WO2022166592A1 - 取代嘧啶并吡啶酮类抑制剂及其制备方法和应用 - Google Patents

取代嘧啶并吡啶酮类抑制剂及其制备方法和应用 Download PDF

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WO2022166592A1
WO2022166592A1 PCT/CN2022/072814 CN2022072814W WO2022166592A1 WO 2022166592 A1 WO2022166592 A1 WO 2022166592A1 CN 2022072814 W CN2022072814 W CN 2022072814W WO 2022166592 A1 WO2022166592 A1 WO 2022166592A1
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substituted
alkyl
group
unsubstituted
cycloalkyl
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PCT/CN2022/072814
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English (en)
French (fr)
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吕彬华
崔大为
张青
柴传柯
韩吉来
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苏州泽璟生物制药股份有限公司
上海泽璟医药技术有限公司
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Publication of WO2022166592A1 publication Critical patent/WO2022166592A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a substituted pyrimidopyridone inhibitor and a preparation method and application thereof.
  • Lung cancer is one of the important causes of human cancer death.
  • Lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, and NSCLC accounts for 85% of all lung cancer patients.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • the global NSCLC market in 2016 was about US$20.9 billion, of which the US market accounted for half, followed by Japan, Germany and China.
  • the non-small cell lung cancer market has maintained continuous growth, and the global market is expected to reach US$54 billion in 2023 (Nature, 2018;553(7689):446-454).
  • chemotherapy drugs mainly include gemcitabine, paclitaxel and platinum drugs, but these drugs generally have poor selectivity and high toxicity, resulting in relatively strong side effects.
  • molecularly targeted drugs have gradually become a research hotspot due to their obvious advantages such as high selectivity, relatively small toxic and side effects, and the ability to achieve precise treatment.
  • EGFR inhibitors such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertinib, etc.
  • ALK inhibitors such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocartinib, etc. Ni et al
  • VEGFR inhibitors Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Donafenib, etc.
  • KRAS mutations occur in 20-40% of lung adenocarcinomas, and this prevalence is higher in Western (vs Asian) populations (26% vs 11%) and in smokers (vs non-smokers) ( 30% vs 10%).
  • the most common mutations occurred in codons 12 and 13, and the most common mutations included G12C, G12V, and G12D. So far, there are still no approved drugs targeting KRAS mutations on the market.
  • the KRAS protein transitions between inactive and activated states.
  • GDP guanosine diphosphate
  • GTP guanosine triphosphate
  • activated state and can activate downstream signaling pathways.
  • GEF guanine nucleotide exchange factor
  • GAP GTPase activating protein
  • SOS proteins are mainly found to be involved in tumors.
  • the SOS protein is widely expressed in vivo and contains two isoforms, SOS1 and SOS2.
  • SOS 1 plays a key role in mutant KRAS activation and oncogenic signaling. Decreased levels of SOS1 resulted in decreased proliferation and survival in KRAS-mutated tumor cells, but not in KRAS wild-type cell lines. The effect of SOS1 deletion could not be rescued by introducing a SOS1 mutated at the catalytic site, suggesting an important role of SOS1GEF activity in KRAS mutant cancer cells (see WO2019122129A1).
  • SOS1 target proteins are pathologically associated with a variety of diseases, there is a need for novel SOS1 inhibitors for clinical treatment.
  • Highly selective and highly active SOS1 inhibitors can be more effective in the treatment of diseases such as cancer caused by KRAS mutations, and have the potential to reduce off-target effects, so there is a more urgent clinical need.
  • the purpose of the present invention is to provide a new class of compounds with selective inhibitory effect on SOS1 and/or better pharmacodynamic properties and uses thereof.
  • the first aspect of the present invention provides a compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug:
  • Z is selected from the group consisting of substituted or unsubstituted C 1 -C 18 alkylene, deuterated C 1 -C 18 alkylene, and halo C 1 -C 18 alkylene; wherein the substitution is means substituted by one or more (e.g. 2, 3 or 4) R a ;
  • W is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 20 cycloalkylene group, 4-20-membered heterocyclic group; 4) R a is substituted;
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl and substituted or unsubstituted 4- 6-membered heterocyclyl; wherein, the substitution refers to being substituted by one or more (such as 2, 3 or 4) R a ;
  • R 2 are the same or different, each independently selected from the group consisting of -(CH 2 ) m O(CH 2 ) p R 7 , -(CH 2 ) m SR 7 , -(CH 2 ) m COR 7 , -(CH 2 ) 2 ) m C(O)OR 7 , -(CH 2 ) m S(O) q R 7 , -(CH 2 ) m NR 7 R 8 , -(CH 2 ) m C(O)NR 7 R 8 , -(CH 2 ) m NR 7 C(O)R 8 , -(CH 2 ) m NR 7 C(O)NR 8 R 9 , -(CH 2 ) m S(O) q NR 7 R 8 , -( CH 2 ) m NR 7 S(O) q R 8 , -(CH 2 ) m NR 7 S(O) q NR 8 R 9 , wherein H
  • R 3 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 18 cycloalkyl, 4-20-membered heterocyclyl, C 6 -C 14 aryl, 5-14-membered heteroaryl; wherein, the Said substitution refers to substitution by one or more Ra ;
  • R 4 and R 5 are each independently selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 4-6 membered heterocyclyl; wherein the substituted means substituted by one or more (e.g. 2, 3 or 4) R a ;
  • R 6 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, substituted or unsubstituted C 1 -C 6 alkyl and substituted or unsubstituted C 3 -C 6 cycloalkyl; wherein the substituted means substituted by one or more (e.g. 2, 3 or 4) R a ;
  • R a is selected from the group consisting of deuterium, substituted or unsubstituted C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, halo C 1 -C 18 Alkylhydroxy, substituted or unsubstituted C 3 -C 20 cycloalkyl, substituted or unsubstituted C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy base, substituted or unsubstituted C 6 -C 14 aryl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 4-20 membered heterocyclyl, halogen, nitro, hydroxyl, oxo, cyano group, ester group, amine group, amide group, sulfonamide group and urea group; wherein, the substitution in R a
  • n is independently 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5;
  • p is independently 0, 1, 2, 3, 4, or 5;
  • q is independently 1 or 2.
  • the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have the general formula (II ) shown in the structure:
  • R 1 , R 2 , R 3 , R 4 , R 5 , Z, W, and n are defined as described above.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug which has the general formula (III ) shown in the structure:
  • R 1 , R 2 , R 3 , R 4 , Z, W, and n are defined as described above.
  • the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have the general formula (IV ) shown in the structure:
  • R 1 , R 2 , R 3 , R 4 , Z, W, and n are defined as described above.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof has formula (V) Structure shown:
  • R 10 and R 11 are each independently selected from the group consisting of substituted or unsubstituted H, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, and halo C 1 -C 6 alkyl or R 10 and R 11 are cyclized together with the C to which they are attached to form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted 4-6 membered heterocyclyl;
  • substitution refers to substitution with one or more (eg 2, 3 or 4) groups selected from the group consisting of deuterium, C1 - C18 alkyl, deuterated C1 - C18 alkyl, halo-C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14-membered heteroaryl, 4-20-membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine group, amide group, sulfonamide group or urea group;
  • t is 1, 2, 3, 4, 5 or 6;
  • R 1 , R 2 , R 3 , W and n are as described above.
  • W is selected from: substituted or unsubstituted C 3 -C 6 cycloalkylene or substituted or unsubstituted 3-6 membered heterocyclylene; wherein, the substitution refers to being replaced by One or more (eg 2, 3 or 4) groups selected from the group consisting of deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, Halogenated C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy , C 6 -C 10 aryl, 5-10-membered heteroaryl, 4-6-membered heterocyclic, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, amido, sulfonamide
  • W is selected from:
  • R m is selected from: H, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10 membered Heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, amide, sulfonamide and ureido;
  • R b is selected from: H, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycle group, acyl or sulfonyl;
  • n1 0, 1, 2, 3 or 4.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof has formula (VI) the structure shown
  • R 10 , R 11 , R 12 and R 13 are each independently selected from the group consisting of substituted or unsubstituted H, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, and halo C 1 -C 6 alkyl; or R 10 and R 11 are cyclized together with the C to which they are attached to form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted 4-6 membered heterocyclyl; or R 12 and R 13 is cyclized together with the C to which it is attached to form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted 4-6 membered heterocyclyl;
  • R 14 is selected from: OR 15 , SR 15 , COR 15 , C(O)OR 15 , S(O)R 15 , S(O) 2 R 15 , NR 15 R 16 , C(O)NR 15 R 16 , NR 15 C(O)R 16 , NR 15 C(O)NR 16 R 17 , S(O)NR 15 R 16 , S(O) 2 NR 15 R 16 , NR 15 S(O)R 16 , NR 15 S(O) 2 R 16 , NR 15 S(O)NR 16 R 17 , NR 15 S(O) 2 NR 16 R 17 ; wherein R 15 , R 16 and R 17 are each independently selected from the group consisting of hydrogen , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocyclyl and substituted or unsubstituted C 1
  • U is selected from: CR 18 R 19 , NR b , O;
  • R 18 , R 19 and R m are each independently selected from: H, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, amido, sulfonamide and ureido; or R 18 , R 19 and adjacent C are cyclized together to form C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl;
  • R b is selected from: H, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycle group, acyl or sulfonyl;
  • Substitution as described in R 10 , R 11 , R 12 , R 13 , R 15 , R 16 and R 17 refers to substitution by one or more groups selected from the group consisting of deuterium, C 1 -C 6 alkyl, deuterium Substituted C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxyl , oxo group, cyano group, ester group, amine group, amide group, sulfonamide group and urea group;
  • n1 0, 1, 2, 3 or 4;
  • n2 and n3 are each independently 0, 1, 2, 3, or 4; and n2 and n3 are not both 0;
  • n4 is 1, 2, 3, 4 or 5;
  • R 1 and R 3 are as defined above.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof has formula (VII) Structure shown:
  • R 1 , R 3 , R 10 , R 11 , R 12 , R 13 , R 14 , R m , U, n1 , n2 , n3 and n4 are as defined above.
  • R 12 and R 13 are H.
  • U is CH 2 .
  • R 3 is selected from substituted or unsubstituted following group: phenyl or 5-6-membered heteroaryl, wherein, the substitution refers to one or more (such as 2, 3 or 4) selected from the following Group of radicals: deuterium, C1 - C6 alkyl, deuterated C1 - C6 alkyl, haloC1- C6 alkyl, haloC1 - C6 alkyl hydroxyl, C3 - C 6 -cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10-membered heteroaryl group, 4-6 membered heterocyclic group, halogen, nitro, hydroxy
  • R 3 is selected from the group consisting of substituted or unsubstituted groups: phenyl, pyridyl, pyrimidinyl, and pyridazinyl, wherein the substitution refers to being replaced by one or Multiple (eg 2, 3 or 4) groups selected from the group consisting of deuterium, C1 - C6 alkyl, deuterated C1 - C6 alkyl, haloC1-C6 alkyl , halo C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 -aryl, 5-10-membered heteroaryl, 4-6-membered heterocyclic, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, amido
  • R is selected from:
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, and C 1 -C 6 alkyl.
  • R 14 is selected from the following group: OR 15 and NR 15 R 16 , the definitions of R 15 and R 16 are as described above, more preferably, R 14 is selected from: OH, OCH 3 ,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z, W, n, R 10 , R 11 , R 12 , R 13 , R 14 , R m , U , t, n1, n2, n3 and n4 are the corresponding groups of the specific compounds in the examples.
  • the compound is the compound shown in the Examples.
  • the second aspect of the present invention provides a method for preparing a compound of formula (II), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, Among them, including steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , Z, W and n are as defined above.
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising i) one or more of the compounds described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable compounds a salt, hydrate, solvate or prodrug; and ii) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises one or more therapeutic agents selected from the group consisting of PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltu), CD20 antibodies
  • a method for preparing a pharmaceutical composition comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound described in the first aspect of the present invention, its stereoisomers, tautomers
  • the form, pharmaceutically acceptable salt, hydrate, solvate or prodrug are mixed to form a pharmaceutical composition.
  • the compounds of the present invention can be prepared into powders, tablets, granules, capsules, solutions, emulsions, suspensions and the like.
  • the fourth aspect of the present invention provides a compound according to the first aspect, a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or
  • the use of the pharmaceutical composition in the third aspect is to prepare a medicine or a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of SOS1.
  • the disease is cancer.
  • the cancer is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, esophagus cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer, brain cancer tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • a fifth aspect of the present invention provides a non-diagnostic and non-therapeutic method for inhibiting SOS1, comprising the step of: administering to a patient in need an effective amount of the compound described in the first aspect, or a stereoisomer thereof , tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or administer the pharmaceutical composition of the third aspect.
  • the present inventors unexpectedly discovered a new class of compounds with selective inhibitory effect on SOS1 and/or better pharmacodynamic properties. On this basis, the inventors have completed the present invention.
  • alkyl refers to a straight or branched chain or cyclic alkane group containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms.
  • Typical "alkyl” includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more.
  • C1-C18 alkyl refers to straight or branched chain or cyclic alkyl groups, including from 1 to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl n-butyl, tert-butyl, isobutyl (such as ), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl.
  • Substituted alkyl means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
  • alkylene refers to a group formed by removing one hydrogen atom from “alkyl”, such as methylene, ethylene, propylene, isopropylidene (such as ), butylene (such as ), pentylene (such as ), ahexyl (such as ), heptidene (such as )Wait.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group comprising 1-4 rings, each ring containing 3-8 carbon atoms. "Substituted cycloalkyl” means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocycle (excluding heteroaryl), bridged cycloalkyl, bridged cycloalkenyl, Bridged ring heterocycle (excluding heteroaromatic ring), fused cycloalkyl, fused cycloalkenyl, fused ring heterocyclic or fused aryl ring, the above cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups may be optionally substituted. Any two or more atoms on the ring can be further cyclolinked with other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.
  • cycloalkylene refers to a group formed by the removal of two hydrogen atoms from a cycloalkyl group, such as:
  • alkylenecycloalkylene refers to the above-mentioned cycloalkylalkyl or alkylcycloalkyl group formed by removing two hydrogen atoms, wherein "C1-C18 alkylene C3-C20 alkylene”"Cycloalkyl” or "C3-C20 cycloalkylene C1-C18 alkylene” have the same meaning, preferably, C1-C6 alkylene C3-C12 cycloalkylene, including but not limited to: Wait.
  • heterocyclyl refers to fully saturated or partially unsaturated cyclic groups (including, but not limited to, such as 3-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic systems), At least one heteroatom is present in a ring having at least one carbon atom.
  • Each heterocyclic ring containing a heteroatom may carry 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the nitrogen or sulfur may be oxidized or the nitrogen may Quaternized.
  • a heterocyclic group can be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine base, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepanyl gene, 4-piperidinone, tetrahydropyranyl, morpholino, thiomorpholinyl, thiomorpholinosulfoxide, thiomorpholinone, 1,3-dioxanyl and Tetrahydro-1,1-dioxythiophene, etc.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms on the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further cyclically connected; the heterocyclic group can be substituted or unsubstituted, and when substituted,
  • the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate, where
  • heterocyclylene refers to a group formed by removing two hydrogen atoms from the above-mentioned heterocyclyl, including but not limited to:
  • heterocycloalkylene alkylene refers to a group formed by removing two hydrogen atoms from a cycloalkylalkyl group or an alkylcycloalkyl group, wherein "4-20 membered heterocycloalkylene C1-C18 "Alkylene” or "C1-C18 alkylene 4-20 membered heterocycloalkylene” have the same meaning, preferably 4-12 membered heterocycloalkylene C1-6 alkylene, including but not limited to: Wait.
  • aryl refers to an aromatic cyclic hydrocarbon group having 1 to 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic rings, etc.), the aromatic rings of the aryl group can be linked by a single bond (eg, biphenyl), or fused (eg, naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which may be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include fused ring substituents, especially fused cycloalkyl, fused cycloalkenyl, fused ring heterocyclyl or fused ring aryl, the aforementioned cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups may be optionally substituted.
  • heteroaryl refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Thio, oxo, carboxyl and carboxylate groups.
  • C1-C18 alkoxy refers to a straight or branched chain or cyclic alkoxy group having 1 to 18 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropyl oxy and butoxy, etc. Preferably it is a C1-C8 alkoxy group, more preferably a C1-C6 alkoxy group.
  • C1-C18 alkyleneoxy refers to a group obtained by removing one hydrogen atom from "C1-C18 alkoxy”.
  • halogen refers to chlorine, bromine, fluorine, iodine.
  • halo refers to substitution with halogen.
  • deuterated refers to substitution with deuterium.
  • hydroxyl refers to a group with the structure OH.
  • nitro refers to a group with the structure NO2.
  • cyano refers to a group with the structure CN.
  • esters refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.
  • amino refers to a group bearing the structure -NRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.
  • Amido refers to a group with the structure -CONRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.
  • sulfonamido refers to a group with the structure -SO2NRR ', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cyclo Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.
  • ureido refers to a group having the structure -NRCONR'R", wherein R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl , cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine moiety.
  • alkylaminoalkyl refers to a group with the structure -RNHR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different.
  • dialkylaminoalkyl refers to a group with the structure -RNHR'R", where R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted Cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine moiety.
  • heterocyclylalkyl refers to a group bearing the structure -RR', where R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted Cycloalkenyl, aryl or substituted aryl; R' represents heterocycle or substituted heterocycle.
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent.
  • substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples.
  • a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 ureido and so on.
  • a substituent is a non-terminal substituent, it is a subgroup of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl to heterocyclylene, alkoxy to Alkyleneoxy, etc.
  • compounds of the present invention refers to compounds of formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of compounds of formula I.
  • the compound of formula (I) of the present invention has the following structure:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z, W, and n are as defined above.
  • the compound has a structure represented by formula (II):
  • R 1 , R 2 , R 3 , R 4 , R 5 , Z, W, and n are defined as described above.
  • the compound has a structure represented by the general formula (III):
  • R 1 , R 2 , R 3 , R 4 , Z, W, and n are defined as described above.
  • the compound has the structure represented by the general formula (IV):
  • R 1 , R 2 , R 3 , R 4 , Z, W, and n are defined as described above.
  • the compound has a structure represented by formula (V):
  • R 1 , R 2 , R 3 , R 10 , R 11 , W and n are as defined above.
  • the compound has a structure represented by formula (VI)
  • R 1 , R 3 , R 10 , R 11 , R 12 , R 13 , R 14 , R m , U, n1 , n2 , n3 and n4 are as defined above.
  • the compound has a structure represented by formula (VII):
  • R 1 , R 3 , R 10 , R 11 , R 12 , R 13 , R 14 , R m , U, n1 , n2 , n3 and n4 are as defined above.
  • the compound has the structure shown in formula (VIII):
  • R 1 , R 3 and R 14 are as defined above.
  • R 3 is selected from the substituted or unsubstituted subgroups: phenyl or 5-6-membered heteroaryl; more preferably, R 3 is selected from the substituted or unsubstituted subgroups : phenyl, pyridyl, pyrimidinyl, pyridazinyl, wherein the substitution refers to a group selected from the group consisting of one or more (eg 2, 3 or 4): deuterium, C 1 -C 6 alkane group, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy , deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10-membered heteroaryl,
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1 -C 6 alkyl;
  • R 14 is selected from the group consisting of OR 15 and NR 15 R 16 , R 15 and R 16 are as defined above, more preferably R 14 is selected from: OH, OCH 3 ,
  • * represents R or S configuration, preferably R configuration.
  • salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts.
  • the term “salt” refers to salts formed with inorganic or organic acids and bases in the acid or basic form.
  • a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion (“inner salt”) that may be formed is contained in within the scope of the term "salt”.
  • compositions of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
  • the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lactate, maleate
  • Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (such as organic amines) such as benzathine, bicyclohexyl Amine, Hepamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl amines, and salts with amino acids such as arginine, lysine, and the like.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.
  • small halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate
  • Prodrugs and solvates of the compounds of the present invention are also contemplated.
  • the term "prodrug” as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
  • Stereoisomers of all compounds are contemplated by the present invention.
  • Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC).
  • the racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
  • the compound in the present invention the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
  • a mixture of isomers can contain isomers in various ratios.
  • isomers in various ratios.
  • Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
  • the present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers.
  • isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.
  • a synthesis of a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer.
  • a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
  • the compounds of the present invention may be combined with any number of substituents or functional groups to extend their encompassing scope.
  • substituents or functional groups may be combined with any number of substituents or functional groups to extend their encompassing scope.
  • the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent.
  • the substituents may be the same or different at each position.
  • substituted as used herein includes all permissible substitutions of organic compounds.
  • permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence.
  • the present invention is not intended to limit in any way the permitted substituted organic compounds.
  • the present invention contemplates that combinations of substituents and variable groups are well suited for the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds.
  • stable refers to compounds that are stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, as used herein for the above-mentioned purposes.
  • the preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.
  • the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • R 1 , R 2 , R 3 , R 4 , R 5 , Z, W and n are as defined above.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
  • the compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions.
  • the mode and dosage of the original drug may remain unchanged, while the compound of formula I is administered concurrently or subsequently.
  • a pharmaceutical composition containing both one or more known drugs and the compound of formula I may preferably be used.
  • Drug combinations also include administration of a compound of formula I with one or more other known drugs at overlapping time periods.
  • the dose of the compound of formula I or known drugs may be lower than the doses of the compounds of formula I administered alone.
  • Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB- A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab
  • the dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nanometer preparation.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form the pharmaceutical composition.
  • the present invention also provides a method of treatment, which comprises the steps of: administering the compound of general formula (I), or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, as described in the present invention to a subject in need of treatment , or administer the pharmaceutical composition of the present invention for selectively inhibiting SOS1.
  • the present invention has the following main advantages:
  • the compound has a good selective inhibitory effect on SOS1;
  • the compound has better in vitro and in vivo pharmacodynamics, pharmacokinetic properties and lower toxic and side effects.
  • the structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • LC-MS Liquid chromatography-mass spectrometry
  • TLC silica gel plate used Qingdao GF254 silica gel plate, TLC used 0.15-0.20mm, preparative thin layer chromatography used 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or according to the literature data reported in the field.
  • the first step preparation of 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidine
  • the second step dimethyl 2-(6-chloro-5-(1,3-dioxolane-2-yl)-2-methylpyrimidin-4-yl)-2-fluoromalonate preparation
  • Step 3 2-(6-(((R)-1-(3-trifluoromethyl-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolane-2 -Preparation of methyl)-2-methylpyrimidin-4-yl)-2-fluoroacetate
  • Step 4 2-(6-(((R)-1-(3-trifluoromethyl-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolane-2 -yl)-2-methylpyrimidin-4-yl)-2-fluoroacetic acid preparation
  • Step 5 2-(5-(1,3-dioxolane-2-yl)-6-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl) Preparation of ethyl)amino)-2-methylpyrimidin-4-yl)-2-fluoro-N-((1-(hydroxymethyl)cyclopropyl)methyl)acetamide
  • reaction solution was stirred at room temperature for 16 hours, then 30 mL of water and 30 mL of saturated ammonium chloride solution were added, followed by extraction with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were dried and concentrated, and the residue was separated by preparative chromatography to give the desired product (70 mg, yield: 60%).
  • Step 6 (R)-8-Fluoro-4-((1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-((1-(hydroxymethyl) )cyclopropyl)methyl)-2-methylpyridin[4,3-d]pyrimidin-7(6H)-one
  • Step 7 (R)-1-((8-Fluoro-4-((1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7 - Preparation of oxopyridin[4,3-d]pyrimidin-6(7H)-yl)methyl)cyclopropane-1-aminocarbaldehyde
  • Step 8 (R)-6-((1-((dimethylamino)methyl)cyclopropyl)methyl)-8-fluoro-4-((1-(2-fluoro-3-(tri) Preparation of fluoromethyl)phenyl)ethyl)amino)-2-methylpyrid[4,3-d]pyrimidin-7(6H)-one
  • the first step preparation of dimethyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)malonate
  • the resulting mixture was reacted at 80 °C for 16 h, then quenched with ice water (200 mL) and extracted with EtOAc (200 mL*3). The organic phases were combined, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain the target product (7.00 g, yield: 65.3%).
  • the fourth step (R)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolane) Preparation of Alk-2-yl)-2-methylpyrimidin-4-yl)-N-((1-((dimethylamino)methyl)cyclopropyl)methyl)acetamide
  • Table 1 shows the inhibitory activity of the example compounds of the present invention on the binding of KRAS G12C enzyme and SOS1.
  • Example 1 IC50 (nM) Example 1 49 Example 2 17 Example 3 / Example 4 15 Example 5 twenty four Example 6 7.3 Example 7 twenty four Example 8 146 Example 9 >1000 Example 10 74 Example 11 70 Example 12 17 Example 13 9.1
  • the compounds of the examples of the present invention showed good inhibitory activity on the binding of KRAS G12C and SOS1.
  • the diluted compounds to be tested were added to a 384-well cell culture plate, and duplicate wells were set up. An equal volume of DMSO was added to the negative control group and centrifuged at 1000 rpm for 1 min at room temperature.
  • the cells were seeded into a) 384 culture plates, and the negative control group was added with an equal volume of cells. Centrifuge at 1000 rpm for 1 min at room temperature, the final concentration of DMSO of the final compound is 0.5%, and place it in a 37°C, 5% CO2 constant temperature incubator for 7 days.
  • the luminescence value was read with an Envision multi-plate reader.
  • IR(%) (1 ⁇ (RLU compound ⁇ RLU blank control)/(RLU vehicle control ⁇ RLU blank control))*100%.
  • the inhibition rates of different concentrations of compounds were calculated in Excel, and then the GraphPad Prism software was used to plot the inhibition curves and calculate the relevant parameters, including the minimum inhibition rate, the maximum inhibition rate and IC 50 .
  • the experimental results are shown in Table 3.
  • Example 20 Twenty two components: IC50 (nM) Example 4 395 Example 5 646 Example 6 20.4 Example 7 3577 Example 10 1370 Example 13 15 Example 14 69.7 Example 15 65.3 Example 16 68.8 Example 17 247 Example 18 603.4 Example 19 3169 Example 20 twenty two
  • the compounds of the examples of the present invention showed good inhibitory activity on the proliferation of KRAS G12C mutant H358 cells.
  • mice 100 uL of 5x10 6 MIA PaCa-2 tumor cell suspension was subcutaneously inoculated into the right hind flank of nude mice. Mice health were monitored daily, starting when tumors grew to palpable size.
  • the tumor volume calculation formula adopts: 0.5 ⁇ L ⁇ W 2 , where L and W represent the length and width of the tumor, respectively.
  • Tumors grew to -150 mm3 and mice were randomized. Mice were given the corresponding doses (15, 50 mg/Kg) of compound in CMC-Na suspension by gavage every day, and their general status was monitored at the same time. Tumors were measured 3 times a week and body weights were measured twice a week.
  • the compound of the present invention has a good anti-tumor effect.

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Abstract

涉及取代嘧啶并吡啶酮类抑制剂及其制备方法和应用。具体地，该化合物具有式(I)所示结构，还公开了所述化合物的制备方法及其作为SOS1抑制剂的用途，该化合物对SOS1具有很好的选择性抑制作用且具有更好的药效学、药代动力学性能和更低的毒副作用。

Description

取代嘧啶并吡啶酮类抑制剂及其制备方法和应用 技术领域
本发明属于药物领域，具体涉及一种取代嘧啶并吡啶酮类抑制剂及其制备方法和应用。
背景技术
肺癌是人类癌症致死的重要原因之一。按照细胞类型肺癌可以分为小细胞肺癌(SCLC)和非小细胞肺癌(NSCLC)，其中NSCLC占所有肺癌患者的85％。据统计2016年全球NSCLC的市场约为209亿美元，其中美国市场占据一半，其次是日本、德国和中国。从现有趋势来看，非小细胞肺癌市场保持着持续增长，预计2023年全球市场将达到540亿美元(Nature，2018；553(7689):446-454)。
目前NSCLC的主要治疗用药分为化疗药物、分子靶向药物以及肿瘤免疫疗法等。其中化疗药物主要包括吉西他滨、紫杉醇以及铂类药物等，但是这类药物普遍具有选择性差、毒性大从而导致比较强烈的毒副作用。近年来，分子靶向药物因其选择性较高、毒副作用相对较小，能够实现精准治疗等明显优势从而逐渐成为研究热点。现有的NSCLC分子靶向药物包括EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Pyrotinib、Rociletinib、Osimertinib等)，ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼等)，以及VEGFR抑制剂(Sorafenib、Regorafenib、Cabozantinib、Sunitinib、多纳非尼等)(Current Medicinal Chemistry,2019,26,1-39)。
KRAS突变发生在20-40％的肺腺癌中，这一患病率在西方(vs亚洲)人群中更高(26％vs 11％)，在吸烟者(vs非吸烟者)中更高(30％vs 10％)。最常见的突变发生在密码子12和13中，最常见的突变包括G12C、G12V和G12D。到目前为止，市场上仍然没有针对KRAS突变的药物被批准上市。
在细胞内，KRAS蛋白在失活和激活状态之间转变，当KRAS与鸟苷二磷酸(GDP)结合时，它处于失活状态，当它与鸟苷三磷酸(GTP)结合时，它处于激活状态，并且可以激活下游信号通路。KRAS在失活与激活状态之间的转换受到两类因子的调节。一类是鸟嘌呤核苷酸交换因子(GEF)，这类蛋白催化KRAS与GTP的结合，从而促进KRAS的激活，其中包括SOS1蛋白。另一类是GTP酶激活蛋白(GAP)，这类蛋白能够促进与KRAS结合的GTP水解成为GDP，从而抑制KRAS的活性。
到目前为止，已经确定了三大类特定于RAS的GEF，在肿瘤中主要发现SOS蛋白参与。SOS蛋白在体内广泛表达，含有两个亚型SOS1和SOS2。已发表的数据表明，在突变KRAS激活和致癌信号中，SOS 1起着关键作用。SOS1水平的降低导致了携带KRAS突变的肿瘤细胞的增殖率和存活率的降低，而KRAS野生型细胞系则未见影响。SOS1缺失的效果不能通过引入一个在催化位点发生突变的SOS1来挽救，这说明 SOS1GEF活性在KRAS突变癌细胞中的重要作用(参见WO2019122129A1)。
由于不管是突变的还是野生型的KRAS结合GTP都依赖于SOS1，所以选择性的抑制SOS1之后，不管KRAS突变与否，都能阻止SOS1与KRAS的相互作用从而最终抑制KRAS激活。
由于SOS1靶蛋白在病理学上与多种疾病相关，因此目前还需要新型的SOS1抑制剂用于临床治疗。高选择性高活性的SOS1抑制剂可以对KRAS突变导致的癌症等疾病更有效治疗，以及减少脱靶效应的潜力，因而具有更迫切的临床需求。
发明内容
本发明的目的在于提供一类新型的对SOS1有选择性抑制作用和/或更好药效学性能的化合物及其用途。
本发明第一方面，提供一种式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
Figure PCTCN2022072814-appb-000001
式中：
Z选自取代或未取代的下组基团：C 1-C 18亚烷基、氘代C 1-C 18亚烷基和卤代C 1-C 18亚烷基；其中，所述取代是指被一个或多个(如2、3或4)R a取代；
W选自取代或未取代的下组基团：C 3-C 20亚环烷基、4-20元亚杂环基；其中，所述取代是指被一个或多个(如2、3或4)R a取代；
R 1选自下组：氢、氘、卤素、氰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 6环烷基和取代或未取代的4-6元杂环基；其中，所述取代是指被一个或多个(如2、3或4)R a取代；
R 2相同或不同，各自独立地选自下组：-(CH 2) mO(CH 2) pR 7、-(CH 2) mSR 7、-(CH 2) mCOR 7、-(CH 2) mC(O)OR 7、-(CH 2) mS(O) qR 7、-(CH 2) mNR 7R 8、-(CH 2) mC(O)NR 7R 8、-(CH 2) mNR 7C(O)R 8、-(CH 2) mNR 7C(O)NR 8R 9、-(CH 2) mS(O) qNR 7R 8、-(CH 2) mNR 7S(O) qR 8、-(CH 2) mNR 7S(O) qNR 8R 9，其中，CH 2中的H可以任选地被取代；R 7、R 8和R 9各自独立地选自下组：氢、取代或未取代C 1-C 18烷基、取代或未取代C 3-C 20环烷基、取代或未取代4-20元杂环基和取代或未取代C 1-C 18烷氧基；或者在-(CH 2) mNR 7R 8、-(CH 2) mC(O)NR 7R 8、-(CH 2) mS(O) qNR 7R 8中，R 7和R 8与其相连的N原子环合形成取代或未取代4-20元杂环基；或者在-(CH 2) mNR 7C(O)R 8、-(CH 2) mNR 7C(O)NR 8R 9、-(CH 2) mNR 7S(O) qR 8、-(CH 2) mNR 7S(O) qNR 8R 9中，R 8和R 9与其相连的N原子环合形成取代或未取代4-20元杂环基，或者R 7和R 8与其相邻的原子环合形成取代或未取代的4-20元杂环基；其中，所述取代是指被一个或多个(如2、3或4)R a取代；
R 3选自取代或未取代的下组基团：C 3-C 18环烷基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；其中，所述取代是指被一个或多个R a取代；
R 4和R 5各自独立地选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基和4-6元杂环基；其中，所述取代是指被一个或多个(如2、3或4)R a取代；
R 6选自下组：氢、氘、卤素、氨基、氰基、取代或未取代的C 1-C 6烷基和取代或未取代的C 3-C 6环烷基；其中，所述取代是指被一个或多个(如2、3或4)R a取代；
其中，R a选自下组：氘、取代或未取代C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、取代或未取代C 3-C 20环烷基、取代或未取代C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、取代或未取代C 6-C 14芳基、取代或未取代5-14元杂芳基、取代或未取代4-20元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基；其中，R a中所述取代是指被一个或多个(如2、3或4)选自下组的基团取代：氘、C 1-C 6烷基、C 3-C 6环烷基、3-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基；
m独立地为1、2、3、4或5；
n独立地为1、2、3、4或5；
p独立地为0、1、2、3、4或5；
q独立地为1或2。
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(II)所示结构：
Figure PCTCN2022072814-appb-000002
式中，R 1、R 2、R 3、R 4、R 5、Z、W、n的定义如上所述。
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(III)所示结构：
Figure PCTCN2022072814-appb-000003
式中，R 1、R 2、R 3、R 4、Z、W、n的定义如上所述。
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(IV)所示结构：
Figure PCTCN2022072814-appb-000004
式中，R 1、R 2、R 3、R 4、Z、W、n的定义如上所述。
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(V)所示结构：
Figure PCTCN2022072814-appb-000005
式中，
R 10和R 11各自独立地选自取代或未取代的下组基团：H、氘、C 1-C 6烷基、氘代C 1-C 6烷基和卤代C 1-C 6烷基；或者R 10和R 11与其相连的C一起环合形成取代或未取代C 3-C 6环烷基或取代或未取代4-6元杂环基；
所述取代是指被选自下组的一个或多个(如2、3或4)基团取代：氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
t为1、2、3、4、5或6；
R 1、R 2、R 3、W和n的定义如上所述。
在另一优选例中，式I-V中，W选自：取代或未取代C 3-C 6亚环烷基或取代或未取代3-6元亚杂环基；其中，所述取代是指被一个或多个(如2、3或4)选自下组的基团：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基。
在另一优选例中，式I-V中，W选自：
Figure PCTCN2022072814-appb-000006
Figure PCTCN2022072814-appb-000007
其中，R m选自：H、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基；
R b选自：H、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环 基、酰基或磺酰基；
n1为0、1、2、3或4。
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(VI)所示的结构
Figure PCTCN2022072814-appb-000008
式中，
R 10、R 11、R 12和R 13各自独立地选自取代或未取代的下组基团：H、氘、C 1-C 6烷基、氘代C 1-C 6烷基和卤代C 1-C 6烷基；或者R 10和R 11与其相连的C一起环合形成取代或未取代C 3-C 6环烷基或取代或未取代4-6元杂环基；或者R 12和R 13与其相连的C一起环合形成取代或未取代C 3-C 6环烷基或取代或未取代4-6元杂环基；
R 14选自：OR 15、SR 15、COR 15、C(O)OR 15、S(O)R 15、S(O) 2R 15、NR 15R 16、C(O)NR 15R 16、NR 15C(O)R 16、NR 15C(O)NR 16R 17、S(O)NR 15R 16、S(O) 2NR 15R 16、NR 15S(O)R 16、NR 15S(O) 2R 16、NR 15S(O)NR 16R 17、NR 15S(O) 2NR 16R 17；其中，R 15、R 16和R 17各自独立地选自下组：氢、取代或未取代C 1-C 6烷基、取代或未取代C 3-C 6环烷基、取代或未取代4-6元杂环基和取代或未取代C 1-C 6烷氧基；或者在NR 15R 16、C(O)NR 15R 16、S(O)NR 15R 16、S(O) 2NR 15R 16中，R 15和R 16与其相连的N原子环合形成取代或未取代4-6元杂环基；或者在NR 15C(O)R 16、NR 15C(O)N R 16R 17、NR 15S(O)R 16、NR 15S(O) 2R 16、NR 15S(O)NR 16R 17、NR 15S(O) 2NR 16R 17中，R 16和R 17与其相连的N原子环合形成取代或未取代4-6元杂环基，或者R 15和R 16与其相邻的原子环合形成取代或未取代的4-6元杂环基；
U选自：CR 18R 19、NR b、O；
R 18、R 19和R m各自独立地选自：H、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基；或者R 18、R 19和相邻的C一起环合形成C 3-C 6环烷基或4-6元杂环基；
R b选自：H、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、酰基或磺酰基；
R 10、R 11、R 12、R 13、R 15、R 16和R 17中所述取代是指被一个或多个选自下组的基团：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基；
n1为0、1、2、3或4；
n2和n3各自独立地为0、1、2、3或4；且n2和n3不同时为0；
n4为1、2、3、4或5；
R 1和R 3的定义如上所述。
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(VII)所示结构：
Figure PCTCN2022072814-appb-000009
式中，R 1、R 3、R 10、R 11、R 12、R 13、R 14、R m、U、n1、n2、n3和n4的定义如上所述。
在另一优选例中，R 12和R 13为H。
在另一优选例中，U为CH 2。
在另一优选例中，
Figure PCTCN2022072814-appb-000010
为
Figure PCTCN2022072814-appb-000011
在另一优选例中，
Figure PCTCN2022072814-appb-000012
选自：-CH 2OH、-CH 2OCH 3、
Figure PCTCN2022072814-appb-000013
Figure PCTCN2022072814-appb-000014
在另一优选例中，式I-VIII中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其中，R 3选自取代或未取代的下组基团：苯基或5-6元杂芳基，其中，所述取代是指被一个或多个(如2、3或4)选自下组的基团：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基。
在另一优选例中，式I-VIII中，R 3选自取代或未取代的下组基团：苯基、吡啶基、嘧啶基、哒嗪基，其中，所述取代是指被一个或多个(如2、3或4)选自下组的基团：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基。
在另一优选例中，式I-VIII中，R 3选自：
Figure PCTCN2022072814-appb-000015
在另一优选例中，R 1选自下组：氢、氘、卤素、氰基、C 1-C 6烷基。
在另一优选例中，R 14选自下组：OR 15和NR 15R 16，R 15和R 16的定义如上所述，更优选地，R 14选自：OH、OCH 3、
Figure PCTCN2022072814-appb-000016
Figure PCTCN2022072814-appb-000017
在另一优选例中，R 1、R 2、R 3、R 4、R 5、R 6、Z、W、n、R 10、R 11、R 12、R 13、R 14、R m、U、t、n1、n2、n3和n4为实施例中各具体化合物所对应基团。
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其中，所述化合物选自下组：
Figure PCTCN2022072814-appb-000018
Figure PCTCN2022072814-appb-000019
Figure PCTCN2022072814-appb-000020
Figure PCTCN2022072814-appb-000021
Figure PCTCN2022072814-appb-000022
Figure PCTCN2022072814-appb-000023
Figure PCTCN2022072814-appb-000024
在另一优选例中，所述化合物为实施例中所示化合物。
本发明第二方面，提供一种制备式(II)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的方法，其中，包括步骤：
Figure PCTCN2022072814-appb-000025
(i)在惰性溶剂(如甲苯)中，式X-1化合物与乙二醇反应，得到式X-2化合物；
(ii)在惰性溶剂(如二甲亚砜)中，在碱(如碳酸钾、DIPEA、TEA或DMAP)存在下，式X-2化合物与式X-3化合物反应，得到式X-4化合物；
(iii)在碱(如DIPEA、TEA或DMAP)存在下，式X-4化合物与式X-5化合物反应，得到式X-6化合物；
(iv)在惰性溶剂(如二甲亚砜和乙腈的混合溶剂)中，在碱(如NaOH、LiOH)存 在下，式X-6化合物发生水解反应，得到式X-7化合物；
(v)在惰性溶剂(如N，N-二甲基甲酰胺)中，在缩合剂(如HATU)和碱(如DIPEA、TEA、或DMAP)存在下，式X-7化合物与胺(式X-8)发生缩合反应，得到式X-9化合物；
(vi)在惰性溶剂(如异丙醇)中，式X-9化合物在酸性条件(如盐酸)下，脱保护同时发生关环反应，得到通式(II)化合物；
式中，
R 1、R 2、R 3、R 4、R 5、Z、W和n的定义如上所述。
本发明第三方面，提供一种药物组合物，其包含i)一种或多种第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和ii)药学上可接受的载体。
在另一优选例中，所述药物组合物还包括选自下组的一种或多种治疗剂：PD-1抑制剂(如nivolumab、pembrolizumab、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT 1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab、atezolizumab、avelumab、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003,CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab、obinutuzumab、ofatumumab、veltuzumab、tositumomab、131I-tositumomab、ibritumomab、90Y-ibritumomab、90In-ibritumomab、ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。
在另一优选例中，提供一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药进行混合，从而形成药物组合物。
在另一优选例中，本发明化合物可以制备成散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂等。
本发明第四方面，提供一种第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或第三方面所述的药物组合物的用途，用于制备预防和/或治疗与SOS1活性或表达量相关的疾病的药物或药物组合物。
在另一优选例中，所述疾病为癌症。
在另一优选例中，所述癌症选自：肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。
本发明第五方面，提供了一种非诊断性、非治疗性地抑制SOS1的方法，其中，包括步骤：向所需患者施用有效量的如上第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或施用第三方面所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地发现了一类新型的SOS1有选择性抑制作用和/或更好药效学性能的化合物。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
术语“烷基”是指直链或支链或环状烷烃基，包含1-20个碳原子，如1-18个碳原子，尤其指1-18个碳原子。典型的“烷基”包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、
Figure PCTCN2022072814-appb-000026
戊基、异戊基、庚基、4,4–二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基、十二烷基等等。
术语“C1-C18烷基”指的是直链或支链或环状烷基，包括从1-18个碳原子，如甲基、乙基、丙基、异丙基
Figure PCTCN2022072814-appb-000027
正丁基、叔丁基、异丁基(如
Figure PCTCN2022072814-appb-000028
)、正戊基、异戊基、正己基、异己基、正庚基、异庚基。“取代烷基”是指烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔 基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。
术语“亚烷基”是指“烷基”再脱掉一个氢原子所形成的基团，如亚甲基、亚乙基、亚丙基、亚异丙基(如
Figure PCTCN2022072814-appb-000029
)、亚丁基(如
Figure PCTCN2022072814-appb-000030
)、亚戊基(如
Figure PCTCN2022072814-appb-000031
)、亚己基(如
Figure PCTCN2022072814-appb-000032
)、亚庚基(如
Figure PCTCN2022072814-appb-000033
)等。
术语“环烷基”是指完全饱和的环状烃类化合物基团，包括1-4个环，每个环中含有3-8个碳原子。“取代环烷基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选被取代。典型的取代还包括螺环、桥环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、桥环烷基、桥环烯基、桥环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。环上的任意两个或两个以上的原子可以与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。
术语“亚环烷基”是指环烷基脱掉两个氢原子所形成的基团，如：
Figure PCTCN2022072814-appb-000034
Figure PCTCN2022072814-appb-000035
Figure PCTCN2022072814-appb-000036
等。
术语“亚烷基亚环烷基”是指上述的环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团，其中，“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”具有相同含义，优选地，C1-C6亚烷基C3-C12亚环烷基，包括但不限于：
Figure PCTCN2022072814-appb-000037
Figure PCTCN2022072814-appb-000038
Figure PCTCN2022072814-appb-000039
等。
术语“杂环基”是指完全饱和的或部分不饱和的的环状基团(包含但不限于如3-7元单环，6-11元双环，或8-16元三环系统)，其中至少有一个杂原子存在于至少有一个碳原子的环中。每个含有杂原子的杂环可以带有1，2，3或4个杂原子，这些杂原子选自氮原子、氧原子或硫原子，其中氮原子或硫原子可以被氧化，氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接；杂环基团可以是取代的或者未取代的，当被取代 时，取代基优选为一个或多个一下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基，其中，环上的任意两个或两个以上的原子可以与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。
术语“亚杂环基”是指上述杂环基脱掉两个氢原子所形成的基团，包括但不限于：
Figure PCTCN2022072814-appb-000040
Figure PCTCN2022072814-appb-000041
等。
术语“亚杂环烷基亚烷基”是指环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团，其中，“4-20元亚杂环烷基C1-C18亚烷基”或“C1-C18亚烷基4-20元亚杂环烷基”具有相同含义，优选地为4-12元亚杂环烷基C1-6亚烷基，包括但不限于：
Figure PCTCN2022072814-appb-000042
Figure PCTCN2022072814-appb-000043
Figure PCTCN2022072814-appb-000044
等。
术语“芳基”是指芳香环状烃类化合物基团，具有1-5个环，尤其指单环和双环基团，如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等)，芳基基团的芳香环可由单键联接(如联苯)，或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代，尤其是1-3个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、 NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基，尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂芳基”指包含1-4个杂原子、5-14个环原子的杂芳族体系，其中杂原子选自氧、氮和硫。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“C1-C18烷氧基”是指具有1至18个碳原子的直链或支链或环状烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C8烷氧基，更优选C1-C6烷氧基。
术语“C1-C18亚烷氧基”是指“C1-C18烷氧基”脱掉一个氢原子所得基团。
术语“卤素”或“卤”是指氯、溴、氟、碘。
术语“卤代”是指被卤素取代。
术语“氘代”是指被氘取代。
术语“羟基”是指带有结构OH的基团。
术语“硝基”是指带有结构NO 2的基团。
术语“氰基”是指带有结构CN的基团。
术语“酯基”是指带有结构-COOR的基团，其中R代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环。
术语“胺基”是指带有结构-NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。
术语“酰胺基”是指带有结构-CONRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。
术语“磺酰胺基”是指带有结构-SO 2NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。
术语“脲基”是指带有结构-NRCONR'R"的基团，其中R、R'和R"可以独立的代表氢、 烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。
术语"烷基胺基烷基"是指带有结构-RNHR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'可以相同或不同。
术语"二烷基胺基烷基"是指带有结构-RNHR'R"的基团，其中R、R'和R"可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。
术语"杂环基烷基"是指带有结构-RR'的基团，其中R可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基；R'代表杂环或取代的杂环。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。
当取代基为非末端取代基时，其为相应基团的亚基，例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。
活性成分
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括及式I化合物的立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物。
本发明的式(I)化合物具有如下结构：
Figure PCTCN2022072814-appb-000045
式中，R 1、R 2、R 3、R 4、R 5、R 6、Z、W、n的定义如上所述。
优选地，所述化合物具有式(II)所示结构：
Figure PCTCN2022072814-appb-000046
式中，R 1、R 2、R 3、R 4、R 5、Z、W、n的定义如上所述。
优选地，所述化合物具有通式(III)所示结构：
Figure PCTCN2022072814-appb-000047
式中，R 1、R 2、R 3、R 4、Z、W、n的定义如上所述。
优选地，所述化合物具有通式(IV)所示结构：
Figure PCTCN2022072814-appb-000048
式中，R 1、R 2、R 3、R 4、Z、W、n的定义如上所述。
优选地，所述化合物具有式(V)所示结构：
Figure PCTCN2022072814-appb-000049
式中，R 1、R 2、R 3、R 10、R 11、W和n的定义如上所述。
优选地，所述化合物具有式(VI)所示的结构
Figure PCTCN2022072814-appb-000050
式中，R 1、R 3、R 10、R 11、R 12、R 13、R 14、R m、U、n1、n2、n3和n4的定义如上所述。
优选地，所述化合物具有式(VII)所示结构：
Figure PCTCN2022072814-appb-000051
式中，R 1、R 3、R 10、R 11、R 12、R 13、R 14、R m、U、n1、n2、n3和n4的定义如上所述。
优选地，所述的化合物具有式(VIII)所示结构：
Figure PCTCN2022072814-appb-000052
式中，R 1、R 3和R 14的定义如上所述。
优选地，上述各式中，R 3选自取代或未取代的下组基团：苯基或5-6元杂芳基；更优选地，R 3选自取代或未取代的下组基团：苯基、吡啶基、嘧啶基、哒嗪基，其中，所述取代是指被一个或多个(如2、3或4)选自下组的基团：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基；更优选地，R 3选自：
Figure PCTCN2022072814-appb-000053
R 1选自下组：氢、氘、卤素、氰基、C 1-C 6烷基；
R 14选自下组：OR 15和NR 15R 16，R 15和R 16的定义如上所述，更优选地，R 14选自：OH、OCH 3、
Figure PCTCN2022072814-appb-000054
优选地，
Figure PCTCN2022072814-appb-000055
为
Figure PCTCN2022072814-appb-000056
其中，*表示R或S构型，优选地为R构型。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机 或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐，和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或 非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明，其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范 围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的，例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。
制备方法
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
典型地，本发明化合物的制备工艺流程如下，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。
Figure PCTCN2022072814-appb-000057
(i)在惰性溶剂(如甲苯)中，式X-1化合物与乙二醇反应，得到式X-2化合物；
(ii)在惰性溶剂(如二甲亚砜)中，在碱(如碳酸钾、DIPEA、TEA或DMAP)存在下，式X-2化合物与式X-3化合物反应，得到式X-4化合物；
(iii)在碱(如DIPEA、TEA或DMAP)存在下，式X-4化合物与式X-5化合物反应，得到式X-6化合物；
(iv)在惰性溶剂(如二甲亚砜和乙腈的混合溶剂)中，在碱(如NaOH、LiOH)存在下，式X-6化合物发生水解反应，得到式X-7化合物；
(v)在惰性溶剂(如N，N-二甲基甲酰胺)中，在缩合剂(如HATU)和碱(如DIPEA、TEA、或DMAP)存在下，式X-7化合物与胺(式X-8)发生缩合反应，得到式X-9化合物；
(vi)在惰性溶剂(如异丙醇)中，式X-9化合物在酸性条件(如盐酸)下，脱保护同时发生关环反应，得到通式(II)化合物；
式中，
R 1、R 2、R 3、R 4、R 5、Z、W和n定义如上所述。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗以下疾病：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为：PD-1抑制剂(如nivolumab、pembrolizumab、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT 1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab、atezolizumab、avelumab、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003,KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab、obinutuzumab、ofatumumab、veltuzumab、tositumomab、131I-tositumomab、ibritumomab、90Y-ibritumomab、90In-ibritumomab、ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622,OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK 抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。
本发明所述药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2022072814-appb-000058
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述通式(I)化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明所述的药物组合物，用于选择性地抑制SOS1。
与现有技术相比，本发明具有以下主要优点：
(1)所述化合物对SOS1具有很好的选择性抑制作用；
(2)所述化合物具有更好的体内外药效学、药代动力学性能和更低的毒副作用。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数 按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。
NMR是使用Bruker AVANCE-400核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d 6)、氘代丙酮(CD 3COCD 3)、氘代氯仿(CDCl 3)及氘代甲醇(CD 3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。HPLC的测定使用Agilent1100高压色谱仪(Microsorb 5micron C18 100x 3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。
实施例
实施例1(R)-4-((1-(3-三氟甲基-2-氟苯基)乙基)氨基)-6-((1-((二甲基氨基)甲基)环丙基)甲基)-8-氟-2-甲基吡啶并[4,3-d]嘧啶-7(6H)-酮的制备
Figure PCTCN2022072814-appb-000059
第一步：4,6-二氯-5-(1,3-二氧戊环-2-基)-2-甲基嘧啶的制备
将4,6-二氯-2-甲基嘧啶-5-甲醛(1.0g,5.26mmol)加入甲苯(50mL)中，加入乙二醇(326mg，5.26mmol)和对甲苯磺酸(90mg，0.53mmol)。反应液置换氮气3次，然后回流反应3小时。反应液浓缩掉甲苯，加入20毫升二氯甲烷和50毫升饱和碳酸钠溶液，然后用二氯甲烷(3 x 20mL)萃取。合并的有机相干燥过滤后浓缩，残余物用硅胶柱层析(PE:EA＝20:1至10:1)分离，得到目标产物(1.3g，收率：100％)。
LC-MS：m/z 235(M+H) +。
第二步：2-(6-氯-5-(1,3-二氧杂戊烷-2-基)-2-甲基嘧啶-4-基)-2-氟丙二酸二甲酯的制备
将4,6-二氯-5-(1,3-二氧戊环-2-基)-2-甲基嘧啶(1.2g,5.13mmol)加入二甲亚砜(12mL)中，随后加入碳酸钾(1.42g，10.3mmol)和2-氟丙二酸二甲酯(769mg，5.13mmol)。反应液置换氮气1次，然后50℃反应2小时。得到的反应液冷却后加入100mL水稀释，然后用乙酸乙酯萃取(3 x 100mL)。合并的有机相用食盐水(200mL)洗涤后，经无水硫酸钠干燥过滤后减压浓缩，得目标产物(1.78g，收率：99％)。无需纯化直接用于下一步反应。
LC-MS：m/z 349(M+H) +。
第三步:2-(6-(((R)-1-(3-三氟甲基-2-氟苯基)乙基)氨基)-5-(1,3-二氧戊环-2-基)-2-甲基嘧啶-4-基)-2-氟乙酸甲酯的制备
将2-(6-氯-5-(1,3-二氧杂戊烷-2-基)-2-甲基嘧啶-4-基)-2-氟丙二酸二甲酯(1.78g，5.11mmol)溶于二甲基亚砜(10mL)中，加入三乙胺(1.03g，10.22mmol)和1-(3-三氟甲基-2-氟苯基)乙胺(1.06g，5.11mmol)。反应液置换氮气1次，然后加热到80℃反应16小时。冷却至室温，反应液中加入50毫升冰水和50毫升饱和氯化铵溶液，然后用乙酸乙酯(3x100mL)萃取。合并的有机相经无水硫酸钠干燥，过滤后减压浓缩，得目标产物(2.36g，收率：100％)。无需纯化直接用于下一步反应。
LC-MS：m/z 462(M+H) +。
第四步:2-(6-(((R)-1-(3-三氟甲基-2-氟苯基)乙基)氨基)-5-(1,3-二氧戊环-2-基)-2-甲基嘧啶-4-基)-2-氟乙酸的制备
将2-(6-(((R)-1-(3-三氟甲基-2-氟苯基)乙基)氨基)-5-(1,3-二氧戊环-2-基)-2-甲基嘧啶-4-基)-2-氟乙酸甲酯(2.36g,5.12mmol)加入二甲亚砜(10mL)和乙腈(5mL)的混合溶剂中，加入20％氢氧化钠水溶液(4.1mL，20.48mmol)。反应液室温反应1小时后过滤，滤液用制备色谱分离，得到目标产物(870mg，收率：38％)。
LC-MS：m/z 448(M+H) +。
第五步:2-(5-(1,3-二氧杂戊烷-2-基)-6-((R)-1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-2-甲基嘧啶-4-基)-2-氟-N-((1-(羟甲基)环丙基)甲基)乙酰胺的制备
将2-(6-(((R)-1-(3-三氟甲基-2-氟苯基)乙基)氨基)-5-(1,3-二氧戊环-2-基)-2-甲基嘧啶-4-基)-2-氟乙酸(100mg,0.22mmol)加入N，N-二甲基甲酰胺(5mL)中， 随后加入1-(氨甲基)环丙基)甲醇(45mg，0.44mmol)，O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基尿嘧啶六氟磷酸盐(167mg，0.44mmol)和N,N-二异丙基乙胺(114mg，0.88mmol)。反应液室温搅拌反应16小时，然后加入30毫升水和30毫升饱和氯化铵溶液，再用乙酸乙酯(3x50mL)萃取。合并的有机相干燥后浓缩，残余物用制备色谱分离得到目标产物(70mg，收率：60％)。
LC-MS：m/z 531(M+H) +。
第六步:(R)-8-氟-4-((1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-6-((1-(羟甲基)环丙基)甲基)-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮的制备
将2-(5-(1,3-二氧杂戊烷-2-基)-6-((R)-1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-2-甲基嘧啶-4-基)-2-氟-N-((1-(羟甲基)环丙基)甲基)乙酰胺(60mg,0.11mmol)加入异丙醇(3mL)中，随后加入5N浓盐酸(0.1mL)。反应液50度反应1小时，然后浓缩，残余物用制备色谱分离，得到目标产物(40mg，收率：78％)。
LC-MS：m/z 469(M+H) +。
第七步:(R)-1-((8-氟-4-((1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-2-甲基-7-氧代吡啶[4,3-d]嘧啶-6(7H)-基)甲基)环丙烷-1-氨基甲醛的制备
将(R)-8-氟-4-((1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-6-((1-(羟甲基)环丙基)甲基)-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮(20mg,0.04mmol)溶于二氯甲烷(10mL)中，依次加入碳酸氢钠(17mg，0.20mmol)和戴斯-马丁试剂(36mg，0.08mmol)。混合物室温搅拌过夜，随后加入1.5N氢氧化钠(2mL)搅拌10分钟后，再加入饱和碳酸氢钠水溶液(50mL)，然后用二氯甲烷(50mL)萃取。有机相经食盐水(50mL)洗涤后再用无水硫酸钠干燥，然后过滤。滤液减压浓缩得到目标产物(20mg，收率：99％)。无需纯化直接用于下一步反应。
LC-MS：m/z 467(M+H) +。
第八步:(R)-6-((1-((二甲氨基)甲基)环丙基)甲基)-8-氟-4-((1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮的制备
将(R)-1-((8-氟-4-((1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-2-甲基-7-氧代吡啶[4,3-d]嘧啶-6(7H)-基)甲基)环丙烷-1-氨基甲醛(20mg,0.04mmol)溶于甲醇(10mL)中，依次加入2M二甲胺四氢呋喃溶液(0.1mL，0.20mmol)和氰基硼氢化钠(13mg，0.20mmol)。混合物室温搅拌过夜然后减压浓缩，残余物用制备色谱分离得到目标产物(1.52mg，收率：8％)。
LC-MS：m/z 496(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.03(s,1H),8.88(d,J＝8.8Hz,1H),7.80-7.83(t,J＝7.8Hz,1H),7.66-7.69(t,J＝7.7Hz,1H),7.37-7.41(t,J＝7.4Hz,1H),5.72-5.76(m,1H),4.16-4.17(m,1H),2.25(s,3H),2.15(s,3H),1.99-2.00(m,2H),1.59(d,J＝1.59Hz,3H),1.25(s,3H),0.81(s,2H),0.34(s,2H).
按照实施例1的方法以不同的起始原料合成了以下化合物：
实施例2(R)-4-((1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-6-((1-((二甲基氨基)甲基)环丙基)甲基)-8-氟-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000060
LC-MS：m/z 536(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.10(s,1H),8.89(s,1H),7.68–7.56(m,1H),7.37–7.30(m,1H),7.24(t,J＝7.7Hz,1H),5.85–5.70(m,1H),5.34(s,1H),2.36–1.98(m,10H),1.54(m,3H),1.26–1.14(m,9H),0.84(s,2H),0.40(s,2H).
实施例3(R)-4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-8-氟-2-甲基-6-((1-((二甲基氨基)甲基)环丙基)甲基)吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000061
LC-MS：m/z 493(M+H) +。
实施例4(R)-4-((1-(3-(1,1-二氟-2-羟基乙基)-2-氟苯基)乙基)氨基)-8-氟-2-甲基-6-((1-(吗啡啉甲基)环丙基)甲基)吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000062
LC-MS：m/z 550(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.06(s,1H),8.73(d,J＝7.3Hz,1H),8.21(s,1H),7.59(s,1H),7.55(d,J＝7.5Hz,1H),7.50–7.32(m,2H),5.73–5.59(m,1H),4.14(q,J＝13.5Hz,2H),3.84(t,J＝14.2Hz,2H),3.27(s,4H),2.31(s,3H),2.28–2.07(m,6H),1.56(t,J＝12.0Hz,3H),0.84(d,J＝4.6Hz,2H),0.37(d,J＝4.5Hz,2H).
实施例5(R)-4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-8-氟-2-甲基-6-((1-((4-甲基哌嗪-1-基)甲基)环丙基)甲基)吡啶[4,3-d]嘧啶-7(6H)-酮甲酸盐
Figure PCTCN2022072814-appb-000063
LC-MS：m/z 548(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ8.98(s,1H),8.56(d,J＝7.9Hz,1H),8.19(s,1H),6.84(d,J＝6.2Hz,2H),6.73(s,1H),5.56(m,3H),4.17–4.04(m,2H),2.56–2.44(m,8H),2.32(s,3H),2.14(m,2H),1.91(s,3H),1.53(d,J＝7.0Hz,3H),0.84(dd,J＝18.5,10.0Hz,2H),0.35(s,2H).
实施例6(R)-4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-8-氟-2-甲基-6-((1-(吡咯啶-1-基甲基)环丙基)甲基)吡啶[4,3-d]嘧啶-7(6H)-酮甲酸盐
Figure PCTCN2022072814-appb-000064
LC-MS：m/z 519(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.00(s,1H),8.62(d,J＝7.8Hz,1H),8.22(s,1H),6.84(d,J＝4.6Hz,2H),6.72(s,1H),5.66–5.37(m,3H),4.15(s,2H),2.37–2.11(m,9H),1.47(m,7H),0.80(d,J＝4.9Hz,2H),0.35(s,2H).
实施例7(R)-4-((1-(3-(1,1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-8-氟-6-((1-(羟甲基)环丙基)甲基)-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000065
LC-MS：m/z 481(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ8.97(s,1H),8.82(d,J＝7.6Hz,1H),7.63–7.51(m,2H),7.50–7.36(m,2H),5.67(m,2H),4.64(m,1H),4.18(q,J＝13.5Hz,2H),3.84(t,J＝14.1Hz,2H),3.21(t,J＝7.6Hz,2H),2.30(s,3H),1.59(d,J＝7.0Hz,3H),0.69(d,J＝2.9Hz,2H),0.47(s,2H).
实施例8(R)-8-氟-4-((1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-6-((1-(羟甲基)环丙基)甲基)-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000066
LC-MS：m/z 469(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.01(s,1H),8.89(d,J＝6.7Hz,1H),7.78(t,J＝7.3Hz,1H),7.67(t,J＝7.2Hz,1H),7.39(t,J＝7.8Hz,1H),5.81–5.66(m,1H),4.68(t,J＝5.7Hz,1H),4.25(d,J＝13.5Hz,1H),4.14(d,J＝13.5Hz,1H),3.28–3.16(m,2H),2.23(s,3H),1.61(d,J＝7.1Hz,3H),0.71(d,J＝6.4Hz,2H),0.48(s,2H).
实施例9(R)-8-氟-6-((1-(甲氧基甲基)环丙基)甲基)-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000067
LC-MS：m/z 519(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.03(d,J＝7.1Hz,1H),8.94(s,1H),8.57(s,1H),8.38(s,1H),8.30(s,1H),5.71(m,1H),4.25–4.09(m,2H),3.19–3.11(m,4H),3.05(m,1H),2.26(s,3H),1.64(d,J＝7.0Hz,3H),0.80(d,J＝2.8Hz,2H),0.50(s,2H).
实施例10(R)-4-((1-(3-(1,1-二氟-2-羟乙基)苯基)乙基)氨基)-8-氟-6-((1-(甲氧基甲基)环丙基)甲基)-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000068
LC-MS：m/z 477(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ8.94(s,1H),8.85(d,J＝7.7Hz,1H),7.65–7.52(m,2H),7.49–7.37(m,2H),5.64(m,2H),4.15(q,J＝13.5Hz,2H),3.83(t,J＝14.1Hz,2H),3.17–3.04(m,5H),2.31(s,3H),1.56(t,J＝10.8Hz,3H),0.85–0.69(m,2H),0.49(s,2H).
实施例11(R)-4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-8-氟-6-((1-(甲氧基甲基)环丙基)甲基)-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000069
LC-MS：m/z 480(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ8.92(s,1H),8.75(d,J＝7.8Hz,1H),8.34(s,1H),6.84(d,J＝7.7Hz,2H),6.72(s,1H),5.69–5.45(m,3H),4.15(dd,J＝29.7,13.5Hz,2H),3.17–2.99(m,5H),2.30(s,3H),1.52(d,J＝7.0Hz,3H),0.84–0.68(m,2H),0.48(s,2H).
实施例12(R)-4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-6-((1-((环丙基(甲基)氨基)甲基)环丙基)甲基)-8-氟-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮甲酸盐
Figure PCTCN2022072814-appb-000070
LC-MS：m/z 529(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ8.81(s,1H),8.65(d,J＝7.4Hz,1H),8.39(brs,2H),6.84(d,J＝9.1Hz,2H),6.72(s,1H),5.64–5.44(m,3H),4.03(s,2H),2.39–2.24(m,4H),2.23–1.99(m,5H),1.54(d,J＝6.9Hz,3H),1.43(s,2H),0.89(m,1H),0.75(m,1H),0.48–0.20(m,4H).
实施例13(R)-4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-8-氟-6-((1-(((2-甲氧基乙基)(甲基)氨基)甲基)环丙基)甲基)-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮甲酸盐
Figure PCTCN2022072814-appb-000071
LC-MS：m/z 537(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ8.69(s,1H),8.29(d,J＝7.8Hz,1H),8.07(s,1H),6.63–6.55(m,2H),6.48(s,1H),5.38–5.24(m,3H),3.90(s,2H),2.88(m,5H),2.23(m,2H),2.07(s,3H),1.97–1.77(m,5H),1.28(d,J＝7.0Hz,3H),0.55(d,J＝5.6Hz,2H),0.09(s,2H).
实施例14(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-((1-((二甲基氨基)甲基)环丙基)甲基)-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000072
第一步：2-(6-氯-5-(1,3-二氧环戊烷-2-基)-2-甲基嘧啶-4-基)丙二酸二甲酯的制备
4,6-二氯-5-(1,3-二氧环戊烷-2-基)-2-甲基嘧啶(20.0g,85.1mmol,1.00eq)的DMSO(200mL)溶液中加入Cs 2CO 3(55.4g,170mmol,2.00eq)和丙二酸二甲酯(12.4g,93.6mmol,10.8mL,1.10eq)。得到的混合物在80℃反应10h，然后在0℃下用冰水(200mL)淬灭后用EtOAc(250mL*2)萃取。有机相合并后用饱和NaHCO 3水溶液(1000mL*2)洗涤，再经无水Na 2SO 4干燥后过滤。滤液减压浓缩得到目标产物(23.0g,产率：77.7％)。无需进一步，纯化直接用于下一步反应。
LC-MS：m/z 331(M+H) +。
第二步：(R)-2-(6-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-5-(1,3-二氧环戊烷-2-基)-2-甲基嘧啶-4-基)丙二酸二甲酯的制备
2-(6-氯-5-(1,3-二氧环戊烷-2-基)-2-甲基嘧啶-4-基)丙二酸二甲酯(7.33g,22.2mmol,1.00eq)的DMSO(110mL)溶液中加入(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(5.50g,24.4mmol,1.10eq,HCl)和DIEA(5.73g,44.3mmol,7.72mL,2.00eq)。得到的混合物在80℃反应16h，然后用冰水(200mL)淬灭后用EtOAc(200mL*3)萃取。有机相合并后用无水MgSO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析得到目标产物(7.00g,产率：65.3％)。
LC-MS：m/z 484(M+H) +。
第三步：(R)-2-(6-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-5-(1,3-二氧环戊烷-2-基)-2-甲基嘧啶-4-基)乙酸甲酯的制备
(R)-2-(6-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-5-(1,3-二氧环戊烷-2-基)-2-甲基嘧啶-4-基)丙二酸二甲酯(450mg,931umol,1.00eq)的DMSO(20.0mL)溶液中加入LiCl(157mg,3.72mmol,76.3uL,4.00eq)。得到的混合物在120℃反应8h，然后在0℃下用冰水(50mL)淬灭后用EtOAc(250mL*2)萃取。有机相合并后用饱和食盐水(500 mL*3)洗涤，再经无水MgSO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析得到目标产物(2.30g,产率：41.5％)。
LC-MS：m/z 426(M+H) +。
第四步：(R)-2-(6-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-5-(1,3-二氧环戊烷-2-基)-2-甲基嘧啶-4-基)-N-((1-((二甲基氨基)甲基)环丙基)甲基)乙酰胺的制备
(R)-2-(6-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-5-(1,3-二氧环戊烷-2-基)-2-甲基嘧啶-4-基)乙酸甲酯(0.150g,352umol,1.00eq)溶于DMSO(2.00mL)，随后加入NaOH水溶液(282mg,1.41mmol,0.320mL,20.0％purity,4.00eq)。得到的反应液在室温反应30min。随后依次加入TEA(178mg,1.76mmol,245uL,5.00eq)、1-(1-(氨甲基)环丙基)-N,N-二甲基甲胺盐酸盐(174mg,1.06mmol,3.00eq,HCl)以及HATU(469mg,1.23mmol,3.50eq)。得到的反应液在室温反应30min，随后加入H 2O(5mL)和EtOAc(10mL)分层。有机相合并后用饱和食盐水(5mL*2)洗涤，再经无水MgSO 4干燥后过滤。滤液减压浓缩得到目标产物。无需进一步，纯化直接用于下一步反应。
LC-MS：m/z 522(M+H) +。
第五步：(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-((1-((二甲基氨基)甲基)环丙基)甲基)-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮的制备
(R)-2-(6-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-5-(1,3-二氧环戊烷-2-基)-2-甲基嘧啶-4-基)-N-((1-((二甲基氨基)甲基)环丙基)甲基)乙酰胺(0.400g,307umol,40.0％purity,1.00eq)的i-PrOH(4.00mL)溶液中加入HCl(5.00M,306uL,5.00eq)。得到的反应液在50℃反应1h，然后减压浓缩。残余物用制备液相分离得到目标产物(0.0670g,产率：47.5％)。
LC-MS：m/z 460(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.15(s,1H)8.66(br d,J＝7.34Hz,1H)7.68(br t,J＝7.27Hz,1H)7.53(br t,J＝6.79Hz,1H)7.07-7.40(m,2H)6.07(s,1H)5.76(quin,J＝6.85Hz,1H)4.00-4.20(m,2H)2.20(s,3H)2.13(s,6H)1.90-2.02(m,2H)1.56(d,J＝7.09Hz,3H)0.69-0.88(m,2H)0.31(s,2H)。
按照实施例14的方法以不同的起始原料合成了以下化合物：
实施例15(R)-6-((1-(氮杂环丁烷-1-基甲基)环丙基)甲基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000073
LC-MS：m/z 472(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.24(s,1H)8.72(br d, J＝7.34Hz,1H)7.70(br t,J＝7.27Hz,1H)7.53(br t,J＝6.72Hz,1H)7.09-7.37(m,2H)6.04(s,1H)5.78(quin,J＝6.91Hz,1H)4.02-4.15(m,2H)2.96-3.10(m,4H)2.19-2.23(m,3H)2.13(s,2H)1.84-1.97(m,2H)1.58(br d,J＝6.97Hz,3H)0.59-0.73(m,2H)0.22-0.38(m,2H)。
实施例16(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-6-((1-(吡咯啉-1-基甲基)环丙基)甲基)吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000074
LC-MS：m/z 486(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.17(s,1H)8.59(br s,1H)8.20(s,1H)7.68(br t,J＝6.90Hz,1H)7.48-7.58(m,1H)7.06-7.37(m,2H)6.04(s,1H)5.77(br s,1H)4.04-4.21(m,2H)2.33-2.40(m,4H)2.19-2.29(m,5H)1.44-1.61(m,7H)0.72-0.85(m,2H)0.27-0.41(m,2H)。
实施例17(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-6-((1-(吗啡啉甲基)环丙基)甲基)吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000075
LC-MS：m/z 502(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.04(s,1H)8.40(br d,J＝7.00Hz,1H)7.48(br t,J＝7.25Hz,1H)7.36(br t,J＝6.69Hz,1H)6.85-7.21(m,2H)5.88(s,1H)5.59(br t,J＝7.07Hz,1H)3.73-4.05(m,2H)1.91-2.18(m,9H)1.39(br d,J＝7.00Hz,3H)0.66(br s,2H)0.17(br s,2H)。
实施例18(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-6-((1-((4-甲基-2-氧哌嗪-1-基)甲基)环丙基)甲基)吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000076
LC-MS：m/z 529(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ8.91(s,1H)8.35(br d,J＝7.09Hz,1H)7.79(br t,J＝7.21Hz,1H)7.53(br t,J＝6.85Hz,1H)7.01-7.09(m,1H)7.01-7.40(m,1H)6.08(s,1H)5.74(br t,J＝6.66Hz,1H)3.97-4.09(m,2H)3.38(br d,J＝5.14Hz,2H)2.91-3.07(m,2H)2.60(br s,2H)2.20(s,6H)1.90(s,2H)1.59(d,J＝6.97 Hz,3H)0.76-0.91(m,2H)0.52(s,2H)。
实施例19(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-6-((1-((4-甲基-3-氧哌嗪-1-基)甲基)环丙基)甲基)吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000077
LC-MS：m/z 529(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.00(s,1H)8.39(br d,J＝6.88Hz,1H)7.48(br t,J＝7.07Hz,1H)7.36(br t,J＝6.88Hz,1H)6.89-7.22(m,2H)5.88(s,1H)5.30-5.69(m,1H)3.81-4.04(m,2H)2.82-3.01(m,4H)2.62-2.78(m,2H)2.52(s,3H)1.95-2.11(m,5H)1.41(br d,J＝7.00Hz,3H)0.55-0.77(m,2H)0.21(br s,2H)。
实施例20(R)-4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-((1-(吡咯啉-1-基甲基)环丙基)甲基)吡啶[4,3-d]嘧啶-7(6H)-酮
Figure PCTCN2022072814-appb-000078
LC-MS：m/z 501(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.16(s,1H)8.53(br s,1H)8.20(br s,1H)6.85(br d,J＝7.46Hz,2H)6.64-6.76(m,1H)6.07(s,1H)5.35-5.63(m,3H)4.09-4.19(m,2H)2.45(br s,4H)2.33(br s,2H)2.26(s,3H)1.43-1.62(m,7H)0.82(br d,J＝6.11Hz,2H)0.38(br s,2H)。
实施例21生物学测试评价
以下生物学测试例进一步描述解释本发明，但这些实例并非意味着限制本发明的范围。
I.化合物对KRAS  G12C和SOS1结合的抑制实验。
实验步骤
(1)待测化合物梯度稀释：将10mM母液(溶解于100％DMSO)加入384孔测试板中，DMSO最终含量为0.25％。
(2)将5ul Tag1-SOS1溶液加入测试板中，对照组加入5ul稀释缓冲液。
(4)向测试板中加入5ul Tag2-KRAS G12C溶液。
(4)将10ul Anti-Tag1-Tb3+和Anti-Tag2-XL665检测液加入测试板中。1000rpm离心1分钟，室温孵育2hr。
(5)读板
(6)最后应用GraphPad Prism软件计算化合物的IC 50值，并绘出拟合曲线。
本发明中实施例化合物对KRAS  G12C酶和SOS1结合的抑制活性见表1。
表1本发明中实施例化合物抑制活性
IC 50 (nM)
实施例1 49
实施例2 17
实施例3 /
实施例4 15
实施例5 24
实施例6 7.3
实施例7 24
实施例8 146
实施例9 >1000
实施例10 74
实施例11 70
实施例12 17
实施例13 9.1
从表1可以看出：
本发明实施例化合物对于KRAS G12C和SOS1的结合显示出了很好的抑制活性。
II.化合物对H358细胞增殖的抑制实验
实验步骤
1.细胞培养
(a)复苏细胞于T75细胞培养瓶中：
表2 H358细胞的培养
编号 细胞系 培养基(Medium) 传代#T75
1 NCI-H358 RPMI 1640+10％FBS+1％PS 2～3x10 6
(b)当细胞融合度达到80-90％，对细胞进行传代。
2.细胞增殖检测
实验步骤
利用纳升移液系统将稀释好的待测化合物加入384孔细胞培养板中,设置复孔。阴性对照组加入等体积的DMSO，1000rpm室温离心1min。
将细胞接种到a)384培养板中，阴性对照组加入等量等体积细胞。1000rpm室温离心 1min，最终化合物的DMSO终浓度为0.5％，放置于37℃，5％CO2恒温培养箱孵育7天。
加入20μL/well的
Figure PCTCN2022072814-appb-000079
3D至b)384孔细胞培养板中，避光320rpm震荡20min，避光室温孵育2hrs。
用Envision多功能酶标仪读取发光值。
3.数据分析
用下列公式来计算检测化合物的抑制率(Inhibition rate，IR)：IR(％)＝(1–(RLU化合物–RLU空白对照)/(RLU溶媒对照–RLU空白对照))*100％。在Excel中计算不同浓度化合物的抑制率，然后用GraphPad Prism软件作抑制曲线图和计算相关参数，包括最小抑制率，最大抑制率及IC 50。实验结果如表3所示。
表3本发明中实施例化合物H358细胞增殖抑制活性
IC 50 (nM)
实施例4 395
实施例5 646
实施例6 20.4
实施例7 3577
实施例10 1370
实施例13 15
实施例14 69.7
实施例15 65.3
实施例16 68.8
实施例17 247
实施例18 603.4
实施例19 3169
实施例20 22
从表3可以看出：
本发明实施例化合物对于KRAS G12C突变的H358细胞增殖显示出了很好的抑制活性。
药代动力学测试评价
雄性SD大鼠，体重220g左右，禁食过夜后，灌胃给予10mg/kg本发明化合物的溶液[CMC/TW80为载体]。分别在给于本发明化合物后0.5，1.0，2.0，4.0，6.0，8.0，12，24、36和48h采血，用LC/MS/MS测定血浆中本发明化合物的浓度。
由检测结果看出，本发明化合物具有良好的药代动力学特性。
抗肿瘤药效学评价
将100uL含5x10 6MIA PaCa-2肿瘤细胞悬液皮下接种到裸鼠右后侧腹部。每天监 测小鼠健康状况，当肿瘤生长至可触及时开始测量。肿瘤体积计算公式采用:0.5xLxW 2，其中L、W分别代表肿瘤长、宽。肿瘤长至～150mm 3，对小鼠进行随机分组。小鼠每天灌胃给予相应剂量(15、50mg/Kg)化合物的CMC-Na悬液，同时对其一般状态进行监测。肿瘤每周测量3次，体重每周测量两次。
由检测结果看出，本发明化合物具有良好的抗肿瘤效果。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
    Figure PCTCN2022072814-appb-100001
    式中：
    Z选自取代或未取代的下组基团：C 1-C 18亚烷基、氘代C 1-C 18亚烷基和卤代C 1-C 18亚烷基；其中，所述取代是指被一个或多个R a取代；
    W选自取代或未取代的下组基团：C 3-C 20亚环烷基、4-20元亚杂环基；其中，所述取代是指被一个或多个R a取代；
    R 1选自下组：氢、氘、卤素、氰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 6环烷基和取代或未取代的4-6元杂环基；其中，所述取代是指被一个或多个R a取代；
    R 2相同或不同，各自独立地选自下组：-(CH 2) mO(CH 2) pR 7、-(CH 2) mSR 7、-(CH 2) mCOR 7、-(CH 2) mC(O)OR 7、-(CH 2) mS(O) qR 7、-(CH 2) mNR 7R 8、-(CH 2) mC(O)NR 7R 8、-(CH 2) mNR 7C(O)R 8、-(CH 2) mNR 7C(O)NR 8R 9、-(CH 2) mS(O) qNR 7R 8、-(CH 2) mNR 7S(O) qR 8、-(CH 2) mNR 7S(O) qNR 8R 9，其中，CH 2中的H可以任选地被取代；R 7、R 8和R 9各自独立地选自下组：氢、取代或未取代C 1-C 18烷基、取代或未取代C 3-C 20环烷基、取代或未取代4-20元杂环基和取代或未取代C 1-C 18烷氧基；或者在-(CH 2) mNR 7R 8、-(CH 2) mC(O)NR 7R 8、-(CH 2) mS(O) qNR 7R 8中，R 7和R 8与其相连的N原子环合形成取代或未取代4-20元杂环基；或者在-(CH 2) mNR 7C(O)R 8、-(CH 2) mNR 7C(O)NR 8R 9、-(CH 2) mNR 7S(O) qR 8、-(CH 2) mNR 7S(O) qNR 8R 9中，R 8和R 9与其相连的N原子环合形成取代或未取代4-20元杂环基，或者R 7和R 8与其相邻的原子环合形成取代或未取代的4-20元杂环基；其中，所述取代是指被一个或多个R a取代；
    R 3选自取代或未取代的下组基团：C 3-C 18环烷基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；其中，所述取代是指被一个或多个R a取代；
    R 4和R 5各自独立地选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基和4-6元杂环基；其中，所述取代是指被一个或多个R a取代；
    R 6选自下组：氢、氘、卤素、氨基、氰基、取代或未取代的C 1-C 6烷基和取代或未取代的C 3-C 6环烷基；其中，所述取代是指被一个或多个R a取代；
    其中，R a选自下组：氘、取代或未取代C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、取代或未取代C 3-C 20环烷基、取代或未取代C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、取代或未取代C 6-C 14芳基、取代或未取代5-14元杂芳基、取 代或未取代4-20元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基；其中，R a中所述取代是指被一个或多个选自下组的基团取代：氘、C 1-C 6烷基、C 3-C 6环烷基、3-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基；
    m独立地为1、2、3、4或5；
    n独立地为1、2、3、4或5；
    p独立地为0、1、2、3、4或5；
    q独立地为1或2。
  2. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(II)所示结构：
    Figure PCTCN2022072814-appb-100002
    式中，R 1、R 2、R 3、R 4、R 5、Z、W、n的定义如权利要求1所述。
  3. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(III)所示结构：
    Figure PCTCN2022072814-appb-100003
    式中，R 1、R 2、R 3、R 4、Z、W、n的定义如权利要求1所述。
  4. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(IV)所示结构：
    Figure PCTCN2022072814-appb-100004
    式中，R 1、R 2、R 3、R 4、Z、W、n的定义如权利要求1所述。
  5. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(V)所示结构：
    Figure PCTCN2022072814-appb-100005
    式中，
    R 10和R 11各自独立地选自取代或未取代的下组基团：H、氘、C 1-C 6烷基、氘代C 1-C 6烷基和卤代C 1-C 6烷基；或者R 10和R 11与其相连的C一起环合形成取代或未取代C 3-C 6环烷基或取代或未取代4-6元杂环基；
    所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
    t为1、2、3、4、5或6；
    R 1、R 2、R 3、W和n的定义如权利要求1所述。
  6. 如权利要求1-5中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，W选自：取代或未取代C 3-C 6亚环烷基或取代或未取代3-6元亚杂环基；其中，所述取代是指被一个或多个(如2、3或4)选自下组的基团：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基。
  7. 如权利要求1-6中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，W选自：
    Figure PCTCN2022072814-appb-100006
    Figure PCTCN2022072814-appb-100007
    其中，R m选自：H、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基；
    R b选自：H、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环 基、酰基或磺酰基；
    n1为0、1、2、3或4。
  8. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(VI)所示的结构
    Figure PCTCN2022072814-appb-100008
    式中，
    R 10、R 11、R 12和R 13各自独立地选自取代或未取代的下组基团：H、氘、C 1-C 6烷基、氘代C 1-C 6烷基和卤代C 1-C 6烷基；或者R 10和R 11与其相连的C一起环合形成取代或未取代C 3-C 6环烷基或取代或未取代4-6元杂环基；或者R 12和R 13与其相连的C一起环合形成取代或未取代C 3-C 6环烷基或取代或未取代4-6元杂环基；
    R 14选自：OR 15、SR 15、COR 15、C(O)OR 15、S(O)R 15、S(O) 2R 15、NR 15R 16、C(O)NR 15R 16、NR 15C(O)R 16、NR 15C(O)NR 16R 17、S(O)NR 15R 16、S(O) 2NR 15R 16、NR 15S(O)R 16、NR 15S(O) 2R 16、NR 15S(O)NR 16R 17、NR 15S(O) 2NR 16R 17；其中，R 15、R 16和R 17各自独立地选自下组：氢、取代或未取代C 1-C 6烷基、取代或未取代C 3-C 6环烷基、取代或未取代4-6元杂环基和取代或未取代C 1-C 6烷氧基；或者在NR 15R 16、C(O)NR 15R 16、S(O)NR 15R 16、S(O) 2NR 15R 16中，R 15和R 16与其相连的N原子环合形成取代或未取代4-6元杂环基；或者在NR 15C(O)R 16、NR 15C(O)N R 16R 17、NR 15S(O)R 16、NR 15S(O) 2R 16、NR 15S(O)NR 16R 17、NR 15S(O) 2NR 16R 17中，R 16和R 17与其相连的N原子环合形成取代或未取代4-6元杂环基，或者R 15和R 16与其相邻的原子环合形成取代或未取代的4-6元杂环基；
    U选自：CR 18R 19、NR b、O；
    R 18、R 19和R m各自独立地选自：H、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基；或者R 18、R 19和相邻的C一起环合形成C 3-C 6环烷基或4-6元杂环基
    R b选自：H、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、酰基或磺酰基；
    R 10、R 11、R 12、R 13、R 15、R 16和R 17中所述取代是指被1个或多个选自下组的基团：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基；
    n1为0、1、2、3或4；
    n2和n3各自独立地为0、1、2、3或4；且n2和n3不同时为0；
    n4为1、2、3、4或5；
    R 1和R 3的定义如权利要求1所述。
  9. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(VII)所示结构：
    Figure PCTCN2022072814-appb-100009
    式中，R 1、R 3、R 10、R 11、R 12、R 13、R 14、R m、U、n1、n2、n3和n4的定义如权利要求6所述。
  10. 如权利要求1-9中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，R 3选自取代或未取代的下组基团：苯基或5-6元杂芳基，其中，所述取代是指被1个或多个选自下组的基团：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基。
  11. 如权利要求1-10中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，R 1选自下组：氢、氘、卤素、氰基、C 1-C 6烷基。
  12. 如权利要求1-12中任一项所述的具有通式(I)结构的取代嘧啶并吡啶酮类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2022072814-appb-100010
    Figure PCTCN2022072814-appb-100011
    Figure PCTCN2022072814-appb-100012
    Figure PCTCN2022072814-appb-100013
    Figure PCTCN2022072814-appb-100014
    Figure PCTCN2022072814-appb-100015
    Figure PCTCN2022072814-appb-100016
  13. 一种药物组合物，其特征在于，包含i)一种或多种权利要求1-12中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和ii)药学上可接受的载体。
  14. 一种如权利要求1-12中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或权利要求13所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与SOS1活性或表达量相关的疾病的药物或药物组合物。
  15. 如权利要求14所述的用途，其特征在于，所述疾病为癌症，优选地所述癌症选自：肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。
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