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WO2024067744A1 - 杂环取代喹唑啉及其制备方法和应用 - Google Patents

杂环取代喹唑啉及其制备方法和应用 Download PDF

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Publication number
WO2024067744A1
WO2024067744A1 PCT/CN2023/122243 CN2023122243W WO2024067744A1 WO 2024067744 A1 WO2024067744 A1 WO 2024067744A1 CN 2023122243 W CN2023122243 W CN 2023122243W WO 2024067744 A1 WO2024067744 A1 WO 2024067744A1
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group
substituted
alkyl
compound
cancer
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English (en)
French (fr)
Inventor
吕彬华
崔大为
庞旭东
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Priority claimed from CN202211186008.2A external-priority patent/CN117820305A/zh
Priority claimed from CN202310065000.9A external-priority patent/CN118344348A/zh
Application filed by Suzhou Zelgen Biopharmaceutical Co Ltd, Shanghai Zelgen Pharmatech Co Ltd filed Critical Suzhou Zelgen Biopharmaceutical Co Ltd
Publication of WO2024067744A1 publication Critical patent/WO2024067744A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicines, and specifically relates to a heterocyclic substituted quinazoline and a preparation method and application thereof.
  • Lung cancer is one of the major causes of cancer-related death in humans.
  • Lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, of which 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 approximately 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 sustained growth, and the global market is expected to reach US$54 billion in 2023.
  • 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.
  • molecular targeted drugs have gradually become a research hotspot due to their high selectivity, relatively small 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, Oclatinib, etc.
  • VEGFR inhibitors Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Donafenib, etc.
  • KRAS mutations occur in 20-40% of lung adenocarcinomas, with a higher prevalence in Western (vs Asian) populations (26% vs 11%) and in smokers (vs non-smokers) (30% vs 10%).
  • the most common mutations occur in codons 12 and 13, and the most common mutations include G12C, G12V, and G12D. So far, no drugs targeting KRAS mutations have been approved for marketing.
  • KRAS protein switches between inactive and activated states.
  • GDP guanosine diphosphate
  • GTP guanosine triphosphate
  • the conversion of KRAS between inactive and activated states is regulated by two types of factors.
  • One type is guanine nucleotide exchange factors (GEFs), which catalyze the binding of KRAS to GTP, thereby promoting the activation of KRAS, including SOS1 protein.
  • GEFs guanine nucleotide exchange factors
  • GAP GTPase activating protein
  • SOS protein is the main one found to be involved in tumors.
  • SOS proteins are widely expressed in vivo and contain two isoforms, SOS1 and SOS2.
  • Published data indicate that SOS 1 plays a key role in mutant KRAS activation and oncogenic signaling. Reduced levels of SOS1 lead to reduced proliferation and survival rates in tumor cells carrying KRAS mutations, while KRAS wild-type cell lines were not affected.
  • the effects of SOS1 loss cannot be rescued by introducing an SOS1 with a mutation in the catalytic site, indicating an important role for SOS1 GEF activity in KRAS mutant cancer cells.
  • Proteolysis is crucial and strictly regulated in the normal life activities of cells. Its process is mainly completed through the participation of the ubiquitinase system.
  • the protein to be decomposed is marked by the E1, E2 and E3 ubiquitin ligase systems, and then recognized and hydrolyzed by proteases.
  • Proteolysis regulator molecules are bifunctional active compounds. One end of the molecule is tightly bound to the target protein, and the other end is bound to the E3 ubiquitin ligase, and the two ends are connected by various connecting chains.
  • This bifunctional molecule can simultaneously recognize the target protein and the E3 ubiquitin ligase in the body, and after the target protein and the E3 ubiquitin ligase are brought closer, the target protein is ubiquitinated and then hydrolyzed through the ubiquitin-proteasome pathway. After the target protein is hydrolyzed, this bifunctional molecule can be released to participate in the next cycle of proteolysis, thereby having a catalytic effect. Therefore, in clinical practice, a low drug dose can be used to achieve efficient therapeutic effects.
  • SOS1 target protein is pathologically associated with a variety of diseases
  • new SOS1 inhibitors are currently needed for clinical treatment.
  • Highly selective and highly active heterocyclic substituted quinazolines can more effectively treat diseases such as cancer caused by KRAS mutations, as well as have the potential to reduce off-target effects, and therefore have a more urgent clinical need.
  • the purpose of the present invention is to provide a novel heterocyclic substituted quinazoline and a preparation method and application thereof.
  • the present invention provides a compound, a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, wherein the compound is a compound represented by formula (IA), formula (IB) or formula (IC):
  • A is independently selected from the following group of substituted or unsubstituted groups: C 6 -C 14 aryl, or 5-14 membered heteroaryl; wherein the substitution refers to being independently substituted by one or more R;
  • X is independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, -C ⁇ CH, C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, OX 1 , NHX 1 , or NX 1 X 2 ; wherein the substitution refers to being independently substituted by one or more R;
  • X 1 and X 2 are independently selected from the following substituted or unsubstituted groups: C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, or 5-14 membered heteroaryl; wherein the substitution refers to being independently substituted by one or more R;
  • Y 1 and Y 2 are each independently selected from CH or N, and Y 1 and Y 2 are not CH at the same time;
  • n 1 and n 2 are each independently selected from 1, 2 or 3;
  • Z is independently selected from the following group: a substituted or unsubstituted bond, a C 2 -C 18 alkynyl, a C 3 -C 20 cycloalkyl, a 4-20 membered heterocyclyl, a C 3 -C 20 cycloalkylene-C 1 -C 18 alkylene, or a 4-20 membered heterocyclylene-C 1 -C 18 alkylene; wherein the substitution refers to substitution by one or more R;
  • P 1 , P 2 , P 3 , P 6 , and P 7 are each independently selected from CR a , or N; wherein R a is independently selected from the following group: H, deuterium, F, chlorine, bromine, -OC 1 -C 6 alkyl, or -OC 1 -C 6 haloalkyl;
  • P 4 and P 5 are each independently selected from CH 2 or C ⁇ O;
  • P 9 is selected from a bond or NH
  • P 10 is selected from CH or N;
  • Each R is the same or different and is independently selected from the group consisting of H, deuterium, vinyl, ethynyl, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl alcohol, (C 3 -C 6 cycloalkyl)C 1 -C 6 alkyl, (4-6 membered heterocyclyl)C 1 -C 6 alkyl, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, (C 3 -C 6 cycloalkyloxy)C 1 -C 6 alkyl, (4-6 membered heterocyclyloxy)C 1 -C 6 alkyl, (C 1 -C 6 alkyl)vinyl, deuterated (C 1 -C 6 alkyl)vinyl, halogenated (C 1 -C 6 alkyl)vinyl, (C 1 -C
  • A is a substituted or unsubstituted phenyl group; wherein the substitution refers to being independently substituted by one or more R groups.
  • A is selected from:
  • X1 is selected from: substituted or unsubstituted C1 - C8 alkyl, substituted or unsubstituted C1 - C8 oxaalkyl, substituted or unsubstituted C3 - C6 cycloalkyl, substituted or unsubstituted C4 - C6 monooxacycloalkyl; wherein the substitution refers to being independently substituted by one or more R.
  • X1 is selected from:
  • Y 1 is selected from: N
  • Y 2 is selected from: N.
  • Y 1 is selected from: N
  • Y 2 is selected from: CH.
  • Y 1 is selected from: CH
  • Y 2 is selected from: N.
  • Y 1 is selected from: N
  • Y 2 is selected from: N or CH.
  • n1 is 2 and n2 is 2.
  • n1 is 1 and n2 is 1.
  • P 1 , P 2 , and P 3 are each independently selected from CH, CF, or N.
  • P 1 , P 2 , and P 3 are each independently CH or CF.
  • P 1 , P 2 , P 3 , P 6 , P 7 and the bond connecting them form an unsubstituted or one or more Ra- substituted phenyl group.
  • X is independently selected from the following substituted or unsubstituted groups: C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, OX 1 , NHX 1 , or NX 1 X 2 ; wherein the substitution refers to being independently substituted by one or more R;
  • substitution refers to being independently substituted by one or more R.
  • Z is selected from substituted or unsubstituted C 4 -C 6 heterocycloalkylene, or substituted or unsubstituted C 2 -C 6 alkynyl; wherein the substitution refers to being independently substituted by one or more Rs.
  • Z is selected from substituted or unsubstituted C 4 -C 6 heterocycloalkylene; wherein the substitution refers to being independently substituted by one or more R.
  • Z is selected from the following substituted or unsubstituted groups:
  • substitution refers to being independently substituted by one or more R.
  • -L 1 -L 2 - is selected from the group consisting of a substituted or unsubstituted bond, a C 1 -C 6 alkyl,
  • substitution refers to being independently substituted by one or more R.
  • the compound has a structure shown in formula (II):
  • A, X, Y 1 , Y 2 , L 1 , L, Z, P 1 , P 2 , P 3 , P 5 , n 1 , n 2 are as defined above.
  • the compound has a structure shown in formula (III):
  • A, X, Y 1 , Y 2 , L 1 , L, Z, P 1 , P 2 , P 5 , n 1 , n 2 are as defined above.
  • the compound has a structure shown in formula (IV):
  • A, X, Y 1 , Y 2 , L 1 , L, Z, P 2 , P 5 , n 1 , n 2 are as defined above.
  • the compound has a structure shown in formula (V):
  • A, X, Y 2 , L 1 , L, Z, P 2 , P 5 , n 1 , n 2 are as defined above.
  • the compound is selected from the following group:
  • A, X, Y1 , Y2 , L1 , L, Z, P1 , P2 , P3 , P4 , P5 , n1 and n2 of the compound of formula (IA), (IB) or (IC) are independently corresponding groups in the above compounds.
  • the present invention provides a method for preparing the compound of the first aspect of the present invention, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, selected from the following synthetic routes:
  • A, X, Y1 , Y2 , L1 , L, Z, P1 , P2 , P3 , P4 , P5 , n1 and n2 are as defined above.
  • the third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising i) one or more compounds described in the first aspect of the present invention, their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs; and ii) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises one or more therapeutic agents selected from the following group: 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, obin utuzumab, ofatumumab, vel
  • the present invention provides a compound as described in the first aspect of the present invention, its stereoisomers, The variant isomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or the use of the pharmaceutical composition according to the third aspect of the present invention, is used to prepare a pharmaceutical composition for preventing and/or treating diseases related to SOS1 activity or expression.
  • the disease is cancer.
  • the cancer is selected from the following group: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colon cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • the present invention provides a method for preventing and/or treating diseases related to SOS1 activity or expression, comprising the steps of administering to a subject in need thereof an effective amount of the compound as described in the first aspect of the present invention, its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administering the pharmaceutical composition as described in the third aspect of the present invention.
  • the subject is a mammal, such as a human, a rat or a mouse.
  • FIG1 is a graph showing the detection of SOS1 and ⁇ -actin contents in H358 cells after treatment with different concentrations of Compound Example A1 for 6 hours.
  • alkyl refers to a straight or branched chain alkyl group containing several carbon atoms
  • C1 - C18 alkyl refers to a straight or branched chain alkyl group having 1-18 carbon atoms, including alkyl groups of 1, 2, 3 , 4, 5 , 6, 7 , 8 , 9, 10, 11, 12, 13 , 14 , 15, 16, 17 or 18 carbon atoms, and alkyl groups are preferably C1 - C2 , C1-C3, C1- C4 , C1- C5, C1-C6, C1-C7, C1-C8 , C1 - C9 , C1 - C10 , C2 - C3 , C2 - C4 , C2 -C5 , C2 - C6 , C3 - C4 , C3- C5 , C3 - C6 Typical "alkyl” includes, but is not limited to, methyl , eth
  • alkylene by itself or as part of another substituent refers to an "alkyl” radical with one hydrogen atom removed.
  • the alkylene radical may contain 1 to 18 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms.
  • alkenyl refers to a straight or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl may include any number of carbon atoms, wherein "C2-C18 alkenyl” refers to a straight or branched hydrocarbon having 2-18 carbon atoms and at least one double bond, such as C2 , C2- C3 , C2- C4 , C2 - C5 , C2- C6 , C2- C7 , C2- C8 , C2 - C9 , C2- C10 , C3 , C3- C4 , C3-C5, C3 - C6 , C4 , C4 - C5 , C4- C6, C5 , C5 - C6 , and C6 .
  • Alkenyl may have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5 or more.
  • alkenyl groups include, but are not limited to, vinyl (vinyl group), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.
  • alkenyl groups may be substituted or unsubstituted.
  • alkynyl refers to a straight or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond.
  • Alkynyl can include any number of carbon atoms
  • C2-C18 alkynyl refers to a straight or branched hydrocarbon having 2-18 carbon atoms and at least one triple bond, such as C2 , C2- C3 , C2- C4 , C2- C5 , C2- C6 , C2 - C7 , C2 -C8, C2 - C9 , C2- C10 , C3 , C3- C4 , C3 - C5 , C3- C6 , C4 , C4- C5 , C4 - C6 , C5 , C5- C6 , and C6 .
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentenyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group having several carbon atoms
  • C 3 -C 20 cycloalkyl refers to a fully saturated cyclic hydrocarbon group having 3-20 carbon atoms, preferably C 3 -C 4 , C 3 -C 5 , C 3 -C 6 , C 3 -C 7 , C 3 -C 8 , C 3 -C 9 , C 3 -C 10.
  • Substituted C 3 -C 20 cycloalkyl refers to one or more positions in the cycloalkyl being substituted, especially 1-4 substituents, which may be substituted at any position, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
  • cycloalkyl is intended to include “substituted cycloalkyl”.
  • cycloalkylene by itself or as part of another substituent refers to a radical formed by removing two hydrogen atoms from a cycloalkyl group as described above, such as:
  • alkylene cycloalkylene refers to the group formed by removing two hydrogen atoms from the above-mentioned cycloalkylalkyl or alkylcycloalkyl, wherein "C1-C18 alkylene C3-C20 cycloalkylene” 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 a fully saturated or partially unsaturated cyclic group having a number (greater than or equal to 3) of ring atoms and 1-4 heteroatoms
  • 4-20 membered heterocyclyl refers to a fully saturated or partially unsaturated cyclic group having 4-20 ring atoms and 1-4 heteroatoms (including but not limited to 4-7 membered monocyclic, 6-11 membered bicyclic, or 8-12 membered tricyclic system).
  • the nitrogen atom or sulfur atom can be oxidized, and the nitrogen atom can also be quaternized.
  • the 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, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,
  • Polycyclic heterocyclic groups include spirocyclic, fused and bridged heterocyclic groups; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms on the ring.
  • heterocyclylene refers to a group formed by removing two hydrogen atoms from the above heterocyclyl, including but not limited to: wait.
  • heterocycloalkylene alkylene refers to a group formed by removing two hydrogen atoms from a cycloalkylalkyl or 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 compound radical having 1-5 rings, particularly monocyclic and bicyclic radicals such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, particularly 1-3 substituents, which may be substituted at any position.
  • arylene group refers to a group formed by removing two hydrogen atoms from the above aryl groups.
  • heteroaryl refers to a heteroaromatic system containing 1-4 (e.g. 2 or 3) heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur, and the heterocyclic group may include 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms.
  • the heteroaryl group is preferably a 5- to 10-membered ring, more preferably a 5- or 6-membered ring, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazoxinyl, triazolyl and tetrazolyl, etc.
  • pyrrolyl pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazoxinyl, triazolyl and tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted, and when substituted, the substituent is 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.
  • heteroarylene refers to a group formed by removing two hydrogen atoms from the above heteroaryl groups.
  • C1-C18 alkoxy refers to a linear or branched or cyclic alkyloxy group having 1 to 18 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C1-C8 alkoxy group, more preferably a C1-C6 alkoxy group or a C1-C4 alkoxy group.
  • C1-C18 alkyleneoxy refers to a group obtained by removing a hydrogen atom from a "C1-C18 alkoxy” group.
  • halogen refers to chlorine, bromine, fluorine, iodine.
  • halo refers to substitution with halogen.
  • deuterated refers to substitution with deuterium ( 2H ).
  • hydroxyl refers to a group having the structure OH.
  • nitro refers to a group with the structure NO2 .
  • cyano refers to a group having the structure CN.
  • ester group refers to a group with the structure -COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.
  • amine group refers to a group with the structure -NRR', wherein 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 fragment.
  • amido refers to a group having the structure -CONRR', wherein 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 fragment.
  • sulfonamido refers to a group with the structure -SO2NRR ', wherein 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 fragment.
  • urea group 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 fragment.
  • alkylaminoalkyl refers to a group having the structure -RNHR', wherein 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 having the structure -RNHR'R", wherein R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl. R, R' and R" may be the same or different in the dialkylamine fragment.
  • heterocyclylalkyl refers to a group with the structure -RR', wherein R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; and R' represents a heterocycle or a substituted heterocycle.
  • substituted refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent.
  • the specific substituent is a substituent described above, or a substituent appearing in the embodiments.
  • a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.
  • the substitution may be substitution with one or more substituents selected from the following group: for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C8 cycloalkyl, 4-12 membered heterocyclic group, aryl, heteroaryl, C1 - C8 aldehyde group, C2 - C10 acyl group, C2 - C10 ester group, amine group, C1 - C6 alkoxy group, C1 - C10 sulfonyl group, and C1 - C6 urea group, etc.
  • substituents selected from the following group: for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1 - C6 alkyl, C2 - C6 alkenyl, C2 -
  • any heteroatom that does not have sufficient hydrogen atoms to complete its valence is assumed to have sufficient hydrogen atoms to complete its valence.
  • a substituent is a non-terminal substituent, it is a substituent of the corresponding group, for example, alkyl for alkylene, cycloalkyl for cycloalkylene, heterocyclyl for heterocyclylene, alkoxy for alkyleneoxy, and the like.
  • the term "plurality” refers to two or more, such as 2, 3, 4, 5 or 6.
  • compounds of the present invention refers to compounds represented by formula (IA), formula (IB) or formula (IC), and also includes stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds:
  • A, X, Y 1 , Y 2 , L 1 , L, Z, P 1 , P 2 , P 3 , P 4 , P 5 , n 1 , n 2 are as described above.
  • salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts.
  • the term "salt” used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base.
  • the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions (“inner salts”) that may be formed are included in the scope of the term "salt".
  • compositions of the present invention may form salts, for example, compound I reacts with a certain amount of acid or base, such as an equivalent amount, and is salted out in a medium, or freeze-dried in an aqueous solution.
  • the compounds of the present invention contain basic fragments, 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 (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor salt, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide.
  • salts such as hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonates, dodecanoates, and the like.
  • hydroxyethanesulfonates e.g., 2-hydroxyethanesulfonate
  • Certain compounds of the present invention may contain acidic fragments, 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 with organic bases (such as organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromides), etc.
  • alkyl halides such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl
  • dialkyl sulfates such as dimethyl sulfate, diethyl s
  • Prodrugs and solvates of the compounds of the present invention are also within the scope of the invention.
  • the term "prodrug” herein refers to a compound that undergoes chemical transformation by metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when treating 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 (such as amides and imino ethers). All these tautomers are part of the present invention.
  • All stereoisomers of the compounds are contemplated by the present invention.
  • Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer with a particular activity), or may be a mixture, such as a racemate, or a mixture with all other stereoisomers or a portion thereof.
  • the chiral centers of the present invention have two configurations, S or R, according to the theory. The definition was proposed by the International Union of Applied Chemistry (IUPAC) in 1974.
  • Racemic forms can be resolved by physical methods, such as fractional crystallization, or by derivatization into diastereoisomers and separate crystals, or by chiral column chromatography.
  • Individual optical isomers can be obtained from racemates by appropriate methods, including but not limited to conventional methods, such as recrystallization after salt formation with an optically active acid.
  • the compounds of the present invention are prepared, separated and purified to obtain compounds with a weight content of equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), which are listed in the text description. Such "very pure" compounds of the present invention are also considered part of the present invention.
  • All configurational isomers of the compounds of the present invention are within the scope of the invention, whether in mixture, pure or very pure form.
  • the definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures and other mixtures.
  • asymmetric carbon atoms may represent substituents, such as alkyl. All isomers and their mixtures are included in the present invention.
  • the ratio of isomers contained in the mixture of isomers can be various.
  • the mixture of only two isomers there can be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention.
  • Similar ratios that are easily understood by those of ordinary skill in the art, and ratios for more complex mixtures of isomers are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers.
  • isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2H , 3H , 13C , 11C , 14C , 15N , 18O , 17O , 31P , 32P , 35S , 18F and 36Cl , respectively.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention such as radioactive isotopes of 3H and 14C , are also included, which are useful in tissue distribution experiments of drugs and substrates.
  • Tritium, i.e. 3H and carbon-14, i.e. 14C are relatively easy to prepare and detect. They are the first choice among isotopes.
  • Isotopically labeled compounds may be prepared by conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents. The protocols disclosed in the examples can be prepared.
  • a synthesis of a specific enantiomer of the compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture can be separated, and the chiral auxiliary can be removed to obtain the pure enantiomer.
  • a diastereomeric salt can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography, and then the pure enantiomer can be obtained.
  • the compounds of the present invention can be replaced with any number of substituents or functional groups to expand its scope.
  • the term “substituted” appears before or after the term “optional” or “optionally”, and the general formula including substituents in the formulation of the present invention refers to replacing hydrogen free radicals with designated structural substituents. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents can be the same or different at each position.
  • substituted used herein includes all allowed organic compound substitutions. In a broad sense, allowed substituents include non-cyclic, cyclic, branched non-branched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatom nitrogen can have hydrogen substituents or any allowed organic compounds described above to supplement its valence.
  • the present invention is not intended to limit the allowed substitution of organic compounds in any way.
  • the present invention believes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases.
  • stable refers to compounds that are stable and that maintain the structural integrity of the compound over a period of time sufficient to be detected, and preferably over a period of time sufficient to be effective, as used herein for the purposes described above.
  • the preparation method of the compound 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 optionally combined with various synthetic methods described in this specification or known in the art and easily prepared, and such combination can be easily carried out by those skilled in the art to which the present invention belongs.
  • the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • A, X, Y1 , Y2 , L1 , L, Z, P1 , P2 , P3 , P4 , P5 , n1 and n2 are as defined above.
  • compositions Use and methods of administration
  • the pharmaceutical composition of the present invention comprises the above active ingredients and a pharmaceutically acceptable carrier.
  • the compounds of the present invention can reduce the activity and expression of SOS1, promote SOS1 protein degradation and/or reduce the level of SOS1, and thus can be used to prevent and/or treat diseases related to SOS1 activity or expression.
  • the pharmaceutical composition of the present invention can be used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
  • the cancer is a cancer caused by KRAS mutation.
  • the cancer includes (but is not limited to): lung cancer (small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC)), breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colon cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • breast cancer breast cancer
  • prostate cancer esophageal cancer
  • colorectal cancer colorectal cancer
  • bone cancer kidney cancer
  • gastric cancer gastric cancer
  • liver cancer colon cancer
  • melanoma lymphoma
  • blood cancer brain tumor
  • myeloma myeloma
  • soft tissue sarcoma pancreatic cancer
  • the compounds of the present invention may be used in combination with other drugs known to treat or improve similar conditions.
  • the combination When the combination is administered, the original drug administration and dosage can remain unchanged, and the compound of the present invention is taken simultaneously or subsequently.
  • a pharmaceutical composition containing one or more known drugs and the compound may be preferably used.
  • Drug combination also includes taking the compound of the present invention and one or more other known drugs in overlapping time periods.
  • the dosage of the compound or known drug may be lower than the dosage of the compound or known drug when taken alone.
  • the drugs or active ingredients that can be used in combination with the compounds of the present invention 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 forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, film, pill, external ointment, controlled release or sustained release or nano preparation.
  • the pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
  • safe and effective amount means: 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 per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Some examples of pharmaceutically acceptable carriers 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, flavoring agents, 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, etc.
  • the administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods 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 the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrators, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example,
  • Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into 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.
  • the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottons
  • composition may also include 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, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may include 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 the 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.
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill range of a skilled physician.
  • the present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate to form a pharmaceutical composition.
  • the present invention also provides a treatment method, which comprises the steps of administering the compound of the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or administering the pharmaceutical composition of the present invention to a subject in need of treatment, for selectively inhibiting SOS1.
  • the present invention has the following main advantages:
  • the compound can selectively promote the hydrolysis of SOS1 protein, thereby preventing and/or treating diseases related to SOS1 activity or expression (especially high selectivity for tumor cells), with high activity and good safety;
  • the compounds of the present invention can inhibit cell proliferation in a catalytic amount. They can circulate in the cells to degrade target proteins, thereby reducing the dosage, extending the administration cycle, and achieving a safe and effective anti-tumor effect;
  • the compound has better in vitro and in vivo pharmacodynamics, pharmacokinetic properties and/or lower toxic side effects.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • NMR NMR was measured using a Bruker AVANCE-400 NMR spectrometer.
  • the measurement solvents included deuterated dimethyl sulfoxide (DMSO), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol (CD 3 OD).
  • DMSO deuterated dimethyl sulfoxide
  • CD 3 COCD 3 deuterated acetone
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts were measured in parts per million (ppm).
  • LC-MS Liquid chromatography-mass spectrometry
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20 mm, and preparative thin layer chromatography uses 0.4 mm-0.5 mm.
  • 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 using or according to literature data reported in the art.
  • Step 1 Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindole-1,3-dione
  • Step 2 Preparation of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperazine-4-carboxaldehyde
  • Step 1 Preparation of methyl 2-bromo-4-(4-(dimethoxymethyl)piperidin-1-yl)benzoate
  • Step 2 Preparation of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-formylbenzoate
  • the resulting mixture was reacted at 65° C. for 16 h under nitrogen protection, then diluted with ice water (50 mL) and extracted with EtOAc (100 mL*2). The combined organic phase was washed with saturated brine (50 mL*3), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (1.60 g, 4.98 mmol, 61.2% yield).
  • Step 3 Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindole-2-yl)piperidin-2,6-dione
  • Step 4 Preparation of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindole-5-yl)piperidine-4-carboxaldehyde
  • Step 2 Preparation of 3-(5-(3-(4-(dimethoxymethyl)piperidin-1-yl)prop-1-yn-1-yl)-1-oxoisoindole-2-yl)piperidine-2,6-dione
  • Step 3 Preparation of 1-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindole-5-yl)prop-2-yn-1-yl)piperidine-4-carboxaldehyde
  • Step 4 Preparation of N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-bromo-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine
  • Step 5 Preparation of tert-butyl 4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazoline-7-yl)piperazine-1-carboxylate
  • Step 6 Preparation of tert-butyl 4-(4-(((R)-1-(3-(((benzyloxy)carbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazine-1-carboxylate
  • Step 7 Preparation of benzyl (3-((R)-1-((2-methyl-7-(piperazin-1-yl)-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate
  • Step 3 Preparation of 1-(2-chloro-5-(4-(dimethoxymethyl)piperidin-1-carboxyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione
  • HATU (1.06 g, 2.79 mmol, 1.50 eq) and DIEA (481 mg, 3.72 mmol, 648 ⁇ L, 2.00 eq) were added to a solution of 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid (0.500 g, 1.86 mmol, 1.00 eq) in DMF (20 mL). The reaction mixture was reacted at 25°C for 0.5 h, and then 4-(dimethoxymethyl)piperidine (356 mg, 2.23 mmol, 1.20eq).
  • Step 4 Preparation of 1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidine-4-carboxaldehyde
  • Step 1 Preparation of benzyl (3-((1R)-1-((7-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate
  • Step 2 Preparation of 5-(4-((4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
  • Example A6 3-(5-(3-(4-(4-(4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazin-1-yl)piperidin-1-yl)prop-1-yn-1-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione
  • Example B1 (3-((R)-1-((7-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino)ethyl)-5-trifluoromethyl(phenyl)carbamic acid benzyl ester
  • Example B2 1-(5-(4-(4-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione
  • Example B3 1-(5-(4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione
  • Example B4 1-(5-(4-((4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione
  • Example B5 1-(5-(4-(4-(4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione
  • the cells were inoculated into a) 384 culture plate, and the negative control group was added with an equal volume of cells, and the positive control group was added with an equal volume of culture medium only. Centrifuged at 1000 rpm for 1 min at room temperature, and the final DMSO concentration of the compound was 0.5%, and incubated in a 37°C, 5% CO2 constant temperature incubator for 7 days.
  • the luminescence value was read using Envision multi-function microplate reader.
  • the structure of the reference compound BI-3406 is as follows:
  • IR (%) (1-(RLU compound-RLU blank control)/(RLU solvent control-RLU blank control))*100%.
  • the inhibition rates of different concentrations of the compound were calculated in Excel, and then the inhibition curves were plotted and related parameters were calculated using GraphPad Prism software, including the minimum inhibition rate, maximum inhibition rate, and IC 50 .
  • the experimental results are shown in Table 3.
  • Inoculate tumor cells e.g. H358, 5X105-1X06
  • a culture dish (2D, P100mm dish) and culture for 2-4 days until 70-80% saturation;

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Abstract

本发明涉及杂环取代喹唑啉及其制备方法和应用。具体地，本发明化合物具有式(IA)、式(IB)或式(IC)所示结构，且所述化合物对SOS1水解具有很好的选择性调节作用。

Description

杂环取代喹唑啉及其制备方法和应用 技术领域
本发明属于药物领域，具体涉及一种杂环取代喹唑啉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。
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)。
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％vs11％)，在吸烟者(vs非吸烟者)中更高(30％vs10％)。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SOS1 GEF活性在KRAS突变癌细胞中的重要作用。
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。
蛋白水解在细胞的正常生命活动中是至关重要且被严格调控的，其过程主要是通过泛素化酶系统的参与而完成的。待分解的蛋白质通过E1、E2和E3泛素连接酶系统标记，进而被蛋白酶识别并水解。蛋白水解调节剂类分子是一种双功能活性化合物，分子的一端与靶蛋白紧密结合，另一端与E3泛素连接酶相结合，两端并通过各种连接链连接。这种双功能分子在体内可以同时识别靶蛋白和E3泛素连接酶，将靶蛋白和E3泛素连接酶拉近后使靶蛋白被泛素化，然后通过泛素-蛋白酶体途径水解。靶蛋白水解后，这个双功能性分子又可以被释放出来参与到下一周期的蛋白水解过程，从而具有催化效果，因此在临床上可以通过较少的药物给药剂量就可以实现高效的治疗作用。
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。高选择性高活性的杂环取代喹唑啉可以对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杂环取代喹唑啉及其制备方法和应用。
本发明第一方面，提供了一种化合物、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，所述化合物为式(IA)、式(IB)或式(IC)所示的化合物：
各式中：
A独立地选自取代或未取代的下组基团：C6-C14芳基、或5-14元杂芳基；其中，所述取代是指独立地被一个或多个R取代；
X独立地选自取代或未取代的下组基团：H、D、卤素、CN、-C≡CH、C1-C18烷基、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、OX1、NHX1、或NX1X2；其中，所述取代是指独立地被一个或多个R取代；
X1、X2独立地选自取代或未取代的下组基团：C1-C18烷基、C3-C20环烷基、4-20元杂环基、C6-C14芳基、或5-14元杂芳基；其中，所述取代是指独立地被一个或多个R取代；
Y1、Y2各自独立地选自CH或N，且Y1、Y2不同时为CH；
n1、n2各自独立地选自1、2或3；
L1、L2各自独立地选自取代或未取代的下组基团：键、O、C＝O、NH、N(C1-C3烷基)、C2-C18烯基、C2-C18炔基、C1-C18亚烷基、C3-C20亚环烷基、4-20元亚杂环基、C3-C20亚环烷基-C1-C18亚烷基、或4-20元亚杂环基-C1-C18亚烷基；其中，所述取代是指独立地被一个或多个R取代；
Z独立地选自取代或未取代的下组基团：键、C2-C18炔基、C3-C20环烷基、4-20元杂环基、C3-C20亚环烷基-C1-C18亚烷基、或4-20元亚杂环基-C1-C18亚烷基；其中，所述取代是指被一个或多个R取代；
P1、P2、P3、P6、P7各自独立地选自CRa、或N；其中Ra独立地选自下组：H、氘、F、氯、溴、-OC1-C6烷基或-OC1-C6卤代烷基；
P4、P5各自独立地选自CH2或C＝O；
P8选自键或C＝O；
P9选自键或NH；
P10选自CH或N；
各R相同或不同，各自独立地选自：H、氘、乙烯基、乙炔基、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、卤代C1-C6烷基醇、(C3-C6环烷基)C1-C6烷基、(4-6元杂环基)C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、(C3-C6环烷基氧基)C1-C6烷基、(4-6元杂环基氧基)C1-C6烷基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C6环烷基)乙炔基、(4-6元杂环基)乙炔基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、5-10元杂芳基、卤素、硝基、羟基、氧代基(＝O)、氰基、酯基、胺基、酰胺基、砜基或脲基。
在另一优选例中，A为取代或未取代的苯基；其中，所述取代是指独立地被一个或多个R取代。
在另一优选例中，A选自：
在另一优选例中，X1选自：取代或未取代的C1-C8烷基、取代或未取代的C1-C8氧杂烷基、取代或未取代的C3-C6环烷基、取代或未取代的C4-C6单氧杂环烷基；其中，所述取代是指独立地被一个或多个R取代。
在另一优选例中，X1选自：
在另一优选例中，Y1选自：N，Y2选自：N。
在另一优选例中，Y1选自：N，Y2选自：CH。
在另一优选例中，Y1选自：CH，Y2选自：N。
更优选地，Y1选自：N，Y2选自：N或CH。
在另一优选例中，n1为2，n2为2。
在另一优选例中，n1为1，n2为1。
在另一优选例中，P1、P2、P3各自独立地选自CH、CF、或N。
在另一优选例中，P1、P2、P3各自独立地为CH或CF。
在另一优选例中，式IC中，P1、P2、P3、P6、P7及其连接的键形成未取代或一个或多个Ra取代的苯基。
在另一优选例中，X独立地选自取代或未取代的下组基团：C1-C18烷基、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、OX1、NHX1、或NX1X2；其中，所述取代是指独立地被一个或多个R取代；
在另一优选例中，选自取代或未取代的下组基团：
其中，所述取代是指独立地被一个或多个R取代。
在另一优选例中，Z选自取代或未取代的C4-C6亚杂环烷基、或取代或未取代的C2-C6炔基；其中，所述取代是指独立地被一个或多个R取代。
在另一优选例中，Z选自取代或未取代的C4-C6亚杂环烷基；其中，所述取代是指独立地被一个或多个R取代。
在另一优选例中，Z选自取代或未取代的下组基团：
其中，所述取代是指独立地被一个或多个R取代。
在另一优选例中，-L1-L2-选自取代或未取代的下组基团：键、C1-C6烷基、
其中，所述取代是指独立地被一个或多个R取代。
在另一优选例中，所述化合物具有式(II)所示结构：
其中：A、X、Y1、Y2、L1、L、Z、P1、P2、P3、P5、n1、n2如上定义。
在另一优选例中，所述化合物具有式(III)所示结构：
其中：A、X、Y1、Y2、L1、L、Z、P1、P2、P5、n1、n2如上定义。
在另一优选例中，所述化合物具有式(IV)所示结构：
其中：A、X、Y1、Y2、L1、L、Z、P2、P5、n1、n2如上定义。
在另一优选例中，所述化合物具有式(V)所示结构：
其中：A、X、Y2、L1、L、Z、P2、P5、n1、n2如上定义。
在另一优选例中，所述化合物选自下组：










在另一优选例中，式(IA)、式(IB)或式(IC)化合物的A、X、Y1、Y2、L1、L、Z、P1、P2、P3、P4、P5、n1、n2独立地为上述化合物中所对应的基团。
本发明第二方面，提供了一种制备本发明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、溶剂合物或前药的方法，选自以下合成路线：
式(V-I)和式(V-II)化合物通过取代反应、或还原胺化反应、或偶联反应、或酰胺缩合反应等得到式(IA)化合物；
其中：
A、X、Y1、Y2、L1、L、Z、P1、P2、P3、P4、P5、n1、n2如上定义。
LG1或LG2相同或不同，为离去基团，各自优选自：氢、OH、＝O、卤素、OTs、OMs、OTf、B(OH)2等。
本发明第三方面，提供了一种药物组合物，包含i)一种或多种本发明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,ibritumomabtiuxetan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。
本发明第四方面，提供了一种如本发明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，或本发明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，所述癌症选自下组：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，提供了一种预防和/或治疗SOS1活性或表达量相关的疾病的方法，其包括步骤：向有需要的对象施用有效量的如本发明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，或施用本发明第三方面所述的药物组合物。
在另一优选例中，所述对象为哺乳动物，如人、大鼠或小鼠。
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。
附图说明
图1为化合物实施例A1不同浓度处理6小时后，H358细胞中，SOS1和β-actin含量的检测。
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针对SOS1的蛋白水解调节剂。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。
如文本所用，术语“烷基”是指包含若干个碳原子的直链或支链烷基，如“C1-C18烷基”是指具有1-18个碳原子的直链或支链烷基，包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个碳原子的烷基，烷基优选例如C1-C2、C1-C3、C1-C4、C1-C5、C1-C6、C1-C7、C1-C8、C1-C9、C1-C10、C2-C3、C2-C4、C2-C5、C2-C6、C3-C4、C3-C5、C3-C6、C3-C7、C3-C8、C4-C5、C4-C6或C5-6。典型的“烷基”包括但不限于甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、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。本发明中，烷基还包括取代烷基。“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。
术语“亚烷基”本身或作为另一取代基的一部分是指“烷基”再脱掉一个氢原子所形成的基团，亚烷基可包含1-18个碳原子，如包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个碳原子。例如，亚甲基、亚乙基、亚丙基、亚异丙基(如)、亚丁基(如)、亚戊基(如)、亚己基(如)、亚庚基(如)等。
如文本所用，术语“烯基”是指具有至少2个碳原子和至少一个双键的直链或支链烃。烯基可包括任何数量的碳原子数，其中，“C2-C18烯基”是指具有2-18个碳原子和至少一个双键的直链或支链烃，例如C2、C2-C3、C2-C4、C2-C5、C2-C6、C2-C7、C2-C8、C2-C9、C2-C10、C3、C3-C4、C3-C5、C3-C6、C4、C4-C5、C4-C6、C5、C5-C6和C6。烯基可具有任何合适数量的双键，包括但不限于1、2、3、4、5或更多个。烯基的实例包括但不限于乙烯基(乙烯基团))、丙烯基、异丙烯基、1-丁烯基、2-丁烯基、异丁烯基、丁二烯基、1-戊烯基、2-戊烯基、异戊烯基、1，3-戊二烯基、1，4-戊二烯基、1-己烯基、2-己烯基、3-己烯基、1，3-己二烯基、1，4-己二烯基、1，5-己二烯基、2，4-己二烯基、或1，3，5-己三烯基。与上述烷基一样，烯基可以是取代的或未取代的。
如文本所用，术语“炔基”是指具有至少2个碳原子和至少一个三键的直链或支链烃。炔基可包括任何数量的碳原子，“C2-C18炔基”是指具有2-18个碳原子和至少一个三键的直链或支链烃，例如C2、C2-C3、C2-C4、C2-C5、C2-C6、C2-C7、C2-C8、C2-C9、C2-C10、C3、C3-C4、C3-C5、C3-C6、C4、C4-C5、C4-C6、C5、C5-C6和C6。炔基的实例包括但不限于乙炔基、丙炔基、1-丁炔基、2-丁炔基、异丁炔基、仲丁炔基、丁二炔基、1-戊炔基、2-戊炔基、异戊炔基、1，3-戊二炔基、1，4-戊二炔基、1-己炔基、2-己炔基、3-己炔基、1，3-己二炔基、1，4-己二炔基、1，5-己二炔基、2，4-己二炔基、或1，3，5-己三炔基。
如文本所用，术语“环烷基”是指具有若干个碳原子的完全饱和的环状烃类基团，其中，“C3-C20环烷基”是指具有3-20个碳原子的完全饱和的环状烃类基团，优选地为C3-C4、C3-C5、C3-C6、C3-C7、C3-C8、C3-C9、C3-C10。“取代C3-C20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，包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。本发明中，“环烷基”意在包含“取代环烷基”。
术语“亚环烷基”本身或作为另一取代基的一部分是指上述环烷基脱掉两个氢原子所形成的基团，如：
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： 等。
如文本所用，术语“杂环基”是指具有若干个(大于等于3)环原子且具有1‐4个杂原子的完全饱和的或部分不饱和的的环状基团，其中，“4‐20元杂环基”是指具有4‐20个环原子且具有1‐4个杂原子的完全饱和的或部分不饱和的的环状基团(包含但不限于如4‐7元单环，6‐11元双环，或8‐12元三环系统)。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。
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，如包括但不限于： 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： 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。
术语“亚芳基”是指上述芳基脱掉两个氢原子所形成的基团。
术语“杂芳基”指包含1-4(如2或3个)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，杂环基可包括5、6、7、8、9、10、11、12、13或14个环原子。 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“亚杂芳基”是指上述杂芳基脱掉两个氢原子所形成的基团。
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基氧基，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烷氧基或C1-C4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(2H)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NO2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-SO2NRR'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。优选地，如无特别说明，取代可为被选自下组的一个或多个取代基取代：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、4-12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。
如本文所述，术语“多个”是指两个或以上，如2、3、4、5或6。
活性成分
如本文所用，“本发明化合物”指式(IA)、式(IB)或式(IC)所示的化合物，并且还包括所述化合物的立体异构体、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：A、X、Y1、Y2、L1、L、Z、P1、P2、P3、P4、P5、n1、n2如上所述。
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,75th 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”、“任选”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所述化合物的制备方法，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。
式(V-I)和式(V-II)化合物通过取代反应、或还原胺化反应、或偶联反应、或酰胺缩合反应等得到式(IA)化合物；
其中：
A、X、Y1、Y2、L1、L、Z、P1、P2、P3、P4、P5、n1、n2如上定义。
LG1或LG2相同或不同，为离去基团，各自优选自：氢、OH、＝O、卤素、OTs、OMs、 OTf、B(OH)2等。
药物组合物、用途和施用方法
本发明的药物组合物包括上述活性成分及药学上可接受的载体。
本发明的化合物可以降低SOS1的活性、表达量、促进SOS1蛋白降解和/或降低SOS1水平，从而可以用于预防和/或治疗SOS1活性或表达量相关的疾病。本发明所述的药物组合物可用于预防和/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。
在另一优选例中，所述癌症为KRAS突变导致的癌症。
在另一优选例中，所述癌症包括(但并不限于)：肺癌(小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC))、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。
本发明的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，而同时或随后服用本发明的化合物。当本发明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所述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本发明化合物与其它一种或几种已知药物。当本发明化合物与其它一种或几种药物进行药物联用时，所述化合物或已知药物的剂量可能比它们单独用药的剂量低。
可以与本发明的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、ibritumomabtiuxetan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)、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的化合物或其晶型、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)所述化合物能够选择性的促进SOS1蛋白水解，从而预防和/或治疗SOS1活性或表达量相关的疾病(尤其对肿瘤细胞选择性高)，活性高，安全性好；
(2)本发明的化合物可以催化量发挥抑制细胞增殖的效果。细胞内能够循环发挥降解靶蛋白的作用，实现减少给药剂量，延长给药周期，达到安全有效的抗肿瘤效果；
(3)所述化合物具有更好的体内外药效学、药代动力学性能和/或更低的毒副作用。
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)、氘代丙酮(CD3COCD3)、氘代氯仿(CDCl3)及氘代甲醇(CD3OD)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 5 micron 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
中间体1-1 1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌嗪-4-甲醛的制备
第一步：2-(2,6-二氧哌啶-3-基)-5-(4-(羟甲基)哌啶-1-基)异吲哚-1,3-二酮的制备
2-(2,6-二氧哌啶-3-基)-5-氟异吲哚-1,3-二酮(2.00g,7.24mmol,1.00eq)的NMP(10mL)溶液中加入DIEA(2.81g,21.7mmol,3.78mL,3.00eq)和4-哌啶甲醇(1.67g,14.5mmol,2.00eq)。混合物在100℃反应3h，然后加入EtOAc(200mL)和饱和食盐水(200mL)。有机相分离以后用饱和食盐水(200mL)洗涤后用无水硫酸镁干燥后过滤。滤液减压浓缩得到目标产物(2.30g,5.57mmol,77.0％产率)。
LC-MS：m/z 372(M+H)+。
第二步：1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌嗪-4-甲醛的制备
室温下，2-(2,6-二氧哌啶-3-基)-5-(4-(羟甲基)哌啶-1-基)异吲哚-1,3-二酮(2.40g,6.45mmol,1.00eq)的DCM(1.00mL)溶液中加入Dess-Martin(5.48g,12.5mmol,2.00eq)。反应液在25℃反应2h，然后用水(200mL)稀释后用DCM/MeOH(V:V＝5:1,100mL* 3)萃取。合并的有机相用饱和食盐水(100mL*2)洗涤后用无水硫酸镁干燥后过滤.滤液减压浓缩残余物用硅胶柱层析分离得到目标产物。(1.00g,2.48mmol,38.4％产率)。
LC-MS：m/z 370(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.62(s,1H),7.67(d,J＝8.5Hz,1H),7.35(d,J＝2.0Hz,1H),7.26(dd,J＝2.3,8.6Hz,1H),5.07(dd,J＝5.3,12.9Hz,1H),3.94(br d,J＝13.4Hz,2H),3.24-3.11(m,2H),2.95-2.82(m,1H),2.71-2.59(m,2H),2.59-2.53(m,1H),2.07-1.98(m,1H),1.97-1.86(m,2H),1.65-1.48(m,2H).
按照中间体1-1同样方法合成以下化合物：
中间体1-2 1-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)氮杂环丁烷-3-甲醛
LC-MS：m/z 342(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.85(d,J＝1.6Hz,1H),7.65(dd,J＝8.3,18.6Hz,1H),6.89-6.75(m,1H),6.74-6.59(m,1H),5.11-5.01(m,1H),4.22-4.15(m,2H),4.01(t,J＝8.4Hz,1H),3.83(dd,J＝5.7,8.3Hz,1H),3.30(s,1H),2.96-2.76(m,2H),2.59(d,J＝16.6Hz,2H).
中间体1-3 1-(2-(2,6-二氧哌啶-3-基)-6-氟-1,3-二氧异吲哚-5-基)哌嗪-4-甲醛的制备
LC-MS：m/z 388(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.12(s,1H)9.65(s,1H)7.72(d,J＝11.38Hz,1H)7.47(d,J＝7.38Hz,1H)5.11(dd,J＝12.76,5.38Hz,1H)3.49-3.60(m,2H)3.03(br t,J＝10.38Hz,2H)2.80-2.96(m,1H)2.57(br s,2H)1.88-2.10(m,4H)1.57-1.73(m,2H)。
中间体2-1 1-(2-(2,6-二氧哌啶-3-基)-1-氧异吲哚-5-基)哌啶-4-甲醛的制备
第一步：2-溴-4-(4-(二甲氧基甲基)哌啶-1-基)苯甲酸甲酯的制备
2-溴-4-氟苯甲酸甲酯(2.80g,12.0mmol,1.00eq)的DMSO(50.0mL)溶液中加入4-(二甲氧基甲基)哌啶(2.49g,15.6mmol,1.30eq)和DIEA(3.11g,24.0mmol,4.19mL,2.00eq)。混合物在120℃反应20h然后用冰水(50mL)稀释并用EtOAc(100mL*2)萃取。合并的有机相用饱和食盐水(50mL*3)，然后用无水硫酸镁干燥后过滤。滤液减压浓缩得到目标产物(4.20g,11.3mmol,93.9％产率)。无需进一步纯化直接用于下一步反应。
LC-MS：m/z 372(M+H)+。
第二步：4-(4-(二甲氧基甲基)哌啶-1-基)-2-甲酰基苯甲酸甲酯的制备
氮气保护下，2-溴-4-(4-(二甲氧基甲基)哌啶-1-基)苯甲酸甲酯(3.03g,8.14mmol,1.00eq)和2-异腈-2-甲基-丙烷(1.35g,16.9mmol,1.84mL,2.00eq)的DMF(60.0mL)溶液中加入Na2CO3(862mg,8.14mmol,1.00eq)、三环己基磷(228mg,813umol,263uL,0.100eq)、三乙基硅烷(2.84g,24.4mmol,3.90mL,3.00eq)和醋酸钯(182mg,813umol,0.100eq)。得到的混合物在氮气保护下在65℃反应16h，然后用冰水(50mL)稀释并用EtOAc(100mL*2)萃取。合并的有机相用饱和食盐水(50mL*3)，然后用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(1.60g,4.98mmol,61.2％产率)。
LC-MS：m/z 322(M+H)+。
第三步：3-(5-(4-(二甲氧基甲基)哌啶-1-基)-1-氧异吲哚-2-基)哌啶-2,6-二酮的制备
3-氨基哌啶-2,6-二酮盐酸盐(901mg,5.48mmol,1.10eq)的MeOH(20.0mL)溶液中加入AcONa(816mg,9.96mmol,2.00eq)。混合物在25℃反应10min，随后加入4-(4-(二甲氧基甲基)哌啶-1-基)-2-甲酰基苯甲酸甲酯(1.60g,4.98mmol,1.00eq)和AcOH(18M,2.77mL,10.0eq)。得到的混合物在25℃反应20min,随后加入NaBH3CN(625mg,9.96mmol,2.00eq)。得到的混合物在35℃反应16h，然后倒入冰水(10mL)并用饱和碳酸氢钠水溶液调节pH 8。混合物用EtOAc萃取(10mL*3)。合并的有机相用饱和食盐水(10mL)，然后用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(900mg,2.24mmol,45.0％产率)。
LC-MS：m/z 402(M+H)+。
第四步：1-(2-(2,6-二氧哌啶-3-基)-1-氧异吲哚-5-基)哌啶-4-甲醛的制备
3-(5-(4-(二甲氧基甲基)哌啶-1-基)-1-氧异吲哚-2-基)哌啶-2,6-二酮(900mg,2.24mmol,1.00eq)的DCM(6mL)溶液中加入TFA(7.67g,67.2mmol,4.98mL,30.0eq)。反应液在25℃反应1h然后减压浓缩。残余物加入EtOAc(5mL)和MBTE(10mL)，然后过滤，滤液减压浓缩得到目标产物(790mg,2.11mmol,94.2％产率)。
LC-MS：m/z 356(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.95(s,1H)9.63(s,1H)7.52(d,J＝8.44Hz,1H)7.00-7.15(m,2H)5.05(dd,J＝13.20,5.01Hz,1H)4.17-4.39(m,2H)3.79(br d,J＝13.08Hz,3H)2.79-3.09(m,3H)2.54-2.66(m,2H)2.29-2.41(m,1H) 1.87-1.96(m,2H)1.75-1.84(m,1H)1.49-1.67(m,1H)
按照中间体2-1同样方法合成以下化合物：
中间体2-2 3-(1-氧-5-(4-氧哌啶-1-基)异吲哚-2-基)哌啶-2,6-二酮的制备
LC-MS：m/z 342(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),7.57-7.54(m,1H),7.17-7.15(m,1H),7.14-7.10(m,1H),5.08-5.02(m,1H),4.37-4.18(m,2H),3.75(t,J＝6.0Hz,4H),2.95-2.85(m,1H),2.63-2.55(m,1H),2.44(t,J＝5.9Hz,4H),2.41-2.31(m,1H),2.00-1.92(m,1H)
中间体2-3 3-(1-氧-5-(3-氧代氮杂环丁烷-1-基)异吲哚啉-2-基)哌啶-2,6-二酮
LC-MS：m/z 314(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),7.58(d,J＝8.3Hz,1H),6.76-6.65(m,2H),5.05(dd,J＝5.0,13.3Hz,1H),4.79(s,4H),4.39-4.32(m,1H),4.26-4.19(m,1H),2.95-2.85(m,1H),2.59(d,J＝16.8Hz,1H),2.37(dq,J＝4.5,13.2Hz,1H),2.01-1.93(m,1H).
中间体2-4 1-(2-(2,6-二氧哌啶-3-基)-1-氧异吲哚啉-5-基)氮杂环丁烷-3-甲醛
LC-MS：m/z 328(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),9.85(s,1H),7.50(d,J＝1.6Hz,1H),6.58-6.55(m,2H),5.04(d,J＝8.4,1H),5.05-5.03(m,1H),4.34-4.21(m,1H),3.96-3.95(m,2H),3.90-3.88(m,2H),2.93-2.91(m,1H),2.60(m,2H),2.41-2.40(m,1H),1.97-1.95(m,1H).
中间体2-5 3-(1-氧-5-(3-(4-氧哌啶-1-基)氮杂环丁烷-1-基)异吲哚啉-2-基)哌啶-2,6-二酮
LC-MS：m/z 397(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),7.51(d,J＝8.0 Hz,1H),6.54-6.50(m,2H),5.04(dd,J＝1.6,14.4Hz,1H),4.33-4.29(m,1H),4.21-4.18(m,1H),4.07-4.04(m,2H),3.78-3.75(m,2H),3.50(m,1H),2.89(m,1H),2.66-2.64(m,4H),2.60(m,1H),2.39-2.38(m,4H),2.34(m,1H),1.97-1.95(m,1H).
中间体3-1 1-(3-(2-(2,6-二氧哌啶-3-基)-1-氧异吲哚-5-基)丙-2-炔-1-基)哌啶-4-甲醛的制备
第一步：4-(二甲氧基甲基)-1-(丙-2-炔-1-基)哌啶的制备
氮气保护下，4-(二甲氧基甲基)哌啶(4g,25.12mmol,1eq)、3-溴丙-1-炔(4.48g,37.68mmol,3.25mL,1.5eq)和Cs2CO3(20.46g,62.80mmol,2.5eq)的CHCl3(40mL)和H2O(40mL)的混合溶液在20℃反应8hr，然后加入DCM(40mL)和H2O(80mL)分层。有机相用饱和氯化钠水溶液(40mL*2)洗涤，然后经无水硫酸钠干燥后过滤。滤液减压浓缩得到目标产物(4g,16.22mmol,64.57％产率)。无需纯化直接用于下一步反应。
LC-MS：m/z 198(M+H)+。
第二步：3-(5-(3-(4-(二甲氧基甲基)哌啶-1-基)丙-1-炔-1-基)-1-氧异吲哚-2-基)哌啶-2,6-二酮的制备
氮气保护下，4-(二甲氧基甲基)-1-(丙-2-炔-1-基)哌啶(2g,10.14mmol,1eq)、3-(5-溴-1-氧吲哚-2-基)哌啶-2,6-二酮(3.28g,10.14mmol,1eq)、CuI(193.08mg,1.01mmol,0.1eq),TEA(3.08g,30.41mmol,4.23mL,3eq)和PdCl2(PPh3)2(711.60mg,1.01mmol,0.1eq)的DMF(40mL)混合物在60℃反应16hr。得到的混合物在DCM/MeOH(V:V＝10:1，50mL)和H2O(100mL)中分层。有机相用饱和氯化钠水溶液(50mL*2)洗涤，然后经无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(2.8g,5.73mmol,56.56％产率)。
LC-MS：m/z 440(M+H)+。
第三步：1-(3-(2-(2,6-二氧哌啶-3-基)-1-氧异吲哚-5-基)丙-2-炔-1-基)哌啶-4-甲醛的制备
3-(5-(3-(4-(二甲氧基甲基)哌啶-1-基)丙-1-炔-1-基)-1-氧异吲哚-2-基)哌啶-2,6-二酮(1.8g,4.10mmol,1eq)的DCM(10mL)溶液中加入TFA(14.01g,122.87mmol,9.10mL,30eq)。反应液在20℃反应16hr然后减压浓缩。残余物用硅胶柱层析分离得到目标产物(170mg,427.77umol,10.44％产率)。
LC-MS：m/z 394(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.61(s,1H), 8.15(s,1H),7.76-7.64(m,2H),7.56(d,J＝7.7Hz,1H),5.11(dd,J＝5.0,13.2Hz,1H),4.51-4.42(m,1H),4.37-4.31(m,1H),3.57(s,2H),2.98-2.86(m,2H),2.86-2.77(m,2H),2.61(d,J＝17.2Hz,1H),2.40(dd,J＝4.3,13.3Hz,1H),2.36-2.30(m,2H),2.06-1.98(m,1H),1.94-1.83(m,2H),1.62-1.46(m,2H).
按照中间体3-1同样方法合成以下化合物：
中间体3-2
LC-MS：m/z 380(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.75-7.66(m,2H),7.57(d,J＝8.1Hz,1H),5.12(dd,J＝5.1,13.2Hz,1H),4.49-4.40(m,1H),4.38-4.29(m,1H),3.72(s,2H),2.97-2.89(m,1H),2.86(t,J＝5.9Hz,4H),2.61(d,J＝16.3Hz,1H),2.41(t,J＝6.1Hz,4H),2.39-2.33(m,1H),2.06-1.97(m,1H).
中间体4-1(3-((R)-1-((2-甲基-7-(哌嗪-1-基)-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯的制备
第一步：(S)-4-溴-2-硝基-5-((四氢呋喃-3-基)氧基)苯甲酰胺的制备
在圆底烧瓶中依次加入化合物(S)-四氢呋喃-3-醇(10g，115mmol)，和N,N-二甲基甲酰胺(200mL)，搅拌溶解，分批加入钠氢(9.2g，229mmol)，搅拌下缓慢加入4-溴-5-氟-2-硝基苯甲酰胺(20g，76mmol)。加完后室温搅拌反应2小时。加水，浓缩，用乙酸乙酯萃取，有机相浓缩得目标化合物(25g)。无需纯化直接用于下一步反应。
LC-MS:m/z 331(M+H)+。
第二步：(S)-2-氨基-4-溴-5-((四氢呋喃-3-基)氧基)苯甲酰胺的制备
在圆底烧瓶中依次加入化合物(S)-4-溴-2-硝基-5-((四氢呋喃-3-基)氧基)苯甲酰胺(25g，75.8mmol)，铁粉(42g，758mmol)，氯化铵(41g，458mmol)，乙醇(250mL)和水(50mL)。加完后加热回流搅拌反应2小时。过滤，浓缩，所得物加水，用乙酸乙酯萃取，有机相用无水硫酸镁干燥，过滤，浓缩得目标化合物(17g)。无需纯化直接用于下一步反应。
LC-MS:m/z 301(M+H)+。
第三步：(S)-7-溴-2-甲基-6-((四氢呋喃-3-基)氧基)喹唑啉-4-酚的制备
在圆底烧瓶中依次加入化合物(S)-2-氨基-4-溴-5-((四氢呋喃-3-基)氧基)苯甲酰胺(17g，56mmol)，原甲酸三乙酯(68g，560mmol)和乙醇(200mL)。加完后加热至100℃搅拌反应16小时。冷却，过滤，滤饼用乙醇洗涤，干燥得目标化合物(9g)。无需纯化直接用于下一步反应。
LC-MS:m/z 325(M+H)+。
第四步：N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-溴-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-胺的制备
在圆底烧瓶中依次加入化合物(S)-7-溴-2-甲基-6-((四氢呋喃-3-基)氧基)喹唑啉-4-酚(4g，0.012mmol)，(R)-(3-(1-氨基乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯(5g，14.7mmol)，卡特缩合剂(10.9g，24.6mmol)，1,8-二偶氮杂双螺环[5.4.0]十一-7-烯(5.6g，36.9mmol)和N,N-二甲基甲酰胺(50mL)。加完后加热至100℃搅拌反应3小时。通过中压过柱机分离得目标化合物(6g)。
LC-MS:m/z 645(M+H)+。
第五步：4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-甲酸叔丁酯的制备
在圆底烧瓶中依次加入化合物N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-溴-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-胺(2g，3.1mmol)，哌嗪-1-甲酸叔丁酯(1.7g，9.3mmol)，醋酸钯(70mg，0.31mmol)，1,1'-联萘-2,2'-双二苯膦(386mg，0.62mmol)，碳酸铯(3g，9.3mmol)和二氧六环(50mL)。加完后加热至100℃搅拌反应16小时后减压浓缩，残余物通过中压过柱机分离得目标化合物(600mg)。
LC-MS:m/z 617(M+H)+。
第六步：4-(4-(((R)-1-(3-(((苄氧基)羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-甲酸叔丁酯的制备
在圆底烧瓶中依次加入化合物4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-甲酸叔丁酯(600mg，0.97mmol)，碳酸钠(310mg，2.92mmol)，四氢呋喃(5mL)和水(1mL)，加完后，搅拌下滴加氯甲酸苄酯(248mg，1.46mmol)。加完后室温搅拌反应2小时后减压浓缩，残余物通过中压过柱机分离得目标化合物(700mg)。
LC-MS:m/z 751(M+H)+。
第七步：(3-((R)-1-((2-甲基-7-(哌嗪-1-基)-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯的制备
在圆底烧瓶中依次加入化合物4-(4-(((R)-1-(3-(((苄氧基)羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-甲酸叔丁酯(700mg，0.93mmol)，盐酸二氧六环(2mL)。加完后室温搅拌反应2小时后减压浓缩，残余物通过中压过柱机分离得目标化合物(800mg)。
LC-MS:m/z 651(M+H)+。1H NMR(400MHz,DMSO-d6)δ14.55(s,1H),10.32–10.11(m,2H),9.24(s,2H),8.19(s,1H),7.86(s,1H),7.79(s,1H),7.56(s,1H),7.46–7.33(m,5H),7.32–7.02(m,2H),5.86–5.72(m,1H),5.45–5.36(m,1H),5.17(s,2H),4.07–3.97(m,1H),3.92–3.82(m,3H),3.46–3.42(m,4H),3.30–3.28(m,2H),2.58(s,3H),2.46–2.35(m,1H),2.17–1.93(m,2H),1.72(d,J＝7.1Hz,3H).
按照中间体4-1同样方法合成以下化合物：
按照中间体4-2(R)-(3-(1-((6-(2-甲氧基乙氧基)-2-甲基-7-(哌嗪-1-基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯的制备
LC-MS:m/z 639(M+H)+。
按照中间体4-3 1,1-二氟-1-(2-氟-3-((R)-1-((2-甲基-7-(哌嗪-1-基)-6-(((S)-四氢呋喃-3-基)氧)喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇的制备
LC-MS:m/z 560(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.72(t,J＝7.0Hz,1H),7.34–7.18(m,3H),7.07(s,1H),5.93–5.77(m,1H),5.46–5.36(m,1H),5.33(s,1H),4.02(dd,J＝10.3,4.3Hz,1H),3.96–3.77(m,3H),3.66–3.53(m,1H),3.40–3.34(m,4H),3.28–3.19(m,4H),2.45–2.29(m,4H),2.14–2.02(m,1H),1.64(d,J＝7.0Hz,3H),1.23(s,3H),1.20(s,3H).
按照中间体4-4(R)-1,1-二氟-1-(2-氟-3-(1-((6-(2-甲氧基乙氧基)-2-甲基-7-(哌嗪-1-基)喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇的制备
LC-MS:m/z 548(M+H)+。
中间体5-1 1-(4-氯-3-(2,4-二氧四氢嘧啶-1(2H)-基)苯甲酰基)哌啶-4-甲醛
第一步：3-((2-甲酸乙基)胺基)-4-氯苯甲酸的制备
3-胺基-4-氯苯甲酸(5.00g,29.1mmol,1.00eq)的AcOH(50.0mL)和H2O(10.0mL)的混合溶液中加入acrylic acid(12.6g,175mmol,12.0mL,6.00eq)。反应液在100℃反应16h然后过滤。滤饼收集以后真空干燥得到目标产物(7.00g)。勿需进一步纯化，直接用于下一步反应。
1H NMR(400MHz,DMSO-d6)δ13.08-12.08(s,2H),7.38(d,J＝8.1Hz,1H),7.24(d,J＝1.9Hz,1H),7.18(dd,J＝1.9,8.1Hz,1H),5.62-5.52(m,1H),3.40(br d,J＝6.1Hz,2H),2.58(t,J＝6.9Hz,2H)。
第二步：4-氯-3-(2,4-二氧四氢嘧啶-1(2H)-基)苯甲酸的制备
3-((2-甲酸乙基)胺基)-4-氯苯甲酸(7.00g,28.7mmol,1.00eq)的AcOH(100mL)溶液中加入urea(90.0g,1.50mol,80.6mL,52.2eq)。反应液在120℃反应16h，然后0℃下用氢氧化钠条件pH大于7，然后用EtOAc(400mL)萃取。水相分离后倒入并的HCl水溶液(pH＝1)中然后过滤。滤饼收集以后真空干燥得到目标产物(4.00g)。勿需进一步纯化，直接用于下一步反应。
1H NMR(400MHz,DMSO-d6)δ13.86-12.91(m,1H),10.53(s,1H),8.05(d,J＝2.0Hz,1H),7.91(dd,J＝2.1,8.3Hz,1H),7.72(d,J＝8.4Hz,1H),3.85-3.72(m,1H),3.63(td,J＝6.0,12.1Hz,1H),2.82-2.70(m,2H).
第三步：1-(2-氯-5-(4-(二甲氧基甲基)哌啶-1-甲酰)苯基)二氢嘧啶-2,4(1H,3H)-二酮的制备
4-氯-3-(2,4-二氧四氢嘧啶-1(2H)-基)苯甲酸(0.500g,1.86mmol,1.00eq)的DMF(20mL)溶液中加入HATU(1.06g,2.79mmol,1.50eq)和DIEA(481mg,3.72mmol,648μL,2.00eq)。反应液在25℃反应0.5h，随后加入4-(二甲氧基甲基)哌啶(356mg,2.23mmol, 1.20eq)。得到的反应液在25℃反应12h，然后加入H2O(200mL)淬灭反应后用EtOAc(200mL*2)萃取。合并的有机相用饱和食盐水(200mL*2)洗涤后用无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(0.340g,839μmol,45.1％产率)。
1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),7.64(d,J＝8.1Hz,1H),7.55(d,J＝2.0Hz,1H),7.38(dd,J＝2.0,8.4Hz,1H),4.54-4.38(m,1H),4.12-4.06(m,1H),3.85-3.71(m,1H),3.68-3.51(m,2H),3.26(s,6H),3.12-2.95(m,1H),2.81-2.69(m,3H),1.93-1.80(m,1H),1.78-1.53(m,2H),1.21-1.13(m,2H).
第四步：1-(4-氯-3-(2,4-二氧四氢嘧啶-1(2H)-基)苯甲酰基)哌啶-4-甲醛的制备
1-(2-氯-5-(4-(二甲氧基甲基)哌啶-1-甲酰)苯基)二氢嘧啶-2,4(1H,3H)-二酮(0.340g,839μmol,1.00eq)的DCM(20.0mL)溶液中加入TFA(2.87g,25.2mmol,1.87mL,30.0eq)。反应液在25℃反应2h后减压浓缩。残余物加入EtOAc(3mL)和MBTE(12mL)打浆后过滤，饼收集以后真空干燥得到目标产物(190mg,522μmol,62.2％产率)。
LC-MS:m/z 364(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.62(s,1H),7.65(d,J＝8.2Hz,1H),7.57(d,J＝2.0Hz,1H),7.40(dd,J＝2.0,8.2Hz,1H),4.33-4.16(m,1H),3.83-3.69(m,1H),3.69-3.46(m,2H),3.20-3.00(m,2H),2.79-2.70(m,2H),2.70-2.59(m,1H),1.99-1.75(m,2H),1.57-1.42(m,2H).
按照中间体5-1同样方法合成以下化合物：
中间体5-2 1-(2-氯-5-(4-氧哌啶-1-甲酰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
LC-MS:m/z 350(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),7.74-7.65(m,2H),7.52(dd,J＝1.8,8.3Hz,1H),3.96-3.54(m,6H),2.82-2.71(m,2H),2.52-2.36(m,4H).
中间体5-3 1-(4-甲氧基-3-(2,4-二氧四氢嘧啶-1(2H)-基)苯甲酰基)哌啶-4-甲醛
LC-MS:m/z 360(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.43-10.29(m,1H),9.62(s,1H),7.48-7.30(m,2H),7.16(d,J＝8.6Hz,1H),3.85(s,4H),3.60(s,3H),3.48-3.41(m,2H),3.34-3.22(m,2H),2.68(s,3H),1.99-1.78(m,2H),1.48(br dd,J＝3.6,13.1Hz,2H).
中间体5-4 1-(2-甲氧基-5-(4-氧哌啶-1-甲酰基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
LC-MS:m/z 346(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.37(s,1H)7.37-7.54(m, 2H)7.19(d,J＝8.56Hz,1H)3.83-3.96(m,3H)3.77(br s,4H)3.61(br t,J＝6.60Hz,2H)2.69(br t,J＝6.60Hz,2H)2.45(br s,4H).
实施例A1 5-(4-((4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚-1,3-二酮的制备
第一步：(3-((1R)-1-((7-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯的制备
在圆底烧瓶中依次加入化合物(3-((R)-1-((2-甲基-7-(哌嗪-1-基)-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯(40mg，0.06mmol)，1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-甲醛(23mg，0.06mmol)，三乙酰氧基硼氢化钠(26mg，0.12mmol)和二氯甲烷(1mL)。加完后室温搅拌反应2小时。通过中压过柱机分离得目标化合物(40mg)。
LC-MS:m/z 1004(M+H)+。
第二步：5-(4-((4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚-1,3-二酮的制备
在圆底烧瓶中依次加入化合物(3-((1R)-1-((7-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯(40mg，0.04mmol)和三氟乙酸(1mL)。加完后加热回流搅拌反应1小时，然后减压浓缩。残余物用制备液相分离得到目标化合物(8mg)。
LC-MS:m/z 870(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.07(s,1H),7.67(d,J＝8.9Hz,2H),7.33(d,J＝2.6Hz,1H),7.25(dd,J＝8.9,2.4Hz,1H),6.96(s,1H),6.88(s,1H),6.85(s,1H),6.71(s,1H),5.66–5.50(m,3H),5.27–5.23(m,1H),5.08(dd,J＝12.8,5.5Hz,1H),4.11–4.03(m,2H),3.98(dd,J＝10.2,4.3Hz,1H),3.95–3.81(m,3H), 3.21–3.09(m,3H),3.05–2.95(m,2H),2.95–2.84(m,1H),2.65–2.53(m,4H),2.37(s,3H),2.35–2.18(m,3H),2.13–1.96(m,3H),1.95–1.79(m,3H),1.57(d,J＝7.0Hz,3H),1.35–1.12(m,4H).
按照实施例A1同样方法合成以下化合物：
实施例A2 5-(4-((4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚-1,3-二酮
LC-MS:m/z 888(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),7.93(d,J＝8.1Hz,1H),7.71(d,J＝11.4Hz,1H),7.66(s,1H),7.45(d,J＝7.4Hz,1H),6.95(s,1H),6.89(s,1H),6.86(s,1H),6.71(s,1H),5.66–5.48(m,3H),5.26–5.22(m,1H),5.11(dd,J＝12.8,5.5Hz,1H),3.98(dd,J＝10.2,4.3Hz,1H),3.95–3.81(m,3H),3.67–3.59(m,2H),3.20–3.06(m,4H),2.98–2.83(m,3H),2.66–2.52(m,5H),2.35(s,3H),2.34–2.21(m,3H),2.12–2.00(m,2H),1.92–1.73(m,3H),1.56(d,J＝6.9Hz,3H),1.37–1.20(m,2H).
实施例A3 3-(5-(4-((4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)甲基)哌啶-1-基)-1-氧代吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 856(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.02(s,1H),7.67(s,1H),7.51(d,J＝8.5Hz,1H),7.06(d,J＝7.9Hz,2H),6.95(s,1H),6.88(s,1H),6.85(s,1H),6.71(s,1H),5.65–5.46(m,3H),5.27–5.22(m,1H),5.05(dd,J＝13.2,5.1Hz,1H),4.27(dd,J＝49.2,17.1Hz,2H),3.98(dd,J＝10.0,4.2Hz,1H),3.95–3.79(m,5H),3.22–3.05(m,4H),2.97–2.78(m,3H),2.65–2.52(m,4H),2.45–2.19(m,7H),2.12–2.03(m,1H),2.02–1.92(m,1H),1.89–1.75(m,3H),1.57(d,J＝7.0Hz,3H),1.33–1.14(m,3H).
实施例A4 5-(3-((4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)甲基)氮杂环丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚-1,3-二酮
LC-MS:m/z 842(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),7.94(d,J＝8.2Hz,1H),7.65(d,J＝8.5Hz,2H),6.95(s,1H),6.88(s,1H),6.85(s,1H),6.80(d,J＝2.1Hz,1H),6.71(s,1H),6.67(dd,J＝8.4,2.1Hz,1H),5.65–5.48(m,3H),5.26–5.22(m,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.17(t,J＝8.2Hz,2H),3.98(dd,J＝10.1,4.3Hz,1H),3.96–3.81(m,3H),3.73(dd,J＝8.4,5.3Hz,2H),3.20–3.00(m,5H),2.95–2.83(m,1H),2.68(d,J＝7.3Hz,2H),2.65–2.52(m,6H),2.35(s,3H),2.33–2.26(m,1H),2.13–1.96(m,2H),1.56(d,J＝7.1Hz,3H).
实施例A5 3-(5-(4-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧)喹唑啉-7-基)哌嗪-1-基)哌啶-1-基)-1-氧异吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 842(M+H)+。
实施例A6 3-(5-(3-(4-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)哌啶-1-基)丙-1-炔-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 880(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.92(d,J＝8.1Hz,1H),7.76–7.69(m,1H),7.65(s,1H),7.57(d,J＝7.8Hz,1H),6.94(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),6.66(s,1H),5.62–5.51(m,3H),5.34(t,J＝4.8Hz,1H),5.24(s,1H),5.12(d,J＝8.2Hz,1H),4.52–4.30(m,2H),4.01–3.95(m,1H),3.95–3.80(m,2H),3.59–3.54(m,2H),3.46–3.22(m,7H),3.15–3.08(m,2H),2.98–2.90(m,2H),2.72–2.63(m,2H),2.48–2.31(m,4H),2.31–2.18(m,2H),2.07–1.95(m,3H),1.90–1.81(m,1H),1.56(d,J＝7.2Hz,1H),1.53–1.41(m,2H),1.34–1.22(m,3H).
实施例A7 3-(5-(3-(4-((4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)甲基)哌啶-1-基)丙-1-炔-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 894(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.93(d,J＝8.2Hz,1H),7.75–7.69(m,2H),7.65(s,1H),7.57(d,J＝8.2Hz,1H),6.94(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.64–5.50(m,3H),5.27–5.20(m,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.49–4.33(m,2H),3.98(dd,J＝10.1,4.4Hz,1H),3.89–3.82(m,2H),3.59–3.54(m,2H),3.17–3.07(m,4H),2.97–2.82(m,4H),2.70–2.57(m,4H),2.47–2.38(m,2H),2.34(s,3H),2.28–2.19(m,4H),2.11–1.97(m,4H),1.80–1.71(m,2H),1.56(d,J＝7.1Hz,3H),1.21–1.09(m,2H).
实施例A8 3-(5-(3-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)哌啶-1-基)氮杂环丁-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 897(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.07(d,J＝9.4Hz,1H),7.72(s,1H),7.50(d,J＝8.3Hz,1H),7.07–6.78(m,3H),6.70(s,1H),6.59–6.43(m,2H),5.67–5.42(m,3H),5.25(s,1H),5.03(dd,J＝13.2,5.1Hz,1H),4.25(dd,J＝50.5,17.0Hz,2H),4.08–3.79(m,6H),3.70(d,J＝9.8Hz,2H),3.13(s,4H),2.90(t,J＝12.6Hz,4H),2.67(s,3H),2.43–2.20(m,7H),2.14–1.77(m,7H),1.53(t,J＝23.1Hz,5H).
实施例A9 3-(5-(4-((4-(4-(((R)-1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌啶-1-基)甲基)哌啶-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 899(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.02(d,J＝7.5Hz,1H),7.70(s,1H),7.57(t,J＝6.9Hz,1H),7.51(d,J＝8.5Hz,1H),7.34–7.26(m,1H),7.20(t,J＝7.7Hz,1H),7.08–7.02(m,2H),6.94(s,1H),5.86–5.74(m,1H),5.33(s,1H),5.30–5.24(m,1H),5.05(dd,J＝13.3,5.1Hz,1H),4.36–4.17(m,2H),3.99(dd,J＝10.1,4.3Hz,1H),3.96–3.82(m,5H),3.20–3.03(m,4H),2.96–2.79(m,3H),2.64–2.51(m,4H),2.44–2.29(m,2H),2.28(s,3H),2.25–2.19(m,2H),2.12–2.03(m,1H),2.01–1.92(m,1H),1.88–1.77(m,3H),1.59(d,J＝7.0Hz,3H),1.28–1.17(m,9H).
实施例A10 3-(5-(4-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)甲基)哌啶-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 841(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.03(d,J＝6.4Hz,1H),7.66(dd,J＝16.6,9.6Hz,2H),7.56–7.42(m,2H),7.38–7.16(m,2H),7.06(t,J＝12.4Hz,2H),6.93(s,1H),5.80(p,J＝7.0Hz,1H),5.27(d,J＝4.4Hz,1H),5.04(dd,J＝13.3,5.1Hz,1H),4.31(dd,J＝15.5,6.6Hz,1H),4.20(d,J＝16.9Hz,1H),3.98(dt,J＝15.6,7.9Hz,1H),3.93–3.77(m,5H),3.76–3.60(m,1H),3.12(s,3H),2.97–2.76(m,3H),2.67–2.52(m,3H),2.39–2.16(m,8H),2.13–2.01(m,1H),1.95(dd,J＝15.0,9.9Hz,1H),1.81(d,J＝10.5Hz,3H),1.62(t,J＝9.1Hz,3H).
实施例A11 3-(1R)-1-(7-(4-((1-(2-(2,6-二氧哌啶-3-基)-1-氧异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-基)乙基)-2-甲基苯甲腈
LC-MS:m/z 812(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.11(d,J＝6.8Hz,1H),7.75(t,J＝13.0Hz,1H),7.67(d,J＝2.9Hz,1H),7.62(d,J＝7.3Hz,1H),7.49(s, 1H),7.32(dd,J＝33.7,25.9Hz,1H),7.04(d,J＝8.2Hz,2H),6.92(s,1H),5.63(dd,J＝13.8,6.8Hz,1H),5.25(s,1H),5.04(dd,J＝13.3,5.1Hz,1H),4.32(d,J＝16.9Hz,1H),4.20(d,J＝16.9Hz,1H),3.99(dt,J＝10.0,3.8Hz,1H),3.93–3.77(m,5H),3.11(s,4H),2.97–2.76(m,3H),2.74–2.66(m,3H),2.57(d,J＝25.0Hz,3H),2.41–2.14(m,8H),2.05–1.91(m,2H),1.81(d,J＝10.5Hz,3H),1.52(t,J＝14.6Hz,3H).
实施例A12 3-(5-(3-((4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)甲基)氮杂环丁-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 828(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.14(s,1H),7.69(s,1H),7.50(d,J＝8.3Hz,1H),6.96(s,1H),6.88(s,1H),6.85(s,1H),6.71(s,1H),6.54(s,1H),6.50(dd,J＝8.5,1.9Hz,1H),5.65–5.53(m,3H),5.27–5.23(m,1H),5.04(dd,J＝13.3,5.1Hz,1H),4.34–4.16(m,2H),4.09–4.03(m,2H),3.99(dd,J＝10.1,4.3Hz,1H),3.95–3.82(m,3H),3.64–3.57(m,2H),3.22–3.10(m,4H),3.08–2.98(m,1H),2.96–2.85(m,1H),2.76–2.55(m,6H),2.43–2.27(m,5H),2.12–2.03(m,1H),2.03–1.89(m,2H),1.57(d,J＝7.0Hz,3H).
实施例A13 3-(5-(3-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)氮杂环丁-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 814(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),7.95(d,J＝8.1Hz,1H),7.67(s,1H),7.52(d,J＝8.3Hz,1H),6.96(s,1H),6.88(s,1H),6.85(s,1H),6.71(s,1H),6.56(s,1H),6.52(dd,J＝8.2,2.0Hz,1H),5.64–5.50(m,3H),5.29–5.22(m,1H),5.05(dd,J＝13.2,5.1Hz,1H),4.38–4.17(m,2H),4.05(t,J＝7.4Hz,2H),3.99(dd,J＝10.1,4.3Hz,1H),3.96–3.83(m,3H),3.81–3.74(m,2H),3.45–3.36(m,2H),3.24–3.08(m,4H),2.97–2.85(m,1H),2.64–2.53(m,4H),2.42–2.26(m,5H),2.13–2.03(m,1H),2.03–1.92(m,1H),1.56(d,J＝7.1Hz,3H).
实施例A14 3-(5-(4-(4-(6-异丙氧基-2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-7-基)哌嗪-1-基)甲基)哌啶-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 828(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),7.97(d,J＝59.2Hz,1H),7.71(s,1H),7.51(d,J＝8.8Hz,1H),7.05(d,J＝7.9Hz,2H),6.92(s,1H),6.85(d,J＝13.8Hz,2H),6.69(s,1H),5.59–5.51(m,3H),5.03(dd,J＝13.4,5.0Hz,1H),4.87–4.79(m,1H),4.33(d,J＝17.0Hz,1H),4.20(d,J＝17.0Hz,1H),3.89(d,J＝12.8Hz,2H),3.15–3.12(m,2H),2.85(d,J＝10.7Hz,2H),2.61(s,4H),2.39–2.33(m,5H),2.23(s,2H),1.97(d,J＝5.7Hz,1H),1.82(d,J＝10.4Hz,4H),1.55(d,J＝7.1Hz,3H),1.33(d,J＝5.5Hz,6H),1.21(d,J＝17.8Hz,4H).
实施例A15 3-(5-(4-((4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-6-乙氧基-2-甲基喹唑啉-7-基)哌嗪-1-基)甲基)哌啶-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 814(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.08(d,J＝7.9Hz,1H),7.68(s,1H),7.51(d,J＝8.7Hz,1H),7.11–7.00(m,2H),6.93(s,1H),6.89(s,1H),6.86(s,1H),6.71(s,1H),5.64–5.50(m,3H),5.06(dd,J＝13.2,5.1Hz,1H),4.33(d,J＝16.9Hz,1H),4.25–4.11(m,3H),3.95–3.82(m,2H),3.25–3.06(m,4H),2.99–2.78(m,3H),2.65–2.52(m,5H),2.45–2.31(m,4H),2.28–2.18(m,2H),2.02–1.91(m,1H),1.88–1.75(m,3H),1.56(d,J＝7.1Hz,3H),1.44(t,J＝6.9Hz,3H),1.29–1.14(m,2H).
实施例A16 3-((1R)-1-((7-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)-2-甲基-6-吗啉喹唑啉-4-基)氨基)乙基)-2-甲基苯腈
LC-MS:m/z 811(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.22(d,J＝7.1Hz,1H),7.80(dd,J＝8.0,1.4Hz,1H),7.65–7.59(m,2H),7.51(d,J＝8.4Hz,1H),7.35(t,J＝7.8Hz,1H),7.08–7.01(m,2H),6.95(s,1H),5.71–5.60(m,1H),5.05(dd,J＝13.2,5.1Hz, 1H),4.35–4.18(m,2H),3.93–3.85(m,2H),3.85–3.76(m,4H),3.28–3.10(m,7H),2.97–2.77(m,3H),2.72(s,3H),2.65–2.51(m,5H),2.45–2.33(m,2H),2.31(s,3H),2.26–2.18(m,2H),2.01–1.91(m,1H),1.87–1.75(m,3H),1.55(d,J＝7.0Hz,3H),1.30–1.13(m,2H).
实施例A17 3-(5-(4-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-6-吗啉喹唑啉-7-基)哌嗪-1-基)甲基)哌啶-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 840(M+H)+。1H NMR(400MHz,DMSO)δ10.96(s,1H),8.17(d,J＝7.0Hz,1H),7.76–7.57(m,2H),7.50(t,J＝8.9Hz,2H),7.41–7.17(m,2H),7.08(t,J＝12.6Hz,2H),6.98(s,1H),5.83(t,J＝7.1Hz,1H),5.06(dd,J＝13.3,5.1Hz,1H),4.40–4.23(m,1H),4.21(d,J＝16.9Hz,1H),3.90(d,J＝12.9Hz,2H),3.82(s,4H),3.33–2.92(m,9H),2.88(dt,J＝33.6,12.5Hz,3H),2.67–2.53(m,3H),2.40–2.14(m,7H),2.04–1.92(m,1H),1.83(d,J＝10.7Hz,3H),1.61(d,J＝7.1Hz,3H),1.22(d,J＝11.8Hz,2H).
实施例A18 3-(5-(3-((4-(4-(((R)-1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)甲基)氮杂环丁-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 871(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.03(d,J＝7.5Hz,1H),7.70(s,1H),7.57(t,J＝7.2Hz,1H),7.49(d,J＝8.2Hz,1H),7.31(t,J＝7.2Hz,1H),7.21(t,J＝7.7Hz,1H),6.95(s,1H),6.53(s,1H),6.49(d,J＝8.3Hz,1H),5.85–5.77(m,1H),5.34(s,1H),5.30–5.25(m,1H),5.04(dd,J＝13.3,5.2Hz,1H),4.31(d,J＝16.8Hz,1H),4.18(d,J＝16.9Hz,1H),4.10–3.97(m,3H),3.95–3.83(m,3H),3.64–3.55(m,2H),3.19–3.07(m,4H),3.07–2.97(m,1H),2.95–2.84(m,1H),2.71–2.64(m,2H),2.64–2.54(m,5H),2.42–2.30(m,2H),2.28(s,3H),2.13–2.03(m,1H),2.02–1.92(m,1H),1.59(d,J＝7.0Hz,3H),1.24(s,3H),1.21(s,3H).
实施例A19 3-((1R)-1-((7-(4-((1-(2-(2,6-二氧哌啶-3-基)-1-氧异吲哚-5-基)哌啶-4-基)甲基)哌嗪-1-基)-6-乙氧基-2-甲基喹唑林-4-基)胺基)乙基)-2-甲基苯腈
LC-MS:m/z 770(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),9.38(s,1H),8.09(s,1H),8.00(d,J＝7.9Hz,1H),7.63(d,J＝7.6Hz,1H),7.51(d,J＝8.3Hz,1H),7.36(t,J＝7.8Hz,1H),7.15–6.93(m,3H),5.80–5.64(m,1H),5.05(dd,J＝13.2,5.1Hz,1H),4.39–4.13(m,4H),3.97–3.79(m,2H),3.33–3.11(m,4H),2.98–2.78(m,4H),2.77–2.65(m,4H),2.66–2.54(m,3H),2.47–2.17(m,6H),2.02–1.92(m,1H),1.91–1.75(m,3H),1.62(d,J＝7.0Hz,3H),1.44(t,J＝6.9Hz,3H),1.32–1.13(m,2H).
实施例A20 3-(4-((1-(4-(((R)-1-(3-胺基-5-(三氟甲基)苯基)乙基)胺基)-6-甲氧基-2-甲基喹唑林-7-基)哌啶-4-基)胺基)-1-氧异吲哚-2-基)哌啶-2,6-二酮
LC-MS:m/z 717(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.06(d,J＝8.1Hz,1H),7.72(s,1H),7.36(t,J＝7.7Hz,1H),7.03(s,1H),7.01(d,J＝7.4Hz,1H),6.97–6.89(m,3H),6.75(s,1H),5.69–5.55(m,3H),5.47(d,J＝8.0Hz,1H),5.19(dd,J＝13.3,5.1Hz,1H),4.32(d,J＝17.2Hz,1H),4.22(d,J＝17.2Hz,1H),4.00(s,3H),3.73–3.58(m,3H),3.05–2.82(m,3H),2.74–2.64(m,1H),2.46–2.29(m,4H),2.17–2.04(m,3H),1.80–1.66(m,2H),1.61(d,J＝7.0Hz,3H).
实施例B1(3-((R)-1-((7-(4-(1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧)喹唑啉-4-基)氨基)乙基)-5-三氟甲基(苯基)氨基甲酸苄酯
LC-MS:m/z 936(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.94(d,J＝8.1Hz,1H),7.66(s,1H),7.18–7.12(m,2H),6.98–6.90(m,3H),6.88(s,1H),6.85(s,1H),6.71(s,1H),5.64–5.50(m,3H),5.28–5.20(m,1H),3.98(dd,J＝10.1,4.3Hz,1H),3.94–3.82(m,3H),3.74–3.66(m,4H),3.19–3.06(m,4H),2.75–2.64(m,4H),2.59–2.53(m,2H),2.35(s,3H),2.32–2.21(m,2H),2.12–1.95(m,2H),1.87–1.78(m,2H),1.77–1.67(m, 1H),1.56(d,J＝7.0Hz,3H),1.31–1.18(m,4H).
实施例B2 1-(5-(4-(4-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)哌啶-1-羰基)-2-甲氧基苯基)二氢嘧啶-2,4(1H，3H)-二酮
LC-MS:m/z 846(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),7.98(s,1H),7.66(s,1H),7.50–7.33(m,2H),7.17(d,J＝8.5Hz,1H),7.01–6.78(m,3H),6.70(s,1H),5.66–5.45(m,3H),5.24(s,1H),4.06–3.74(m,8H),3.62(t,J＝6.4Hz,3H),3.12(s,5H),2.70(s,5H),2.38–2.25(m,4H),2.04(dd,J＝24.0,9.2Hz,2H),1.85(s,2H),1.56(d,J＝6.9Hz,3H),1.44(d,J＝10.5Hz,2H),1.25(s,2H).
实施例B3 1-(5-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)甲基)哌啶-1-羰基)-2-甲氧基苯基)二氢嘧啶-2,4(1H，3H)-二酮
LC-MS:m/z 860(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),7.95(s,1H),7.65(s,1H),7.41–7.30(m,2H),7.17(d,J＝8.6Hz,1H),6.96–6.78(m,3H),6.70(s,1H),5.65–5.46(m,3H),5.24(s,1H),4.35(t,J＝5.1Hz,1H),4.05–3.76(m,7H),3.61(t,J＝6.6Hz,2H),3.45(dt,J＝12.1,7.0Hz,1H),3.20–3.02(m,4H),2.79–2.60(m,3H),2.53(s,3H),2.38–2.18(m,6H),2.07(d,J＝11.0Hz,1H),1.81(d,J＝44.6Hz,4H),1.55(d,J＝7.0Hz,3H),1.08(dd,J＝16.6,9.6Hz,3H).
实施例B4 1-(5-(4-((4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)甲基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
LC-MS:m/z 864(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.96(d,J＝8.1Hz,1H),7.69–7.62(m,2H),7.57(d,J＝2.0Hz,1H),7.40(dd,J＝8.3,2.0Hz,1H),7.32(d,J＝4.5Hz,1H),6.94(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.65–5.51(m,3H),5.29–5.20(m,1H),4.55–4.43(m,1H),3.98(dd,J＝10.0,4.3Hz,1H),3.95–3.81(m,3H),3.80–3.73(m,1H),3.67–3.56(m,2H),3.20–3.00(m,6H),2.85–2.69(m,3H),2.57–2.52(m,2H),2.35(s,3H),2.33–2.25(m,1H),2.25–2.18(m,2H),2.12–2.02(m,1H),1.93–1.77(m,2H),1.74–1.64(m,1H),1.56(d,J＝7.0Hz,3H),1.18–1.04(m,2H).
实施例B5 1-(5-(4-(4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)哌啶-1-羰基)-2-氯苯基)二氢嘧啶-2,4(1H,3H)-二酮
LC-MS:m/z 850(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.06(s,1H),7.70–7.63(m,2H),7.60(d,J＝2.1Hz,1H),7.43(dd,J＝8.3,2.1Hz,1H),6.94(s,1H),6.88(s,1H),6.85(s,1H),6.71(s,1H),5.66–5.50(m,3H),5.27–5.21(m,1H),4.55–4.39(m,1H),3.98(dd,J＝10.2,4.3Hz,1H),3.95–3.81(m,3H),3.81–3.73(m,1H),3.70–3.57(m,2H),3.20–3.01(m,5H),2.89–2.79(m,0H),2.94–2.78(m,1H),2.79–2.73(m,2H),2.72–2.63(m,3H),2.59–2.52(m,2H),2.41–2.25(m,4H),2.12–2.02(m,1H),1.99–1.85(m,1H),1.85–1.70(m,1H),1.56(d,J＝7.0Hz,3H),1.53–1.40(m,2H).
实施例P01(3-(5-(4-((4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)甲基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲基特戊酸甲酯
LC-MS:m/z 970(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝8.0Hz,1H),7.67(s,1H),7.53(d,J＝8.3Hz,1H),7.10–7.03(m,2H),6.95(s,1H),6.89(s,1H),6.86(s,1H), 6.71(s,1H),5.68–5.51(m,5H),5.29–5.20(m,2H),4.36(d,J＝16.7Hz,1H),4.17(d,J＝16.7Hz,1H),3.98(dd,J＝10.1,4.3Hz,1H),3.95–3.82(m,5H),3.20–3.05(m,4H),2.91–2.79(m,3H),2.61–2.53(m,4H),2.42–2.19(m,7H),2.13–1.97(m,2H),1.89–1.76(m,3H),1.56(d,J＝7.1Hz,3H),1.29–1.15(m,3H),1.12(s,9H).
实施例P02 3-(5-(4-((4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)哌嗪-1-基)甲基)哌啶-1-基)-1-氧代异吲哚-2-基)-1-甲基哌啶-2,6-二酮
LC-MS:m/z 870(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.94(d,J＝8.2Hz,1H),7.66(s,1H),7.52(d,J＝9.4Hz,1H),7.09–7.03(m,2H),6.95(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.63–5.50(m,3H),5.26–5.22(m,1H),5.11(dd,J＝13.4,5.1Hz,1H),4.27(dd,J＝51.6,16.2Hz,2H),3.98(dd,J＝10.0,4.3Hz,1H),3.94–3.81(m,5H),3.19–3.07(m,4H),3.04–2.93(m,4H),2.90–2.67(m,4H),2.63–2.52(m,2H),2.44–2.20(m,7H),2.12–2.03(m,1H),2.03–1.94(m,1H),1.83(d,J＝11.8Hz,3H),1.56(d,J＝7.1Hz,3H),1.32–1.16(m,3H).实施例生物学测试评价
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。
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
(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。阳性对照组加入等体积的培养基；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，阳性对照组仅加入等体积的培养基。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。
参照化合物BI-3406结构如下：
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IC50。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

化合物对SOS1蛋白水解的调节实验
实验步骤
(1)接种肿瘤细胞(例如H358，5X105～1X06)在培养皿(2D，P100mm dish)培养2-4天，至70-80％饱和；
(2)更换10ml新鲜培养液后，继续培养箱内温孵过夜，然后加入相同浓度的本发明的PROTAC候选物以及对照pair的SOSi，轻微摇动混匀。
(3)细胞继续培养1～24小时，做同浓度下(0.1或者1uM)时间曲线(1，2，4，6，8，24,48)或者6、24或48小时下剂量曲线(0.0001，0.001，0.01，0.1，1，10uM)。
(4)在所设计的时间或者浓度终点，弃去培养液，把培养皿转移到冰上，用50毫升冰冷PBS清洗3次，尽量吸干剩余液体，然后加入冰冷裂解液(含detergent例如triton,NP40等)以及蛋白水解酶抑制剂。
(5)用细胞刮刀在冰上把细胞刮下，然后转移到1.5毫升离心管内，4度高速离心20分钟，取上清液液，并转移到新的管内。测定蛋白含量后，蛋白上清液用4X上胶液混合，加热(100度，5-10分钟)，冷却后加入10X抗氧剂成最终上胶样品，并于-20度保存。
(6)样品做Western-blot，用SDS-PAGE胶跑电泳，样品可上样10-50微克总蛋白，电转硝酸纤维膜后，切好条带和各自抗体温孵。然后用标记2抗温孵后，做自发光显色，拍照。
(7)最后应用GraphPad Prism软件计算化合物的IC50值，并绘出拟合曲线。
实验结果表明，本发明的化合物实施例A1(图1)具有靶向降解SOS1蛋白的作用。
药代动力学测试评价
雄性SD大鼠，体重220g左右，禁食过夜后，IP或者PO给予本发明化合物的溶液[5％EtOH,15％solutol in D5W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，和24采血，用LC/MS/MS测定血浆中本发明化合物的浓度。
实验结果表明，本发明化合物通过IP或者PO给药具有良好的药代动力学特性。
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. 一种化合物、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，所述化合物为式(IA)、式(IB)或式(IC)所示的化合物：
    各式中：
    A独立地选自取代或未取代的下组基团：C6-C14芳基、或5-14元杂芳基；其中，所述取代是指独立地被一个或多个R取代；
    X独立地选自取代或未取代的下组基团：H、D、卤素、CN、-C≡CH、C1-C18烷基、C3-C20环烷基、4-20元杂环基、C6-C14芳基、5-14元杂芳基、OX1、NHX1、或NX1X2；其中，所述取代是指独立地被一个或多个R取代；
    X1、X2独立地选自取代或未取代的下组基团：C1-C18烷基、C3-C20环烷基、4-20元杂环基、C6-C14芳基、或5-14元杂芳基；其中，所述取代是指独立地被一个或多个R取代；
    Y1、Y2各自独立地选自CH或N，且Y1、Y2不同时为CH；
    n1、n2各自独立地选自1、2或3；
    L1、L2各自独立地选自取代或未取代的下组基团：键、O、C＝O、NH、N(C1-C3烷基)、C2-C18烯基、C2-C18炔基、C1-C18亚烷基、C3-C20亚环烷基、4-20元亚杂环基、C3-C20亚环烷基-C1-C18亚烷基、或4-20元亚杂环基-C1-C18亚烷基；其中，所述取代是指独立地被一个或多个R取代；
    Z独立地选自取代或未取代的下组基团：键、C2-C18炔基、C3-C20环烷基、4-20元杂环基、C3-C20亚环烷基-C1-C18亚烷基、或4-20元亚杂环基-C1-C18亚烷基；其中，所述取代是指被一个或多个R取代；
    P1、P2、P3、P6、P7各自独立地选自CRa、或N；其中Ra独立地选自下组：H、氘、F、氯、溴、-OC1-C6烷基或-OC1-C6卤代烷基；
    P4、P5各自独立地选自CH2或C＝O；
    P8选自键或C＝O；
    P9选自键或NH；
    P10选自CH或N；
    各R相同或不同，各自独立地选自：H、氘、乙烯基、乙炔基、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、卤代C1-C6烷基醇、(C3-C6环烷基)C1-C6烷基、(4-6元杂环基)C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、(C3-C6环烷基氧基)C1-C6烷基、(4-6元杂环基氧基)C1-C6烷基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C6环烷基)乙炔基、(4-6元杂环基)乙炔基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、5-10元杂芳基、卤素、硝基、羟基、氧代基(＝O)、氰基、酯基、胺基、酰胺基、砜基或脲基。
  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，A独立地为取代或未取代的苯基；其中，所述取代是指独立地被一个或多个R取代。
  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，A独立地选自：
  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，X1独立地选自：取代或未取代的C1-C8烷基、取代或未取代的C1-C8氧杂烷基、取代或未取代的C3-C6环烷基、取代或未取代的C4-C6单氧杂环烷基；其中，所述取代是指独立地被一个或多个R取代。
  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，X1选自：
  6. 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，独立地选自取代或未取代的下组基团：
    其中，所述取代是指独立地被一个或多个R取代。
  7. 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，Z独立地选自取代或未取代的C4-C6亚杂环烷 基、或取代或未取代的C2-C6炔基；其中，所述取代是指独立地被一个或多个R取代。
  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，Z选自取代或未取代的下组基团：
    其中，所述取代是指独立地被一个或多个R取代。
  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，-L1-L2-独立地选自取代或未取代的下组基团：键、C1-C6烷基、
    其中，所述取代是指独立地被一个或多个R取代。
  10. 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，其特征在于具有式(II)所示结构：
    其中：A、X、Y1、Y2、L1、L、Z、P1、P2、P3、P5、n1、n2如权利要求1所述。
  11. 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，所述化合物具有式(III)所示结构：
    其中：A、X、Y1、Y2、L1、L、Z、P1、P2、P5、n1、n2如权利要求1所定义。
  12. 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：所述化合物选自下组：










  13. 一种药物组合物，包含i)一种或多种如权利要求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；和ii)药学上可接受的载体。
  14. 一种如权利要求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，或包含其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，所述癌症选自下组：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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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
WO2025265060A1 (en) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Therapeutic compositions and methods for managing treatment-related effects
WO2026006747A1 (en) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Ras inhibitors
WO2026015801A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015825A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Use of ras inhibitor for treating pancreatic cancer
WO2026015796A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015790A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022061348A1 (en) * 2020-09-16 2022-03-24 Biotheryx, Inc. Sos1 protein degraders, pharmaceutical compositions thereof, and their therapeutic applications
CN115043817A (zh) * 2021-03-09 2022-09-13 苏州泽璟生物制药股份有限公司 Sos1蛋白水解调节剂及其制备方法和应用
WO2022197862A1 (en) * 2021-03-17 2022-09-22 Biotheryx, Inc. Sos1 protein degraders, pharmaceutical compositions thereof, and their therapeutic applications
WO2022266248A1 (en) * 2021-06-16 2022-12-22 Biotheryx, Inc. Sos1 protein degraders, pharmaceutical compositions thereof, and their therapeutic applications
US20230293702A1 (en) * 2022-03-16 2023-09-21 Biotheryx, Inc. Quinazolines, pharmaceutical compositions, and therapeutic applications

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022061348A1 (en) * 2020-09-16 2022-03-24 Biotheryx, Inc. Sos1 protein degraders, pharmaceutical compositions thereof, and their therapeutic applications
CN115043817A (zh) * 2021-03-09 2022-09-13 苏州泽璟生物制药股份有限公司 Sos1蛋白水解调节剂及其制备方法和应用
WO2022188819A1 (zh) * 2021-03-09 2022-09-15 苏州泽璟生物制药股份有限公司 Sos1蛋白水解调节剂及其制备方法和应用
WO2022197862A1 (en) * 2021-03-17 2022-09-22 Biotheryx, Inc. Sos1 protein degraders, pharmaceutical compositions thereof, and their therapeutic applications
WO2022266248A1 (en) * 2021-06-16 2022-12-22 Biotheryx, Inc. Sos1 protein degraders, pharmaceutical compositions thereof, and their therapeutic applications
US20230293702A1 (en) * 2022-03-16 2023-09-21 Biotheryx, Inc. Quinazolines, pharmaceutical compositions, and therapeutic applications

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
WO2025265060A1 (en) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Therapeutic compositions and methods for managing treatment-related effects
WO2026006747A1 (en) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Ras inhibitors
WO2026015801A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015825A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Use of ras inhibitor for treating pancreatic cancer
WO2026015796A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015790A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder

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