WO2024078436A1 - 杂环并嘧啶类化合物、药物组合物及其应用 - Google Patents

杂环并嘧啶类化合物、药物组合物及其应用 Download PDF

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WO2024078436A1
WO2024078436A1 PCT/CN2023/123495 CN2023123495W WO2024078436A1 WO 2024078436 A1 WO2024078436 A1 WO 2024078436A1 CN 2023123495 W CN2023123495 W CN 2023123495W WO 2024078436 A1 WO2024078436 A1 WO 2024078436A1
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alkyl
cycloalkyl
optionally substituted
compound
membered
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French (fr)
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祝伟
孙天文
高冬林
汪涛
陈祥
李正涛
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海南先声再明医药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure belongs to the field of medical technology, and relates to a class of heterocyclic pyrimidine compounds, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and uses thereof as ubiquitin-specific protease 1 (USP1) inhibitors in preventing or treating diseases associated with USP1.
  • USP1 ubiquitin-specific protease 1
  • Ubiquitination is a reversible process involving a family of deubiquitinating enzymes (DUBs) that regulate a variety of cellular processes by deubiquitinating substrates.
  • DUBs are encoded by approximately 100 human genes and are classified into six families, the largest of which is the ubiquitin-specific proteases (USPs) with more than 50 members.
  • USPs ubiquitin-specific proteases
  • DUBs and their substrate proteins are frequently dysregulated in cancer, a phenomenon that supports the hypothesis that targeting specific DUB enzymes can enhance the ubiquitination and degradation of oncogenic substrates and regulate the activity of other key proteins involved in tumor growth, survival, differentiation, and maintenance of the tumor microenvironment (Hussain, S., et.al., "DUBs and cancer: The role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors.” Cell Cycle 8, 1688-1697 (2009)).
  • Ubiquitin-specific protease 1 is a cysteine isopeptidase of the USP subfamily in DUBs.
  • the full-length human USP1 consists of 785 amino acids, including a catalytic triad consisting of Cys90, His593 and Asp751 (Nijman, S.M.B., et al. "The deubiquitinating enzyme USP1 regulates the fanconi anemia pathway.” Mol. Cell 17, 331-339 (2005)).
  • USP1 plays a role in DNA damage repair. USP1 itself is relatively inactive, and only when it combines with the auxiliary factor UAF1 to form a complex required for deubiquitinase activity can it obtain full enzyme activity.
  • the USP1/UAF1 complex deubiquitinates monoubiquitinated PCNA (proliferating cell nuclear antigen) and monoubiquitinated FANCD2 (Fanconi anemia complementation group D2), two proteins that play important roles in the trans-translational synthesis (TLS) and Fanconi anemia (FA) pathways, respectively. Both pathways are required for the repair of DNA damage caused by DNA cross-linking agents such as cisplatin and mitomycin C (MMC).
  • the USP1/UAF1 complex also deubiquitinates FANCI (Fanconi anemia complementation group I).
  • the significance of these findings was further confirmed by experiments showing that mice lacking USP1 are highly sensitive to DNA damage. Interestingly, the expression of USP1 is significantly increased in many cancers. Blocking USP1 to inhibit DNA repair can induce apoptosis in multiple myeloma cells and also enhance the sensitivity of lung cancer cells to cisplatin.
  • USP1 protein targeted inhibition of USP1 protein is a potential approach to prevent or treat cancer and other diseases. Therefore, the development of small molecule inhibitors of USP1 is necessary.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 3a , R 3b , R 4 , R 5a , R 5b are each independently selected from H, halogen, CN, OH, NH 2 , -C(O)OR x , -C(O)R x , -NHC(O)R x , -OC 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclyl, and the NH 2 , -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R x ;
  • R 3a , R 3b and the carbon atom to which they are attached together form a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or the 4-10 membered heterocyclic group is optionally substituted by R x ;
  • R 5a , R 5b and the carbon atom to which they are attached together form a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or the 4-10 membered heterocyclic group is optionally substituted by R x ;
  • Ring A is selected from C 6 -C 10 aryl or 5-10 membered heteroaryl, and the C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally substituted by Ra ;
  • Ring B is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C 4 -C 10 cycloalkenyl or C 3 -C 10 cycloalkyl, wherein the C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C 4 -C 10 cycloalkenyl or C 3 -C 10 cycloalkyl is optionally substituted with R b ;
  • Ring C is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the C 6 -C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted by R c ;
  • Each of Ra , Rb , and Rc is independently selected from halogen, CN, OH, NH2 , -C(O) ORx , -C(O) Rx , C1 - C6 alkyl, -OC1 - C6 alkyl, C3 - C10 cycloalkyl, or 4-10 membered heterocyclyl, wherein the NH2 , C1 - C6 alkyl, -OC1- C6 alkyl, C3 - C10 cycloalkyl, or 4-10 membered heterocyclyl is optionally substituted by Rx ;
  • R b , R c and the atoms to which they are attached together form a C 4 -C 10 cycloalkenyl group or a 4-10 membered heterocyclic group, and the C 4 -C 10 cycloalkenyl group or the 4-10 membered heterocyclic group is optionally substituted by R x ;
  • R 1 and R 2 are independently selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclyl, wherein the OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R x ;
  • R 1 , R 2 and the atoms to which they are attached together form a C 3 -C 10 cycloalkyl group or a 4-7 membered heterocyclic group, and the C 3 -C 10 cycloalkyl group or the 4-7 membered heterocyclic group is optionally substituted by R x ;
  • Rx is selected from halogen, CN, OH, NH2 or C1 - C6 alkyl, wherein the OH, NH2 or C1 - C6 alkyl is optionally substituted by C1 - C6 alkyl, C3 - C10 cycloalkyl or 4-7 membered heterocyclyl;
  • the condition is that when Selected from when R 5a is selected from halogen, CN, OH, NH 2 , -C(O)OR x , -C(O)R x , -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl or 4-9 membered heterocyclyl, and the NH 2 , -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl or 4-9 membered heterocyclyl is optionally substituted by R x ;
  • R 5a , R 5b and the carbon atom to which they are attached form a C 4 -C 10 cycloalkyl group or a 4-9 membered heterocyclic group, and the C 4 -C 10 cycloalkyl group or the 4-9 membered heterocyclic group is optionally substituted by R x .
  • R 3a , R 3b , R 4 , R 5a , R 5b are independently selected from H, —C(O)OR x , —C(O)R x , —OC 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or 4-10 membered heterocyclyl, wherein the —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with R x .
  • R 3a , R 3b , R 4 , R 5a , R 5b are independently selected from H, C 1 -C 6 deuterated alkyl, C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl is optionally substituted with R x .
  • R 3a , R 3b , R 4 , R 5a , R 5b are independently selected from H, CH 3 , CD 3 or cyclopropyl.
  • R 3a , R 3b are independently selected from H, C 1 -C 6 deuterated alkyl, or C 1 -C 6 alkyl, said C 1 -C 6 alkyl being optionally substituted with R x .
  • R 4 is selected from H or C 1 -C 6 alkyl, which is optionally substituted with R x .
  • R 5a is selected from halogen, CN, OH, NH 2 , -C(O)OR x , -C(O)R x , -OC 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, or 4-9 membered heterocyclyl, and the NH 2 , -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, or 4-9 membered heterocyclyl is optionally substituted with R x .
  • R 5a is selected from C 1 -C 6 deuterated alkyl, C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl is optionally substituted with R x .
  • R 5b is selected from H or C 1 -C 6 alkyl, which is optionally substituted with R x .
  • R 5a , R 5b and the carbon atom to which they are attached form a C 3 -C 10 cycloalkyl group, and the C 3 -C 10 cycloalkyl group is optionally substituted with R x .
  • R 5a , R 5b and the carbon atom to which they are attached form a C 4 -C 10 cycloalkyl group, and the C 4 -C 10 cycloalkyl group is optionally substituted with R x .
  • R 5a , R 5b and the carbon atom to which they are attached form a C 4 -C 6 cycloalkyl group, and the C 4 -C 6 cycloalkyl group is optionally substituted with R x .
  • R 5a , R 5b and the carbon atom to which they are attached form a cyclobutyl group, which is optionally substituted with R x .
  • Ring A is selected from 5-10 membered heteroaryl, which is optionally substituted with Ra .
  • Ring A is selected from 5-6 membered heteroaryl, which is optionally substituted with Ra .
  • Ring A is selected from pyrimidinyl, which is optionally substituted with Ra .
  • Ring B is selected from C 6 -C 10 aryl or 5-10 membered heteroaryl, wherein the C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally substituted with R b .
  • Ring B is selected from C 6 -C 10 aryl, which is optionally substituted with R b .
  • Ring B is selected from phenyl, which is optionally substituted with R b .
  • Ring B is selected from phenyl.
  • Ring C is selected from 5-10 membered heteroaryl or 4-10 membered heterocyclyl, which is optionally substituted with R c .
  • Ring C is selected from 5-6 membered heteroaryl or 4-8 membered heterocyclyl, wherein the 5-6 membered heteroaryl or 4-8 membered heterocyclyl is optionally substituted with R c .
  • ring C is selected from pyrazolyl, imidazolyl or The pyrazolyl, imidazolyl or Optionally substituted with R c .
  • each of Ra , Rb , and Rc is independently selected from halogen, C1 - C6 alkyl, -OC1 - C6 alkyl, C3- C 10 cycloalkyl or 4-10 membered heterocyclyl, wherein the C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R x .
  • each Ra , Rb , Rc is independently selected from halogen, C1 - C6 alkyl, -OC1 - C6 alkyl, C3 - C6 cycloalkyl or 4-6 membered heterocyclyl, and the C1 - C6 alkyl, -OC1 - C6 alkyl, C3 - C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with Rx .
  • each Ra , Rb , Rc is independently selected from C1 - C6 alkyl, -OC1 - C6 alkyl, C3 - C6 cycloalkyl, or 4-6 membered heterocyclyl, and the C1 - C6 alkyl, -OC1 - C6 alkyl, C3 - C6 cycloalkyl, or 4-6 membered heterocyclyl is optionally substituted with Rx .
  • each Ra , Rb , Rc is independently selected from CH3 , CH( CH3 ) 2 , -O- CH3 , cyclopropyl, oxetanyl, or tetrahydropyrrolyl, said CH3 , CH( CH3 ) 2 , -O- CH3 , cyclopropyl, oxetanyl, or tetrahydropyrrolyl being optionally substituted with Rx .
  • each Ra , Rb , Rc is independently selected from CH3 , CH( CH3 ) 2 , CF3 , -O- CH3 , -O- CHF2 , cyclopropyl, oxetanyl, or
  • each Ra is independently selected from -OC1 - C6 alkyl or C3 - C10 cycloalkyl, said -OC1 - C6 alkyl or C3-C10 cycloalkyl being optionally substituted with Rx .
  • each Ra is independently selected from -O- CH3 or cyclopropyl, which -O- CH3 or cyclopropyl is optionally substituted with Rx .
  • each Ra is independently selected from -O- CH3 , -O- CHF2 , or cyclopropyl.
  • each R c is independently selected from C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or 4-10 membered heterocyclyl, and the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with R x .
  • each R c is independently selected from CH 3 , CH(CH 3 ) 2 , cyclopropyl, oxetanyl, or tetrahydropyrrolyl, said CH 3 , CH(CH 3 ) 2 , cyclopropyl, oxetanyl, or tetrahydropyrrolyl being optionally substituted with R x .
  • each R c is independently selected from CH 3 , CH(CH 3 ) 2 , CF 3 , cyclopropyl, oxetanyl, or
  • R b , R c , and the atoms to which they are attached together form a 4-10 membered heterocyclyl, which is optionally substituted with R x .
  • R 1 and R 2 are independently selected from H, halogen, C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl is optionally substituted with R x .
  • R 1 and R 2 are both H.
  • R x is selected from halogen, NH 2 or C 1 -C 6 alkyl, said NH 2 or C 1 -C 6 alkyl optionally substituted with C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl.
  • R x is selected from halogen or C 1 -C 6 alkyl.
  • R x is selected from F or CH 3 .
  • the present disclosure also provides a compound selected from the following or a pharmaceutically acceptable salt thereof:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) or the above-mentioned compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for treating a disease mediated by USP1 in a mammal, comprising administering a therapeutically effective amount of formula (I) or the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.
  • the present disclosure provides use of formula (I) or the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a disease mediated by USP1.
  • the present disclosure provides use of formula (I) or the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a disease mediated by USP1.
  • the present disclosure provides formula (I) or the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a disease mediated by USP1.
  • the USP1-mediated disease is a tumor.
  • the tumor is, for example, a solid tumor, an adenocarcinoma, or a hematological tumor.
  • any embodiment of any aspect of the present invention may be combined with other embodiments without contradiction .
  • any technical feature in any embodiment of any aspect of the present invention may be applicable to the technical feature in other embodiments without contradiction.
  • tautomer refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present disclosure may exhibit tautomerism.
  • Tautomeric compounds may exist in two or more interconvertible species.
  • Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates.
  • the present disclosure includes all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.
  • the compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, non- Enantiomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention.
  • Substituents such as alkyl groups may contain additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms, and all of which are involved in the substituents and their mixtures are also within the definition of the compounds of the present invention.
  • the compounds of the present invention containing asymmetric atoms can be isolated in optically pure form or in racemic form, and the optically pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), polysubstituted (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2 , etc.) or fully substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3 , etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or cannot be synthesized will be introduced.
  • any variable eg, Ra , Rb
  • its definition at each occurrence is independent. For example, if a group is substituted with 2 Rb , each Rb has an independent option.
  • L 1 When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary.
  • L 1 When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary.
  • L 1 When L 1 is selected from “C 1 -C 3 alkylene-O", L 1 can connect ring Q and R 1 from left to right to form “ring QC 1 -C 3 alkylene-OR 1 ", or connect ring Q and R 1 from right to left to form “ring QOC 1 -C 3 alkylene-R 1 ".
  • Cm - Cn herein refers to an integer number of carbon atoms in the range of mn.
  • C1 - C10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 , which may be linear or branched.
  • C1 - C10 alkyl is understood to mean a linear or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, 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-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 1 -C 1 -C 1 -C 1 -C 1
  • C 1 -C 3 alkyl may be understood to mean a straight or branched saturated alkyl group having 1 to 3 carbon atoms.
  • the "C 1 -C 10 alkyl” may include a range such as “C 1 -C 6 alkyl” or “C 1 -C 3 alkyl”, and the “C 1 -C 6 alkyl” may further include a "C 1 -C 3 alkyl”.
  • deuterated alkyl means that hydrogen on an alkyl group is replaced by deuterium, including monodeuterated alkyl and polydeuterated alkyl.
  • C 1-6 deuterated alkyl means C 1-6 alkyl as defined above substituted by one or more deuterium, including but not limited to CD 3 , CH 2 CD 3 and the like.
  • alkenyl refers to an unsaturated fatty acid group consisting of a straight or branched chain of carbon and hydrogen atoms and having at least one double bond. Aliphatic hydrocarbon group.
  • C 2 -C 10 alkenyl is understood to mean a straight or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C 2 -C 10 alkenyl” is preferably "C 2 -C 6 alkenyl", further preferably "C 2 -C 4 alkenyl", and further preferably C 2 or C 3 alkenyl.
  • alkenyl contains more than one double bond
  • the double bonds may be separated or conjugated with each other.
  • alkenyl group 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, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-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.
  • C 2 -C 10 alkynyl may be understood to mean a straight or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • Examples of “C 2 -C 10 alkynyl” include, but are not limited to, ethynyl (-C ⁇ CH), propynyl (-C ⁇ CCH 3, -CH 2 C ⁇ CH), but-1-ynyl, but-2-ynyl or but-3-ynyl.
  • C 2 -C 10 alkynyl may include “C 2 -C 3 alkynyl", examples of “C 2 -C 3 alkynyl” include ethynyl (-C ⁇ CH), prop-1-ynyl (-C ⁇ CCH 3 ), prop-2-ynyl (-CH 2 C ⁇ CH).
  • cycloalkyl refers to a fully saturated carbocyclic ring that exists in the form of a monocyclic, cyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally a 3- to 10-membered ring.
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monocyclic, cyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like.
  • C 3 -C 10 cycloalkyl may include "C 3 -C 6 cycloalkyl".
  • C 3 -C 6 cycloalkyl may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms. Specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • cycloalkenyl refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally a 5- to 8-membered ring. Specific examples of the cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl, etc.
  • 3-10 membered heterocyclyl refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned in the ring atoms.
  • “3-10 membered heterocyclic group” includes “4-7 membered heterocyclic group”, wherein specific examples of 4 membered heterocyclic group include but are not limited to azetidinyl or oxetanyl; specific examples of 5 membered heterocyclic group include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclic group include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7 membered heterocyclic group include but
  • the heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrole-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include but are not limited to hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.
  • the heterocyclic group may be a benzo-fused ring group of the above 4-7-membered heterocyclic group, specific examples of which include but are not limited to dihydroisoquinolinyl and the like.
  • “4-10 membered heterocyclyl” may include “5-10 membered heterocyclyl", “4-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “6-8 membered heterocyclyl”, “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered heterocycloalkyl”, etc., and “4-7 membered heterocyclyl” may further include "4-6 membered heterocyclyl", “5-6 membered heterocyclyl”, “4-7 membered heterocycloalkyl”, “4-6 membered heterocycloalkyl”, "5-6 membered heterocycloalky
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group with a conjugated ⁇ electron system.
  • the aryl group may have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms.
  • C 6 -C 20 aryl is understood to mean an aryl group having 6 to 20 carbon atoms.
  • a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl; or a ring having 9 carbon atoms
  • C 6 -C 10 aryl is understood to mean an aryl group having 6 to 10 carbon atoms.
  • C 6 aryl a ring having 6 carbon atoms
  • C 9 aryl a ring having 9 carbon atoms
  • C 9 aryl a ring having 10 carbon atoms
  • C 10 aryl a ring having 13 carbon atoms
  • fluorenyl a ring having 14 carbon atoms
  • C 14 aryl a ring having 14 carbon atoms
  • C 6 -C 10 aryl is understood to mean an aryl group having 6 to 10 carbon atoms. In particular, it is a ring having 6 carbon atoms ("C 6 aryl”), for example phenyl; or a ring having 9 carbon atoms (“C 9 aryl”), for example indanyl or indenyl; or a ring having 10 carbon atoms (“C 10 aryl”), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • C 6 -C 20 aryl group may include "C 6 -C 10 aryl group”.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monocyclic or bicyclic aromatic ring systems: which have 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and which contain 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S.
  • the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or azinyl, in
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • terapéuticaally effective amount means an amount of a compound of the present disclosure that (i) treats a particular disease, condition or disorder, (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • the amount of a compound of the disclosure that constitutes a "therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on his or her knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or an organic acid, and a salt formed between a compound and an inorganic base or an organic base.
  • composition refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl , etc., respectively.
  • Certain isotopically labeled compounds of the present disclosure can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
  • Positron emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or sugar-coated core.
  • suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.
  • the daily dosage is 0.01 mg/kg to 200 mg/kg body weight, in the form of single or divided doses.
  • the ratio of mixed solvents is the volume ratio.
  • the eluent is 10%-75% acetonitrile-water
  • the volume ratio of acetonitrile to water in the gradient elution process is 10:90-75:25.
  • % refers to wt %.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 -6 (ppm).
  • the solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • THF tetrahydrofuran
  • Ti(OEt) 4 tetraethyl titanate
  • Toluene toluene
  • n-BuLi n-butyl lithium
  • EA ethyl acetate
  • DCM dichloromethane
  • DIEA N,N-diisopropylethylamine
  • Boc 2 O di-tert-butyl dicarbonate
  • m-CPBA m-chloroperbenzoic acid
  • DMF N,N-dimethylformamide
  • dioxane dioxane
  • CDI N,N'-carbonyldiimidazole
  • XPhos Pd G2 chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II); MeI: iodomethan
  • Example 1 7'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclobutane-1,4'-pyrimido[4,5-d]pyrimidin]-2'(3'H)-one (Compound 1)
  • Cyclobutanone 1A (10.0 g, 142.0 mmol) and intermediate 1B (15.7 g, 130 mmol) were dissolved in tetrahydrofuran (100 mL), and tetraethyl titanate (88.8 g, 389.0 mmol) was added to react at 50°C for 5 hours. Ice water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, and then saturated sodium bicarbonate aqueous solution (20.0 mL) was added and stirred for 1 hour.
  • Step 9 Synthesis of 7'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclobutane-1,4'-pyrimido[4,5-d]pyrimidin]-2'(3'H)-one (Compound 1)
  • the intermediate 1L (40.0 mg, 86.4 ⁇ mol), (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boric acid (36.8 mg, 190.0 ⁇ mol), potassium phosphate (55.0 mg, 259.0 ⁇ mol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (27.2 mg, 34.6 ⁇ mol) were added to a mixed solution of dioxane (1.0 mL) and water (50 uL). The resulting reaction solution was stirred at 100 ° C under nitrogen protection for 4 hours.
  • reaction solution was concentrated and the residue was purified by preparative chromatography (Waters Xbridge C 18 150*19 mm, 10 ⁇ m, eluent 10%-75% acetonitrile-water) to obtain the title compound 1 (14 mg, yield 28%).
  • intermediate 12A (8.8 g, 37.0 mmol), 2-iodopropane (12.6 g, 74.0 mmol), potassium carbonate (10.2 g, 74.0 mmol) and N,N-dimethylformamide (100 mL) were added to the reaction flask, and the resulting mixture was stirred at 60°C for 2 hours.
  • the reaction solution was poured into 200 mL of ice water and extracted with 100 mL of ethyl acetate three times.
  • the intermediate 12B (3.4 g, 12.2 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium aluminum hydride (924.1 mg, 24.4 mmol) was added in batches at 0°C. The resulting mixture was stirred at 0°C for 1 hour and then slowly returned to room temperature and continued to stir for 1 hour. After the reaction solution was cooled to 0°C, 0.1 mL of water, 0.1 mL of 15% sodium hydroxide aqueous solution and 0.2 mL of water were added in sequence. The resulting mixture was stirred at room temperature for 1 hour and then filtered through diatomaceous earth, and the filter cake was rinsed with dichloromethane. The filtrate was concentrated to obtain the intermediate 12C (3.4 g, yield: 100%), which was used directly in the next step. m/z (ESI): 284.1 [M + H] + .
  • the intermediate 12I (100.0 mg, 215.1 ⁇ mol) was added to anhydrous N,N-dimethylformamide (2 mL), followed by potassium carbonate (59.4 mg, 430.3 ⁇ mol) and iodomethane (61.1 mg, 430.3 ⁇ mol). The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was added to 20 mL of water and extracted with ethyl acetate three times (20 mL*3).
  • Step 8 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methyl-5,8-dihydropteroidine-6,7-dione (Compound 12)
  • intermediate 6I was used to replace intermediate 12C in step 3
  • intermediate 14M was used to replace (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid in step 8 to prepare compound 14.
  • Step 1 Synthesis of 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-nitropyrimidin-4-amine (15A)
  • Step 2 Synthesis of 2-chloro-N 4 -(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidine-4,5-diamine (15B)
  • compound 15A 0.5 g, 1.2 mmol
  • reduced iron powder 0.68 g, 12 mmol, 10 eq
  • ammonium chloride 0.65 g, 12 mmol, 10 eq
  • the resulting mixture was stirred at 80 ° C for 2 hours.
  • 50 mL of ethyl acetate was added to the reaction solution for dilution and filtered while hot. The filter cake was rinsed with ethyl acetate.
  • Step 5 Synthesis of 2-chloro-5-(methyl-d3)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (15F)
  • Step 6 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(methyl-d3)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridin-6(5H)-one (Compound 15)
  • step 1 Using a route and synthesis method similar to steps 1 to 6 in Example 9, the intermediate 1I in step 1 was replaced by compound D in the following table, and deuterated iodomethane was replaced by iodomethane to prepare the corresponding compounds 17-19 in the table.
  • intermediate 17AA (2.3 g, 7.2 mmol) to N,N-dimethylformamide (20 mL), then add palladium acetate (161.1 mg, 719.1 ⁇ mol), triphenylphosphine (377.2 mg, 1.4 mmol), intermediate 17AB (1.06 g, 10.8 mmol), triethylamine (1.45 g, 14.4 mmol), stir evenly, and react at 100 ° C for 3 hours.
  • intermediate 17AC (1.54 g, 4.9 mmol) was added to ethanol (20 mL), and palladium hydroxide (150.0 mg) and palladium carbon (150.0 mg) were added, stirred evenly, replaced with hydrogen three times, and stirred at room temperature for 3 hours under hydrogen atmosphere.
  • the reaction liquid was filtered and the filtrate was concentrated to obtain the crude intermediate 17AD (1.1 g, yield: 65%), which was directly used for the next step reaction.
  • the intermediate 17AE (300.0 mg, 876.0 ⁇ mol) was added to N,N-dimethylformamide (10 mL), and then cesium carbonate (570.0 mg, 1.7 mmol) was added, and the temperature was raised to 100°C, and the reaction was stirred for 1 hour.
  • the intermediate 18AA (3.6 g, 20 mmol) was added to 20 mL of hexafluoroisopropanol, and triethylamine (5.1 g, 50.5 mmol) and the intermediate 18AB (2.5 g, 20 mmol) were added.
  • the resulting mixture was heated to 70°C and stirred for 1 hour.
  • the reaction solution was concentrated, and 50 mL of water was added, and extracted with ethyl acetate (30 mL*3).
  • the organic phases were combined and concentrated under reduced pressure.
  • intermediate 19AA (3.6 g, 20 mmol) to a mixed solvent of 5 mL water and 25 mL tetrahydrofuran, and add sodium bicarbonate (3.5 g, 41.6 mmol). After stirring for 30 minutes, add intermediate 19AB (3.2 g, 20 mmol). After the resulting mixture reacts at room temperature for 30 minutes, it is heated to 70°C and stirred for 30 minutes.
  • Example 12 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(1-(oxetane-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (Compound 20)
  • Step 1 Synthesis of ethyl 2-chloro-4-((4-(1-(oxetane-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine-5-carboxylate (20C)
  • ethyl 2,4-dichloropyrimidine-5-carboxylate (220 mg, 1.0 mmol, 1.0 eq) was dissolved in acetonitrile (10 mL), and then (4-(1-(oxetane-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methylamine 20B (300 mg, 1.0 mmol, 1.0 eq) and triethylamine (200 mg, 2.0 mmol, 2.0 eq) were added in sequence. The resulting mixture was stirred at room temperature for 10 hours.
  • Step 2 Synthesis of 2-(2-chloro-4-((4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)propan-2-ol (20D)
  • the intermediate 20C (0.3 g, 0.62 mmol) was dissolved in tetrahydrofuran (10 mL), and then methylmagnesium bromide (3.0 M, 1.75 mL) was added in batches under ice bath conditions, and the reaction was kept under ice bath conditions overnight. Water (10 mL) was added to quench, and ethyl acetate (10 mL*3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure.
  • Step 3 Synthesis of 7-chloro-1-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,4-dimethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (20E)
  • N,N'-Carbonyldiimidazole (0.18g, 1.1mmol) was dissolved in dichloromethane (2.0mL), followed by the addition of diisopropylethylamine (0.16g, 1.2mmol, 0.21mL), and then intermediate 20D (0.18g, 38.5mmol), and the reaction was stirred overnight at room temperature.
  • Ammonium chloride solution (10mL) was added to quench, followed by extraction with dichloromethane (10mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure.
  • Step 4 Synthesis of 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (Compound 20)
  • compound 20E 75 mg, 0.15 mmol
  • (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid 1M 62 mg, 0.32 mmol
  • 1,4-dioxane 3.0 mL
  • 0.5 mL of water was added, followed by tris(bisbenzylideneacetone)bispalladium (83 mg, 0.091 mmol, 0.1 eq), tricyclohexylphosphine (51 mg, 0.18 mmol), and potassium carbonate (0.38 g, 2.7 mmol).
  • the resulting mixture was subjected to microwave reaction at 100 °C under nitrogen atmosphere for 30 minutes.
  • Example 13 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(1-(1-methylpyrrolidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (Compound 21)
  • the intermediate 21BA (2.8 g, 11.7 mmol) was dissolved in N,N-dimethylformamide (20.0 mL), and then the intermediate 21BB (3.0 g, 11.7 mmol) and potassium carbonate (4.9 g, 35.3 mmol) were added and reacted at 80°C for 12 h.
  • reaction solution was filtered, and the residue obtained after the filtrate was concentrated was purified by reverse phase C18 silica gel column (eluent: 5-50% acetonitrile aqueous solution) to obtain intermediate 21B (200 mg, yield: 50%).
  • Example 14 7-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazine (Compound 22)
  • intermediate 22A was prepared by replacing intermediate 20B with intermediate 1I in step 1. Then, using a synthetic method similar to step 4 in Example 12, intermediate 22A was replaced with intermediate 20E to prepare intermediate 22B.
  • Test Example 1 USP1 enzyme in vitro activity detection experiment
  • the USP1 enzyme (Recombinant human his6-USP1/His6-UAF1 Complex Protein, CF) used in the experiment was purchased from R&D, catalog number E-568-050. Store at -80°C after aliquoting.
  • the detection kit (Ub-CHOP2-Reporter Deubiquitination Assay Kit) was purchased from Lifesensors, with the catalog number PR1101. It was stored at -80°C after aliquoting.
  • the kit contains a ubiquitinated reporter enzyme, which becomes active after being deubiquitinated by USP1/UAF1. After catalyzing the substrate, the substrate is excited by a 485nm laser to generate an emission light signal of 531nm.
  • the test compound was dissolved in DMSO to 10 mM.
  • the compound and pure DMSO were added to each well of a 384-well plate using a compound dilution and sample pipetting instrument. The highest concentration started from 3 ⁇ M, and the sample was diluted 3 times for a total of 8 concentration points. 50 nL of the test compound or DMSO (as a control) was added to each well. The instrument used different ratios to obtain the gradient dilution sample concentration.
  • the enzyme was diluted with a freshly prepared reaction solution (20 mM Tris-HCl (pH 8.0), 2 mM CaCl 2 , 2 mM ⁇ -mercaptoethanol, 0.05% CHAPS (CHAPS was diluted with ddH 2 O)).
  • x represents the logarithmic form of the compound concentration
  • A, B, C and D are four parameters.
  • the IC50 value is further calculated using Xlfit as the compound concentration required for 50% enzyme activity inhibition in the best fitting curve.
  • Test Example 2 USP1 inhibitor inhibition experiment on MDA-MB-436 cell proliferation:
  • MDA-MB-436 The cells used in the experiment, MDA-MB-436, were purchased from Kebai Biotechnology Co., Ltd., with the catalog number CBP60385. The cells were subcultured with DMEM medium (containing 10% FBS), and frozen in liquid nitrogen when the cell generation number was low. The cells used in the experiment did not exceed 15 generations.
  • Luminescent Cell Viability Assay was purchased from Promega under the catalog number G7573. Store at -30°C after aliquoting.
  • the kit is a homogenous assay for detecting the number of viable cells in culture by quantitatively measuring ATP.
  • the luminescent signal produced by the kit is proportional to the amount of ATP present, which is directly proportional to the number of cells in the culture.
  • the cultured cells were digested with 0.25% Trypsin-EDTA Solution, collected and centrifuged, and resuspended with culture medium DMEM (containing 10% FBS) to adjust the concentration.
  • the cells were seeded on a 384-well plate (400 cells/20 ⁇ L/well) and cultured overnight in a cell culture incubator at 37°C and 5% CO 2.
  • the compounds and pure DMSO were added to each well of the 384-well plate using an ECHO instrument. The highest concentration started from 10 ⁇ M, and the concentration was diluted 4 times, with a total of 8 concentration points. 100nL of the test compound or DMSO (as a control) was added to each well.
  • the instrument obtained the gradient dilution sample concentration through different ratios.
  • the chemiluminescent value [RLU] background on day 0 was obtained by CTG test on day 0 of the drug-free DMSO-added group in parallel.
  • the inhibition rate (Inhibition rate, %) of the compound on proliferation [1-([RLU] cpd.–[RLU] background)/([RLU] cell–[RLU] background)] ⁇ 100%, and the inhibitory activity GI 50 value of the compound on proliferation was calculated using the four-parameter Logistic Model method.
  • x represents the logarithmic form of the compound concentration
  • A, B, C and D are four parameters.
  • GI50 values were further calculated using Xlfit as the compound concentration required for 50% inhibition of proliferation in the best-fit curve.
  • the inhibitory activity of the disclosed compounds on MDA-MB-436 proliferation was determined by the above test, and the measured GI 50 values are shown in Table 2.

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Abstract

本公开公开了作为USP1抑制剂的式(I)化合物或其药学上可接受的盐，包含所述化合物或其药学上可接受的盐的药物组合物，以及它们在预防或治疗由USP1介导的疾病中的用途。

Description

杂环并嘧啶类化合物、药物组合物及其应用
本公开要求2022年10月09日向中国国家知识产权局提交的，专利申请号为202211229728.2，发明名称为“杂环并嘧啶类化合物、药物组合物及其应用”的在先申请的优先权，上述在先申请的全文通过引用的方式结合于本公开中。
技术领域
本公开属于医药技术领域，涉及一类杂环并嘧啶类化合物，或其药学上可接受的盐，含有它们的药物组合物以及作为泛素特异性蛋白酶1(USP1)抑制剂在预防或治疗与USP1相关的疾病中的用途。
背景技术
泛素化是一个可逆的过程，它涉及一系列去泛素化酶(DUBs)，通过将底物去泛素化来调控多种细胞过程。DUBs由大约100个人类基因编码，分为6个家族，其中最大的家族是拥有50多个成员的泛素特异性蛋白酶(USPs)。DUBs和它们的底物蛋白在癌症中经常失调，这个现象支持了靶向特定DUB酶可以通过提高致癌底物的泛素化和降解及调控参与肿瘤的生长、生存、分化和肿瘤微环境维护的其他关键蛋白质的活性这一假说(Hussain,S.,et.al.,"DUBs and cancer:The role of deubiquitinating enzymes as oncogenes,non-oncogenes and tumor suppressors."Cell Cycle 8,1688-1697(2009))。
泛素特异性蛋白酶1(USP1)是DUBs中USP亚家族的半胱氨酸异肽酶。全长的人类USP1由785个氨基酸组成，包括一个由Cys90、His593和Asp751组成的催化三元组(Nijman,S.M.B.,et al."The deubiquitinating enzyme USP1 regulates the fanconi anemia pathway."Mol.Cell 17,331-339(2005))。USP1在DNA损伤修复中发挥作用。USP1自身相对不活跃，只有与辅助因子UAF1结合形成去泛素化酶活性所需的复合体才能获得完整的酶活性。USP1/UAFl复合物去泛素化的单泛素化PCNA(proliferating cell nuclear antigen)和单泛素化的FANCD2(Fanconi anemia complementation group D2)，这两种蛋白分别在转译合成(TLS)和范科尼贫血(Fanconi anemia,FA)通路中发挥重要作用。这两种途径是修复DNA交联剂如顺铂和丝裂霉素C(MMC)引起的DNA损伤所必需的。USP1/UAF1复合物也去泛素化FANCI(Fanconi anemia complementation group I)。这些发现的重要性进一步通过实验证实，即缺乏USP1的小鼠对DNA损伤高度敏感。有趣的是，USP1的表达在许多癌症中被显著增加。阻断USP1以抑制DNA修复，可以在多发性骨髓瘤细胞中诱导细胞凋亡，也可以增强肺癌细胞对顺铂的敏感性。这些表明，USP1是某些癌症的化学疗法的有希望的靶标。
综上所述，靶向抑制USP1蛋白是一种潜在的预防或治疗癌症和其他疾病的方法。因此，开发USP1的小分子抑制剂是必要的。
发明内容
一方面，本公开提供了式(I)所示化合物或其药学上可接受的盐，
其中，
选自以下结构:
R3a、R3b、R4、R5a、R5b各自独立地选自H、卤素、CN、OH、NH2、-C(O)ORx、-C(O)Rx、-NHC(O)Rx、-O-C1-C6烷基、C1-C6氘代烷基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基或4-10元杂环基，所述NH2、-O-C1-C6烷基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基或4-10元杂环基任选地被Rx取代；
或者R3a、R3b与其连接的碳原子共同形成C3-C10环烷基或4-10元杂环基，所述C3-C10环烷基或4-10元杂环基任选地被Rx取代；
或者R5a、R5b与其连接的碳原子共同形成C3-C10环烷基或4-10元杂环基，所述C3-C10环烷基或4-10元杂环基任选地被Rx取代；
环A选自C6-C10芳基或5-10元杂芳基，所述C6-C10芳基或5-10元杂芳基任选地被Ra取代；
环B选自C6-C10芳基、5-10元杂芳基、4-10元杂环基、C4-C10环烯基或C3-C10环烷基，所述C6-C10芳基、5-10元杂芳基、4-10元杂环基、C4-C10环烯基或C3-C10环烷基任选地被Rb取代；
环C选自C6-C10芳基、5-10元杂芳基或4-10元杂环基，所述C6-C10芳基、5-10元杂芳基或4-10元杂环基任选地被Rc取代；
每一个Ra、Rb、Rc各自独立地选自卤素、CN、OH、NH2、-C(O)ORx、-C(O)Rx、C1-C6烷基、-O-C1-C6烷基、C3-C10环烷基或4-10元杂环基，所述NH2、C1-C6烷基、-O-C1-C6烷基、C3-C10环烷基或4-10元杂环基任选地被Rx取代；
或者，Rb、Rc与其连接的原子共同形成C4-C10环烯基或4-10元杂环基，所述C4-C10环烯基或4-10元杂环基任选地被Rx取代；
R1、R2独立地选自H、卤素、CN、OH、NH2、C1-C6烷基、C3-C10环烷基或4-10元杂环基，所述OH、NH2、C1-C6烷基、C3-C10环烷基或4-10元杂环基任选地被Rx取代；
或者，R1、R2与其连接的原子共同形成C3-C10环烷基或4-7元杂环基，所述C3-C10环烷基或4-7元杂环基任选地被Rx取代；
Rx选自卤素、CN、OH、NH2或C1-C6烷基，所述OH、NH2或C1-C6烷基任选地被C1-C6烷基、C3-C10环烷基或4-7元杂环基取代；
条件是，当选自时，R5a选自卤素、CN、OH、NH2、-C(O)ORx、-C(O)Rx、-O-C1-C6烷基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基或4-9元杂环基，所述NH2、-O-C1-C6烷基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基或4-9元杂环基任选地被Rx取代；
或者，R5a、R5b与其连接的碳原子形成C4-C10环烷基或4-9元杂环基，所述的C4-C10环烷基或4-9元杂环基任选地被Rx取代。
在一些实施方案中，R3a、R3b、R4、R5a、R5b独立地选自H、-C(O)ORx、-C(O)Rx、-O-C1-C6烷基、C1-C6氘代烷基、C1-C6烷基、C3-C10环烷基或4-10元杂环基，所述-O-C1-C6烷基、C1-C6烷基、C3-C10环烷基或4-10元杂环基任选地被Rx取代。
在一些实施方案中，R3a、R3b、R4、R5a、R5b独立地选自H、C1-C6氘代烷基、C1-C6烷基或C3-C10环烷基，所述C1-C6烷基或C3-C10环烷基任选地被Rx取代。
在一些实施方案中，R3a、R3b、R4、R5a、R5b独立地选自H、CH3、CD3或环丙基。
在一些实施方案中，R3a、R3b独立地选自H、C1-C6氘代烷基或C1-C6烷基，所述C1-C6烷基任选地被Rx取代。
在一些实施方案中，R4选自H或C1-C6烷基，所述C1-C6烷基任选地被Rx取代。
在一些实施方案中，R5a选自卤素、CN、OH、NH2、-C(O)ORx、-C(O)Rx、-O-C1-C6烷基、C1-C6氘代烷基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基或4-9元杂环基，所述NH2、-O-C1-C6烷基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基或4-9元杂环基任选地被Rx取代。
在一些实施方案中，R5a选自C1-C6氘代烷基、C1-C6烷基或C3-C10环烷基，所述C1-C6烷基或C3-C10环烷基任选地被Rx取代。
在一些实施方案中，R5b选自H或C1-C6烷基，所述C1-C6烷基任选地被Rx取代。
在一些实施方案中，R5a、R5b与其连接的碳原子形成C3-C10环烷基，所述的C3-C10环烷基任选地被Rx取代。
在一些实施方案中，R5a、R5b与其连接的碳原子形成C4-C10环烷基，所述的C4-C10环烷基任选地被Rx取代。
在一些实施方案中，R5a、R5b与其连接的碳原子形成C4-C6环烷基，所述的C4-C6环烷基任选地被Rx取代。
在一些实施方案中，R5a、R5b与其连接的碳原子形成环丁基，所述环丁基任选地被Rx取代。
在一些实施方案中，选自以下结构:
在一些实施方案中，选自以下结构:
在一些实施方案中，环A选自5-10元杂芳基，所述5-10元杂芳基任选地被Ra取代。
在一些实施方案中，环A选自5-6元杂芳基，所述5-6元杂芳基任选地被Ra取代。
在一些实施方案中，环A选自嘧啶基，所述嘧啶基任选地被Ra取代。
在一些实施方案中，环B选自C6-C10芳基或5-10元杂芳基，所述C6-C10芳基或5-10元杂芳基任选地被Rb取代。
在一些实施方案中，环B选自C6-C10芳基，所述C6-C10芳基任选地被Rb取代。
在一些实施方案中，环B选自苯基，所述苯基任选地被Rb取代。
在一些实施方案中，环B选自苯基。
在一些实施方案中，环C选自5-10元杂芳基或4-10元杂环基，所述5-10元杂芳基或4-10元杂环基任选地被Rc取代。
在一些实施方案中，环C选自5-6元杂芳基或4-8元杂环基，所述5-6元杂芳基或4-8元杂环基任选地被Rc取代。
在一些实施方案中，环C选自吡唑基、咪唑基或所述吡唑基、咪唑基或任选地被Rc取代。
在一些实施方案中，每一个Ra、Rb、Rc独立地选自卤素、C1-C6烷基、-O-C1-C6烷基、C3- C10环烷基或4-10元杂环基，所述C1-C6烷基、-O-C1-C6烷基、C3-C10环烷基或4-10元杂环基任选地被Rx取代。
在一些实施方案中，每一个Ra、Rb、Rc独立地选自卤素、C1-C6烷基、-O-C1-C6烷基、C3-C6环烷基或4-6元杂环基，所述C1-C6烷基、-O-C1-C6烷基、C3-C6环烷基或4-6元杂环基任选地被Rx取代。
在一些实施方案中，每一个Ra、Rb、Rc独立地选自C1-C6烷基、-O-C1-C6烷基、C3-C6环烷基或4-6元杂环基，所述C1-C6烷基、-O-C1-C6烷基、C3-C6环烷基或4-6元杂环基任选地被Rx取代。
在一些实施方案中，每一个Ra、Rb、Rc独立地选自CH3、CH(CH3)2、-O-CH3、环丙基、氧杂环丁基或四氢吡咯基，所述CH3、CH(CH3)2、-O-CH3、环丙基、氧杂环丁基或四氢吡咯基任选地被Rx取代。
在一些实施方案中，每一个Ra、Rb、Rc独立地选自CH3、CH(CH3)2、CF3、-O-CH3、-O-CHF2、环丙基、氧杂环丁基或
在一些实施方案中，每一个Ra独立地选自-O-C1-C6烷基或C3-C10环烷基，所述-O-C1-C6烷基或C3-C10环烷基任选地被Rx取代。
在一些实施方案中，每一个Ra独立地选自-O-CH3或环丙基，所述-O-CH3或环丙基任选地被Rx取代。
在一些实施方案中，每一个Ra独立地选自-O-CH3、-O-CHF2或环丙基。
在一些实施方案中，每一个Rc独立地选自C1-C6烷基、C3-C10环烷基或4-10元杂环基，所述C1-C6烷基、C3-C10环烷基或4-10元杂环基任选地被Rx取代。
在一些实施方案中，每一个Rc独立地选自CH3、CH(CH3)2、环丙基、氧杂环丁基或四氢吡咯基，所述CH3、CH(CH3)2、环丙基、氧杂环丁基或四氢吡咯基任选地被Rx取代。
在一些实施方案中，每一个Rc独立地选自CH3、CH(CH3)2、CF3、环丙基、氧杂环丁基或
在一些实施方案中，Rb、Rc以及它们所连接的原子共同形成4-10元杂环基，所述4-10元杂环基任选地被Rx取代。
在一些实施方案中，R1、R2独立地选自H、卤素、C1-C6烷基或C3-C10环烷基，所述C1-C6烷基或C3-C10环烷基任选地被Rx取代。
在一些实施方案中，R1和R2均为H。
在一些实施方案中，Rx选自卤素、NH2或C1-C6烷基，所述NH2或C1-C6烷基任选地被C1-C6烷基、C3-C10环烷基或4-7元杂环基取代。
在一些实施方案中，Rx选自卤素或C1-C6烷基。
在一些实施方案中，Rx选自F或CH3。
本公开还提供了选自以下的化合物或其药学上可接受的盐：

另一方面，本公开提供药物组合物，其包含本公开式(I)或上述化合物或其药学上可接受的盐和药学上可接受的辅料。
另一方面，本公开提供治疗哺乳动物由USP1介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式(I)或上述化合物或其药学上可接受的盐、或其药物组合物。
另一方面，本公开提供式(I)或上述化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗由USP1介导的疾病的药物中的用途。
另一方面，本公开提供式(I)或上述化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗由USP1介导的疾病中的用途。
另一方面，本公开提供预防或者治疗由USP1介导的疾病的式(I)或上述化合物或其药学上可接受的盐、或其药物组合物。
在一些实施方案中，所述USP1介导的疾病为肿瘤。
在一些实施方案中，所述肿瘤例如实体瘤、腺癌或血液学肿瘤。
本发明的任一方面的任一实施方案，在不出现矛盾的前提下，均可以与其他实施方案进行组合。此外，在本发明任一方面的任一实施方案中，在不出现矛盾的前提下，任一技术特征可以适用于其他实施方案中的该技术特征。术语定义和说明
除非另有说明，本公开中所用的术语具有下列含义，本公开中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
本文中表示连接位点。
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚楔键表示一个立体中心的绝对构型，用黑实键和虚键表示一个立体中心的相对构型(如脂环化合物的顺反构型)。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本公开化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本公开包含化合物的所有互变异构形式。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和非对映异构体。
本公开的化合物可以具有不对称原子如碳原子、硫原子、氮原子、磷原子或不对称双键，因此本公开的化合物可以存在特定的几何或立体异构体形式。特定的几何或立体异构体形式可以是顺式和反式异构体、E型和Z型几何异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非 对映异构体、(D)-异构体、(L)-异构体，以及其外消旋混合物或其它混合物，例如对映异构体或非对映体富集的混合物，以上所有这些异构体以及它们的混合物都属于本公开化合物的定义范围之内。烷基等取代基中可存在另外的不对称碳原子、不对称硫原子、不对称氮原子或不对称磷原子，所有取代基中涉及到的这些异构体以及它们的混合物，也均包括在本公开化合物的定义范围之内。本公开的含有不对称原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来，光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，是指乙基可以是未被取代的(CH2CH3)、单取代的(CH2CH2F、CH2CH2Cl等)、多取代的(CHFCH2F、CH2CHF2、CHFCH2Cl、CH2CHCl2等)或完全被取代的(CF2CF3、CF2CCl3、CCl2CCl3等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
当任何变量(例如Ra、Rb)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，如果一个基团被2个Rb所取代，则每个Rb都有独立的选项。
当本文中涉及到的连接基团若没有指明其连接方向，则其连接方向是任意的。例如当结构单元中的L1选自“C1-C3亚烷基-O”时，此时L1既可以按照与从左到右的方向连接环Q和R1构成“环Q-C1-C3亚烷基-O-R1”，也可以按照从右到左的方向连接环Q和R1构成“环Q-O-C1-C3亚烷基-R1”。
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元表示R5可在苯环上的任意一个位置发生取代。
本文中的Cm-Cn是指具有m-n范围中的整数个碳原子。例如“C1-C10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
术语“烷基”是指通式为CnH2n+1的烃基，该烷基可以是直链或支链的。术语“C1-C10烷基”可理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和烃基。所述烷基的具体实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等；术语“C1-C6烷基”可理解为表示具有1至6个碳原子的烷基，具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等。术语“C1-C3烷基”可理解为表示具有1至3个碳原子的直链或支链饱和烷基。所述“C1-C10烷基”可以包含“C1-C6烷基”或“C1-C3烷基”等范围，所述“C1-C6烷基”可以进一步包含“C1-C3烷基”。
术语“氘代烷基”是指烷基上的氢被氘取代，包括单氘代烷基和多氘代烷基。例如，术语“C1-6氘代烷基”意指被一个或多个氘取代的如上所定义的C1-6烷基，包括但不仅限于CD3、CH2CD3等等。
术语“烯基”是指由碳原子和氢原子组成的直链或支链的且具有至少一个双键的不饱和脂 肪族烃基。术语“C2-C10烯基”可理解为表示直链或支链的不饱和烃基，其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子，“C2-C10烯基”优选“C2-C6烯基”，进一步优选“C2-C4烯基”，更进一步优选C2或C3烯基。可理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或共轭。所述烯基的具体实例包括但不限于乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基或(Z)-1-甲基丙-1-烯基等。
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。术语“C2-C10炔基”可理解为表示直链或支链的不饱和烃基，其包含一个或多个三键并且具有2、3、4、5、6、7、8、9或10个碳原子。“C2-C10炔基”的实例包括但不限于乙炔基(-C≡CH)、丙炔基(-C≡CCH3、-CH2C≡CH)、丁-1-炔基、丁-2-炔基或丁-3-炔基。“C2-C10炔基”可以包含“C2-C3炔基”，“C2-C3炔基”实例包括乙炔基(-C≡CH)、丙-1-炔基(-C≡CCH3)、丙-2-炔基(-CH2C≡CH)。
术语“环烷基”是指完全饱和的且以单环、并环、桥环或螺环等形式存在的碳环。除非另有指示，该碳环通常为3至10元环。术语“C3-C10环烷基”可理解为表示饱和的单环、并环、螺环或桥环，其具有3、4、5、6、7、8、9或10个碳原子。所述环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基，降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、螺[4.5]癸烷基等。术语“C3-C10环烷基”可以包含“C3-C6环烷基”，术语“C3-C6环烷基”可理解为表示饱和的单环或双环烃环，其具有3、4、5或6个碳原子，具体实例包括但不限于环丙基、环丁基、环戊基或环己基等。
术语“环烯基”是指不完全饱和的且以单环、并环、桥环或螺环等形式存在的非芳香族碳环。除非另有指示，该碳环通常为5至8元环。所述环烯基的具体实例包括但不限于环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基或环庚二烯基等。
术语“杂环基”是指完全饱和的或部分饱和的(整体上不是具有芳香性的杂芳族)单环、并环、螺环或桥环基团，其环原子中含有1、2、3、4或5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O)2-、-S(＝O)-、-P(＝O)2-、-P(＝O)-、-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-或-NHC(＝O)NH-等。术语“3-10元杂环基”是指环原子数目为3、4、5、6、7、8、9或10的杂环基，且其环原子中含有1、2、3、4或5个独立选自上文所述的杂原子或杂原子团。“3-10元杂环基”包括“4-7元杂环基”，其中，4元杂环基的具体实例包括但不限于氮杂环丁烷基或氧杂环丁烷基；5元杂环基的具体实例包括但不限于四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、4,5-二氢噁唑基或2,5-二氢-1H-吡咯基；6元杂环基的具体实例包括但不限于四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、三噻烷基、四氢吡啶基或4H-[1,3,4]噻二嗪基；7元杂环基的具体实例包括但不限于二氮杂环庚烷基。所述杂环基还可以是双环基，其中，5,5元双环基的具体实例包括但不限于六氢环戊并[c]吡咯-2(1H)-基；5,6元双环基的具体实例包括但不限于六氢吡咯并[1,2-a]吡嗪-2(1H)-基、5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪基或5,6,7,8-四氢咪唑并[1,5-a]吡嗪基。任选地，所述杂环基可以是上述4-7元杂环基的苯并稠合环基，具体实例包括但不限于二氢异喹啉基等。“4-10元杂环基”可以包含“5-10元杂环基”、“4-7元杂环基”、“5-6元杂环基”、“6-8元杂环基”、“4-10元杂环烷基”、“5-10元杂环烷基”、“4-7元杂环烷基”、“5-6元杂环烷基”、“6-8元杂环烷基”等范围，“4-7元杂环基”进一步可以包含“4-6元杂环基”、“5-6元杂环基”、“4-7元杂环烷基”、“4-6元杂环烷基”、“5-6元杂环烷基”等范围。本公开中尽管有些双环类杂环基部分地含有一个苯环或一个杂芳环，但所述杂环基整体上仍是无芳香性的。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。术语“C6-C20芳基”可理解为具有6～20个碳原子的芳基。特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或者具有9个碳原子 的环(“C9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基；或者具有13个碳原子的环(“C13芳基”)，例如芴基；或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。术语“C6-C10芳基”可理解为具有6～10个碳原子的芳基。特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或者具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基。术语“C6-C20芳基”可以包含“C6-C10芳基”。
术语“杂芳基”是指具有芳香性的单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C的芳香环基。术语“5-10元杂芳基”可理解为包括这样的单环或双环芳族环系：其具有5、6、7、8、9或10个环原子，特别是5或6或9或10个环原子，且其包含1、2、3、4或5个，优选1、2或3个独立选自N、O和S的杂原子。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基或噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并***基、吲唑基、吲哚基或异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基等以及它们的苯并衍生物，例如喹啉基、喹唑啉基或异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基或吩噁嗪基等。术语“5-6元杂芳基”指具有5或6个环原子的芳族环系，且其包含1-3个，优选1-2个独立选自N、O和S的杂原子。
术语“卤”或“卤素”是指氟、氯、溴或碘。
术语“治疗有效量”意指：(i)治疗特定疾病、病况或病症，(ii)减轻、改善或消除特定疾病、病况或病症的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或病症的一种或多种症状发作的本公开化合物的用量。
构成“治疗有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指药学上可接受的酸或碱的盐，包括化合物与无机酸或有机酸形成的盐，以及化合物与无机碱或有机碱形成的盐。
术语“药物组合物”是指一种或多种本公开的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本公开的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising可理解为开放的、非排他性的意义，即“包括但不限于”。
本公开还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。
某些同位素标记的本公开化合物(例如用3H及14C标记)可用于化合物和/或底物组织分布分析中。氚化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本公开化合物。
本公开的药物组合物可通过将本公开的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本公开化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本公开的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本公开的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本文所述的式(Ⅰ)化合物或上述化合物或其药学上可接受的盐的所有施用方法中，每天给药的剂量为0.01mg/kg到200mg/kg体重，以单独或分开剂量的形式。
具体实施方式
下面通过实施例对发明进行详细描述，但并不意味着对本公开的任何不利限制。本文已经详细地描述了本公开，其中也公开了其具体实施方式，对本领域的技术人员而言，在不脱离本公开精神和范围的情况下针对本公开具体实施方式进行各种改变和改进将是显而易见的。本公开所使用的所有试剂是市售的，无需进一步纯化即可使用。
除非另作说明，混合溶剂表示的比例是体积混合比例。如“洗脱剂为10％-75％的乙腈-水”表示梯度洗脱过程中，乙腈与水的体积用量比为10:90-75:25。
除非另作说明，否则，％是指wt％。
化合物经手工或软件命名，市售化合物采用供应商目录名称。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10-6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)；“IC50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。
缩略词：
THF：四氢呋喃；Ti(OEt)4：钛酸四乙酯；Toluene：甲苯；n-BuLi：正丁基锂；EA：乙酸乙酯；DCM：二氯甲烷；DIEA：N,N-二异丙基乙胺；Boc2O：二碳酸二叔丁酯；m-CPBA：间氯过氧苯甲酸；DMF：N,N-二甲基甲酰胺；dioxane：二氧六环；CDI：N,N'-羰基二咪唑；XPhos Pd G2：氯(2-二环己基膦基-2,4,6-三异丙基-1,1-联苯基)[2-(2-氨基-1,1-联苯)]钯(II)；MeI：碘甲烷；Cs2CO3：碳酸铯；2-iodo-propane：2-碘丙烷；LiAlH4：氢化铝锂；Acetone：丙酮；EtOH：无水乙醇；TEA或Et3N：三乙胺；CD3I：氘代碘甲烷；Pd(OAc)2：醋酸钯；PPh3：三苯基膦；Pd(OH)2：氢氧化钯；SOCl2：氯化亚砜；HFIP：六氟异丙醇；KF：氟化钾；MeCN或CH3CN：乙腈；MeMgBr：甲基溴化镁；Pd2(dba)3：三(双亚苄基丙酮)双钯；PCy3：三环己基膦；TsOH：对甲苯磺酸；CH2O：甲醛。
实施例1：7'-(4-环丙基-6-甲氧基嘧啶-5-基)-1'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-1'H-螺[环丁烷-1,4'-嘧啶并[4,5-d]嘧啶]-2'(3'H)-酮(化合物1)
步骤1：中间体1C的合成
将环丁酮1A(10.0g,142.0mmol)和中间体1B(15.7g,130mmol)溶于四氢呋喃(100mL)中，再加入钛酸四乙酯(88.8g,389.0mmol)于50℃下反应5小时。向反应液中加入冰水(100mL)和乙酸乙酯(100mL)，然后再加入饱和碳酸氢钠水溶液(20.0mL)搅拌1小时。将所得混合物过滤，滤饼用乙酸乙酯洗涤，滤液用无水硫酸钠干燥，过滤，浓缩得粗品后，经过硅胶柱纯化(洗脱剂为石油醚：乙酸乙酯＝10:1-3:1)得到中间体1C(13g,收率58％)。
步骤2：中间体1E的合成
将化合物1D(1.5g,6.4mmol)溶于甲苯(12.0mL)中，氮气置换3次，于-78℃下逐滴加入正丁基锂(1.6M,4.7mL)，-78℃下反应5min，然后将中间体1C(1.0g,5.8mmol)溶于甲苯(12.0mL)中并逐滴加入到上述反应液中，于-78℃下搅拌反应30min。反应液直接浓缩，所得粗品经硅胶柱纯化(洗脱剂为二氯甲烷：甲醇＝100:1-10:1)得到中间体1E(0.9g,收率47％)。m/z(ESI):334.1[M+H]+.
步骤3：中间体1F的合成
将中间体1E(300mg,898μmol)溶于盐酸-乙酸乙酯(2.0mol/L，3.0mL)中，于室温反应1小时。反应液加入乙酸乙酯(10mL)稀释，然后加入水(20mL)萃取，将分离所得水相用饱和碳酸钠溶液调节到pH＝9,再用乙酸乙酯(15mL*3)萃取。所得有机相经无水硫酸钠干燥后，过滤，浓缩得到粗品化合物1F(300mg,粗品)，可以直接用于下一步。
步骤4：中间体1G的合成
加入上一步制备得到的中间体1F(300.0mg,约0.90mmol)溶于二氯甲烷(3.0mL)中，再加入N,N-二异丙基乙胺(422.0mg,568.0μL)和二碳酸二叔丁酯(570.0mg,600.0μL)。所得混合物于室温搅拌反应2小时。将反应液直接浓缩，残留物经硅胶柱纯化(洗脱剂为石油醚：乙酸乙酯＝100:1-10:1)得到中间体1G(280mg,收率94％)。m/z(ESI):330.1[M+H]+.
步骤5：中间体1H的合成
将中间体1G(280.0mg,0.85mmol)溶于二氯甲烷(3.0mL)中，加入间氯过氧苯甲酸(465.0mg,2.3mmol)。所得混合物在室温下搅拌反应3小时。于反应液中加入二氯甲烷(10mL)稀释，再用饱和硫代硫酸钠水溶液(5.0mL)洗涤，分离所得有机相再用饱和碳酸氢钠水溶液(10.0mL)洗涤并浓缩。残留物经硅胶柱纯化(洗脱剂为石油醚：乙酸乙酯＝10:1-3:1)得到中间体1H(190mg，收率62％)。m/z(ESI):362.1[M+H]+.
步骤6：中间体1J的合成
将化合物1I(106.0mg,414.0μmol)溶于N,N-二甲基甲酰胺(1.0mL)中，再加入N,N-二异丙基乙胺(161.0mg,1.2mmol)，然后加入中间体1H(150.0mg,414.0μmol)，所得混合物于室温搅拌反应3小时。反应液经浓缩后，残留物经硅胶柱纯化(洗脱剂为石油醚：乙酸乙酯＝10:1-2:1)得到中间体1J(100mg,收率45％)。m/z(ESI):537.1[M+H]+.
步骤7：中间体1K的合成
将中间体1J(80.0mg,149.0μmol)溶于盐酸-二氧六环(1.0mL)中，于室温反应1小时。反应液直接浓缩得到中间体1K(80mg,粗品)直接用于下一步。
步骤8：中间体1L的合成
将中间体1K(50.0mg,114.5μmol)溶于二氯甲烷(3.0mL)中，再加入N,N-二异丙基乙胺(68.3mg,528.0μmol)和N,N'-羰基二咪唑(45.6mg,281.5μmol)，所得混合物于室温反应1小时。反应液经浓缩后，残留物经硅胶柱纯化(洗脱剂为石油醚：乙酸乙酯＝10:1-3:1)得到中间体1L(40mg,收率82％)。m/z(ESI):463.0[M+H]+.
步骤9：7'-(4-环丙基-6-甲氧基嘧啶-5-基)-1'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-1'H-螺[环丁烷-1,4'-嘧啶并[4,5-d]嘧啶]-2'(3'H)-酮(化合物1)的合成
将中间体1L(40.0mg,86.4μmol),(4-环丙基-6-甲氧基-嘧啶-5-基)硼酸(36.8mg，190.0μmol),磷酸钾(55.0mg，259.0μmol)，氯(2-二环己基膦基-2,4,6-三异丙基-1,1-联苯基)[2-(2-氨基-1,1-联苯)]钯(II)(27.2mg,34.6μmol)，加入到二氧六环(1.0mL)和水(50uL)的混合溶液中。所得反应液在100℃、氮气保护下搅拌反应4小时。将反应液浓缩，残留物经制备色谱纯化(Waters Xbridge C18 150*19mm,10μm,洗脱剂为10％-75％的乙腈-水)得标题化合物1(14mg，产率28％)。
LC-MS:m/z(ESI):577.1[M+H]+.
1H NMR(400MHz,CDCl3)δ8.80(s,1H),8.66(s,1H),7.55-7.48(m,4H),7.29(s,1H),5.80(s,1H),5.32(s,2H),3.92(s,3H),3.73(s,3H),2.76-2.64(m,2H),2.62-2.46(m,2H),2.13-2.01(m,2H),1.71-1.68(m,1H),1.24-1.19(m,2H),0.87-0.82(m,2H).
实施例2：7'-(4-环丙基-6-甲氧基嘧啶-5-基)-3'-甲基-1'-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-1'H-螺[环丁烷-1,4'-嘧啶并[4,5-d]嘧啶]-2'(3'H)-酮(化合物2)
将化合物1(10.0mg,17.3μmol)溶于N,N-二甲基甲酰胺(0.5mL)中，加入碳酸铯(16.9mg,52.0μmol)和碘甲烷(4.9mg,34.7μmol)。所得混合物于室温搅拌反应2h。反应液中加入0.5mL水，所得溶液直接经制备色谱纯化(Waters Xbridge C18 150*19mm,10μm,洗脱剂为10％-75％的乙腈-水)得标题化合物2(2.3mg,收率22％)。
LC-MS:m/z(ESI):591.2[M+H]+.
1H NMR(400MHz,CDCl3)δ8.81(s,1H),8.66(s,1H),7.55-7.46(m,4H),7.29(s,1H),5.34(s,2H),3.93(s,3H),3.73(s,3H),3.26(s,3H),3.04-2.93(m,2H),2.52-2.41(m,2H),2.13-2.04(m,2H),1.71-1.69(m,1H),1.23-1.17(m,2H),0.89-0.84(m,2H).
实施例3
采用实施例1中步骤2至步骤9类似的路线和合成方法，用下表中的化合物A替换步骤2中的中间体1C，制得表格中对应的化合物3-5。

实施例4
采用实施例1步骤2至步骤9类似的路线和合成方法，用下表中的化合物B替换步骤2中的中间体1C，并使用下表中的化合物C替换步骤6中的1I，制得表格中对应的化合物6和化合物7。
实施例5
采用实施例2中类似的合成方法，用化合物3、4、6、7分别替换化合物1，制得表格中对应的化合物8-11。

实施例6：2-(4-环丙基-6-甲氧基嘧啶-5-基)-8-(4-(1-异丙基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-5-甲基-5,8-二氢蝶啶-6,7-二酮(化合物12)
步骤1：中间体12B的合成
室温下，在反应瓶中加入中间体12A(8.8g,37.0mmol)，2-碘丙烷(12.6g,74.0mmol)，碳酸钾(10.2g,74.0mmol)和N,N-二甲基甲酰胺(100mL)，所得混合物在60℃下搅拌反应2小时。将反应液倒入200mL冰水中，并用100mL乙酸乙酯萃取3次。有机相合并后用饱和食盐水洗涤并浓缩，所得残留物经过硅胶柱纯化(洗脱剂为石油醚：乙酸乙酯＝10:1-1:1)得中间体12B(3.4g，收率：33％)。m/z(ESI):280.1[M+H]+.
步骤2：中间体12C的合成
室温下，将中间体12B(3.4g,12.2mmol)溶解于四氢呋喃中(30mL)，在0℃分批加入氢化铝锂(924.1mg,24.4mmol)。所得混合物在0℃下搅拌反应1小时后缓慢恢复到室温并继续搅拌反应1小时。将反应液冷却至0℃后，依次加入0.1mL水，0.1mL 15％氢氧化钠水溶液和0.2mL水。所得混合物在室温搅拌1小时后经硅藻土过滤，并用二氯甲烷淋洗滤饼。滤液浓缩后得中间体12C(3.4g，收率：100％)，直接用于下一步。m/z(ESI):284.1[M+H]+.
步骤3：中间体12E的合成
室温下，将2,4-二氯-5-硝基嘧啶(1.2g,6.0mmol)溶解于四氢呋喃中(30mL)，加入N,N-二异丙基乙胺(1.6g,12.0mmol)。反应液冷却至0℃后，搅拌下加入中间体12C(1.7g,6.0mmol,1eq.)。所得混合物在0℃搅拌反应0.5小时后缓慢恢复到室温，并继续反应2小时。所得反应液经浓缩得到粗品，并经硅胶柱纯化(洗脱剂为石油醚:乙酸乙酯＝5:1-1:1)得中间体 12E(1.4g,收率：52％)。m/z(ESI):441.1[M+H]+.
步骤4：中间体12F的合成
室温下，将还原铁粉(1.8g,31.8mmol)加入到水(10mL)和乙醇(30mL)中，加入氯化铵(1.7g,31.8mmol)，后加入中间体12E(1.4g,3.2mmol)。所得混合物在80℃下反应2小时后，加入100mL乙酸乙酯稀释。混合物经过滤，滤饼用乙酸乙酯淋洗，滤液合并后经饱和食盐水洗涤后浓缩，得粗品中间体12F(1.4g,收率：100％)直接用于下一步。m/z(ESI):411.1[M+H]+.
步骤5：中间体12H的合成
室温下，将12F(1.2g,2.9mmol)加入到丙酮(20mL)中，随后加入碳酸钾(806.2mg,5.8mmol)。将反应液冷却至0℃，搅拌下缓慢加入2-氯-2-氧代乙酸乙酯(398.8mg,2.9mmol)，并在该温度下反应2小时。将反应液浓缩，残留物经硅胶柱纯化(洗脱剂为石油醚:乙酸乙酯＝2:1-1:1)得中间体12H(1.2g，收率：80％)。m/z(ESI):511.1[M+H]+.
步骤6：中间体12I的合成
将中间体12H(1.2g,2.4mmol)加入到无水乙醇(10mL)中，随后加入三乙胺(474.5mg,4.7mmol)。所得混合物在120℃加热搅拌2小时后浓缩，所得残留物经硅胶柱纯化(洗脱剂为石油醚:乙酸乙酯＝2:1-1:1)得中间体12I(600mg，收率：55％)。m/z(ESI):465.1[M+H]+.
步骤7：中间体12J的合成
将中间体12I(100.0mg,215.1μmol)加入到无水N,N-二甲基甲酰胺(2mL)中，随后加入碳酸钾(59.4mg,430.3μmol)和碘甲烷(61.1mg,430.3μmol)。所得混合物在室温下搅拌反应2小时。将反应液加入20mL水中，并用乙酸乙酯萃取三次(20mL*3)。有机相合并后再用饱和食盐水洗涤，并经过无水硫酸钠干燥后，过滤，浓缩，所得残留物经硅胶柱纯化(洗脱剂为石油醚:乙酸乙酯＝2:1-1:1)得中间体12J(100mg,收率：97％)。m/z(ESI):479.1[M+H]+.
步骤8：2-(4-环丙基-6-甲氧基嘧啶-5-基)-8-(4-(1-异丙基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-5-甲基-5,8-二氢蝶啶-6,7-二酮(化合物12)的合成
将中间体12J(100.0mg,208.8μmol),(4-环丙基-6-甲氧基-嘧啶-5-基)硼酸(83.5mg,430.3μmol),磷酸钾(91.2mg,430.3μmol),XPhos Pd G2(33.9mg,43.0μmol)加入到二氧六环(4mL)和水(0.4mL)中，所得混合物在氮气保护下100℃搅拌反应4小时。将反应液浓缩后加入3mL乙腈，经过滤除去固体。所得滤液经制备色谱纯化(Waters Xbridge C18 150*19mm,10μm,洗脱剂为10％-75％的乙腈-水)纯化后得标题化合物12(50mg,收率：39％)。
LC-MS:m/z(ESI):593.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.67(s,1H),8.18(s,J＝1.4Hz,1H),7.54–7.42(m,4H),5.45(s,2H),4.40(d,J＝6.6Hz,1H),3.81(s,3H),3.61(s,3H),1.70–1.61(m,1H),1.38(d,J＝6.7Hz,6H),1.03–0.95(m,2H),0.77–0.68(m,2H).
实施例7：2-(4-环丙基-6-甲氧基嘧啶-5-基)-5-甲基-8-(4-(5-甲基-3-(三氟甲基)-1H-吡唑-1-基)苄基)-5,8-二氢蝶啶-6,7-二酮(化合物13)
采用实施例6中步骤3至步骤8类似的路线和合成方法，用中间体6I替换步骤3中的中间体12C，制得化合物13。
MS m/z(ESI):565.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.67(s,1H),7.61–7.41(m,4H),6.75(s,1H),5.44(s,2H),3.80(s,3H),3.60(s,3H),2.30(s,3H),1.72–1.57(m, 1H),1.06–0.94(m,2H),0.83–0.65(m,2H).
实施例8：2-(4-环丙基-6-二氟甲氧基嘧啶-5-基)-5-甲基-8-(4-(5-甲基-3-(三氟甲基)-1H-吡唑-1-基)苄基)-5,8-二氢蝶啶-6,7-二酮(化合物14)
采用实施例6中步骤3至步骤8类似的路线和合成方法，用中间体6I替换步骤3中的中间体12C，并由中间体14M替换步骤8中的(4-环丙基-6-甲氧基-嘧啶-5-基)硼酸，制得化合物14。
MS m/z(ESI):601.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.80(s,1H),8.01–7.63(m,2H),7.63–7.59(m,2H),7.50(m,2H),5.45(s,2H),3.74(s,3H),3.62(s,3H),1.78(m,1H),1.06(m,2H),0.82(m,2H).
实施例9：2-(4-环丙基-6-甲氧基嘧啶-5-基)-5-(甲基-d3)-8-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-7,8-二氢蝶啶-6(5H)-酮(化合物15)
步骤1：2-氯-N-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-5-硝基嘧啶-4-胺(15A)的合成
室温下，将2,4-二氯-5-硝基嘧啶(0.71g,3.7mmol)和N,N-二异丙基乙基胺(1.0g，7.8mmol，2.0eq)溶解于到四氢呋喃中(20mL)。冷却至0℃后，于反应液中加入1I(0.93g,3.7mmol,1.0eq)。所得混合物在0℃搅拌反应0.5小时后缓慢恢复到室温反应2小时。将反应液加入到冰水中(50mL)，用乙酸乙酯萃取(50mL*3)。有机相合并后用饱和食盐水洗涤一次(50mL)，减压蒸馏除去溶剂后，将所得残留物用硅胶柱纯化(石油醚:乙酸乙酯＝5:1-3:1)得黄色固体15A(0.90g，收率60％)。m/z(ESI):413[M+H]+。
步骤2：2-氯-N4-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)嘧啶-4,5-二胺(15B)的合成
室温下，将化合物15A(0.5g，1.2mmol)，还原铁粉(0.68g，12mmol,10eq)加入到水(5 mL)和乙醇(5mL)中，后加入氯化铵(0.65g,12mmol,10eq)。所得混合物在80℃下搅拌反应2小时。于反应液中加入50mL乙酸乙酯稀释后趁热过滤，滤饼用乙酸乙酯淋洗。有机相减压蒸馏除去溶剂后，所得残留物用硅胶柱纯化(石油醚:乙酸乙酯＝1:1)得黄褐色固体15B(0.35g，收率76％)。m/z(ESI):383[M+H]+。
步骤3：2-氯-N-(2-氯-4-((4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)嘧啶-5-基)乙酰胺(15D)的合成
室温下，将15B(0.5g,1.3mmol)溶解到无水N,N-二甲基甲酰胺中(10mL)中，将所得溶液冷却至0℃后缓慢加入氯乙酰氯(0.15g,1.3mmol,1eq)，然后加入碳酸钾(0.36g,2.61mmol,2eq)。所得混合物在0℃反应2小时后，加入水(30mL)淬灭，并用乙酸乙酯萃取(20mL*3)。所得有机相合并后用饱和食盐水洗涤(50mL)并用无水硫酸钠干燥。有机相减压蒸馏除去溶剂后，所得残留物用硅胶柱纯化(石油醚:乙酸乙酯＝5:1-1:1)得白色固体15D(0.4g，收率67％)。m/z(ESI):459[M+H]+。
步骤4：2-氯-8-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-7,8-二氢蝶啶-6(5H)-酮(15E)的合成
室温下，将15D(0.3g,0.65mmol)溶解于无水N,N-二甲基甲酰胺中(10mL)中，加入碳酸钾(0.18g,1.3mmol,2eq)。所得混合物加热至50℃搅拌反应2小时后，加入水(30mL)淬灭，并用乙酸乙酯萃取(20mL*3)。所得有机相合并后用饱和食盐水(50mL)洗涤并用无水硫酸钠干燥过滤，有机相减压蒸馏除去溶剂后，所得残留物用硅胶柱纯化(石油醚:乙酸乙酯＝5:1-1:1)得白色固体15E(0.12g，收率44％)。m/z(ESI):423[M+H]+。
步骤5：2-氯-5-(甲基-d3)-8-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-7,8-二氢蝶啶-6(5H)-酮(15F)的合成
将中间体15E(200.0mg,473.1μmol)加入到N,N-二甲基甲酰胺(2mL)中，加入碳酸铯(308.3mg,946.1μmol)。将反应液冷却至0℃，搅拌下缓慢加入氘代碘甲烷(82.3mg,567.7μmol)，0℃反应2小时。所得反应液浓缩后所得残留物经硅胶柱(洗脱剂为石油醚：乙酸乙酯＝1:1-1:4)纯化得中间体15F(160.0mg,363.8μmol,收率77％)。m/z(ESI):440.8[M+H]+.
步骤6：2-(4-环丙基-6-甲氧基嘧啶-5-基)-5-(甲基-d3)-8-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-7,8-二氢蝶啶-6(5H)-酮(化合物15)的合成
将中间体15F(50.0mg,113.7μmol),(4-环丙基-6-甲氧基-嘧啶-5-基)硼酸(39.7mg,204.6μmol),磷酸钾(72.4mg,341.0μmol),XPhos Pd G2(17.8mg,22.7μmol)，加入到1,4-二氧六环(2mL)和水(0.4mL)中。所得混合物在氮气保护下100℃搅拌反应4小时。反应液浓缩后，将反应液浓缩后加入3mL乙腈，经过滤除去固体。所得滤液经制备色谱纯化(Waters Xbridge C18 150*19mm,10μm,洗脱剂为10％-75％的乙腈-水)得化合物15(25.0mg,45.2μmol,收率40％)。
LC-MS:m/z(ESI):554.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.14(s,1H),7.93(s,1H),7.67(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),4.83(s,2H),4.23(s,2H),3.86(s,3H),3.76(s,3H),1.76-1.83(m,1H),0.99-1.02(m,2H),0.82-0.86(m,2H).
实施例10：2-(4-环丙基-6-二氟甲氧基嘧啶-5-基)-5-(甲基-d3)-8-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-7,8-二氢蝶啶-6(5H)-酮(化合物16)
采用实施例9中步骤6类似的合成方法，由中间体14M替换(4-环丙基-6-甲氧基-嘧啶-5-基)硼酸，制得化合物16。
LC-MS:m/z(ESI):590.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.18(s,1H),7.92(s,1H),7.74(t,J＝62.7Hz,1H),7.65(d,J＝8.0Hz,2H),7.49(d,J＝8.3Hz,2H),4.85(s,2H),4.24(s,2H),3.76(s,3H),1.93(m,1H),1.07(m,2H),0.94(m,2H).
实施例11
采用实施例9中步骤1至步骤6类似的路线和合成方法，由下表中的化合物D替代步骤1中的中间体1I，并用碘甲烷替代步骤5中的氘代碘甲烷，制得表格中对应的化合物17-19。
其中，中间体17A的合成：
第一步：中间体17AC的合成
氮气保护下，将中间体17AA(2.3g,7.2mmol)加入到N,N-二甲基甲酰胺(20mL)中，再加入醋酸钯(161.1mg,719.1μmol)，三苯基膦(377.2mg,1.4mmol)，中间体17AB(1.06g,10.8mmol)、三乙胺(1.45g,14.4mmol)，搅拌均匀，100℃反应3小时。将反应液倒入100mL水中，乙酸乙酯(50mL*3)萃取，所得有机相合并后用饱和食盐水(50mL)洗涤并用无水硫酸钠干燥过滤，有机相减压蒸馏除去溶剂后，所得残留物用硅胶柱纯化(洗脱剂为二氯甲烷:甲醇＝20：1-10：1)得中间体17AC(1.5g，收率：72％)。m/z(ESI):320.1[M+H]+.
第二步：中间体17AD的合成
氮气保护下，将中间体17AC(1.54g,4.9mmol)加入到乙醇(20mL)中，再加入氢氧化钯(150.0mg)，钯碳(150.0mg)，搅拌均匀，氢气置换三次，在氢气氛围下室温搅拌反应3小时。将反应液过滤，滤液浓缩，得粗品中间体17AD(1.1g，收率：65％)，直接用于下一步反应。m/z(ESI):324.1[M+H]+.
第三步：中间体17AE的合成
将中间体17AD(500.0mg,1.5mmol)加入到氯仿(20mL)中，冰水浴降温至0℃，缓慢加入氯化亚砜(184.0mg,1.5mmol)，然后恢复至室温，搅拌反应3小时。将反应液浓缩，残留物用硅胶柱纯化(洗脱剂为二氯甲烷:甲醇＝20：1)得中间体17AE(300mg，收率：60％)。m/z(ESI):342.1[M+H]+.
第四步：中间体17AF的合成
将中间体17AE(300.0mg,876.0μmol)加入到N,N-二甲基甲酰胺(10mL)中，再加入碳酸铯(570.0mg,1.7mmol)，升温至100℃，搅拌反应1小时。将反应液浓缩，残留物用硅胶柱纯化(洗脱剂为二氯甲烷:甲醇＝20：1)得中间体17AF(100mg，收率：37％)。m/z(ESI):306.1[M+H]+.
第五步：中间体17A的合成
将中间体17AF(100.0mg,327μmol)加入到四氢呋喃(5.0mL)中，搅拌下缓慢分批加入氢化铝锂(62.9mg,1.7mmol)。混合物室温下反应2小时。于反应液中加入1.0g十水合硫酸钠，常温搅拌过夜。将反应液用10mL乙酸乙酯稀释后过滤，将滤液浓缩，得粗品中间体17A(100mg)直接用于下一步。m/z(ESI):310.1[M+H]+.
中间体18A的合成：
第一步：中间体18AC的合成
将中间体18AA(3.6g,20mmol)加入到20mL六氟异丙醇中，加入三乙胺(5.1g,50.5mmol)和中间体18AB(2.5g,20mmol)。所得混合物加热至70℃搅拌反应1小时。将反应液浓缩，并加入50mL水，用乙酸乙酯萃取(30mL*3)，有机相合并后减压浓缩，所得残留物经硅胶柱纯化(洗脱剂为石油醚：乙酸乙酯＝5:1-1:2)，得目标中间体18AC(3.4g,收率75.9％)。 m/z(ESI):224.1[M+H]+.
第二步：中间体18A的合成
将中间体18AC(2.0g,8.9mmol)加入四氢呋喃(20mL)中，随后在低温下加入氢化铝锂(667mg,17.6mmol)，反应在常温下搅拌2小时。0℃下逐滴加入水(1.0mL)，再依次加入水(1.0mL)、15％氢氧化钠水溶液(1.0mL)、水(3.0mL)淬灭过量的氢化铝锂后垫硅藻土过滤，滤饼用二氯甲烷淋洗，合并有机相旋干，滤液浓缩后所得残留物经反相C18硅胶柱纯化(洗脱剂为5-50％的乙腈水溶液)得中间体18A(1.8g,收率：88％)。m/z(ESI):228.2[M+H]+.
中间体19A的合成：
第一步：中间体19AC的合成
将中间体19AA(3.6g,20mmol)加入到5mL水和25mL四氢呋喃的混合溶剂中，加入碳酸氢钠(3.5g,41.6mmol)。搅拌30分钟后，加入中间体19AB(3.2g,20mmol)。所得混合物常温反应30分钟后，加热至70℃继续搅拌反应30分钟。将反应液加入50mL水中，乙酸乙酯萃取(30mL*3)，有机相合并后减压浓缩，所得残留物经硅胶柱纯化(洗脱剂为石油醚：乙酸乙酯＝5:1-1:2)，得目标中间体19AC(695mg,收率16.5％)。m/z(ESI):210.1[M+H]+.
第二步：中间体19AE的合成
将中间体19AC(690.5mg,3.3mmol)加入到乙腈(20mL)中，随后加入氟化钾(575.6mg,9.9mmol)、溴二氟甲烷膦酸二乙酯(1.8g,6.6mmol)。在60℃下反应过夜。反应结束后，旋干溶剂，将反应液加入水中，乙酸乙酯萃取(30mL*3)，浓缩后所得残留物经硅胶柱纯化(洗脱剂为石油醚：乙酸乙酯＝5:1-1:2)得中间体19AE(727mg,收率：85％)。m/z(ESI):260.2[M+H]+.
第三步：中间体19A的合成
将中间体19AE(710mg,2.7mmol)加入到四氢呋喃(20mL)中，随后在低温下加入氢化铝锂(207.6mg,5.5mmol)，反应在常温下搅拌2小时。0℃下逐滴加入水(1.0mL)，再依次加入水(1.0mL)、15％氢氧化钠水溶液(1.0mL)、水(3.0mL)淬灭过量的氢化铝锂后垫硅藻土过滤，滤饼用二氯甲烷淋洗，合并有机相旋干，滤液浓缩后所得残留物经反相C18硅胶柱纯化(洗脱剂为5-50％的乙腈水溶液)得中间体19A(680mg,收率：94％)。m/z(ESI):264.2[M+H]+.
实施例12：7-(4-环丙基-6-甲氧基嘧啶-5-基)-4,4-二甲基-1-(4-(1-(氧杂环丁烷-3-基)-4-(三氟甲基)-1H-咪唑-2-基)苄基)-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮(化合物20)
步骤1:2-氯-4-((4-(1-(氧杂环丁烷-3-基)-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)氨基)嘧啶-5-羧酸乙酯(20C)的合成
室温下，将2,4-二氯嘧啶-5-羧酸乙酯(220mg,1.0mmol,1.0eq)溶于乙腈(10mL)中，然后再依次加入(4-(1-(氧杂环丁烷-3-基)-4-(三氟甲基)-1H-咪唑-2-基)苯基)甲胺20B(300mg,1.0mmol,1.0eq),三乙胺(200mg,2.0mmol,2.0eq)，所得混合物在室温搅拌反应10小时。向反应体系中加入水(10mL)，所得溶液用乙酸乙酯萃取3次(10mL*3)，合并有机相并用饱和食盐水洗涤(10mL)，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，所得残留物经硅胶柱(洗脱剂为石油醚：乙酸乙酯＝2:1-1:2)纯化得到中间体20C(360mg,收率75％)。m/z(ESI):482.1[M+H]+。
步骤2:2-(2-氯-4-((4-(1-(氧杂环丁烷-3-基)-4-(三氟甲基)-1H-咪唑-2-基)苄基)氨基)嘧啶-5-基)丙烷-2-醇(20D)的合成
将中间体20C(0.3g,0.62mmol)溶于四氢呋喃(10mL)中，随后在冰浴条件下分批加入甲基溴化镁(3.0M,1.75mL)，保持冰浴条件下反应过夜。加水(10mL)淬灭，乙酸乙酯(10mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，所得残留物经硅胶柱(洗脱剂为石油醚：乙酸乙酯＝2:1-1:2)纯化得中间体20D(285mg,0.61mmol,收率81％)。LC-MS:m/z(ESI):468.1[M+H]+；
步骤3:7-氯-1-(4-(1-(氧杂环丁烷-3-基)-4-(三氟甲基)-1H-咪唑-2-基)苄基)-4,4-二甲基-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮(20E)的合成
将N,N'-羰基二咪唑(0.18g,1.1mmol)溶于二氯甲烷(2.0mL)中，随后加入二异丙基乙基胺(0.16g,1.2mmol,0.21mL)，再加入中间体20D(0.18g,38.5mmol)，反应在常温下搅拌过夜。加入氯化铵溶液(10mL)淬灭，随后使用二氯甲烷萃取(10mL*3)，合并有机相，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，所得残留物经硅胶柱(洗脱剂为石油醚：乙酸乙酯＝2:1-1:2)纯化得中间体20E(160mg,收率84％)。m/z(ESI):494.1[M+H]+；
步骤4:7-(4-环丙基-6-甲氧基嘧啶-5-基)-4,4-二甲基-1-(4-(1-(氧杂环丁烷-3-基)-4-(三氟甲基)-1H-咪唑-2-基)苄基)-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮(化合物20)的合成
室温下，将化合物20E(75mg,0.15mmol),(4-环丙基-6-甲氧基嘧啶-5-基)硼酸1M(62mg,0.32mmol)溶于1,4-二氧六环(3.0mL),再加入0.5mL水,然后加入三(双亚苄基丙酮)双钯(83mg,0.091mmol,0.1eq),三环己基膦(51mg,0.18mmol),碳酸钾(0.38g,2.7mmol)。所得混合物在100℃氮气氛围下微波反应30分钟。所得反应液浓缩，残留物用3mL乙腈溶解后过滤，所得滤液经制备色谱纯化(Waters Xbridge C18 150*19mm,10μm,洗脱剂为10％-75％的乙腈-水)得化合物20(13mg,收率14％)。
LC-MS:MS m/z(ESI):608.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.66(s,1H),8.48(m,1H),7.58–7.31(m,4H),5.48 (m,1H),5.24(s,2H),4.82(m,4H),3.82(s,3H),1.78(s,6H),1.73(m,1H),1.00(m,2H),0.80(m,2H).
实施例13：7-(4-环丙基-6-甲氧基嘧啶-5-基)-4,4-二甲基-1-(4-(1-(1-甲基吡咯烷-3-基)-4-(三氟甲基)-1H-咪唑-2-基)苄基)-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮(化合物21)
采用实施例12中步骤1-4类似的合成路线及方法，用中间体21B替换中间体20B，制得化合物21。
LC-MS:m/z(ESI):635.3[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.66(s,1H),8.00(s,1H),7.51(d,J＝8.2Hz,2H),7.43(d,J＝8.1Hz,2H),5.25(s,2H),4.80–4.68(m,1H),3.82(s,3H),3.03–2.94(m,1H),2.89–2.80(m,1H),2.58–2.54(m,1H),2.46–2.38(m,1H),2.29(s,3H),2.26–2.18(m,1H),1.99–1.90(m,1H),1.79(s,6H),1.74–1.65(m,1H),1.03–0.96(m,2H),0.82–0.73(m,2H).
中间体21B的合成：
第一步：中间体21BC的合成
将中间体21BA(2.8g,11.7mmol)溶于N,N-二甲基甲酰胺(20.0mL)中，再加入中间体21BB(3.0g,11.7mmol)和碳酸钾(4.9g,35.3mmol)，于80℃反应12h。反应液中加入水(60.0mL)稀释，用乙酸乙酯(30.0mL*3)萃取，有机相合并后减压蒸馏除去溶剂后，所得残留物用硅胶柱纯化(二氯甲烷:甲醇＝20：1)得中间体21BC(550mg,收率：15％)。m/z(ESI):321.2[M+H]+.
第二步：中间体21B的合成
将中间体21BC(400.0mg，1.25mmol)溶于四氢呋喃(4.0mL)中，于-20℃下分批加入氢化铝锂(105.0mg，2.8mmol)，室温下反应20min。0℃下逐滴加入水(1.0mL)，再依次加入水(1.0mL)，15％氢氧化钠(1.0mL)，水(3.0mL)淬灭过量的氢化铝锂，将反应液过滤，滤液浓缩后所得残留物经反相C18硅胶柱纯化(洗脱剂为5-50％的乙腈水溶液)得中间体21B(200mg，收率：50％)。m/z(ESI):325.3[M+H]+.
实施例14：7-(4-环丙基-6-甲氧基嘧啶-5-基)-4,4-二甲基-1-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苯甲基)-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪(化合物22)
采用实施例12中步骤1-2类似的合成路线及方法，在步骤1中用中间体1I替换中间体20B，制得中间体22A。再采用实施例12中步骤4类似的合成方法，用中间体22A替换中间体20E，制得中间体22B。
将中间体22B(80.0mg,0.15mmol),对甲苯磺酸(7.7mg,0.044mmol)加入到甲苯(0.5mL)和甲醛水溶液(0.5mL)中。所得混合物在110℃反应0.5小时，减压蒸馏除去溶剂，所得残留物经制备色谱纯化(Waters Xbridge C18 150*19mm,10μm,洗脱剂为10％-75％的乙腈-水)后得标题化合物22(20mg,收率：24％)。
LC-MS:m/z(ESI):552.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.31(s,1H),7.92(s,1H),7.69–7.65(m,2H),7.41(d,J＝8.2Hz,2H),4.98(s,2H),4.83(s,2H),3.83(s,3H),3.76(s,3H),1.72(m,1H),1.57(s,6H),0.97(m,2H),0.81(m,2H).
实施例15：2-(4-环丙基-6-二氟甲氧基嘧啶-5-基)-5-甲基-8-(4-(1-甲基-4-(三氟甲基)-1H-咪唑-2-基)苄基)-7,8-二氢蝶啶-6(5H)-酮(化合物23)
采用实施例9中步骤5-6类似的合成方法，用碘甲烷替代步骤5中的氘代碘甲烷，并且用中间体14M替换(4-环丙基-6-甲氧基-嘧啶-5-基)硼酸，制得标题化合物23。
LC-MS:m/z(ESI):587.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.19(s,1H),7.93(m,1H),7.82(s,1H),7.64(m,2H),7.52–7.47(m,2H),4.85(s,2H),4.24(s,2H),3.76(s,3H),3.31(s,3H),1.93(m,1H),1.07(m,2H),0.93(m,2H).
测试例1：USP1酶体外活性检测实验
实验仪器：

实验材料：
实验所用USP1酶(Recombinant human his6-USP1/His6-UAF1 Complex Protein,CF)，购自R&D，货号E-568-050。分装后-80℃保存。
检测用试剂盒(Ub-CHOP2-Reporter Deubiquitination Assay Kit)购自Lifesensors公司，货号为PR1101。分装后-80℃保存。试剂盒包含泛素化的报告酶，当被USP1/UAF1去泛素化后，产生活性，催化底物后，使底物受485nm激光激发产生531nm的发射光信号。
实验所需其它试剂及耗材信息如下：
实验方法：
待测化合物用DMSO溶解至10mM。使用化合物稀释及加样仪将化合物及纯DMSO打到384孔板的每个孔上，最高浓度从3μM开始，3倍稀释，共8个浓度点，每孔加入50nL待测化合物或DMSO(作为对照)，仪器通过不同的比例来获得梯度稀释的样品浓度。用新鲜配制的反应液(20mM Tris-HCl(pH 8.0),2mM CaCl2,2mMβ-巯基乙醇,0.05％CHAPS(用ddH2O稀释CHAPS)))稀释酶。每个孔加入5μL稀释好的酶反应液，离心震荡混合酶与化合物，再离心后冰上放置。用反应液稀释试剂盒报告***和底物，每个孔加入5μL稀释好的液体，离心混合。在室温孵育0.5个小时。荧光信号使用Envision读板仪(PerkinElmer激发光波长485nm，发射光波长530nm)测量每个孔中的荧光信号。化合物对酶活的抑制活性IC50值用四参数Logistic Model方法计算。
下列公式中x代表化合物浓度的对数形式；F(x)代表效应值(该浓度条件下对酶活的抑制率)：F(x)＝(A+((B-A)/(1+((C/x)^D))))。A,B,C和D为四个参数。用Xlfit将IC50值进一步计算为最佳拟合曲线中50％酶活抑制所需的化合物浓度。
测试结果见表1。
表1 USP1酶体外抑制活性

测试例2：USP1抑制剂对MDA-MB-436细胞增殖抑制实验：
实验仪器：
实验材料：
实验所用细胞MDA-MB-436，购自科佰生物科技有限公司，货号CBP60385。细胞用DMEM培养基(含有10％FBS)传代培养，在细胞代数低时在液氮冻存，实验所用细胞不超过15代。
检测用试剂盒(Luminescent Cell Viability Assay)购自Promega公司，货号为G7573。分装后-30℃保存。试剂盒是通过对ATP进行定量测定来检测培养物中活细胞数目的一种均质检测方法。试剂盒产生发光信号与存在的ATP量成正比，而ATP量直接与培养物中的细胞数量成正比。
实验所需其它试剂及耗材信息如下：
实验方法：
将培养的细胞用0.25％Trypsin-EDTA Solution消化，收集离心，用培养液DMEM(含有10％FBS)调整浓度重悬，将细胞种在384孔板上(400细胞/20μL/孔)，37℃,5％CO2细胞培养箱中培养过夜。使用ECHO仪器将化合物及纯DMSO打到384孔板的每个孔上，最高浓度从10μM开始，4倍稀释，共8个浓度点，每孔加入100nL待测化合物或DMSO(作对照)，仪器通过不同的比例来获得梯度稀释的样品浓度。每个孔加入30μL培养液，离心震荡混合再离心后，在细胞培养箱培养7天(有一列细胞加药当天加CTG检测)。第7天后，每个孔加入25μL CTG检测液，离心震荡混合再离心后室温避光放置10分钟。化学发光信号使用Envision读板仪(PerkinElmer,发射波长400-700nm)测量每个孔中的信号，加药组获得第7天的化学发光值[RLU]cpd，未加药单加DMSO组获得第7天的的化学发光值[RLU]cell，平行的未加药单加DMSO组第0天CTG测试获得第0天的的化学发光值[RLU]background。化合物对增殖的抑制率(Inhibition rate，％)＝[1-([RLU]cpd.–[RLU]background)/([RLU]cell–[RLU]background)]×100％，化合物对增殖的抑制活性GI50值用四参数Logistic Model方法计算。下列公式中x代表化合物浓度的对数形式；F(x)代表效应值(该浓度条件下对增殖的抑制率):F(x)＝(A+((B-A)/(1+((C/x)^D))))。A,B,C和D为四个参数。用Xlfit将GI50值进一步计算为最佳拟合曲线中50％增殖抑制所需的化合物浓度。
本公开化合物对MDA-MB-436增殖抑制活性通过以上的试验进行测定，测得的GI50值见表2。
表2本公开化合物对MDA-MB-436细胞增殖抑制活性

Claims (15)

  1. 一种式(I)所示化合物或其药学上可接受的盐，
    其中，
    选自以下结构:
    R3a、R3b、R4、R5a、R5b各自独立地选自H、卤素、CN、OH、NH2、-C(O)ORx、-C(O)Rx、-NHC(O)Rx、-O-C1-C6烷基、C1-C6氘代烷基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基或4-10元杂环基，所述NH2、-O-C1-C6烷基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基或4-10元杂环基任选地被Rx取代；
    或者R3a、R3b与其连接的碳原子共同形成C3-C10环烷基或4-10元杂环基，所述C3-C10环烷基或4-10元杂环基任选地被Rx取代；
    或者R5a、R5b与其连接的碳原子共同形成C3-C10环烷基或4-10元杂环基，所述C3-C10环烷基或4-10元杂环基任选地被Rx取代；
    环A选自C6-C10芳基或5-10元杂芳基，所述C6-C10芳基或5-10元杂芳基任选地被Ra取代；
    环B选自C6-C10芳基、5-10元杂芳基、4-10元杂环基、C4-C10环烯基或C3-C10环烷基，所述C6-C10芳基、5-10元杂芳基、4-10元杂环基、C4-C10环烯基或C3-C10环烷基任选地被Rb取代；
    环C选自C6-C10芳基、5-10元杂芳基或4-10元杂环基，所述C6-C10芳基、5-10元杂芳基或4-10元杂环基任选地被Rc取代；
    每一个Ra、Rb、Rc各自独立地选自卤素、CN、OH、NH2、-C(O)ORx、-C(O)Rx、C1-C6烷基、-O-C1-C6烷基、C3-C10环烷基或4-10元杂环基，所述NH2、C1-C6烷基、-O-C1-C6烷基、C3-C10环烷基或4-10元杂环基任选地被Rx取代；
    或者，Rb、Rc与其连接的原子共同形成C4-C10环烯基或4-10元杂环基，所述C4-C10环烯基或4-10元杂环基任选地被Rx取代；
    R1、R2独立地选自H、卤素、CN、OH、NH2、C1-C6烷基、C3-C10环烷基或4-10元杂环基，所述OH、NH2、C1-C6烷基、C3-C10环烷基或4-10元杂环基任选地被Rx取代；
    或者，R1、R2与其连接的原子共同形成C3-C10环烷基或4-7元杂环基，所述C3-C10环烷基或4-7元杂环基任选地被Rx取代；
    Rx选自卤素、CN、OH、NH2或C1-C6烷基，所述OH、NH2或C1-C6烷基任选地被C1-C6烷基、C3-C10环烷基或4-7元杂环基取代；
    条件是，当选自时，R5a选自卤素、CN、OH、NH2、-C(O)ORx、 -C(O)Rx、-O-C1-C6烷基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基或4-9元杂环基，所述NH2、-O-C1-C6烷基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基或4-9元杂环基任选地被Rx取代；
    或者，R5a、R5b与其连接的碳原子形成C4-C10环烷基或4-9元杂环基，所述的C4-C10环烷基或4-9元杂环基任选地被Rx取代。
  2. 根据权利要求1所述的式(I)化合物或其药学上可接受的盐，其中，R3a、R3b、R4、R5a、R5b独立地选自H、-C(O)ORx、-C(O)Rx、-O-C1-C6烷基、C1-C6氘代烷基、C1-C6烷基、C3-C10环烷基或4-10元杂环基，所述-O-C1-C6烷基、C1-C6烷基、C3-C10环烷基或4-10元杂环基任选地被Rx取代；
    或者，R3a、R3b、R4、R5a、R5b独立地选自H、C1-C6氘代烷基、C1-C6烷基或C3-C10环烷基，所述C1-C6烷基或C3-C10环烷基任选地被Rx取代。
  3. 根据权利要求1-2中任一项所述的式(I)化合物或其药学上可接受的盐，其中，R5a、R5b与其连接的碳原子形成C3-C10环烷基，所述的C3-C10环烷基任选地被Rx取代。
  4. 根据权利要求1-3中任一项所述的式(I)化合物或其药学上可接受的盐，其中，R5a、R5b与其连接的碳原子形成C4-C10环烷基，所述的C4-C10环烷基任选地被Rx取代。
  5. 根据权利要求1-4中任一项所述的式(I)化合物或其药学上可接受的盐，其中，环A选自5-10元杂芳基，所述5-10元杂芳基任选地被Ra取代；
    或者，环A选自5-6元杂芳基，所述5-6元杂芳基任选地被Ra取代。
  6. 根据权利要求1-5中任一项所述的式(I)化合物或其药学上可接受的盐，其中，环B选自C6-C10芳基或5-10元杂芳基，所述C6-C10芳基或5-10元杂芳基任选地被Rb取代；
    或者，环B选自C6-C10芳基，所述C6-C10芳基任选地被Rb取代。
  7. 根据权利要求1-6中任一项所述的式(I)化合物或其药学上可接受的盐，其中，环C选自5-10元杂芳基或4-10元杂环基，所述5-10元杂芳基或4-10元杂环基任选地被Rc取代；
    或者，环C选自5-6元杂芳基或4-8元杂环基，所述5-6元杂芳基或4-8元杂环基任选地被Rc取代。
  8. 根据权利要求1-7中任一项所述的式(I)化合物或其药学上可接受的盐，其中，每一个Ra、Rb、Rc独立地选自卤素、C1-C6烷基、-O-C1-C6烷基、C3-C10环烷基或4-10元杂环基，所述C1-C6烷基、-O-C1-C6烷基、C3-C10环烷基或4-10元杂环基任选地被Rx取代。
  9. 根据权利要求1-8中任一项所述的式(I)化合物或其药学上可接受的盐，其中，R1、R2独立地选自H、卤素、C1-C6烷基或C3-C10环烷基，所述C1-C6烷基或C3-C10环烷基任选地被Rx取代。
  10. 根据权利要求1-9中任一项所述的式(I)化合物或其药学上可接受的盐，其中，Rx选自卤素、NH2或C1-C6烷基，所述NH2或C1-C6烷基任选地被C1-C6烷基、C3-C10环烷基或4-7元杂环基取代。
  11. 根据权利要求1-10中任一项所述的式(I)化合物或其药学上可接受的盐，其中，选自以下结构:
  12. 选自以下的化合物或其药学上可接受的盐：

  13. 药物组合物，其包含权利要求1-12中任一项所述的化合物或其药学上可接受的盐和药学上可接受的辅料。
  14. 治疗哺乳动物由USP1介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的权利要求1-12中任一项所述的化合物或其药学上可接受的盐、或权利要求13所述的药物组合物。
  15. 权利要求1-12中任一项所述的化合物或其药学上可接受的盐、或权利要求13所述的药物组合物在制备预防或者治疗由USP1介导的疾病的药物中的用途。
PCT/CN2023/123495 2022-10-09 2023-10-09 杂环并嘧啶类化合物、药物组合物及其应用 WO2024078436A1 (zh)

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