or A 1 is C(R 3a ) and A 3 is N(R 3c ).
  • R 3a and R 3c are each independently selected from hydrogen and C 1-10 alkyl; wherein each alkyl is unsubstituted or substituted by at least one substituent independently selected from RX3 .
  • one of R3a and R3c is selected from C1-10 alkyl and the other is hydrogen.
  • R3a and R3c are each independently selected from C1-10 alkyl.
  • R 7 and R 8 together with the atoms to which they are attached form a ring, and formula (II) has the structure of formula (II-1):
  • X 1 , X 2 , and X 3 are as defined in formula (I-1);
  • a 1 , A 2 , A 3 , R 1 , R 2 , R 4 , R 5 , R 6 , and E are as defined in formula (II).
  • Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and E of formula (II-1) are as defined in formula (I).
  • A1 is selected from N( R3a ), C( R3aR3a ') and C( R3a ),
  • A2 is selected from N(R3b), C(R3bR3b') and C(R3b), and R3a or R3a ' and R3b or R3b ' together with the atoms to which they are attached form a ring Q, and formula (II) has the structure of the following formula (II-2):
  • Y is selected from N and C;
  • Y2 is selected from N and C;
  • Ring Q is a C 3-10 monocyclic hydrocarbon ring or a 4-12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms or a 5-10 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms; wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, preferably selected from oxygen, sulfur and nitrogen;
  • h is selected from 0, 1, 2, 3, 4, 5 and 6;
  • a 3 , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , RX3 , and E are as defined in formula (II).
  • ring Q is a C 5-6 monocyclic hydrocarbon ring. In one embodiment, ring Q is a 5-6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms. In one embodiment, ring Q is a 5 membered heterocyclic ring containing 1, 2 or 3 heteroatoms. In one embodiment, ring Q is a 6 membered heteroaromatic ring containing 1 or 2 heteroatoms.
  • ring Q is selected from in Indicates the site where loop Q is connected to loop A.
  • ring A is selected from a benzene ring, a cyclohexene and a 6-membered heteroaromatic ring, which is substituted by g substituents independently selected from R 3.
  • the 6-membered heteroaromatic ring contains 1 to 3 N atoms, and the other ring atoms are carbon atoms.
  • ring A is selected from a benzene ring, pyridine and cyclohexene, especially a benzene ring.
  • ring A is selected from a benzene ring, a cyclohexene ring and a 6-membered heteroaromatic ring, and formula (I) has the structure of formula (III):
  • a 4 is selected from N, C(R 3d R 3d′ ) and C(R 3d );
  • A6 is selected from N, C( R3fR3f ' ) and C( R3f );
  • ring Q is a C 5-6 monocyclic hydrocarbon ring. In one embodiment, ring Q is a 5-6 membered heterocyclic ring containing 1, 2 or 3 heteroatoms. In one embodiment, ring Q is a 5 membered heterocyclic ring containing 1, 2 or 3 heteroatoms. In one embodiment, ring Q is a 6 membered heteroaromatic ring containing 1 or 2 heteroatoms. In one embodiment, ring Q is selected from
  • formula (I) has the structure of formula (Ia) or formula (Ib).
  • formula (I-1) has the structure of formula (Ia-1) or formula (Ib-1).
  • formula (II) has the structure of formula (IIa) or formula (IIb).
  • formula (II-1) has the structure of formula (IIa-1) or formula (IIb-1).
  • formula (III) has the structure of formula (IIIa) or formula (IIIb).
  • the compound of the present invention has a structure of formula (Ia), (Ia-1), (IIa), (IIa-1), (IIIa) or (IIIa-1).
  • the compound of the present invention has a structure of formula (Ib), (Ib-1), (IIb), (IIb-1), (IIIb) or (IIIb-1).
  • the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
  • the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
  • the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
  • the present invention provides an antibody-drug conjugate comprising a compound of the present invention, an antibody capable of binding to a target, and a linker connecting the compound of the present invention and the antibody.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotope compound, metabolite or prodrug thereof, and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be administered in any manner as long as it achieves the effect of preventing, alleviating, preventing or treating human or animal symptoms.
  • various suitable dosage forms can be prepared according to the route of administration.
  • it can be administered orally or parenterally to a patient in the form of a conventional preparation.
  • the conventional preparations are such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.
  • the dosage of the compound administered to a subject can be adjusted to a considerable extent.
  • the dosage can vary depending on the specific route of administration and the needs of the subject, and can be subject to the judgment of a healthcare professional.
  • the present invention or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites or prodrugs or pharmaceutical compositions of the present invention can be used to prevent or treat PKMYT1-mediated diseases, or diseases responsive to the inhibition of PKMYT1, including but not limited to abnormal cell proliferation diseases, such as cancer.
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention, optionally in combination with a second therapeutic agent, for use in treating a cell proliferation disorder.
  • the disease, disorder or condition is selected from a cancerous proliferative disease (eg, cancer).
  • a cancerous proliferative disease eg, cancer
  • the disease, disorder or condition is cancer, for example selected from: (a) a solid tumor or a blood-borne tumor selected from the following cancers: bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer; (b) a hematopoietic tumor of the lymphoid lineage selected from the following: leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, (c) a hematopoietic neoplasm of the myeloid lineage selected from the group consisting of acute and chronic myeloid leukemias, myelodysplastic syndromes and promye
  • the disease, disorder or condition is selected from CCNE1 amplified cancer. In one embodiment, the disease, disorder or condition is selected from uterine sarcoma, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, liver cancer and endometrial cancer.
  • the disease, disorder or condition is selected from FBXW7 mutant cancer, such as a cancer with an inactivating mutation in the FBXW7 gene.
  • the disease, disorder or condition is selected from a blood tumor, a glioma, a liver cancer (e.g., hepatocellular carcinoma), a uterine cancer (e.g., endometrial carcinoma), a colorectal cancer (e.g., colorectal adenocarcinoma), a breast cancer, a lung cancer (e.g., non-small cell lung cancer (NSCLC)), a gastric cancer, an esophageal cancer, an esophageal junction adenocarcinoma, a bladder cancer (e.g., urothelial bladder carcinoma), a head and neck cancer (e.g., head and neck squamous cell carcinoma), a cervical cancer (e.g., cervical squamous cell carcinoma), a melanoma,
  • the disease, disorder or condition is selected from a TP53 mutant cancer, such as a cancer in which the TP53 gene has an inactivating mutation.
  • the disease, disorder or condition is breast cancer or ovarian cancer.
  • the compound of the present invention or its pharmaceutically acceptable salt or the pharmaceutical composition of the present invention can be used alone or in combination with other therapeutic agents.
  • an adjuvant can enhance the therapeutic effect of the compounds of the present invention (for example, the therapeutic benefit of using an adjuvant alone is minimal, but when used in combination with another drug, the therapeutic benefit of the individual can be enhanced), or, for example, the compound of the present invention combined with another therapeutic agent that also has therapeutic effects can enhance the therapeutic benefit of the individual.
  • the combined use of another drug for treating cancer may enhance the clinical benefit.
  • Therapies that can be combined include but are not limited to physical therapy, psychotherapy, radiotherapy, chemotherapeutic agents, small molecule targeted therapeutic agents (such as kinase inhibitors, immune agonists), immunotherapy (anti-PD-1, anti-PDL-1, CAR-T cells), etc. Regardless of the disease, disorder or condition, the two therapies should have an additive effect or a synergistic effect to benefit the individual's treatment.
  • the other therapeutic agent is selected from inhibitors of WEE family members, such as WEE1 inhibitors.
  • the other therapeutic agent is selected from cancer therapeutic agents targeting DNA, such as those that directly destroy Therapeutic agents for DNA structure or DNA topoisomerase inhibitors. Examples of therapeutic agents that directly damage DNA structure include, but are not limited to, DNA double strand breakers, DNA alkylating agents, and DNA intercalators.
  • the additional therapeutic agent is selected from a WEE1 inhibitor, a FEN1 (flap-specific endonuclease 1) inhibitor, a TOP1 (DNA topoisomerase I) inhibitor, a RRM1 (ribonucleotide reductase catalytic subunit M1) inhibitor, a RRM2 (ribonucleotide reductase regulatory subunit M2) inhibitor, an AURKB (aurora kinase B) inhibitor, a TOP2A (DNA topoisomerase II ⁇ ) inhibitor, an ATR (ataxia telangiectasia mutated and RAD-3-related protein kinase) inhibitor, a TTK (TTK protein kinase) inhibitor, a SOD1 (superoxide dismutase 1) inhibitor, a SOD2 (superoxide dismutase 2) inhibitor, a BUB1 (BUB1 mitotic checkpoint serine/threonine kinase B) inhibitor, a CDC7 (
  • novel small molecule PKMYT1 inhibitor provided by the present invention shows outstanding PKMYT1 inhibitory activity and cell proliferation inhibitory activity.
  • the compounds of the present invention can prevent or treat diseases mediated by PKMYT1, or diseases responsive to the inhibition of PKMYT1, including but not limited to abnormal cell proliferation diseases such as cancer, and have good prospects for development as drugs.
  • the inventors also unexpectedly found that the torsional isomers of at least a portion of the compounds of the present invention can be obtained by chromatography. Some of the torsional isomers separated show differences in activity. By obtaining torsional isomers, the activity of the compounds of the present invention is further improved, and the above-mentioned excellent properties can be achieved.
  • LCMS SHIMADZ LCMS2020, chromatographic column: Waters SunFire TM C18 5 ⁇ m 50*4.6 mm; mobile phase A: H 2 O (containing 0.1% formic acid); mobile phase B: CH 3 CN (containing 0.1% formic acid).
  • the compound of formula (I) or its pharmaceutically acceptable salt can be synthesized by different methods, some exemplary methods are provided below and in the Examples. Other synthetic methods can be easily proposed by those skilled in the art based on the information disclosed in the present invention.
  • the compound of formula (I) can be prepared and synthesized by various methods from an amide or thioamide compound M1 known in the literature or well known to those skilled in the art and an active methylene reagent M2.
  • w1 in M1 is a leaving group, for example, selected from halogen, OTf, in particular halogen.
  • M1 and M2 are subjected to a substitution reaction or a coupling reaction to obtain an intermediate M3, and the intermediate M3 is subjected to a condensation reaction to obtain a compound of formula (I).
  • the coupling reaction is an Ullmann reaction or a Buchwald reaction.
  • the active methylene reagent M2 is malononitrile
  • the condensation reaction is, for example, an intramolecular Thorpe-Ziegler cyclization.
  • the condensation reaction is carried out in the presence of a palladium reagent, for example, Pd(dppf) Cl2 can be used.
  • the condensation reaction is carried out under heating conditions.
  • the following process is completed in one synthesis step: M1 and M2 react to obtain M3, and M3 is converted into a compound of formula (I).
  • the synthesis step is carried out in the presence of a base, such as sodium alkoxide or sodium hydride, in particular sodium hydride.
  • the synthesis step is carried out in an ether solvent, such as ethylene glycol dimethyl ether.
  • the amide or thioamide compound M1 as the starting material can be prepared by a known method, for example, by using the corresponding carboxyl compound and amino compound to obtain the target amide through acid-amine condensation, or by using the corresponding amide The compound is subjected to thiolation reaction to obtain the target thioamide.
  • Some substituents of the compound of formula (I) can be converted to groups by known methods.
  • M2 is malononitrile and the compound of formula (I) is prepared by intramolecular Thorpe-Ziegler cyclization
  • the cyano group of the Thorpe-Ziegler cyclization product can be converted to an amide group by known methods, such as hydrolysis.
  • the intermediate 1-2 (900 mg) was dissolved in 1,4-dioxane (10.00 mL) and water (1.00 mL), and 2,4,6-trimethylboroxane (405 mg), potassium carbonate (594 mg) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (157 mg) were added in sequence, and the mixture was heated and stirred at 120°C for 2 hours under argon protection. After cooling to room temperature, the mixture was directly extracted with ethyl acetate (3x30.0 mL), and the organic phase was washed with saturated brine (2x20.0 mL) and filtered.
  • the intermediate 2-2 (600 mg) was dissolved in acetic acid (6 mL), and liquid bromine (79 mg) was added, and the mixture was reacted at 25°C for 3 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction solution until no bubbles were generated, and the mixture was extracted with ethyl acetate (3x10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the intermediate 2-3 (500 mg).
  • N,N-diisopropylamine (373 mg) was dissolved in tetrahydrofuran (3 mL) at room temperature, and n-butyl lithium (1.6 M, 2.1 mL) was added at -68 ° C.
  • n-butyl lithium 1.6 M, 2.1 mL
  • a solution of 2-bromo-5-methylthiophene (500 mg) in tetrahydrofuran (1.00 mL) was slowly added at -68 ° C, and the mixture was stirred at -68 ° C for 2 hours.
  • Carbon dioxide gas was introduced at -68 ° C, and then the reaction system was warmed to room temperature and reacted at room temperature for 1 hour.
  • the intermediate 3-2 (250 mg) was dissolved in 1,4-dioxane (10.00 mL), and 3-methoxy-2,6-dimethylaniline (258 mg) and propylphosphonic anhydride (1.45 g) were added in sequence.
  • the reaction system was heated and stirred at 70 ° C for 16 hours.
  • water (10.0 mL) was added to the reaction solution to quench, and it was extracted with ethyl acetate (3x10.0 mL).
  • the organic phase was washed with saturated brine (2x10.0 mL), dried over anhydrous sodium sulfate, and filtered.
  • the intermediate 3-4 (60 mg) was dissolved in concentrated sulfuric acid (0.50 mL), and the mixture was heated and stirred at 40 ° C for 3 hours. After cooling to room temperature, the reaction solution was diluted with dichloromethane (5.0 mL), and the pH was adjusted to 7-8 with a saturated sodium bicarbonate solution, extracted with dichloromethane (3x5.0 mL), and the organic phase was washed with saturated brine (2x5.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the intermediate 3-5 (40 mg).
  • 2-Methylthiazole-4-carboxylic acid (1.00 g) was dissolved in tetrahydrofuran (10.00 mL) at room temperature, and n-butyl lithium (1.6 M, 10.9 mL) was slowly added dropwise at -68 ° C, and the mixture was stirred at -68 ° C for 1 hour.
  • Liquid bromine (0.42 mL) was slowly added at -68 ° C, and then the reaction system was warmed to room temperature and reacted at room temperature for 2 hours. Water (10.0 mL) was added to the reaction solution, and the unreacted raw materials were removed by extraction with ethyl acetate (3x10.0 mL).
  • the intermediate 9-2 (400 mg) was dissolved in dimethyl sulfoxide (4.00 mL), and 2-cyanoacetamide (105.9 mg), potassium carbonate (290.0 mg) and cuprous iodide (20.0 mg) were added in sequence.
  • the reaction system was heated and stirred at 85 ° C in a sealed tube under argon protection for 3 hours. After cooling to room temperature, water (10.0 mL) was added to the reaction solution, and it was extracted with ethyl acetate (3x30.0 mL). The organic phase was washed with saturated brine (3x20.0 mL), dried over anhydrous sodium sulfate, and filtered.
  • the intermediate 10-5 (230 mg) was dissolved in concentrated sulfuric acid (1.5 mL), reacted at room temperature for 1 hour, and then heated to 75 ° C for 1 hour.
  • LCMS MS m/z (ESI): 263.0 [M+H] + .
  • the intermediate 12-2 (4.70 g) was dissolved in ethanol (40.00 mL), and sodium hydroxide (1.43 g) was added under argon protection. The reaction system was heated and stirred at 70 ° C overnight. After cooling to room temperature, the reaction solvent was concentrated, and water (50.0 mL) was added to dilute it. The pH was adjusted to 3-4 with 1N hydrochloric acid. Solids precipitated and filtered. The filter cake was washed with 1% hydrochloric acid and vacuum dried to obtain intermediate 12-3 (4.0 g).
  • the intermediate 12-3 (1.2 g, 5.10 mmol) was dissolved in thionyl chloride (15.00 mL), and heated and stirred in an oil bath at 80 ° C for 75 minutes. After cooling to room temperature, the reaction solution was concentrated, the residue was dissolved in dry toluene (5.0 mL), and added dropwise to a pyridine (5 mL) solution of 3-methoxy-2,6-dimethylaniline (1.16 g) under an ice bath. After the addition was complete, the reaction system was warmed to room temperature and reacted overnight under argon protection.
  • 5-Bromothiazol-2-amine (10.00 g) was dissolved in dichloromethane (100.0 mL) at room temperature, and triethylamine (14.1 g), 4-dimethylaminopyridine (682.4 mg) and di-tert-butyl dicarbonate (14.6 g) were added in sequence, and the mixture was stirred and heated at 25°C for 2 hours.
  • the reaction solution was diluted with water (100.0 mL) and extracted with dichloromethane (3 ⁇ 200.0 mL). The organic phases were combined and washed with saturated brine (3 ⁇ 500.0 mL), dried over anhydrous sodium sulfate, and filtered.
  • the intermediate 17-3 (400 mg) was dissolved in N, N-dimethylformamide (6.00 mL), and N-iodosuccinimide (229 mg) was added, and the reaction was stirred at room temperature overnight.
  • Potassium fluoride (6 mg) and cuprous iodide (21 mg) were placed in a microwave tube at room temperature, purged with nitrogen, and stirred in an oil bath at 60°C for 1 hour.
  • a solution of trimethyltrifluoromethylsilane 120 mg) in N-methylpyrrolidone (0.50 mL) was added, and the reaction system was stirred in an oil bath at 50°C for 45 minutes.
  • a solution of intermediate 17-4 (20 mg) in N,N-dimethylformamide (0.50 mL) was added, and the reaction system was stirred in an oil bath at 80°C overnight. Water (5.0 mL) was added to the reaction solution for dilution, and extracted with ethyl acetate (3 ⁇ 5.0 mL).
  • the intermediate 23-2 (250 mg) was dissolved in N, N-dimethylformamide (3.00 mL), tributyl (1-ethoxyvinyl) tin (265 mg) and XPhos-Pd-G2 (39 mg) were added, and the reaction system was replaced with argon three times, and then heated and stirred at 100 ° C for 2 hours under argon protection.
  • the reaction solution was poured into water (20.0 mL), extracted with ethyl acetate (3 ⁇ 20.0 mL), and the organic phase was washed with saturated brine (2 ⁇ 20.0 mL), dried over anhydrous sodium sulfate, and filtered.
  • the intermediate 23-2 (200 mg) was dissolved in N, N-dimethylformamide (20.00 mL), and 2-(trimethyltinyl)thiazole (291 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29 mg) were added in sequence.
  • the reaction system was heated and stirred at 80°C under argon protection for 2 hours. After cooling to room temperature, the mixture was diluted with water (10.0 mL), extracted with ethyl acetate (3 ⁇ 10.0 mL), and the organic phase was washed with saturated brine (2 ⁇ 10.0 mL), dried over anhydrous sodium sulfate, and filtered.
  • step 1.1 the 3-methoxy-2,6-dimethylaniline in step 1.1 was replaced with 5-methyl-1H-indazol-4-amine to obtain the target compound 6-amino-2-methyl-5-(5-methyl-1H-indazol-4-yl)-4-oxo-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxamide (Compound 036).
  • the intermediate 43-2 (10 g) was dissolved in ethanol (100 mL), and an ethanol solution of sodium ethoxide (0.5 N, 100 mL) was added under argon protection, and then the temperature was raised to 60 ° C for 16 hours. Water (100.0 mL) was added to the reaction solution to quench, and it was extracted with ethyl acetate (3 ⁇ 100.0 mL).
  • the intermediate 43-3 (4.8 g) was dissolved in water (48 mL), hydrogen bromide (7.68 mL) was added, and the mixture was cooled to -5°C.
  • Cuprous bromide (12.3 g) was added, the mixture was heated to room temperature and stirred for 30 minutes, and then heated to 100°C in an oil bath and stirred for 2 hours. The mixture was cooled to room temperature, and the reaction solution was extracted with ethyl acetate (3 ⁇ 100.0 mL).
  • the intermediate 43-4 (900.0 mg) was dissolved in tetrahydrofuran (9.00 mL), cooled to 0°C, sodium hydride (232.6 mg) was added, stirred for 30 minutes, iodomethane (825.6 mg) was added, and the mixture was heated and stirred in a 50°C oil bath for 16 hours.
  • water (20.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 ⁇ 20.0 mL). The organic phase was washed with saturated brine (2 ⁇ 20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • 2,4-Dibromothiophene (10 g) was dissolved in ether (10 mL), and n-butyl lithium (25.8 mL, 1.6 M) was slowly added at -68 ° C, and stirred for 0.5 hours.
  • a solution of dimethyl disulfide (4.28 g) in tetrahydrofuran (5 mL) was slowly added at -68 ° C, and continued to stir for 0.5 hours, and then the temperature was raised to 0 ° C and stirred for 1 hour.
  • Saturated ammonium chloride solution 100 mL was slowly added to the reaction solution to quench, and extracted with ethyl acetate (3 ⁇ 100 mL).
  • Example 28 replacing intermediate 50-3 with 44-6 to obtain the target product 6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2-(methylthio)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carboxamide (Compound 044).
  • lithium diisopropylamide (36.9 ml, 2M) was dissolved in tetrahydrofuran (10 ml), and a mixture of 4-methylthiophene-3-carboxylic acid (5 g) and tetrahydrofuran (40 ml) was slowly added, and stirred at -68°C for 0.5 h.
  • a solution of carbon tetrabromide (12.8 g) in tetrahydrofuran (10 ml) was slowly added dropwise, and stirred at -68°C for 30 minutes. The reaction solution was heated to 25°C and stirred for 2 hours.
  • the intermediate 46-2 (200 mg) was dissolved in dioxane (5 mL) and water (0.5 mL), and potassium cyclopropyl trifluoroborate (355 mg), potassium carbonate (132.6 mg), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (35 mg) were added, and the gas was replaced three times under nitrogen protection, and the reaction was carried out at 100°C for 16 hours. Water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mLx3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the remaining demethylation method refers to the above step 25.4.
  • potassium ethylene trifluoroborate in step 25.1 was replaced with 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborane to obtain compound 6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2-isopropyl-3-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carboxamide (Compound 048).
  • Example 28 6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-2-(methylthio)-4-oxo-4,5-dihydrothieno [3,2-c]pyridine-7-carboxamide (Compound 050), (S)-6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-2-( methylthio )-4-oxo-4,5- dihydrothieno[3,2-c]pyridine-7-carboxamide (Compound 050-1) and (R)-6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-2-(methylthio)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carboxamide ( Compound 050-2)
  • the intermediate 50-2 (145 mg) was dissolved in dioxane (2 mL) and water (0.2 mL), and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane (0.22 mL), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (54 mg) and potassium carbonate (72 mg) were added, and the reaction solution was heated to 100 ° C for 16 hours. After cooling to room temperature, water (5 mL) was added to the reaction solution for dilution, and it was extracted with ethyl acetate (3 ⁇ 10 mL).
  • the intermediate 50-3 (77 mg) was dissolved in dichloromethane (1.0 mL) at room temperature, trifluoroacetic acid (0.10 mL) was added, and the reaction was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7, and extracted with dichloromethane (3 ⁇ 5.0 mL). The organic phase was washed with saturated brine (2 ⁇ 5.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by slurrying with petroleum ether (5.0 mL) to obtain intermediate 50-4 (52 mg). LCMS: MS m/z (ESI): 372.1 [M+H] + .
  • the intermediate 50-4 (52 mg) was dissolved in a mixed solution of ethanol (3.0 mL) and water (1.0 mL), and (dimethylphosphonic acid) platinum (II) hydrogen complex (3.3 mg) was added. After replacing with argon three times, the reaction system was stirred in an oil bath at 50°C under argon protection for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to obtain 6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-2-(methylthio)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carboxamide (Compound 050) (5.66 mg).
  • the intermediate 45-4 (200 mg) was dissolved in acetonitrile (4.0 mL), 1-(trifluoromethyl)-1,2-benzidoyl-3(1H)-one (559 mg) and potassium carbonate (122 mg) were added, and the reaction solution was replaced with argon three times and reacted at 80°C for 12 hours.
  • the intermediate 1-2 (1.00 g) was dissolved in 1,4-dioxane (10.00 mL) and water (1.00 mL), and isopropenylboronic acid pinacol ester (400 mg), potassium carbonate (658 mg) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (193 mg) were added in sequence.
  • the reaction system was heated in an oil bath at 100°C for 4 hours under argon protection. After cooling to room temperature, water (10.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 ⁇ 10.0 mL).
  • the intermediate 53-3 (2 g) was dissolved in acetic acid (20 mL), and liquid bromine (0.5 mL) was added. The reaction was stirred at 50 ° C in a closed reaction system for 16 hours. After cooling to room temperature, a saturated aqueous sodium thiosulfate solution (30 mL) was added to the reaction solution to quench, and extracted with ethyl acetate (3 ⁇ 50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (EA/PE: 0% to 0.5%) to obtain the intermediate 53-3 (1.4 g). LCMS: MS m/z (ESI): 292.0 [M+H] + .
  • LCMS MS m/z (ESI): 281.9 [M+H] + .
  • the intermediate 54-2 (1.50 g) was dissolved in ethanol (10.00 mL) and water (5 mL), and sodium hydroxide (320.1 mg) was added under argon protection.
  • the reaction system was heated and stirred in a 50°C oil bath overnight. After cooling to room temperature, the reaction solution After concentration under reduced pressure, solids precipitated. Water (5.0 mL) was added to dissolve the solids. The pH was adjusted to 3-4 with 1N hydrochloric acid. Solids precipitated. After stirring at room temperature for 30 minutes, the mixture was filtered and the filter cake was dried under vacuum to obtain intermediate 54-3 (1.36 g).
  • the intermediate 54-3 (500 mg) was dissolved in thionyl chloride (6 mL), and the mixture was heated and stirred in an oil bath at 80°C for 75 minutes.
  • the reaction solution was concentrated under reduced pressure, and the residue was dissolved in dry toluene (5.0 mL) and added dropwise to a pyridine solution of 3-((4-methoxybenzyl)oxy)-2,6-dimethylaniline (759.5 mg) under an ice bath. After the addition was complete, the reaction system was warmed to room temperature and reacted overnight under argon protection.
  • the reaction solution was concentrated under reduced pressure, and the residue was diluted with water (10.0 mL) and extracted with ethyl acetate (3 ⁇ 10.0 mL).
  • LCMS MS m/z (ESI): 513.3 [M+H] + .
  • the intermediate 23-2 (1.0 g) was dissolved in N, N-dimethylformamide (10.0 mL), (tributyltinyl) methanol (944 mg) and XPhos-Pd-G2 (308 mg) were added in sequence, and the reaction system was heated and stirred in an oil bath at 80°C for 2 hours. After cooling to room temperature, water (20.0 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (3 ⁇ 20.0 mL). The organic phase was washed with saturated brine (2 ⁇ 20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the intermediate 59-3 (110 mg) was dissolved in dichloromethane (4.00 mL), and diethylamine (88 mg) was added. After stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (153 mg) was added and stirred at room temperature for 1 hour. Water (10.00 mL) was added to the reaction solution for dilution, and it was extracted with dichloromethane (3 ⁇ 10.0 mL). The organic phase was washed with saturated brine (2 ⁇ 10.0 mL), dried over anhydrous sodium sulfate, and filtered.
  • the intermediate 23-2 (120 mg) was dissolved in concentrated sulfuric acid (2.0 mL) at room temperature, and the reaction system was stirred in an oil bath at 40 ° C for 2 hours. After cooling to room temperature, a saturated sodium bicarbonate solution was added to the reaction solution for neutralization, and extracted with ethyl acetate (3 ⁇ 5.0 mL). The organic phase was washed with saturated brine (2 ⁇ 5.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by slurrying with petroleum ether (15.0 mL), filtered, and the filter cake was washed with petroleum ether (3 ⁇ 10.0 mL) and dried in vacuo to obtain the intermediate 60-2 (60 mg).
  • the intermediate 104-6 (150 mg) was dissolved in N,N-dimethylformamide (1.5 mL), and tetrahydropyran-4-carboxylic acid (51 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (114 mg), 1-hydroxybenzotriazole (80 mg) and N,N-diisopropylethylamine (154 mg).
  • the intermediate 108-2 (1.40 g) was dissolved in isopropanol (12.0 mL) and water (2.0 mL), and the reaction system was heated and stirred in an oil bath at 70°C for 0.5 hours. After cooling to room temperature, the reaction solution was poured into water (20.0 mL), extracted with dichloromethane (3 ⁇ 20.0 mL), and the organic phase was washed with saturated brine (2 ⁇ 20.0 mL), dried over anhydrous sodium sulfate, and filtered.
  • the intermediate 108-3 (200 mg) was dissolved in toluene (4.0 mL) at room temperature, and benzophenone imine (190 mg), sodium tert-butoxide (118 mg) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (409 mg) and tris(dibenzylideneacetone)dipalladium (200 mg), after replacing with argon three times, the reaction system was heated to 90°C and stirred overnight.
  • intermediate 12-2 (36 mg) and intermediate 108-5 (20 mg) were dissolved in 1,4-dioxane (1.0 mL), and trimethylaluminum (0.8 mL, 1.6 M) was added dropwise under stirring.
  • the gas was replaced with argon three times, and the reaction system was stirred in a sealed tube in an oil bath at 120°C for 5 hours.
  • the reaction was stopped, and the reaction solution was poured into methanol (3.0 mL), extracted with dichloromethane (3 ⁇ 20.0 mL), and the organic phase was washed with saturated brine (2 ⁇ 20.0 mL), dried over anhydrous sodium sulfate, and filtered.
  • the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-TLC to obtain intermediate 108-6 (20 mg).
  • LCMS MS m/z (ESI): 381.0 [M+H] + .
  • the intermediate 108-7 (10 mg) was dissolved in ethanol (3.0 mL) and water (1.0 mL) at room temperature, and (dimethylphosphonic acid) platinum (II) hydrogen complex (1 mg) was added. After replacing with argon three times, the reaction system was stirred in an oil bath at 100°C under argon protection for 24 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid preparative chromatography to obtain the target product 6-amino-2,3-dimethyl-5-(5-methylbenzo[d]isothiazol-4-yl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carboxamide (Compound 108) (1.13 mg).
  • the intermediate 109-2 (5.77 g) was dissolved in trifluoroacetic acid (20.0 mL), and methanesulfonic acid (1.0 mL) was added, and the reaction was stirred at 25°C for 20 minutes.
  • Ethyl acetate (50.0 mL) was added to the reaction solution, and the mixture was extracted with water (3 ⁇ 100 mL).
  • the pH of the aqueous phase was adjusted to 8-9 with ammonia water, and extracted with ethyl acetate (3 ⁇ 150 mL).
  • the organic phase was washed with saturated brine (2 ⁇ 100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the intermediate 109-3 (2.2 g).
  • the intermediate 109-4 (2.50 g) was dissolved in methanol (10.00 mL) and water (5.00 mL), and lithium hydroxide (628 mg) was added.
  • the reaction system was stirred in an oil bath at 25°C for 4 hours. The reaction was stopped, and the methanol was removed by concentration under reduced pressure.
  • the pH was adjusted to 3-4 with 1N hydrochloric acid solution, and extracted with ethyl acetate (3 ⁇ 50.0 mL).
  • the organic phase was washed with saturated brine (2 ⁇ 50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the intermediate 109-5 (2.0 g).
  • the intermediate 110-2 (10.0 g) was dissolved in 1,4-dioxane (100 mL), 5-methyl-1H-indazole-4-amine (6.27 g) and trimethylaluminum (1.6 M, 132.8 mL) were added, and the gas was replaced with argon three times.
  • the reaction solution was heated to 120 ° C for 6 hours. The temperature was lowered to 0 ° C, and the reaction solution was slowly added to methanol (300 mL) to quench.
  • the intermediate 110-5 (4 g) was dissolved in a mixed solvent of 1,4-dioxane (40 mL) and water (4 mL), potassium trifluoro(vinyl)borate (3.88 g), potassium carbonate (3.34 g) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (707 mg) were added in sequence, replaced with argon three times, and reacted at 110°C for 16 hours.
  • the intermediate 110-7 (140 mg) was dissolved in a mixed solvent of ethanol (3 mL) and water (1 mL), and (dimethylphosphonic acid) platinum (II) hydrogen complex (17 mg) was added, replaced with argon three times, and the reaction solution was heated to 100°C for 16 hours. The solvent was removed under reduced pressure, and the mixture was slurried with a mixed solvent of dichloromethane and methanol (10:1, 1.5 mL).
  • the intermediate 111-4 (5.00 g) was dissolved in 1,4-dioxane (50 mL), and the intermediate 111-5 (3.03 g) was added.
  • Trimethylaluminum (1.6 M, 59.3 mL) was added under stirring, and the reaction was stirred at 120 ° C for 3 hours under argon protection.
  • the reaction solution was slowly added to methanol (200 mL) at 0 ° C to quench, concentrated under reduced pressure, diluted with water (100 mL), extracted with ethyl acetate (3 ⁇ 100 mL), and the organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the intermediate 111-7 (2.00 g) was dissolved in a mixed solution of ethanol (21.0 mL) and water (7.0 mL), and (dimethylphosphonic acid) platinum (II) hydrogen complex (245 mg) was added, replaced with argon three times, and heated in an oil bath at 100°C for 16 hours. After cooling to room temperature, solids precipitated, which were filtered and the filter cake was purified by slurrying with methanol (20 mL) to obtain the compound 6-amino-5-(5-chloro-1H-indazol-4-yl)-2-ethyl-3-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carboxamide (1.48 g).
  • LCMS MS m/z(ESI):402.1[M+H] + .
  • the intermediate 112-2 (1.28 g) was dissolved in ethylene glycol dimethyl ether (25.0 mL), and malononitrile (433 mg), sodium tert-butoxide (630 mg) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (240 mg) were added in sequence. After replacing with argon three times, the reaction system was heated and stirred in an oil bath at 100°C under argon protection for overnight reaction. The reaction was stopped, and water (50.0 mL) was added to the reaction solution for dilution.
  • the intermediate 110-5 (530 mg) was dissolved in dichloromethane (5.0 mL), 3,4-dihydro-2H-pyran (215 mg) was added, and p-toluenesulfonic acid (22 mg) was added when cooled to 0°C.
  • the reaction system was heated to 30°C and stirred for 1 hour.
  • the reaction was stopped, water (10.0 mL) was added to the reaction solution for dilution, and it was extracted with dichloromethane (2 ⁇ 10.0 mL).
  • the organic phase was washed with saturated sodium bicarbonate solution (2 ⁇ 10.0 mL) and saturated sodium chloride solution (2 ⁇ 10.0 mL) in sequence, dried over anhydrous sodium sulfate, and filtered.
  • the intermediate 114-2 (487 mg) was dissolved in 1,4-dioxane (5.0 mL) and water (0.5 mL), and potassium cyclopropyl trifluoroborate (722 mg), potassium carbonate (55 mg), cesium fluoride (44 mg) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (71 mg) were added in sequence.
  • the reaction system was reacted at 100°C for 1 hour in a microwave under argon protection. After cooling to room temperature, water (10.0 mL) was added to the reaction solution for dilution, and extracted with ethyl acetate (3 ⁇ 10.0 mL).
  • the intermediate 114-3 (240 mg) was dissolved in a methanol solution of hydrochloric acid (5.0 mL, 4 M), and the reaction system was stirred at 25°C for 1 hour. The reaction was stopped, the reaction solution was concentrated, tetrahydrofuran (10.0 mL) was added to dissolve, water (10.0 mL) was added to dilute, and extracted with ethyl acetate (3 ⁇ 10.0 mL). The organic phase was washed with saturated sodium bicarbonate solution (2 ⁇ 20.0 mL) and saturated brine (2 ⁇ 20.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the intermediate 114-4 (158 mg).
  • Intermediate 120-2 (0.8 g) was dissolved in phosphorus oxychloride (5 mL), stirred at room temperature for 0.5 hours, and then heated to 100°C for 6.5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, toluene (5 mL) was added, and the residual phosphorus oxychloride was removed by concentration under reduced pressure to obtain intermediate 120-3 (954 mg), which was directly used in the next step.
  • 2,2,6,6-tetramethylpiperidine (30.0 g) was dissolved in ultra-dry tetrahydrofuran (160.0 mL) at room temperature, replaced with argon three times, and n-butyl lithium (84.0 mL, 2.5 M) was slowly added at -20°C using a constant pressure feed funnel, and the reaction system was stirred at 0°C for 0.5 hours.
  • the intermediate 127-2 (32.0 g) was dissolved in dimethyl sulfoxide (320.0 mL), hydrazine hydrate (81.8 mL) was added, and the mixture was stirred at 120°C for 8 hours. The reaction was stopped, and the reaction solution was slowly added into water (3.2 L) and stirred for 1 hour. The pH was adjusted to 5 with 3M hydrochloric acid, and solids precipitated. The filter cake was filtered and dried to obtain the intermediate 127-3 (23.7 g).
  • the intermediate 127-3 (23.7 g) was dissolved in dichloromethane (200.0 mL), 3,4-dihydro-2H-pyran (26.1 g) was added, and p-toluenesulfonic acid (1.77 g) was added when the temperature was lowered to 0°C, and then the reaction system was stirred at 30°C for 1 hour. The reaction was stopped, and water (300.0 mL) was added to the reaction solution for dilution, and the mixture was extracted with dichloromethane (3 ⁇ 100.0 mL).
  • the intermediate 127-4 (400 mg) was dissolved in 1,4-dioxane (100.0 mL), and benzophenone imine (13.9 g), cesium carbonate (37.4 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.40 g) and palladium acetate (868 mg) were added in sequence, and the atmosphere was replaced with argon three times.
  • the reaction system was reacted at 110°C for 16 hours. The reaction was stopped, and water (150.0 mL) was added to the reaction solution for dilution, and extracted with ethyl acetate (3 ⁇ 150.0 mL).
  • Compound 127 was chirally resolved by SFC to obtain compound (S)-6-amino-2-ethyl-5-(7-fluoro-5-methyl-1H-indazol-4-yl)-3-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carboxamide (compound 127-P1).
  • This series of compounds has atropisomerism in their structures, and two stable isomers can be obtained by chiral SFC separation.
  • the results of the aforementioned biological test examples show that the two isomers show large differences in activity, both in enzyme inhibition and cell proliferation inhibition.
  • Two representative molecular compounds 047 and 112 were selected, and single crystal cultivation and structural analysis were carried out on the isomers with poor inhibitory activity to determine their absolute configuration.
  • the single crystal cultivation method includes: gas-liquid diffusion and slow solvent evaporation crystallization.
  • compound 047-2 is obtained by gas-liquid diffusion in an ethanol and n-pentane system to obtain plate-like crystals
  • compound 112-P1 is obtained by slow solvent evaporation in an ethanol and n-pentane system to obtain block crystals.
  • the single crystal structure analysis data is shown in the table below.
  • both test compounds are in R configuration. From this result, it can be inferred that the isomer with better inhibitory activity is S configuration.
  • the present invention further improves the activity of the compound by obtaining the torsional isomer.
  • the inhibition of the compound on PKMYT1 kinase was detected by ADP-Glo assay.
  • the reaction buffer (Assay buffer): 50mM HEPES, 10mM MgCl, 1mM EGTA, 0.01% Brij-35, 2mM DTT, and then dilute the MYT1 enzyme (Carna, 05-176, final concentration of 20nM) and the reaction substrate (ATP with a final concentration of 40 ⁇ M and inactivated CDK1 with a final concentration of 40nM, Signalchem C22-14G) with the reaction buffer. Dilute the test compound 3 times into 10 concentrations, with a starting concentration of 3 ⁇ M.
  • the inhibition of the compound on WEE1 kinase was detected by ADP-Glo assay.
  • the reaction buffer (Assay buffer): 50mM HEPES, 10mM MgCl, 1mM EGTA, 0.01% Brij-35, 2mM DTT, and then Dilute WEE1 enzyme (Carna, 05-177, final concentration of 10 nM) and reaction substrate (ATP with a final concentration of 20 ⁇ M and Poly (Lys-Tyr, 4:1) with a final concentration of 400 ng/ ⁇ L, BPS Bioscience, 79910) with reaction buffer. Dilute the test compound 3 times to 10 concentrations, with a starting concentration of 3 ⁇ M.
  • HCC1569 cells ATCC, CRL-2330
  • a 96-well flat-bottom cell culture plate Corning, #3603
  • DMSO dilute it to 10 concentration points at a ratio of 1:3.
  • CD-1 mice were purchased from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd., Sibeifu (Beijing) Biotechnology Co., Ltd. and Sibeifu (Suzhou) Biotechnology Co., Ltd.
  • DMSO, Solutol, PEG400, acetonitrile, Methanol and VETPGS were purchased from Sigma-Aldrich.
  • the LC-MS/MS system was Waters Acquity UPLC class I plus connected in series with AB Sciex Triple Quad 6500+, and the chromatographic column was Agilent Poroshell 120EC-C18 4 ⁇ m (50 ⁇ 2.1mm). All data were collected and processed by Analyst software, and pharmacokinetic parameters were calculated using Phoenix Build 8.3.
  • mice Six female CD-1 mice (20-30 g, 6-8 weeks) were randomly divided into two groups according to body weight, with three mice in each group.
  • the first group was given the test compound by tail vein injection at a dose of 1 mg/kg or 0.5 mg/kg, and the solvent was 5% DMSO + 5% Solutol + 90% Saline solution;
  • the second group was orally given the test compound at a dose of 2 mg/kg or 5 mg/kg, and the solvent was 5% DMSO/20% PEG400/75% (15% VETPGS aqueous solution).
  • the first group of animals were fed and watered normally before the experiment, while the second group of animals were fasted overnight before the experiment and fed 2 hours after the administration.
  • Mouse plasma samples were added with acetonitrile solution containing internal standard compounds and vortexed for 0.5min, then centrifuged at 3900rpm for 15min, the supernatant obtained by centrifugation was transferred and diluted 3 times with aqueous solution, and 2 ⁇ L was injected into the LC-MS/MS system for quantitative analysis.
  • sample concentration a female CD-1 mouse plasma standard curve (linear range: 0.5-1000ng/mL) and quality control samples (1, 2, 5, 50, 400, 800ng/mL) were used.
  • HCC1569 is a human breast cancer cell.
  • a model was established using NOD SCID female mice.
  • 0.2 mL (3 ⁇ 10 6 ) of HCC1569 cells were subcutaneously inoculated on the right back of each mouse.
  • group administration began.
  • the compound was orally administered twice a day.
  • the tumor diameter was measured twice a week and at the end of administration.
  • TGI% tumor growth inhibition rate
  • TGI (%) [(1-(average tumor volume at the end of administration of a treatment group-average tumor volume at the beginning of administration of the treatment group))/(average tumor volume at the end of treatment of the solvent control group-average tumor volume at the beginning of treatment of the solvent control group)] ⁇ 100%.

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Abstract

La présente invention concerne le domaine de la chimie pharmaceutique, et concerne en particulier une classe de composés utilisés en tant qu'inhibiteur de PKMYT1, ou un sel pharmaceutiquement acceptable de ceux-ci, un procédé de préparation associé, une composition pharmaceutique de ceux-ci, et leur utilisation dans le traitement de maladies associées à PKMYT1.
PCT/CN2024/085203 2023-03-31 2024-04-01 Composé en tant qu'inhibiteur de pkmyt1 WO2024199524A1 (fr)

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