WO2024078436A1 - Composé pyrimidine hétérocyclique, composition pharmaceutique et application associées - Google Patents

Composé pyrimidine hétérocyclique, composition pharmaceutique et application associées 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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Chinese (zh)
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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

La présente invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci qui agit en tant qu'inhibiteur de USP1, une composition pharmaceutique comprenant le composé ou le sel pharmaceutiquement acceptable de celui-ci, et une utilisation de celui-ci dans la prévention ou le traitement de maladies médiées par USP1.
PCT/CN2023/123495 2022-10-09 2023-10-09 Composé pyrimidine hétérocyclique, composition pharmaceutique et application associées WO2024078436A1 (fr)

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Citations (10)

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