WO2021037018A1 - 二氢或四氢喹唑啉类化合物及其中间体、制备方法和应用 - Google Patents

二氢或四氢喹唑啉类化合物及其中间体、制备方法和应用 Download PDF

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WO2021037018A1
WO2021037018A1 PCT/CN2020/111031 CN2020111031W WO2021037018A1 WO 2021037018 A1 WO2021037018 A1 WO 2021037018A1 CN 2020111031 W CN2020111031 W CN 2020111031W WO 2021037018 A1 WO2021037018 A1 WO 2021037018A1
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cancer
compound
formula
group
alkyl
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PCT/CN2020/111031
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French (fr)
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李安虎
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南京创济生物医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to a dihydro or tetrahydroquinazoline compound, its racemate, enantiomer, diastereomer, pharmaceutically acceptable salt or solvate , An intermediate compound used to synthesize the compound and its preparation method, as well as a pharmaceutical composition containing the compound and its application.
  • RAS is a type of protein called small GTPases. Its role is to transmit signals within the cell and act as a link between receptors located on the cell surface (such as EGFR, FGFR, ERBB2-4) and the downstream and cell growth, differentiation and survival ( growth, differentiation, and survival) related paths (such as RAF-MEK-ERK, PI3K-AKT-mTOR and RALGDS-RA) bridges (J. Downward, Nat. Rev. Cancer 2003, 3(1), 11-22) .
  • RAS is switched on by signals from upstream, it then turns on other proteins, and finally turns on the above-mentioned genes and signal transmission pathways involved in cell growth, differentiation, and survival. Mutations in the RAS gene can cause permanently activated RAS proteins. These mutant proteins can cause unexpected and overactive signal transduction in cells even in the absence of external signals. Overactive RAS signaling may eventually lead to cancer (D.S. Goodsell, The Oncologist 1999, 4, 263-264).
  • the three RAS genes (KRAS, HRAS and NRAS) are the most common oncogenes in human cancers.
  • the frequency of permanently activated RAS mutations in all human tumors is between 20%-25%, and in some types Up to 90% of all cancers (eg, pancreatic cancer) (J. Downward, Nat. Rev. Cancer 2003, 3(1), 11-22).
  • Figure 1 shows the mutation rates of three human RAS genes (H. Adderley, FH Blackhall, and CRLindsay, EBioMedicine 2019, 41, 711-716).
  • KRAS accounts for the highest proportion of 86%, followed by NRAS at 11%, and HRAS at least 3%.
  • KRAS mutations mainly occur in three tumors: lung cancer (22.1%), colorectal cancer (40.5%) and pancreatic cancer (73.6%).
  • KRAS mutants mainly include G12C, G12D, G12V and G12R.
  • KRAS has gained the reputation of being undruggable.
  • the reason is The surface of the KRAS protein is relatively smooth, with only some shallow pockets, lacking a pocket suitable for the binding of drug molecules.
  • Professor Shokat’s laboratory reported a breakthrough in the research of irreversible inhibitors for KRAS G12C mutants (J.M.Ostrem, U.Peters, M.L.Sos, J.A.Wells, K.M.Shokat, Nature 2013,503,548-551).
  • Their research results sparked an upsurge in the development of KRAS G12C inhibitors, and a series of irreversible inhibitors have been reported one after another.
  • Kessler et al reported a class of isoindolin-1-one compounds as reversible KRAS inhibitors (D.Kessler et al.Proc.Natl.Acad.Sci.USA.2019 Jul 22.pii:201904529.doi : 10.1073/pnas.1904529116).
  • WO2019/099524A1 and WO2017/201161A1 disclose a class of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine compounds as KRAS G12C inhibitors.
  • Marx et al reported a class of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidines as KRAS G12C inhibitors (WO2020/047192).
  • WO2019/155399A1 discloses a class of tetrahydroquinazoline compounds as KRAS G12C inhibitors.
  • WO2020/035031A1 reported a class of silk ring compounds as KRAS G12C inhibitors.
  • One of the objectives of the present invention is to disclose a class of KRAS G12C inhibitors with potential clinical application value.
  • the purpose of the present invention is to provide a dihydro or tetrahydroquinazoline compound with KRAS G12C protein inhibitory activity, its racemates, enantiomers, diastereomers, and pharmaceutically acceptable salts Or solvate.
  • Another object of the present invention is to provide a compound containing the above-mentioned dihydro or tetrahydroquinazoline, its racemate, enantiomer, diastereomer, pharmaceutically acceptable salt or solvate
  • Pharmaceutical compositions of, and the above-mentioned dihydro or tetrahydroquinazoline compounds, their racemates, enantiomers, diastereomers, pharmaceutically acceptable salts or solvates, and pharmaceutical combinations The application of the drug in the treatment of diseases caused by the abnormal activity of KRAS G12C.
  • Another object of the present invention is to provide a method for synthesizing the above-mentioned dihydro or tetrahydroquinazoline compounds, their racemates, enantiomers, diastereomers, pharmaceutically acceptable salts or Solvate intermediate compound and its preparation method.
  • a dihydro or tetrahydroquinazoline compound, its racemate, enantiomer, diastereomer, pharmaceutically acceptable salt or solvate, the molecular structure of the compound is as formula (I ) Shows:
  • Cy is a C 3-12 cycloalkyl group or a C 3-12 heteroalicyclic group
  • R 1 is a C 2-12 alkenyl group or a C 2-12 alkynyl group, and one or more hydrogens in the R 1 may be optionally substituted by the same or different G 1;
  • R 2 is selected from hydrogen, C 1-12 alkyl, C 3-12 cycloalkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-12 aryl, C 5-12 heteroaryl or C 3-12 heteroalicyclic group, and one or more hydrogens in R 2 may be optionally substituted by the same or different G 2;
  • R 3 and R 4 are the same or different, and each independently represents one or more of the same or different hydrogen, deuterium, halogen, OH, CN, NO 2 , CO 2 H, CONH 2 , SH, CH 2 CN, CH 2 F , CHF 2 , CF 3 , CH 2 CH 2 CN, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 OH, CH 2 CH 2 OH, OCH 2 F, OCHF 2 , OCF 3 , NRR ', C 1-12 alkyl, C 3-12 cycloalkyl, C 3-12 heteroalicyclic, C 1-12 alkoxy, C 3-12 cycloalkoxy or C 3-12 heteroalicyclic Oxy;
  • Ar is a C 6-12 aryl group or a C 5-12 heteroaryl group, and one or more hydrogens in the Ar may be optionally substituted by the same or different G 3;
  • R and R' are the same or different, each independently selected from hydrogen, deuterium, OH, CN, C 1-12 alkyl, C 3-12 cycloalkyl, C 3-12 heteroalicyclic, C 1-12 alkane Oxy group, C 3-12 cycloalkoxy group or C 3-12 heteroaliphatic epoxy group;
  • G 1 , G 2 and G 3 are the same or different, each independently selected from one or more of the same or different deuterium, halogen, OH, CN, NO 2 , CO 2 H, SH, CH 2 CN, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 CN, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , OCH 2 F, OCHF 2 , OCF 3 , C 1-12 alkyl, C 3-12 ring Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-12 aryl, C 5-12 heteroaryl or C 3-12 heteroalicyclic group, wherein the C 1-12 alkyl , C 3-12 cycloalkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-12 aryl, C 5-12 heteroaryl or C 3-12 heteroalicyclic group or Multiple hydrogens may optionally be substituted by the same or different deuterium, halogen, CN
  • One or more hydrogens in G 1 , G 2 and G 3 may optionally be further substituted with the same or different deuterium, halogen, OH, OCH 3 , CN, CH 2 CN, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 CN, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , OCH 2 F, OCHF 2 , OCF 3 , C 1-12 alkyl or C 3-12 cycloalkyl substitution;
  • n 0, 1, or 2.
  • the R 1 may also be- CH 2 -halogen
  • the two identical or different C 1-12 Alkyl groups can be connected to each other and form a 5-18 membered spiro ring together with the Cy ring.
  • R 3 represents two identical or different C 1-12 alkyl groups connected to two adjacent atoms on the Cy ring
  • the two identical or different C The 1-12 alkyl groups may be connected to each other and form a 5-18 membered fused ring together with the Cy ring.
  • R 3 represents two identical or different C 1-12 alkyl groups attached to two non-adjacent atoms on the Cy ring
  • the two identical or different The C 1-12 alkyl groups may be connected to each other and form a 5-18 membered bridged ring together with the Cy ring.
  • Cy1 is a C 3-12 heteroalicyclic group containing two N atoms, preferably, any one selected from Cy1-1 to Cy1-9:
  • R 3a represents one or more of the same or different hydrogen, deuterium, halogen, OH, CN, NO 2 , CO 2 H, CONH 2 , SH, CH 2 CN, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 CN, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 OH, CH 2 CH 2 OH, OCH 2 F, OCHF 2 , OCF 3 , NRR', C 1-12 alkyl, C 3-12 cycloalkyl, C 3-12 heteroalicyclic, C 1-12 alkoxy, C 3-12 cycloalkoxy or C 3-12 heteroalicyclic epoxy;
  • R 3a represents at least two identical or different C 1-12 alkyl groups
  • the two identical or different C 1-12 alkyl groups may be connected to each other and pass through one or two of the piperazine ring to which they are connected.
  • R 3a represents two identical or different C 1-12 alkyl groups
  • R 3b represents one or more of the same or different hydrogen, deuterium, halogen, CN, CO 2 H, CONH 2 , CH 2 CN, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 CN, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 OH, CH 2 CH 2 OH or C 1-12 alkyl;
  • R 3b represents at least two identical or different C 1-12 alkyl groups
  • the two identical or different C 1-12 alkyl groups may be connected to each other and pass through one or two of the piperazine ring to which they are connected.
  • R 2 , Ar, *, m, R 1a , R 1b and R 1c are as defined above.
  • the present invention also provides an intermediate compound for synthesizing the above-mentioned dihydro or tetrahydroquinazoline compound, the structural formula of the intermediate compound is (IIa) or (IIb):
  • Ar' is a C 6-12 aryl group or a C 5-12 heteroaryl group, and one or more hydrogens in the Ar' may be optionally substituted by the same or different G 4;
  • Each Z independently represents the same or different halogen
  • R 55 , R 66 and R 77 are the same or different, and are each independently selected from hydrogen, deuterium, C 1-12 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, and C 5-12 heteroaryl Or C 3-12 heteroalicyclic group, one or more hydrogens in R 55 , R 66 and R 77 may be optionally substituted with the same or different deuterium, OH, OCH 3 , CN, NO 2 , CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 or C 1-12 alkyl substitution; when R 66 and R 77 are connected to the same nitrogen atom, they can be connected to each other and together with the nitrogen atom
  • the Ar' is selected from phenyl, naphthyl, imidazolyl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, triazolyl, tetrazolyl, pyridine Group, pyrimidinyl, triazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, indolyl, indazolyl, azaindolyl, azaindazole Group, benzimidazolyl, benzothiazolyl, benzoxazolyl, azabenzimidazolyl, azabenzothiazolyl, azabenzoxazolyl, imidazopyrazinyl, imidazopyridyl , Imidazopyridazinyl, thiazolopyrazinyl, thiazo
  • the present invention also provides a preparation method of the above-mentioned intermediate compound as shown in Scheme A, which includes step 1 to step 2 or step 1 to step 3.
  • W represents C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, C 5-12 heteroaryl or C 3-12 Heteroalicyclic group; preferably C 1-12 alkyl or C 3-12 cycloalkyl; more preferably methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cycloalkyl Propyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • Step 1 The compound of formula II-1 is reacted with the compound of formula II-2 to obtain the compound of formula II-3;
  • Step 2 The compound of formula II-3 and the compound of formula II-4 undergo a condensation reaction to obtain an intermediate compound as shown in formula IIa;
  • Step 3 The intermediate compound of formula IIa is reacted with halogenating reagent to obtain the intermediate compound of formula IIb.
  • Step 1 Under the conditions of rhodium catalyst Rh catalyst, ligand L and base Base-1, the compound of formula II-1 and the compound of formula II-2 are reacted in solvent Solvent-1 to obtain the compound of formula II-3;
  • Step 2 In the presence of the base Base-1, the compound of formula II-3 and the compound of formula II-4 undergo a condensation reaction in the solvent Solvent-1 to obtain the intermediate compound of formula IIa;
  • the rhodium catalyst Rh catalyst is selected from the group consisting of two (ethylene) rhodium chloride (I) dimer, diethylene (acetyl acetone) rhodium (I), (acetyl acetone) (1,5-cyclooctadiene) rhodium (I), (acetylacetone) dicarbonyl rhodium (I), (acetylacetone) (norbornane) rhodium (I), (2,5-norbornane) rhodium chloride (I) dimer, two ( Acetyl cyanide) (1,5-cyclooctadiene) rhodium(I) tetrafluoroborate or bis(norbornane) rhodium(I) tetrafluoroborate;
  • Ligand L has the following structure: Wherein, W 1 is selected from C 6-12 aryl, C 5-12 heteroaryl or C 3-12 cycloalkyl; W 2 is selected from C 1-12 alkyl or C 3-12 cycloalkyl; One or more hydrogens in W 1 and W 2 can be optionally substituted by the same or different deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl , Methoxy, ethoxy, trifluoromethoxy, trifluoromethyl or dimethylamino substitution;
  • each base Base-1 is independently selected from K 3 PO 4 , K 2 HPO 4 , Na 3 PO 4 , Na 2 HPO 4 , Li 2 CO 3 , Na 2 CO 3 , NaHCO 3.
  • each solvent Solvent-1 is independently selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichloromethane, dichloroethane, methanol, ethanol , N-propanol, isopropanol, n-butanol, tert-butanol, water, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, ethyl acetate or a mixture of two or more of them;
  • the halogenating reagent Halogenating Reagent is selected from POCl 3 , POBr 3 , SOCl 2 , PCl 3 , PCl 5 , PBr 3 , PPh 3 + CCl 4 , PPh 3 + CBr 4 , PPh 3 + Cl 2 , PPh 3 + Br 2 , PPh 3 +I 2 , cyanuric chloride or oxalyl chloride.
  • the present invention also provides a method for preparing the above-mentioned dihydro or tetrahydroquinazoline compounds.
  • the method may consist of the steps shown in Scheme 1:
  • the compound of formula II-1 can be purchased, and the compound of formula II-2 can be synthesized according to literature methods (for example, K. Yahata et al. Org. Lett. 2014, 16, 3680-3683);
  • PG stands for the common N protecting group in organic chemistry, including but not limited to Boc (i.e. -CO 2 Bu-t), CBZ (i.e. -CO 2 CH 2 Ph), Bn (i.e. -CH 2 Ph), PMB (i.e.- CH 2 C 6 H 4 -OCH 3 -p) etc.;
  • Deprotection represents the removal of the protecting group from N.
  • the protecting group is Boc (ie -CO 2 Bu-t)
  • commonly used deprotection reagents include but are not limited to HCl, trifluoroacetic acid, H 2 SO 4, etc.
  • the protecting group is When it is CBZ (ie -CO 2 CH 2 Ph)
  • the commonly used deprotection reagents include but are not limited to concentrated HCl, H 2 +Pd/C, etc.
  • the protecting group is Bn (ie -CH 2 Ph)
  • the commonly used deprotection reagents Protective reagents include but are not limited to H 2 +Pd/C, H 2 +Pd(OH) 2 , H 2 +Pd/C+HCl, etc.
  • deprotection reagents include but are not limited to trifluoroacetic acid, ceric ammonium nitrate, etc.;
  • the present invention also provides another intermediate compound for synthesizing the above-mentioned dihydro or tetrahydroquinazoline compound, and the structural formula of the intermediate compound is (IIc):
  • Z 1 and Z 2 are the same or different, and each independently represents halogen, OH, CF 3 SO 3 , SH, CH 3 S, CH 3 S(O), or CH 3 S(O) 2 .
  • the present invention also provides a preparation method of the above-mentioned intermediate compound as shown in Scheme B, including steps 1 to 4,
  • Step 1 The compound of formula II-10 is reacted with the compound of formula II-11 to obtain the compound of formula II-12;
  • Step 2 The compound of formula II-12 and the compound of formula II-13 undergo a condensation reaction to obtain a compound of formula II-14;
  • Step 3 The compound of formula II-14 is reacted with methyl iodide to obtain the compound of formula II-15;
  • Step 4 Trifluoromethanesulfonylation of the compound of formula II-10 to obtain the intermediate compound of formula (IIc);
  • Step 1 The compound of formula II-10 is reacted with the compound of formula II-11 in the presence of base-1 to obtain the compound of formula II-12;
  • Step 3 The compound of formula II-14 is reacted with methyl iodide in the presence of base-1 to obtain the compound of formula II-15;
  • the present invention also provides another preparation method of the above-mentioned dihydro or tetrahydroquinazoline compounds.
  • the method may consist of the steps shown in Scheme 2:
  • the present invention also provides a compound comprising at least one of the above-mentioned dihydro or tetrahydroquinazoline compounds, racemates, enantiomers, diastereomers, pharmaceutically acceptable salts or solvates thereof Pharmaceutical composition.
  • the above-mentioned pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier or diluent.
  • the aforementioned dihydro or tetrahydroquinazoline compounds their racemates, enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, solvates or prodrugs
  • a suitable pharmaceutically acceptable carrier and pharmaceutically commonly used auxiliary agents are prepared into a pharmaceutical composition that is convenient for administration.
  • the preparation form of the pharmaceutical composition includes: oral agent, injection, anal suppository, nasal inhalation, eye drops or skin patch.
  • the various dosage forms of the above-mentioned pharmaceutical composition can be prepared by methods commonly used in the pharmaceutical industry. For example, mixing, dissolving, granulating, grinding, emulsifying, capsule, sugar coating, freeze drying, freeze spraying, etc.
  • the above-mentioned pharmaceutical composition is used to treat diseases caused by abnormal KRAS activity in mammals, such as human patients.
  • the above-mentioned dihydro or tetrahydroquinazoline compounds, their racemates, enantiomers, diastereomers, pharmaceutically acceptable salts or solvates are used in pharmaceutical compositions
  • the content range is 0.001-100%.
  • the effective dose of the pharmaceutical composition applied to mammals including humans is 0.1-500 mg per kilogram of body weight per day, and the optimized dose is 0.1-100 mg per kilogram of body weight per day.
  • the compound of the present invention exerts its pharmacological effects in inhibiting KRAS activity and treating diseases (such as cancer) caused by abnormal KRAS activity.
  • the present invention also provides the aforementioned dihydro or tetrahydroquinazoline compounds, their racemates, enantiomers, diastereomers, pharmaceutically acceptable salts or solvates, or the aforementioned Application of the pharmaceutical composition in the treatment of diseases caused by abnormal KRAS activity.
  • the KRAS is a KRAS G12C mutant
  • the disease is a tumor, including solid tumors and liquid tumors.
  • the tumor is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, colorectal cancer, and anal cancer , Stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vagina cancer, vaginal cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, soft tissue Sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, bladder cancer, kidney or ureter cancer, kidney cancer, adrenal cancer, renal cell carcinoma, renal pelvis cancer, brain glioma, brainstem glioma, nerve Endocrine gliomas, gliomas, central nervous system (CNS) neoplasms, spinal axis tumors, pituitary adenomas, gastrointestinal cancer, gastrointestinal cancer, gastrointestinal
  • the present invention also provides a medicine for treating diseases caused by the abnormal activity of KRAS mutants, comprising any one or any of the above-mentioned dihydro or tetrahydroquinazoline compounds or their pharmaceutically acceptable salts and solvents Compounds, prodrugs, or racemates, enantiomers, diastereomers, or different enantiomers of any one or several of the above-mentioned dihydro or tetrahydroquinazoline compounds Or a mixture of diastereomers in any ratio, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the above-mentioned drugs for treating diseases caused by the abnormal activity of KRAS mutants further comprise one or more pharmaceutically acceptable carriers or/and diluents.
  • the preparation form of the above-mentioned drug is as follows:
  • the route of administration of the above-mentioned drugs can be: (1) oral: such as tablets, capsules, etc.; (2) injection: such as intravenous injection, subcutaneous injection, intramuscular injection, eyeball injection, intraperitoneal injection, etc.; (3) anal injection Plugs: such as suppositories, gels, etc.; (4) Nostril inhalation: such as sprays, aerosols, etc.; (5) Eye drops; (6) Skin patches.
  • Drug delivery systems can also be used, such as liposomes, sustained-release technology, controlled-release technology, etc.
  • the preferred method is oral and injection, and the more preferred method is oral.
  • the frequency of use of the above-mentioned drugs varies according to the compound used or its pharmaceutical composition and the disease to which it is applied.
  • the pharmaceutical composition of the present invention is usually administered 1 to 6 times a day, and the frequency of administration is optimized. It is administered 1-3 times a day.
  • the packaging and storage of the above-mentioned medicines are similar to those of general western medicines.
  • solid dosage forms of medicines can be directly put into glass, plastic, paper or metal bottles, and desiccant, etc. should be placed in the bottle to maintain the quality of the medicine;
  • Drugs in dosage forms are generally packed in glass, plastic or metal bottles or tubes;
  • drugs in misted dosage forms are generally packed in pressure-resistant metal or plastic containers with pressure relief valves and other devices.
  • dihydro or tetrahydroquinazoline compounds of the present invention can be used together with other anti-tumor drugs including but not limited to chemotherapeutic drugs, targeted therapy drugs or immunotherapy drugs to achieve synergistic or additive ( additive) effect;
  • the dihydro or tetrahydroquinazoline compounds of the present invention can be used together with other tumor therapies, such as surgery, radiation therapy, interventional therapy, and the like.
  • a dihydro or tetrahydroquinazoline compound, its racemate, enantiomer, diastereomer, pharmaceutically acceptable salt or solvate of the present invention can be used as a An effective drug for the treatment of diseases caused by the abnormal activity of KRAS.
  • Solvents commonly used in the preparation of the compounds of the present invention include but are not limited to water, methanol, ethanol, isopropanol, n-propanol, N-butanol, isobutanol, tert-butanol, 2-methoxyethanol, 2,2,2-trifluoroethanol, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, Dioxane, 1,2-dimethoxyethane, ethyl acetate, diethyl ether, methyl tert-butyl ether, hexane, cyclohexane, toluene, acetonitrile, dimethyl sulfoxide, dimethyl methyl Amide, dimethylacetamide or a combination of two or more of these solvents.
  • the base includes but is not limited to organic bases, for example, MeNH 2 , Me 2 NH, Me 3 N, EtNH 2 , Et 2 NH, Et 3 N, n-PrNH 2 , n-Pr 2 NH, n-Pr 3 N, i-PrNH 2 , i-Pr 2 NH, i-Pr 3 N, n-BuNH 2 , n-Bu 2 NH , N-Bu 3 N, s-BuNH 2 , s-Bu 2 NH, s-Bu 3 N, i-BuNH 2 , i-Bu 2 NH, i-Bu 2 NH, i-Bu 3 N, t-BuNH 2 , t-Bu 2 NH, t-Bu 3 N, i-Pr 2 NEt, 2-amino-2-(hydroxymethyl)propane-1,3-diol, cyclopropylamine,
  • the base also includes but is not limited to inorganic bases, for example, ammonia, ammonia, LiOH, NaOH, KOH, RbOH, CsOH, Cs 2 CO 3 , Rb 2 CO 3 , Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , KHCO 3 , LiF, NaF, KF, RbF, CsF, K 3 PO 3 , K 2 HPO 4 , KH 2 PO 4 , Na 3 PO 3 , Na 2 HPO 4 , NaH 2 PO 4 , Li 3 PO 3 , Li 2 HPO 4 , LiH 2 PO 4 , NaH, LiH, KH, RbH, CsH, CaO, Ca(OH) 2 , Ca 2 CO 3 , Ba(OH) 2 , MgO, Mg(OH) 2. Mg 2 CO 3, etc., or a combination of two or more of the above-mentioned bases.
  • inorganic bases for example, ammonia, ammoni
  • Pd catalyst includes but is not limited to Pd/C, Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , PdCl 2 , Pd(OAc) 2 , Pd(O 2 CCF 3 ) 2 , PdCl 2 (dppf), PdCl 2 (dppp), Pd(PPh 3 ) 2 Cl 2 , Pd(PhCN) 2 Cl 2 , Pd(OH) 2 , RuPhos Pd G2(CAS #:1375325-68-0), RuPhos Pd G3(CAS#:1445085-77-7), RuPhos Pd G4(CAS#:1599466-85-9), one or several combinations.
  • Pd catalyst includes but is not limited to Pd/C, Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , PdCl 2 , Pd(OAc) 2 , Pd(O 2 CCF 3 ) 2 , PdCl 2 (dppf
  • Coupling reagents commonly used to prepare the compounds of the present invention include but are not limited to DCC, EDC, HATU, TBTU, PyBOP, HCTU, One or several combinations of BOP, T3P, DIC, HOBt, HOAt, CDI, DEPBT, COMU, etc.
  • the reaction to prepare the compound of the present invention is usually carried out at room temperature, but sometimes needs to be reduced to -78°C or heated to 200°C; the reaction is usually carried out under the aforementioned solvent, temperature and conventional stirring conditions, but sometimes needs to be carried out in a microwave oven; When the alkalis, reagents, and catalysts used are sensitive to water or oxygen, the reaction needs to be carried out under anhydrous and oxygen-free conditions. In this case, protic solvents cannot be used.
  • substitution means that any group is mono- or poly-substituted by a designated substituent to the degree that such mono- or poly-substitution (including multiple substitutions at the same position) is chemically permissible, and each substituent may be located Any available position on the group can be connected via any available atom on the substituent. "Any available position” refers to any position on the group that can be chemically obtained by methods known in the art or methods taught herein, and does not produce excessively unstable molecules. When there are two or more substituents on any group, each substituent is defined independently of any other substituents, and therefore may be the same or different.
  • C 1-4 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl and C 4 alkyl.
  • the compound of the present invention refers to the compound of formula (I) and all pure and mixed stereoisomers, geometric isomers, tautomers, racemates, Enantiomers, diastereomers, N-oxides, S-oxides, solvates, metabolites, prodrugs and isotopically labeled compounds and any pharmaceutically acceptable salts.
  • solvent refers to a stable substance formed by the compound of the present invention and commonly used chemical solvents through covalent bond, hydrogen bond, ionic bond, van der Waals force, complexation, inclusion, etc.
  • the solvent may be: methanol , Ethanol, propanol, butanol, ethylene glycol, propylene glycol, polyethylene glycol, acetone, acetonitrile, ether, methyl tert-butyl ether, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, etc. .
  • Hydrophilate refers to a solvate in which the solvent is water.
  • “Pharmaceutically acceptable” means that the compound or composition must be chemically, pharmacologically, and/or toxicologically compatible with the other ingredients constituting the formulation and/or the mammal to be treated with it.
  • Prodrug refers to the conversion of the compound of the present invention into another compound by chemical synthesis or physical methods, and after the compound is administered to a mammal, it is converted into the compound of the present invention in the animal's body.
  • the “prodrug” method is usually used to overcome the poor or poor physicochemical properties or druggability of the drug molecule itself.
  • stereo isomers means that compounds have the same molecular formula and molecular weight, but different compounds are formed due to the different bonding modes and/or spatial arrangement order between the atoms.
  • the compounds are called isomers or stereoisomers. When these stereoisomers are mirror images of each other, they look alike but cannot completely overlap, just like left-handed and right-handed, these compounds are called enantiomers.
  • the absolute configuration of enantiomers is usually indicated by (R)- and (S)- or R- and S-.
  • Tautomers refers to structural isomers with different energies that can cross the low energy barrier to convert into each other.
  • Valence tautomers include some bond-forming electrons that recombine and undergo interconversion.
  • the compound of the present invention may exist tautomers (Tautomers), rotamers (rotamers), cis-trans isomers, of these concepts can be in J.March “Advanced Organic Chemistry,” 4 th edition of Find and understand. As long as these isomers have the same or similar effect of inhibiting KRAS activity as the compound of the present invention, these isomers are also encompassed in the present invention.
  • the compound of the present invention is administered to a mammal (such as a human), according to common knowledge in the art, it is possible to be metabolized into various metabolites (metabolites) by different enzymes in the animal body, as long as these metabolites have the same characteristics as those described in the present invention.
  • the compounds have similar effects of inhibiting KRAS activity, and these metabolites are also included in the present invention.
  • “Pharmaceutical composition” refers to combining one or more of the compounds described in the present invention, a pharmaceutically acceptable salt or solvate or hydrate or prodrug with other chemical ingredients (such as a pharmaceutically acceptable carrier or dilution Agent) the preparation obtained by mixing.
  • the purpose of the pharmaceutical composition is to facilitate the process of administration to animals.
  • a pharmaceutically acceptable carrier in addition to including a pharmaceutically acceptable carrier, it may also include auxiliary agents commonly used in pharmacology, such as antibacterial agents, antifungal agents, antimicrobial agents, quality-preserving agents, and conditioning agents. Colorants, solubilizers, thickeners, surfactants, complexing agents, proteins, amino acids, fats, carbohydrates, vitamins, minerals, trace elements, sweeteners, pigments, flavors or their combination, etc.
  • “Pharmaceutically acceptable carrier” or “diluent” refers to the inactive ingredients in the pharmaceutical composition, including but not limited to: calcium carbonate, calcium phosphate, magnesium carbonate, silica gel, various sugars (such as lactose, mannitol, etc.) , Starch, cyclodextrin, magnesium stearate, cellulose, acrylic acid polymer, methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil, hydrogenated castor oil, polyethylene Oxygenated hydrogenated castor oil, sesame oil, corn oil, peanut oil, etc.
  • “Pharmaceutically acceptable salt” refers to a salt formed by a chemical reaction between the compound of the present invention and an inorganic acid, organic acid, inorganic base, or organic base, and this salt retains the biological activity and effectiveness of the compound of the present invention.
  • the inorganic acid or organic acid includes but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, perchloric acid, acetic acid, citric acid, oxalic acid, lactic acid, malic acid, salicylic acid , Tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, substituted benzenesulfonic acid (for example, p-toluenesulfonic acid), camphorsulfonic acid, isonicotinic acid, oleic acid, tannic acid, pantothenic acid, ascorbic acid, butyric acid Diacid, maleic acid, gentisic acid, fumaric acid, gluconic acid, uronic acid, glucaric acid or sucrose acid, formic acid, benzoic acid, glutamic acid, pamoic acid, sorbic acid
  • Alkyl refers to a straight-chain or branched saturated hydrocarbon group with the specified number of carbon atoms, for example, C 1-12 alkyl refers to a straight-chain or branched group with a minimum of 1 and a maximum of 12 carbon atoms .
  • the C 0 alkyl group represents a single covalent bond.
  • the alkyl group in the present invention includes but is not limited to: methyl, ethyl, propyl, butyl, isopropyl, neopentyl, 2-methyl-1-hexyl and the like.
  • the alkyl group in the present invention sometimes also refers to an "alkylene group", and an alkylene group refers to a group formed by the loss of a hydrogen atom from an alkyl group.
  • One or all of the hydrogen atoms in the alkyl or alkylene group may be optionally substituted by the following groups: cycloalkyl, aryl, heteroaryl, heteroalicyclic, halogen, amino, hydroxyl, cyano, nitro, Carboxy, mercapto, oxo, alkoxy, aryloxy, alkyl mercapto, aryl mercapto, carbonyl, thiocarbonyl, C-amide, N-amide, O-aminocarbonyloxy, N- Aminocarbonyloxy, O-thioaminocarbonyloxy, N-thioaminocarbonyloxy, C-ester group, O-ester group and -NR a R b , wherein Ra and R b are respectively selected from
  • Cycloalkyl or “cycloalkane” refers to a mono-, bi- or polycyclic hydrocarbon group with the specified number of carbon atoms. When bicyclic or polycyclic, it can be a "fused ring” (two or more rings). Sharing two adjacent carbon atoms), “spiro” (two or more rings sharing one carbon atom) or “bridged ring” (two or more rings sharing two or more non-adjacent Carbon atoms), for example, a C 1-12 cycloalkyl group refers to a hydrocarbon group containing at least 1 and at most 12 mono-, di- or polycyclic hydrocarbon groups. C 0 cycloalkyl represents a single covalent bond.
  • Cycloalkyl groups may contain double bonds or triple bonds, but do not have a fully conjugated ⁇ -electron system.
  • the cycloalkyl group in the present invention sometimes also refers to a cycloalkylene group, that is, a group formed by a cycloalkyl group losing one hydrogen atom.
  • the cycloalkyl groups in the present invention include but are not limited to: cyclopropyl, cyclobutyl, cyclohexyl, cyclopentenyl, cycloheptatrienyl, adamantane, etc. (for example, Table A):
  • One or all of the hydrogen atoms in the cycloalkyl or cycloalkane can be substituted by the following groups: alkyl, aryl, heteroaryl, heteroalicyclic, halogen, amino, hydroxyl, cyano, nitro, carboxyl, mercapto, Oxo, alkoxy, aryloxy, alkyl mercapto, aryl mercapto, carbonyl, thiocarbonyl, C-amide, N-amide, O-aminocarbonyloxy, N-aminocarbonyloxy , O-thioaminocarbonyloxy, N-thioaminocarbonyloxy, C-ester group, O-ester group and -NR a R b , where Ra and R b are each selected from: hydrogen, alkyl , a cycloalkyl group, an aryl group, an acetyl group, a carbonyl group, a sulfonyl group, a triflu
  • Heteroalicyclyl (heteroalicyclyl or heterocycloalkyl)" or “heteroalicycle (heteroalicycle or heterocycloalkane)” or “heteroalicycle (heteroalicycle or heterocycloalkane)” refers to a monocyclic or bicyclic ring composed of 3 to 18 non-hydrogen ring atoms Or a polycyclic system, in which at least one ring atom is a heteroatom selected from O, N, S or P, and the remaining ring atoms are carbon atoms.
  • a C 8 heteroalicyclic group refers to 8 non-hydrogen ring atoms.
  • C 8 here does not mean 8 carbon atoms, but means 8 ring atoms composed of carbon atoms, O, N, S, or P. In addition to single bonds, this ring may also contain double or triple bonds, but these double or triple bonds do not constitute a fully conjugated aromatic structure.
  • These monocyclic, bicyclic or polycyclic ring systems can exist in the form of fused rings, bridged rings or spiro rings.
  • the heteroalicyclic group in the present invention sometimes also refers to a heteroalicyclic group, that is, a group formed by the heteroalicyclic group losing one hydrogen atom.
  • heteroalicyclic group or heteroalicyclic ring in the present invention includes, but is not limited to: piperidine, morpholine, piperazine, pyrrolidine, indoline, tetrahydropyridine, tetrahydrofuran, tropine, etc. (for example, Table B):
  • One or all of the hydrogen atoms in the heteroalicyclic group or heteroalicyclic ring can be substituted by the following groups: alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halogen, amino, hydroxyl, cyano, nitro Group, carboxyl, mercapto, oxo, alkoxy, aryloxy, alkyl mercapto, aryl mercapto, carbonyl, thiocarbonyl, C-amide, N-amide, O-aminocarbonyloxy, N-aminocarbonyloxy, O-thioaminocarbonyloxy, N-thioaminocarbonyloxy, C-ester group, O-ester group and -NR a R b , where R a and R b are selected respectively from: hydrogen, an alkyl group, a cycloalkyl group, an aryl group, an acetyl group, a carbonyl group, a s
  • alkenyl refers to a straight or branched hydrocarbon group containing at least two carbon atoms and at least one double bond.
  • C 2-12 alkenyl refers to a straight or branched hydrocarbon group containing at least 2 and at most 12 carbon atoms.
  • the branch contains an unsaturated group with at least one double bond.
  • the alkenyl in the present invention includes but is not limited to: vinyl, 2-propenyl, 1-pentenyl and the like.
  • Alkynyl refers to a straight or branched hydrocarbon group containing at least two carbon atoms and at least one triple bond.
  • C 2-12 alkynyl refers to a straight or branched hydrocarbon group containing at least 2 and at most 12 carbon atoms.
  • the branch contains an unsaturated group with at least one triple bond.
  • the alkynyl group in the present invention includes but is not limited to: vinyl, 2-propenyl, 1-pentenyl and the like.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Alkoxy refers to an alkyl group having the specified number of carbon atoms connected to other groups through an oxygen atom. Alkoxy in the present invention includes but is not limited to: methoxy, ethoxy, propoxy, butoxy, cyclopentyloxy, cyclohexyloxy, isopropoxy, neopentyloxy, 2- Methyl-1-hexyloxy and so on.
  • Cycloalkoxy refers to a cycloalkyl group having the specified number of carbon atoms connected to other groups through an oxygen atom.
  • the cycloalkoxy in the present invention includes but is not limited to: cyclopropoxy, cyclobutoxy, cyclohexaneoxy and the like.
  • Heteroalicyclic group means that the heteroalicyclic group is connected to other groups through an oxygen atom.
  • Heteroaliphatic epoxy groups in the present invention include, but are not limited to: piperidin-4-yloxy, oxetan-3-yloxy and the like.
  • Aryl refers to a monocyclic, bicyclic or polycyclic group consisting of a specified number of carbon atoms, at least one of which has a fully conjugated ⁇ -electron system and conforms to the N+2 rule, that is, it is aromatic, but the entire group It is not necessary to be all conjugated.
  • C 6 aryl refers to phenyl.
  • Aryl groups can also appear in the form of arylene groups, that is, there are two or more points of attachment to other groups in the aryl structure.
  • the aryl group in the present invention includes but is not limited to: phenyl, naphthyl, indenyl, indanyl, tetralin and the like.
  • One or all of the hydrogen atoms in the aryl group may be substituted by the following groups: alkyl, cycloalkyl, heteroaryl, heteroalicyclic, halogen, amino, hydroxyl, cyano, nitro, carboxy, mercapto, oxy ( oxo), alkoxy, aryloxy, alkyl mercapto, aryl mercapto, carbonyl, thiocarbonyl, C-amide, N-amide, O-aminocarbonyloxy, N-aminocarbonyloxy, O- Thioaminocarbonyloxy, N-thioaminocarbonyloxy, C-ester group, O-ester group and -NR a R b , wherein Ra and R b are selected from hydrogen, alkyl, cycloalkane, respectively group, an aryl group, an acetyl group, a carbonyl group, a sulfonyl group, a trifluoromethanes
  • Heteroaryl refers to a monocyclic, bicyclic or polycyclic group consisting of a specified number of non-hydrogen ring atoms, in which at least one ring atom is a heteroatom selected from O, N, S or P, and the remaining ring atoms are carbon atoms And, at least one of the rings has a fully conjugated ⁇ -electron system and conforms to the N+2 rule, that is, it is aromatic, but the entire group does not have to be fully conjugated.
  • a C 5 heteroaryl group means that there are 5 non- An aromatic ring group composed of hydrogen ring atoms, in which at least one ring atom is selected from O, N, S or P, and the remaining ring atoms are carbon atoms.
  • Heteroaryl groups can also appear in the form of heteroarylene groups, that is, there are two or more points of attachment to other groups in the heteroaryl structure.
  • Heteroaryl groups in the present invention include but are not limited to: arsenic, arsenicone, tetrahydroarsenicone, imididine, pyrazine, pyridazine, imidazole, thiazole, thiophene, furan, indole, azaindole, Benzimidazole, indoline, indolinone, quinazol, etc. (for example, Table C):
  • One or all of the hydrogen atoms in the heteroaryl group can be substituted by the following groups: alkyl, cycloalkyl, aryl, heteroalicyclic, halogen, amino, hydroxyl, cyano, nitro, carboxy, mercapto, oxy ( oxo), alkoxy, aryloxy, alkyl mercapto, aryl mercapto, carbonyl, thiocarbonyl, C-amide, N-amide, O-aminocarbonyloxy, N-aminocarbonyloxy, O- Thioaminocarbonyloxy, N-thioaminocarbonyloxy, C-ester group, O-ester group and -NR a R b , wherein Ra and R b are selected from hydrogen, alkyl, and cycloalkyl, respectively , an aryl group, an acetyl group, a carbonyl group, a sulfonyl group, a trifluoromethane
  • nitrogen atom-containing heteroaryl group refers to a heteroaryl group, but the heteroaryl group contains at least one nitrogen atom.
  • the nitrogen atom-containing heteroaryl group in the present invention includes but is not limited to: pyridyl, quinolinyl, pyrazinyl, pyridazinyl and the like.
  • Aryloxy refers to an aryl group connected to another group through an oxygen atom.
  • the aryloxy group in the present invention includes but is not limited to: phenoxy group, naphthoxy group, and the like.
  • Heteroaryloxy refers to a heteroaryl group connected to another group through an oxygen atom.
  • the heteroaryloxy group in the present invention includes but is not limited to: 4-pyridinyloxy, 2-thienyloxy and the like.
  • Amino refers to H 2 N- wherein a hydrogen atom or a substituted H 2 N-, i.e., R a HN- and R a R b N-.
  • substitution by oxy include, but are not limited to, the substances shown in Table D:
  • Niro refers to -NO 2 .
  • Carboxy refers to -CO 2 H.
  • Alkylmercapto refers to alkyl-S-.
  • Aryl mercapto refers to aryl-S-.
  • Trifluoromethanesulfonyl refers to CF 3 SO 2 -.
  • Porture ring refers to
  • Figure 1 shows the mutation rates of three human RAS genes (KRAS, HRAS and NRAS).
  • Figure 2 shows the tumor growth inhibition of the vehicle control group, treatment group 1 and treatment group 2 in Example 22.
  • Figure 3 shows the body weight changes of mice in the vehicle control group, treatment group 1 and treatment group 2 in Example 22.
  • Figure 4 shows the 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methyl) prepared in Example 16. Pyrrolidin-2-yl)methoxy)-5,6-dihydroquinazolin-4-yl)piperazin-2-yl)acetonitrile formate (Ex.16) and AMG-510 for anti-tumor experiments Comparison of the results.
  • nM Nanomolar (concentration unit)
  • Ti(OEt) 4 Titanium tetraethoxide
  • Pd(PPh 3 ) 2 Cl 2 Bis(triphenylphosphine) palladium(II) dichloride
  • DIPEA or DIEA Diisopropylethylamine
  • RuPhos Pd G3 RuPhos-G3-Palladacycle(CAS#1445085-77-7)
  • LiHMDS Lithium bis(trimethylsilyl)amide
  • Tf 2 O Trifluoromethanesulfonic anhydride
  • Proton and carbon NMR spectra were obtained on Varian 300 or 400 MHz or Bruker 300 or 400 MHz instruments (deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc. are solvents, with or without tetramethylsilane as internal Mark).
  • the mass spectrum was obtained by a liquid chromatography-mass spectrometer (Waters or Agilent instruments in the United States). High-performance liquid chromatography uses Waters or Agilent high-performance liquid chromatographs, unless otherwise specified.
  • the THF solution of lithium diisopropylamide (LDA, 2M) was added dropwise to the solution of cyclohex-2-enone (P1-1, 15.1mL, 156mmol) in THF (450mL) within 10 minutes , 85.8mL, 171.6mmol), the resulting mixture was stirred at this temperature for 45 minutes, then ethyl cyanoformate (P1-2, 18.3mL, 187mmol) was added dropwise, after the addition, stirred at -78°C for 4 hours, TLC showed that the reaction was complete.
  • LDA lithium diisopropylamide
  • the first step the preparation of 1-benzyl-4-tert-butyl (R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid diester (P3-3): at 0°C, To (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (P3-1, 7.50g, 34.6mmol) and Na 2 CO 3 (11.0g, 104mmol) in ethyl acetate (70.0 Benzyl chloroformate (P3-2, 7.39 mL, 52.0 mmol) was added dropwise to a solution of mL) and water (70.0 mL). The resulting reaction mixture was stirred at 25°C for 12 hours.
  • the reaction mixture was diluted with ethyl acetate (250 mL), washed successively with 1M hydrochloric acid (150 mL), water (150 mL), saturated aqueous sodium bicarbonate solution (150 mL) and saturated brine (150 mL), and the organic phase was dried over anhydrous sodium sulfate , Filter, and concentrate the filtrate under reduced pressure to obtain 1-benzyl-4-tert-butyl(R)-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylic acid diester (P3-4, 20.0g, crude product), yellow oil. Without purification, it was directly used in the next reaction.
  • the third step Preparation of 1-benzyl-4-tert-butyl (S)-2-(cyanomethyl)piperazine-1,4-dicarboxylic acid diester (P3-5): To 1-benzyl 4-tert-butyl(R)-2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylic acid diester (P3-4, 20.0g, 46.7mmol) Sodium cyanide (4.57g, 93.4mmol) was added to the solution of dimethylacetamide (500mL), and the resulting mixture was stirred at 55°C for 24 hours. TLC showed that the reaction was complete.
  • the fourth step Preparation of (S)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester hydrochloride (Int-3): To 1-benzyl-4-tert-butyl (S) -2-(Cyanomethyl)piperazine-1,4-dicarboxylic acid diester (P3-5, 10.0g, 27.8mmol) in dichloromethane (50mL) was added 4M HCl in dioxane solution ( 34.8 mL, 139.2 mmol), the resulting mixture was stirred at 25°C for 24 hours, and TLC showed that the reaction was complete.
  • Example 1 2-((S)-1-acryloyl-4-((S)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-( Preparation of naphthalene-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (Ex.1):
  • the first step Preparation of ethyl (4S)-4-(naphthalene-1-yl)-2-oxocyclohexanecarboxylate (I-2): under nitrogen, naphthalene-1-ylboronic acid (I- 1,11.5g, 66.8mmol), two (ethylene) chlororhodium dimer ([RhCl(C 2 H 4 ) 2 ] 2 , 184mg, 0.473mmol) and (R)-N-cinnamyl-2-methyl
  • propane-2-sulfinamide Int-2, 207mg, 0.872mmol
  • dioxane 60.0mL
  • ethyl 2-oxocyclohex-3-enecarboxylate Int -1, 11.2 g, 66.6 mmol
  • Step 2 Preparation of (S)-7-(naphthalene-1-yl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (I-3) : To (4S)-4-(naphthalene-1-yl)-2-oxocyclohexanecarboxylic acid ethyl ester (I-2, 21.0g, 70.9mmol) in ethanol (250mL) was added urea (5.57g) , 92.6 mmol), stirred at 25° C. for 15 minutes, NaOMe (7.67 g, 141 mmol) in MeOH (200 mL) was added, and the resulting mixture was stirred at 80° C.
  • the third step Preparation of (S)-2,4-dichloro-7-(naphthalene-1-yl)-5,6,7,8-tetrahydroquinazoline (I-4): (S) -7-(Naphthalene-1-yl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (I-3, 10.0g, 34.21mmol) in trichloro The suspension in phosphorus oxychloride (POCl 3 , 80 mL, 860 mmol) was stirred at 120°C for 2 hours, the resulting reaction mixture was concentrated under reduced pressure, and the residue was dissolved in phosphorus oxychloride (POCl 3 , 80 mL, 860 mmol) and heated at 120°C.
  • phosphorus oxychloride POCl 3 , 80 mL, 860 mmol
  • reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated brine (100 mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a light yellow oil.
  • the sixth step 2-((S)-4-((S)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl) )-5,6,7,8-Tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (I-8) preparation: under nitrogen, to (S)-2-(cyano Methyl)-4((S)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7, 8-Tetrahydroquinazolin-4-yl)piperazine-1-carboxylic acid benzyl ester (I-7, 0.548g, 0.868mmol) in methanol (6mL) and tetrahydrofuran (6mL) solution was added 10% Pd/C (50.0 mg, 0.0868 mmol), the resulting mixture was degassed, and then stir
  • the seventh step 2-((S)-1-acryloyl-4-((S)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-( Preparation of naphthalene-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (Ex.1): At 0°C, go to 2-( (S)-4-((S)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7 , 8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (I-8, 0.457g, 0.92mmol) and diisopropylethylamine (DIPEA, 0.8mL, 4.60mmol) Acrylic chloride (0.226 mL, 2.78 mmol) was added dropwise to the
  • Example 7 2-((S)-1-((E)-4-(1H-pyrazol-1-yl)but-2-enoyl)-4-((S)-2-((( S)-1-Methylpyrrolidone)-2-yl)methoxy)-7-(naphthalene-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine- Preparation of 2-yl)acetonitrile (Ex.7):
  • Example 8 2-((S)-4-((S)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalene-1-yl) )-5,6,7,8-tetrahydroquinazolin-4-yl)-1-((E)-3-(pyridin-3-yl)acryloyl)piperazin-2-yl)acetonitrile carboxylic acid Preparation of salt (Ex. 8):
  • Example 9 2-((S)-1-(3-cyclopropylpropionyl)-4-((S)-2-(((S)-1-methylpyrrolidin-2-yl)methan (Oxy)-7-(naphthalene-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile formate (Ex. 9) :
  • Example 12 2-((2S)-4-((S)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalene-1- Yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-1-(oxirane-2-carbonyl)piperazin-2-yl)acetonitrile formate (Ex. 12) Preparation:
  • Example 13 2-((S)-1-acryloyl-4-(7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidine-2 Preparation of -yl)methoxy)-5,6-dihydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (Ex. 13):
  • the first step the preparation of 2'-fluoro-6'-methoxy-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one (XIII-3): in N 2 Next, add 3-oxocyclohex-1-ene-(2-fluoro-6-methoxyphenyl)boronic acid (XIII-1,20.0g, 81.9mmol, 1.00eq) in THF (200mL) solution 1- Trifluoromethanesulfonate (XIII-2, CAS#109459-28-1.
  • the second step 2'-fluoro-6'-methoxy-5-oxo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid ethyl ester (XIII -4)
  • Preparation At -70°C, 2'-fluoro-6'-methoxy-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one (XIII -3,21.0g, 95.3mmol, 1.00eq) in THF (210mL) was added dropwise LiHMDS (1.00M, 191mL, 191mmol, 2.00eq), then the mixture was stirred at 0 °C for 2 hours, and then the reaction mixture was cooled To -70°C, ethyl cyanoformate (P1-2, 11.2mL, 114mmol, 1.20eq) was added, and the resulting mixture was stirred at 25°C for 3 hours.
  • the third step Preparation of 7-(2-fluoro-6-methoxyphenyl)-5,6-dihydroquinazoline-2,4-diol (XIII-5): 2'-fluoro- 6'-Methoxy-5-oxo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid ethyl ester (XIII-4, 25.5g, 87.2mmol, The mixture of 1.00eq) and urea (41.9g, 698mmol, 8.00eq) was stirred at 170°C for 2 hours, and LC-MS showed that the reaction was complete.
  • reaction mixture was slowly quenched with water at 100°C, and then extracted with ethyl acetate (20.0 mL ⁇ 3).
  • the combined organic phase was washed with saturated brine (10.0 mL ⁇ 2), and dried over anhydrous Na 2 SO 4 , After filtration, the filtrate was concentrated in vacuo to obtain a residue, which was recrystallized with isopropanol (120 mL) to obtain compound XIII-5 (15.0 g, 52.0 mmol, yield: 59%) as a pale yellow solid.
  • the fourth step Preparation of 2,4-dichloro-7-(2-fluoro-6-methoxyphenyl)-5,6-dihydroquinazoline (XIII-6): at 25°C, 7-(2-Fluoro-6-methoxyphenyl)-5,6-dihydroquinazoline-2,4-diol (XIII-5, 9.00g, 31.2mmol, 1.00eq) was added POCl 3 (100mL, 1.08mol, 34.6eq), the resulting mixture was stirred at 110°C for 3 hours, LC-MS showed that the reaction was complete.
  • the reaction mixture was cooled to room temperature, and slowly poured into water (200 mL), and extracted with ethyl acetate (80.0 mL ⁇ 3).
  • the combined organic phase was washed with saturated brine (100 mL ⁇ 2) and washed with anhydrous Na 2 SO 4 After drying, filtering, and vacuum concentration of the filtrate, the product XIII-6 (6.00 g, 18.5 mmol, yield: 59.1%) was obtained as a yellow solid, and it was used directly in the next step without further purification.
  • the seventh step 2-((S)-4-(7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy )-5,6-Dihydroquinazolin-4-ylpiperazin-2-yl)acetonitrile (XIII-10): at 0°C, go to (S)-2-(cyanomethyl)-4 -(7-(2-Fluoro-6-methoxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6-dihydroquinazole Lin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (XIII-9,800mg, 1.35mmol, 1.00eq) in DCM ( 1.00mL) was added BBr 3 (0.39mL, 4.05mmol, 3.00eq), The resulting mixture was stirred at 0°C for 0.5 hours, and
  • the eighth step 2-((S)-1-acryloyl-4-(7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidine-2- (Yl)methoxy)-5,6-dihydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (Ex.13): at 0°C, go to 2-((S)- 4-(7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6-dihydroquinazoline -4-ylpiperazin-2-yl)acetonitrile (XIII-10, 300mg, 0.627mmol, 1.00eq) and TEA (95.9 ⁇ L, 0.689mmol, 1.10eq) in THF (1.00mL) solution was added acryloyl chloride (I- 9,25.6 ⁇ L, 0.313mmol, 0.50eq),
  • the first step the preparation of ethyl 4-(naphthalene-1-yl)-2-oxocyclohexyl-3-enecarboxylate (XIV-2): under N 2 and -70 °C, to 3-(naphthalene- 1-yl) cyclohex-2-enone (2, CAS#42160-94-1, prepared according to the literature method: Y. Fall et al. Tetrahedron 2009, 65,489-495, 9.00g, 40.5mmol, 1.00eq) LiHMDS (1.0M, 44.5mL, 44.5mmol, 1.10eq) was added to the THF (100mL) solution.
  • the fourth step preparation of 2-(methylthio)-7-(naphthalene-1-yl)-5,6-dihydroquinazolin-4-yl trifluoromethanesulfonate (XIV-5): At 0°C, add 2,6-lutidine (2.91g, 27.2mmol, 3.16mL, 3.00eq) to the DCM (30mL) solution of compound XIV-4 (2.90g, 9.05mmol, 1.00eq), and then Trifluoromethanesulfonic anhydride (Tf 2 O, 3.1 g, 10.8 mmol, 1.79 mL, 1.20 eq) was added, and the resulting mixture was stirred at 0°C for 2 hours.
  • 2,6-lutidine (2.91g, 27.2mmol, 3.16mL, 3.00eq)
  • Trifluoromethanesulfonic anhydride Tf 2 O, 3.1 g, 10.8 mmol, 1.79 mL, 1.20 e
  • the seventh step (S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalene-1- Yl)-5,6-dihydroquinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (XIV-8): At 0°C, the compound XIV-7 (0.500g, 0.92 mmol, 1.00eq) and (S)-(1-methylpyrrolidin-2-yl)methanol (211.8mg, 218.4 ⁇ L, 1.84mmol, 2.00eq) in toluene (2mL) solution was added t-BuONa (176.8mg , 1.84mmol, 2.00eq), the resulting mixture was stirred at 0°C for 0.5 hours, LC-MS showed that the reaction was complete.
  • the eighth step 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5, Preparation of 6-dihydroquinazolin-4-yl)piperazin-2-yl)acetonitrile trifluoroacetate (XIV-9): At 25°C, go to compound XIV-8 (0.15g, 0.25mmol, TFA (0.3 mL, 4.05 mmol, 16.1 eq) was added to a solution of 1.00 eq) in DCM (1.0 mL), and the resulting mixture was stirred at 25° C. for 1 hour. LC-MS showed that the reaction was complete.
  • the ninth step 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalene-1- Yl)-5,6-dihydroquinazolin-4-yl)piperazin-2-yl)acetonitrile formate (Ex.
  • Example 15 2-((S)-1-acryloyl-4-(7-(8-methylnaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2 Preparation of -yl)methoxy)-5,6-dihydroquinazolin-4-yl)piperazin-2-yl)acetonitrile formate (Ex. 15):
  • Example 17 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy )-5,6-Dihydroquinazolin-4-yl)-1-(2,3,3-trideuteroprop-2-enoyl)piperazin-2-yl)acetonitrile formate (Ex. 17) Preparation:
  • Example 18 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy )-5,6-Dihydroquinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile formate (Ex.18):
  • Example 21 2-((S)-1-((E)-but-2-enoyl)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S )-1-Methylpyrrolidin-2-yl)methoxy)-5,6-dihydroquinazolin-4-yl)piperazin-2-yl)acetonitrile trifluoroacetate (Ex. 21) Preparation:
  • MIA PaCa-2 human pancreatic cancer cells were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA);
  • RPMI-1640 medium and fetal bovine serum (FBS) were purchased from GIBCO (Grand Island, NY, USA);
  • Matrigel was purchased from BD Company (Franklin Lake, NJ, USA).
  • MIA PaCa-2 cells were cultured in RPMI-1640 medium containing 10% FBS and maintained in a 37°C saturated humidity incubator with 5% CO 2.
  • mice When the tumor volume of the inoculated mice reached about 200mm 3 , 24 mice were selected and randomly divided into 3 groups according to the tumor volume (vehicle control (vehicle: 10% Tween-80 + 40% PEG400 + 10% (5%) w/v) citric acid aqueous solution + 40% water) group, treatment group 1 and treatment group 2), each group has 8 animals, so that the tumor volume difference in each group is less than 10% of the average.
  • the diary of the grouping is Day 0, and the administration is started according to the weight of the mice. The oral administration is administered once a day for 2 consecutive weeks. After the administration, the observation is extended for 1 week.
  • the vehicle control group is the same volume of vehicle (0.2 mL) as the treatment group 1 and treatment group 2 for each mouse daily
  • the treatment group 1 is the daily oral administration of 3 mg/kg per mouse (Ex.1 Weight/body weight) 2-((S)-1-acryloyl-4-((S)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy group prepared in Example 1) )-7-(naphthalene-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (Ex.1)
  • treatment group 2 is each Mice orally take 10mg/kg (Ex.1 weight/body weight) daily 2-((S)-1-acryloyl-4-((S)-2-(((S)-1- (Methylpyrrolidin-2-yl)methoxy)-7-(naphthalen
  • mice The body weight and tumor volume of the mice were measured twice a week, and the clinical symptoms of the animals were observed and recorded daily.
  • mice According to relevant regulations on animal welfare, if an individual experimental mouse meets any of the following conditions during the experiment, the mouse will be removed from the experimental group and euthanized. 1.
  • the body weight of mice has decreased by more than 20% compared with Day 0 (BWL ⁇ 20%); 2.
  • the mice have severe adverse reactions, such as blindness, paralysis, etc.; 3.
  • the tumor volume is greater than 2000mm 3 ; 4.
  • the tumor surface is open Ulcers.
  • the experiment period was 21 days. After the last weighing at the end of the experiment, the remaining mice were euthanized with CO 2 and the tumors were taken out, weighed, and photographed and recorded, and then the experiment was ended.
  • mice After the experiment, the average tumor weight and tumor growth inhibition (TGI) results of mice in the vehicle control group, treatment group 1 and treatment group 2 are shown in Table 1.
  • TGI tumor growth inhibition
  • tumor regression TR (V treatment day0 -V treatment day21 )/V treatment day0 ⁇ 100%(V treatment day0 : average volume of mouse tumors in treatment group 2 before administration; V treatment day21 : treatment group 2 The average tumor volume of mice after 14 days of administration and 7 days after drug withdrawal).
  • Example 1 2-((S)-1-acryloyl-4-((S)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7- prepared in Example 1 (Naphthalene-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (Ex.1) inhibits phosphorylation in MIA PaCa-2 pancreatic cancer cells
  • ERK Phospho-ERK
  • Staurosporine was purchased from Sigma-Aldrich (Address: PO Box 14508, St. Louis, MO 63178, USA);
  • the MIA PaCa-2 cell strain was purchased from American Type Culture Collection (ATCC, address: 10801 University Boulevard, Manassas, VA 201110, USA);
  • MIA PaCa-2 was cultured in Dulbecco's Modified Eagle's Medium containing 2.5% horse serum, and all media supplemented with 10% fetal bovine serum, 100 ⁇ g/mL penicillin and 100 ⁇ g/mL streptomycin. The cultures were kept at 37°C, 5% CO 2 and 95% air humid atmosphere.
  • MIA PaCa-2 cells Inoculate MIA PaCa-2 cells at 1 ⁇ 10 4 cells/well in 100 ⁇ L of complete medium in a 96-well plate, and then incubate overnight at 37°C and 5% CO 2;
  • Example 2 Using the same method as described above, the compounds prepared in Example 2 to Example 21 were tested and compared with AMG-510. The results are summarized in Table 2.
  • Example IC 50 value Staurosporine 86.2 AMG-510 55.8 Ex.1 2.35 Ex. 2 7.19 Ex.3 6920 Ex.4 5.23 Ex.5 471 Ex.6 244 Ex.7 >10,000 Ex. 8 7870 Ex.9 450 Ex.10 108 Ex.11 >10,000 Ex.12 607 Ex.13 320 Ex.14 51.5 Ex.15 39.4 Ex.16 18.6 Ex.17 20.2 Ex.18 27.6
  • the IC 50 values of the compounds prepared in the examples of the present invention can reach the lowest single-digit nM level, and show relatively strong inhibitory activity on phosphorylated ERK in cells, so they can be used for the treatment of abnormal KRAS activity.
  • the invention provides a class of dihydro or tetrahydroquinazoline compounds as shown in formula (I), their racemates, enantiomers, diastereomers, pharmaceutically acceptable salts or
  • the solvate also discloses an intermediate compound for synthesizing the compound and a preparation method thereof, as well as a pharmaceutical composition containing the compound and its application.
  • the compound is a KRAS G12C inhibitor, which can be used to treat diseases caused by abnormal KRAS activity, such as tumors, and has good economic value and application prospects.

Abstract

本发明涉及了一类如式(I)所示的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，同时还公开了用于合成该化合物的中间体化合物及其制备方法，以及包含该化合物的药物组合物及其应用。该化合物是KRAS G12C抑制剂，可用于治疗因KRAS异常活性所引起的疾病，例如肿瘤等。(I)

Description

二氢或四氢喹唑啉类化合物及其中间体、制备方法和应用
交叉引用
本申请要求2019年8月26日提交的专利名称为“二氢或四氢喹唑啉类化合物及其中间体、制备方法和应用”的第201910790018.9号中国专利申请的优先权，其全部公开内容通过引用整体并入本文。
技术领域
本发明涉及药物化学领域，具体涉及一种二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，用于合成该化合物的中间体化合物及其制备方法，以及包含该化合物的药物组合物及其应用。
背景技术
RAS是一类称为小GTPases的蛋白，其作用是在细胞内传输信号，充当连接位于细胞表面的受体(例如EGFR、FGFR、ERBB2-4)与细胞内下游与细胞生长，分化和存活(growth,differentiation,and survival)相关路径(例如RAF-MEK-ERK，PI3K-AKT-mTOR和RALGDS-RA)的桥梁(J.Downward,Nat.Rev.Cancer 2003,3(1),11-22)。当RAS被上游来的信号打开(switched on)，它随后打开其他蛋白，最终打开上述参与细胞生长，分化和存活的基因和信号传输路径。RAS基因突变会导致产生永久激活(permanently activated)的RAS蛋白，这些突变蛋白即使在缺乏外来信号的情况下，也会引起细胞内意想不到的和过度活跃的(unintended and overactive)信号传导。过度活跃的RAS信号传导最终可能导致癌症(D.S.Goodsell,The Oncologist 1999,4,263-264)。
三种RAS基因(KRAS，HRAS和NRAS)是人类癌症中最常见的致癌基因，永久激活的RAS突变在所有人类肿瘤中的发生率(frequencies)在20％-25％之间，在某些类型的癌症(例如，胰腺癌)中更高达90％(J.Downward,Nat.Rev.Cancer 2003,3(1),11-22)。
图1为三种人类RAS基因的突变发生率(H.Adderley,F.H.Blackhall,and C.R.Lindsay,EBioMedicine 2019,41,711-716)，如图1所示，在所有RAS突变肿瘤中，KRAS占比最高为86％，其次为NRAS占11％，HRAS最少为3％。其中，KRAS突变主要发生在三种肿瘤中：肺癌(22.1％)，结直肠癌(40.5％)和胰腺癌(73.6％)。KRAS的突变体主要包括G12C，G12D，G12V和G12R四种。
尽管KRAS的高突变率使它成为抗肿瘤药物开发的理想生物靶点，在过去 的三十年中，所有针对KRAS的药物研发几乎全部失败，因此，KRAS获得不可成药(undruggable)的名声，原因是KRAS蛋白表面相对光滑，只有一些比较浅的口袋(shallow pocket)，缺乏一个适合药物分子结合的口袋。直到2013年Shokat教授实验室报道了针对KRAS G12C突变体的不可逆体抑制剂研究的突破性进展(J.M.Ostrem,U.Peters,M.L.Sos,J.A.Wells,K.M.Shokat,Nature 2013,503,548-551)。他们的研究结果激起了KRAS G12C抑制剂的研发热潮，一系列的不可逆抑制剂被陆续报道。
Janes et al报道了一类喹唑啉化合物(quinazolines)作为KRAS G12C不可逆抑制剂(M.R.Janes et al.Cell 2018,172,578-589)。
Fell and colleagues报道了一类四氢吡啶并嘧啶化合物(tetrahydropyridopyrimidines)作为KRAS G12C不可逆抑制剂(J.B.Fell et al.ACS Med.Chem.Lett.2018,9,1230-1234)。
Lanman and colleagues报道了一类吡啶并[2,3-d]嘧啶-2(1H)-酮化合物作为不可逆KRAS G12C抑制剂(WO2018/217651)。
最近，Kessler et al报道了一类异吲哚啉-1-酮化合物作为可逆的KRAS抑制剂(D.Kessler et al.Proc.Natl.Acad.Sci.USA.2019 Jul 22.pii:201904529.doi:10.1073/pnas.1904529116)。
WO2019/099524A1和WO2017/201161A1披露了一类5,6,7,8-四氢吡啶并[3,4-d]嘧啶化合物作为KRAS G12C抑制剂。
Marx et al报道了一类5,6,7,8-四氢吡啶并[3,4-d]嘧啶作为KRAS G12C抑制剂(WO2020/047192)。
WO2019/155399A1披露了一类四氢喹唑啉化合物作为KRAS G12C抑制剂。
最近，WO2020/035031A1报道了一类绸环化合物作为KRAS G12C抑制剂。
尽管KRAS G12C抑制剂研发取得良好的进展，目前还没有批准用于临床治疗KRAS阳性肿瘤的药物。本发明的目的之一就是公开一类具有潜在临床运用价值的KRAS G12C抑制剂。
发明内容
本发明的目的是提供一种具有KRAS G12C蛋白抑制活性的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物。
本发明另一个目的是提供一种含有上述二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物的药物组合物，及上述二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，以及药物组合物在治疗因KRAS G12C异 常活性所引起的疾病中的应用。
本发明还有一个目的是提供一种用于合成上述二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物的中间体化合物及其制备方法。
为实现上述目的，本发明采用如下技术方案：
一种二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，该化合物分子结构式如式(I)所示：
Figure PCTCN2020111031-appb-000001
式中：
Cy为C 3-12环烷基或C 3-12杂脂环基；
X为C＝O、C＝S或S(＝O) m；
Y为O、NRR’或S(＝O) m；
R 1为C 2-12烯基或C 2-12炔基，且所述R 1中的一个或多个氢可任选地被相同或不同的G 1取代；
R 2选自氢、C 1-12烷基、C 3-12环烷基、C 2-12烯基，C 2-12炔基，C 6-12芳基、C 5-12杂芳基或C 3-12杂脂环基，且所述R 2中的一个或多个氢可任选地被相同或不同的G 2取代；
R 3和R 4相同或者不同，各自独立地代表一个或多个相同或不同的氢、氘、卤素、OH、CN、NO 2、CO 2H、CONH 2、SH、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2OH、CH 2CH 2OH、OCH 2F、OCHF 2、OCF 3、NRR’、C 1-12烷基、C 3-12环烷基、C 3-12杂脂环基、C 1-12烷氧基、C 3-12环烷氧基或C 3-12杂脂环氧基；
当存在两个或多个相同或不同的R 3时，在化学上可行的情况下，其中任意两个相邻或不相邻的R 3可以彼此键合，并且通过与其相连的Cy上的原子一起形成环，所形成的环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子；
Ar为C 6-12芳基或C 5-12杂芳基，且所述Ar中的一个或多个氢可任选地被相 同或不同的G 3取代；
Figure PCTCN2020111031-appb-000002
代表单键或者双键；当
Figure PCTCN2020111031-appb-000003
代表单键时，*代表所示碳原子为手性碳原子，可以以R-构型、S-构型或者R-构型和S-构型任意比例的混合形式存在；
其中：
R和R’相同或不同，各自独立地选自氢、氘、OH、CN、C 1-12烷基、C 3-12环烷基、C 3-12杂脂环基、C 1-12烷氧基、C 3-12环烷氧基或C 3-12杂脂环氧基；
G 1、G 2和G 3相同或不同，各自独立地选自一个或多个相同或不同的氘、卤素、OH、CN、NO 2、CO 2H、SH、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、OCH 2F、OCHF 2、OCF 3、C 1-12烷基、C 3-12环烷基、C 2-12烯基、C 2-12炔基、C 6-12芳基、C 5-12杂芳基或C 3-12杂脂环基，其中所述C 1-12烷基、C 3-12环烷基、C 2-12烯基、C 2-12炔基、C 6-12芳基、C 5-12杂芳基或C 3-12杂脂环基中的一个或多个氢可任选地被相同或不同的氘、卤素、CN、NO 2、C 1-12烷基、C 3-12环烷基、C 2-12烯基、C 2-12炔基、C 6-12芳基、C 5-12杂芳基、C 3-12杂脂环基、R 5O-、R 6R 7N-、R 5S(＝O) m-、R 6R 7NS(＝O) m-、R 5C(＝O)-、R 6R 7NC(＝O)-、R 5OC(＝O)-、R 5C(＝O)O-、R 6R 7NC(＝O)O-、R 5C(＝O)NR 8-、R 6R 7NC(＝O)NR 8-、R 5OC(＝O)NR 8-、R 5S(＝O) mNR 8-、R 6R 7NS(＝O) mNR 8-、R 6R 7NC(＝NR 9)NR 8-、R 6R 7NC(＝CHNO 2)NR 8-、R 6R 7NC(＝N-CN)NR 8-、R 6R 7NC(＝NR 9)-、R 5S(＝O)(＝NR 9)NR 8-或R 6R 7NS(＝O)(＝NR 9)-取代；
R 5、R 6、R 7、R 8和R 9相同或不同，各自独立地选自氢、氘、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 3-12环烷基、C 6-12芳基、C 5-12杂芳基或C 3-12杂脂环基；当R 6和R 7连接在同一氮原子上时，可通过彼此连接与该氮原子一起形成一个杂脂环，优选为C 3-12杂脂环，所述杂脂环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子；且R 5、R 6、R 7、R 8和R 9中的一个或多个氢可任选地被相同或不同的氘、卤素、OH、OCH 3、CN、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、OCH 2F、OCHF 2、OCF 3、C 1-12烷基或C 3-12环烷基取代；
G 1、G 2和G 3中的一个或多个氢可任选地进一步被相同或不同的氘、卤素、OH、OCH 3、CN、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、OCH 2F、OCHF 2、OCF 3、C 1-12烷基或C 3-12环烷基取代；
m＝0、1或2。
上述二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物中，所述R 1还可以为-CH 2-卤素、
Figure PCTCN2020111031-appb-000004
Figure PCTCN2020111031-appb-000005
在本发明的一个实施方案中，当上述R 3代表至少两个相同或不同的C 1-12烷基时，所述两个相同或不同的C 1-12烷基可以彼此连接，并且通过与其相连的Cy环上的一个或两个原子与Cy环一起形成一个5-18元的螺环、稠环或桥环，所述的螺环、稠环或桥环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子。
在本发明的一个实施方案中，当上述R 3代表连接在Cy环上同一个原子上的两个相同或不同的C 1-12烷基时，所述两个相同或不同的C 1-12烷基可以彼此连接，并与Cy环一起形成一个5-18元的螺环，所述5-18元的螺环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子。
在本发明的一个实施方案中，当上述R 3代表连接在Cy环上相邻的两个原子上的两个相同或不同的C 1-12烷基时，所述两个相同或不同的C 1-12烷基可以彼此连接，并与Cy环一起形成一个5-18元的稠环，所述5-18元的稠环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子。
在本发明的一个实施方案中，当上述R 3代表连接在Cy环上不相邻的两个原子上的两个相同或不同的C 1-12烷基时，所述两个相同或不同的C 1-12烷基可以彼此连接，并与Cy环一起形成一个5-18元的桥环，所述5-18元的桥环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子。
优选地，上述二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物中，所述化合物的结构式为(Ia)：
Figure PCTCN2020111031-appb-000006
式中所述，
X、R 1-R 4、Ar、*、
Figure PCTCN2020111031-appb-000007
的定义同上；
Cy1为包含两个N原子的C 3-12杂脂环基，优选的，选自Cy1-1至Cy1-9中的任意一种：
Figure PCTCN2020111031-appb-000008
优选地，上述二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物中，所述化合物的结构式为(Ib)或(Ic)：
Figure PCTCN2020111031-appb-000009
式中所述，
X 1为C＝O或S(＝O) m；
R 1-R 3、Ar、*、
Figure PCTCN2020111031-appb-000010
m的定义同上。
优选地，上述二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物中，所述化合物的结构式为(Id)、(Ie)、If)、(Ig)、(Ih)或(Ii)：
Figure PCTCN2020111031-appb-000011
式中所述，
R 3a代表一个或多个相同或不同的氢、氘、卤素、OH、CN、NO 2、CO 2H、CONH 2、SH、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2OH、CH 2CH 2OH、OCH 2F、OCHF 2、OCF 3、NRR’、C 1-12烷基、C 3-12环烷基、C 3-12杂脂环基、C 1-12烷氧基、C 3-12环烷氧基或C 3-12杂脂环氧基；
当R 3a代表至少两个相同或不同的C 1-12烷基时，所述两个相同或不同的C 1-12烷基可以彼此连接，并且通过与其相连的哌嗪环上的一个或两个原子与哌嗪环一起形成一个5-18元的螺环、稠环或桥环，所述的螺环、稠环或桥环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子；
R 1a、R 1b和R 1c相同或不同，各自独立地选自氢、氘、卤素、CN、NO 2、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3或C 1-12烷基，其中所述C 1-12烷基中的氢可任选地被一个或多个独立的氘、卤素、CN、NO 2、R 5O-、R 6R 7N-、R 5S(＝O) m-、R 6R 7NS(＝O) m-、R 5C(＝O)-、R 6R 7NC(＝O)-、R 5OC(＝O)-、R 5C(＝O)O-、R 6R 7NC(＝O)O-、R 5C(＝O)NR 8-、R 6R 7NC(＝O)NR 8-、R 5OC(＝O)NR 8-、R 5S(＝O) mNR 8-或R 6R 7NS(＝O) mNR 8-取代；
R 2、Ar、*、
Figure PCTCN2020111031-appb-000012
m、R、R’、R 5、R 6、R 7、R 8的定义同上。
在本发明的一个实施方案中，当上述R 3a代表两个相同或不同的C 1-12烷基时，所述两个相同或不同的C 1-12烷基可以彼此连接，并且通过与R 3a相连的哌嗪环上的一个或两个原子与哌嗪环一起形成一个5-18元的螺环、稠环或桥环，所述的螺环、稠环或桥环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子。
优选地，上述二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物中，所述化合物的结构式为(Ij)、(Ik)、(Il)、(Im)、(In)、(Io)、(Ip)、(Iq)、(Ir)、(Is)、(It)或(Iu)：
Figure PCTCN2020111031-appb-000013
Figure PCTCN2020111031-appb-000014
式中所述，
R 3b代表一个或多个相同或不同的氢、氘、卤素、CN、CO 2H、CONH 2、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2OH、CH 2CH 2OH或C 1-12烷基；
当R 3b代表至少两个相同或不同的C 1-12烷基时，所述两个相同或不同的C 1-12烷基可以彼此连接，并且通过与其相连的哌嗪环上的一个或两个原子与哌嗪环一起形成一个5-18元的螺环、稠环或桥环，所述的螺环、稠环或桥环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子；
R 2、Ar、*、m、R 1a、R 1b和R 1c的定义同上。
在本发明的一个实施方案中，当上述R 3b代表两个相同或不同的C 1-12烷基时，所述两个相同或不同的C 1-12烷基可以彼此连接，并且通过与其相连的哌嗪环上的一个或两个原子与哌嗪环一起形成一个5-18元的螺环、稠环或桥环，所述的螺环、稠环或桥环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子。
优选地，上述二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物中，所述化合物的结构式是下面任意一种：
Figure PCTCN2020111031-appb-000015
Figure PCTCN2020111031-appb-000016
Figure PCTCN2020111031-appb-000017
Figure PCTCN2020111031-appb-000018
Figure PCTCN2020111031-appb-000019
Figure PCTCN2020111031-appb-000020
Figure PCTCN2020111031-appb-000021
Figure PCTCN2020111031-appb-000022
Figure PCTCN2020111031-appb-000023
式中所示，*的定义同上。
优选地，上述二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对 映异构体、药学上可接受的盐或溶剂合物中，所述化合物的结构式是下面任意一种：
Figure PCTCN2020111031-appb-000024
优选地，上述二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物中，所述化合物的结构式是下面任意一种：
Figure PCTCN2020111031-appb-000025
本发明还提供用于合成上述二氢或四氢喹唑啉类化合物的中间体化合物，所述中间体化合物的结构式为(IIa)或(IIb)：
Figure PCTCN2020111031-appb-000026
式中：
Ar’为C 6-12芳基或C 5-12杂芳基，且所述Ar’中的一个或多个氢可任选地被相同或不同的G 4取代；
每一个Z独立地代表相同或者不同的卤素；
#代表所示碳原子是手性碳原子，可以以R-构型、S-构型或者R-构型和S-构型任意比例的混合形式存在；
其中：
G 4选自一个或多个相同或不同的氘、卤素、OH、CN、NO 2、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 3-12环烷基、C 6-12芳基、C 5-12杂芳基、C 3-12杂脂环基、R 55O-、R 66R 77N-、R 55S(＝O) m-、R 66R 77NS(＝O) m-、R 55C(＝O)-、R 66R 77NC(＝O)-或R 55OC(＝O)-，其中所述C 1-12烷基、C 2-12烯基、C 2-12炔基、C 3-12环烷基、C 6-12芳基、C 5-12杂芳基、C 3-12杂脂环基、R 55O-、R 66R 77N-、R 55S(＝O) m-、R 66R 77NS(＝O) m-、R 55C(＝O)-、R 66R 77NC(＝O)-或R 55OC(＝O)-中的一个或多个氢可任选地被相同或不同的氘、卤素、OH、CN、NO 2、OCH 3、OCH 2F、OCHF 2、CH 2F、CHF 2、CF 3、OCF 3或C 1-12烷基取代；
R 55、R 66和R 77相同或不同，各自独立地选自氢、氘、C 1-12烷基、C 3-12环烷基、C 6-12芳基、C 5-12杂芳基或C 3-12杂脂环基，所述R 55、R 66和R 77中的一个或多个氢可任选地被相同或不同的氘、OH、OCH 3、CN、NO 2、CH 2F、CHF 2、CF 3、OCH 2F、OCHF 2、OCF 3或C 1-12烷基取代；当R 66和R 77连接在同一氮原子上时，可通过彼此连接并与该氮原子一起形成一个杂脂环，优选为C 3-12杂脂环，所述杂脂环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子；
m的定义同上。
优选的，上述中间体化合物中，所述Ar’选自苯基、萘基、咪唑基、噻唑基、恶唑基、呋喃基、噻酚基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、三嗪基、哒嗪基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、吲哚基、吲唑基、氮杂吲哚基、氮杂吲唑基、苯并咪唑基、苯并噻唑基、苯并恶唑基、氮杂苯并咪唑基、氮杂苯并噻唑基、氮杂苯并恶唑基、咪唑并吡嗪基、咪唑并吡啶基、咪唑并哒嗪基、噻唑并吡嗪基、噻唑并吡啶基、噻唑并哒嗪基、恶唑并吡嗪基、恶唑并吡啶基、恶唑并哒嗪基、吡咯并吡嗪基、噻酚并吡啶基或呋喃并哒嗪基。
本发明还提供如Scheme A所示的上述中间体化合物的制备方法，包括步骤1至步骤2或步骤1至步骤3，
Figure PCTCN2020111031-appb-000027
其中：
Ar’、#和Z的定义同上；
W代表C 1-12烷基、C 2-12烯基、C 2-12炔基、C 3-12环烷基、C 6-12芳基、C 5-12杂芳基或C 3-12杂脂环基；优选C 1-12烷基或C 3-12环烷基；更进一步优选甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基或环己基；
步骤1：式II-1化合物与式II-2化合物反应得到式II-3化合物；
步骤2：式II-3化合物与式II-4化合物发生缩合反应得到如式IIa所示的中间体化合物；
步骤3：式IIa中间体化合物与卤化试剂Halogenating Reagent反应得到式IIb中间体化合物。
优选的，
步骤1:在铑催化剂Rh catalyst、配体L和碱Base-1的条件下，式II-1化合物与式II-2化合物在溶剂Solvent-1中反应得到式II-3化合物；
步骤2:在碱Base-1存在的条件下，式II-3化合物与式II-4化合物在溶剂Solvent-1中发生缩合反应得到式IIa中间体化合物；
更优选的，
所述铑催化剂Rh catalyst选自二(乙烯)氯化铑(I)二聚体、二乙烯(乙酰基丙酮)铑(I)、(乙酰基丙酮)(1,5-环辛二烯)铑(I)、(乙酰基丙酮)二羰基铑(I)、(乙酰基丙酮)(降冰片)铑(I)、(2,5-降冰片)氯化铑(I)二聚体、二(乙氰)(1,5-环辛二烯)铑(I)四氟硼酸盐或二(降冰片)铑(I)四氟硼酸盐；
配体L具有如下结构：
Figure PCTCN2020111031-appb-000028
其中，W 1选自C 6-12芳基、C 5-12杂芳基或C 3-12环烷基；W 2选自C 1-12烷基或C 3-12环烷基；所述W 1和W 2中的一个或多个氢可任选地被相同或不同的氘、卤素、甲基、乙基、正丙基、异丙基、环丙基、正丁基、叔丁基、甲氧基、乙氧基、三氟甲氧基、三氟甲基或二甲基氨基取代；
所述步骤1和步骤2中，每一个碱Base-1独立地选自K 3PO 4、K 2HPO 4、Na 3PO 4、Na 2HPO 4、Li 2CO 3、Na 2CO 3、NaHCO 3、K 2CO 3、KHCO 3、Cs 2CO 3、CsF、LiOH、NaOH、KOH、CsOH、Ca(OH) 2、Ba(OH) 2、氢化钠、氢化钾、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、LiN(SiMe 3) 2、NaN(SiMe 3) 2或KN(SiMe 3) 2；
所述步骤1和步骤2中，每一个溶剂Solvent-1独立地选自乙醚、甲基叔丁基醚、四氢呋喃、甲基四氢呋喃、二恶烷、二氯甲烷、二氯乙烷、甲醇、乙醇、 正丙醇、异丙醇、正丁醇、叔丁醇、水、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、乙酸乙酯或它们两种或多种的混合物；
所述卤化试剂Halogenating Reagent选自POCl 3、POBr 3、SOCl 2、PCl 3、PCl 5、PBr 3、PPh 3+CCl 4、PPh 3+CBr 4、PPh 3+Cl 2、PPh 3+Br 2、PPh 3+I 2、氰尿酰氯或草酰氯。
本发明还提供了上述二氢或四氢喹唑啉类化合物的一种制备方法，作为一种实施方式，该方法可由Scheme 1所示的步骤组成：
Figure PCTCN2020111031-appb-000029
其中：
式II-1化合物可购买，式II-2化合物可以按照文献方法(例如，K.Yahata  et al.Org.Lett.2014,16,3680-3683)合成；
W、Ar、Z、X、#、Cy1、R 1、R 2、R 3、Rh catalyst、L和Halogenating Reagent的定义同上；
PG代表有机化学中常见的N保护基，包括但不限于Boc(即-CO 2Bu-t)、CBZ(即-CO 2CH 2Ph)、Bn(即-CH 2Ph)、PMB(即-CH 2C 6H 4-OCH 3-p)等；
Deprotection代表从N上脱去保护基，当保护基是Boc(即-CO 2Bu-t)时，常用的脱保护试剂包括但不限于HCl、三氟乙酸、H 2SO 4等,当保护基是CBZ(即-CO 2CH 2Ph)时，常用的脱保护试剂包括但不限于浓HCl、H 2+Pd/C等,当保护基是Bn(即-CH 2Ph)时，常用的脱保护试剂包括但不限于H 2+Pd/C、H 2+Pd(OH) 2、H 2+Pd/C+HCl等，当保护基是PMB(即-CH 2C 6H 4-OCH 3-p)时，常用的脱保护试剂包括但不限于三氟乙酸、硝酸铈铵(ceric ammonium nitrate)等；
Base、Solvent、Pd catalyst和Coupling Reagent的意思见“术语定义”部分。
本发明还提供用于合成上述二氢或四氢喹唑啉类化合物的另一种中间体化合物，所述中间体化合物的结构式为(IIc)：
Figure PCTCN2020111031-appb-000030
式中：
Ar’的定义同上；
Z 1和Z 2相同或者不同，各自独立地代表卤素、OH、CF 3SO 3、SH、CH 3S、CH 3S(O)或CH 3S(O) 2。
本发明还提供如Scheme B所示的上述中间体化合物的制备方法，包括步骤1至步骤4，
Figure PCTCN2020111031-appb-000031
Ar’和W的定义同上；
步骤1：式II-10化合物与式II-11化合物反应得到式II-12化合物；
步骤2：式II-12化合物与式II-13化合物发生缩合反应得到如式II-14化合物；
步骤3：式II-14化合物与碘甲烷反应得到式II-15化合物；
步骤4：三氟甲磺酰化式II-10化合物得到式(IIc)所示的中间体化合物；
更优选的，
步骤1：式II-10化合物与式II-11化合物在碱Base-1存在下反应得到式II-12化合物；
步骤3：式II-14化合物与碘甲烷在碱Base-1存在下反应得到式II-15化合物；
所述碱Base-1的定义同上。
本发明还提供了上述二氢或四氢喹唑啉类化合物的另外一种制备方法，作为一种实施方式，该方法可由Scheme 2所示的步骤组成：
Figure PCTCN2020111031-appb-000032
W、Ar、Cy1、R 1、R 2、R 3、PG、Base、Solvent、Deprotection和Coupling Reagent的定义同上或见“术语定义”部分。
本发明还提供包含至少一种上述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物的药物组合物。
优选的，上述药物组合物中，还包含至少一种药学上可接受的载体或稀释剂。
优选的，上述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐、水合物、溶剂合物或前药通过制剂(formulation)过程，与适合的药学上可接受的载体及药学上常用的辅剂制备成利于给药的药物组合物。
优选的，上述药物组合物中，所述药物组合物的制剂形式包括：口服剂、注射剂、肛塞剂、鼻孔吸入剂、滴眼剂或皮肤贴剂。
优选的，上述药物组合物的各种剂型可以采用医药工业常用的方法制备。例如，混合、溶解、制粒、研磨、乳化、胶囊、糖衣、冷冻干燥、冷冻喷雾等。
优选的，上述药物组合物用于治疗哺乳动物，如人类病人，因KRAS异常活性引起的疾病。
优选的，上述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物在药物组合物中的含量范围为0.001－100％。该药物组合物施用于包括人在内的哺乳动物的有效剂量为每日每千克体重0.1－500毫克，优化的剂量为每日每千克体重使用0.1－100毫克。在这个有效剂量范围内，本发明中的化合物发挥其抑制KRAS活性及治疗因异常KRAS活性异常引起的疾病(例如癌症)的药理作用。
本发明还提供了上述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，或上述的药物组合物在治疗因KRAS异常活性所引起的疾病中的应用。优选的，所述KRAS为KRAS G12C突变体，所述疾病为肿瘤，包括实体瘤和液体瘤。
优选的，上述应用中，所述肿瘤选自肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、结直肠癌、肛门区癌、胃癌、结肠癌、乳腺癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、阴户癌、何杰金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、膀胱癌、肾或输尿管癌、肾癌、肾上腺癌、肾细胞癌、肾盂癌、脑胶质瘤、脑干神经胶质瘤、神经内分泌胶质肿瘤、神经胶质瘤、中枢神经中枢系统(CNS)赘生物、脊柱轴肿瘤、垂体腺瘤、胃肠间质肿瘤、结肠直肠癌、非小细胞肺癌、小细胞肺癌、肥大细胞增多症、胶质瘤、肉瘤、淋巴瘤中的一种或任意几种的组合。
本发明还提供一种治疗因KRAS突变体异常活性所引起的疾病的药物，包含任意一种或任意几种上述二氢或四氢喹唑啉类化合物或其在药学上可接受的盐、溶剂合物、前药，或任意一种或任意几种上述二氢或四氢喹唑啉类化合物的消旋体、对映异构体、非对映异构体、或不同对映异构体或非对映异构体按照任意比例的混合物，或其在药学上可接受的盐、溶剂合物或前药。
优选的，上述治疗因KRAS突变体异常活性所引起的疾病的药物中，还包含一种或几种药学上可接受的载体或/及稀释剂。
优选的，上述药物的制剂形式如下：
(1)口服剂、(2)注射剂、(3)肛塞剂、(4)鼻孔吸入剂、(5)滴眼剂或(6)皮肤贴剂。
优选的，上述药物的给药途径可以为：(1)口服：例如片剂、胶囊等；(2)注射：例如静脉注射、皮下注射、肌肉注射、眼球注射、腹腔注射等；(3)肛塞：例如栓剂、凝胶剂等；(4)鼻孔吸入：例如喷雾剂、气雾剂等；(5)滴眼剂；(6)皮肤贴剂。也可使用药物释放系统，例如，脂质体(liposome)、缓释技术、控释技术等，其中优先选用的方法为口服及注射，更优先选用的方法为口服。
优选的，上述药物的使用频率依所使用的化合物或其药物组合物及应用的疾病而有所变化，本发明中的药物组合物通常是每日给药1－6次，优化的给药频率为每日给药1－3次。
优选的，上述药物的包装和保存和一般西药类似，例如固体剂型的药物可直接装入玻璃、塑料、纸质或金属瓶中，瓶内最好放入干燥剂等以保持药物的质量；液体剂型的药物一般装入玻璃、塑料或金属瓶或软管中；起雾剂型的药物一般装入耐压的附有减压阀等装置的金属或塑料容器中。
经过一系列的实验证明，本发明的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物具有如下有益效果：
(1)通过抑制肿瘤细胞中Phospho-ERK试验，可以看出本发明的二氢或四氢喹唑啉类化合物对KRAS下游蛋白具有很强的抑制作用；
(2)通过对动物肿瘤模型的抑制试验可以看到，该二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物可以显著抑制肿瘤，且没有明显的毒性；
(3)本发明的二氢或四氢喹唑啉类化合物可与其他抗肿瘤药物包括但不限于化疗药物、靶向治疗药物或免疫治疗药物共同使用从而起到协同(synergistic)或加合(additive)效应；
(4)本发明的二氢或四氢喹唑啉类化合物可以与其他的肿瘤疗法，例如手术、放射线疗法、介入疗法等一同使用。
由此可见，本发明一种二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物可以作为一种有效治疗因KRAS异常活性所引起的疾病的药物。
术语的定义
以下为本发明中所涉及的术语定义。
根据本领域普通技术人员的公知常识，化学反应多数情况下需要在溶剂中进行，制备本发明的化合物常用的溶剂(Solvent)包括但不限于水、甲醇、乙醇、异丙醇、正丙醇、正丁醇、异丁醇、叔丁醇、2-甲氧基乙醇、2,2,2-三氟乙醇、二氯甲烷、1,2-二氯乙烷、氯仿、四氢呋喃、甲基四氢呋喃、二氧六环、1,2-二甲氧基乙烷、乙酸乙酯、乙醚、甲基叔丁基醚、己烷、环己烷、甲苯、乙腈、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺或这些溶剂中的两种或几种的组合。
本发明化合物的制备过程中，有些步骤需要在碱(Base)的存在发生反应，所述的碱包括但不限于有机碱，例如，MeNH 2、Me 2NH、Me 3N、EtNH 2、Et 2NH、Et 3N、n-PrNH 2、n-Pr 2NH、n-Pr 3N、i-PrNH 2、i-Pr 2NH、i-Pr 3N、n-BuNH 2、n-Bu 2NH、n-Bu 3N、s-BuNH 2、s-Bu 2NH、s-Bu 3N、i-BuNH 2、i-Bu 2NH、i-Bu 3N、t-BuNH 2、t-Bu 2NH、t-Bu 3N、i-Pr 2NEt、2-氨基-2-(羟甲基)丙烷-1,3-二醇、环丙胺、二环丙胺、环丁胺、二环丁胺、环戊胺、二环戊胺、环己胺、二环己胺、吡啶、DBU、DABCO、四甲基胍、五甲基胍、四乙基胍、五乙基胍、吗啉、1-甲基吗啉、哌啶、1-甲基哌啶、1-乙基哌啶、哌嗪、1-甲基哌嗪、1-乙基哌嗪、1,4-二甲基哌嗪、1,4-二乙基哌嗪、吡咯烷、1-甲基吡咯烷、1-乙基吡咯烷、MeONa、MeOK、MeOLi、EtOLi、EtONa、EtOK、n-PrOLi、n-PrONa、n-PrOK、i-PrOLi、i-PrONa、i-PrOK、n-BuOLi、n-BuONa、n-BuOK、i-BuOLi、i-BuONa、i-BuOK、s-BuOLi、s-BuONa、s-BuOK、t-BuOLi、t-BuONa、t-BuOK、n-BuLi、s-BuLi、t-BuLi、NaN(SiMe 3) 2、LiN(SiMe 3) 2、KN(SiMe 3) 2等。所述的碱也包括但不限于无机碱，例如，氨气、氨水、LiOH、NaOH、KOH、RbOH、CsOH、Cs 2CO 3、Rb 2CO 3、Li 2CO 3、Na 2CO 3、K 2CO 3、NaHCO 3、KHCO 3、LiF、NaF、KF、RbF、CsF、K 3PO 3、K 2HPO 4、KH 2PO 4、Na 3PO 3、Na 2HPO 4、NaH 2PO 4、Li 3PO 3、Li 2HPO 4、LiH 2PO 4、NaH、LiH、KH、RbH、CsH、CaO、Ca(OH) 2、Ca 2CO 3、Ba(OH) 2、MgO、Mg(OH) 2、Mg 2CO 3等，或上述碱中的两种或几种的组合。
制备本发明的化合物有些步骤需要使用钯催化剂(Pd catalyst)，所述钯催化剂包括但不限于Pd/C、Pd(PPh 3) 4、Pd 2(dba) 3、PdCl 2、Pd(OAc) 2、Pd(O 2CCF 3) 2、PdCl 2(dppf)、PdCl 2(dppp)、Pd(PPh 3) 2Cl 2、Pd(PhCN) 2Cl 2、Pd(OH) 2、RuPhos Pd G2(CAS#:1375325-68-0)、RuPhos Pd G3(CAS#:1445085-77-7)、RuPhos Pd G4(CAS#:1599466-85-9)等的一种或几种组合。
化学反应有些情况下需要在偶联试剂(Coupling Reagent)存在的情况下发生，制备本发明的化合物常用的偶联试剂(Coupling Reagent)包括但不限于DCC、EDC、HATU、TBTU、PyBOP、HCTU、BOP、T3P、DIC、HOBt、HOAt、CDI、DEPBT、COMU的一种或几种组合等。
制备本发明的化合物的反应通常在室温下进行，但有时需要降低至-78℃或加热至200℃；反应通常在前述的溶剂及温度及常规搅拌条件下进行，但有时需要在微波炉中进行；当使用的碱、试剂、催化剂对水或氧气敏感时，反应需在无水无氧条件下进行，在这种情况下，不能使用质子性溶剂。
“取代”在本文中是指任何基团由指定取代基单取代或多取代至这种单取代或多取代(包括在相同部位的多重取代)在化学上允许的程度，每个取代基可以位于该基团上任何可利用的位置，其可以通过所述取代基上任何可利用的原子连接。“任何可利用的位置”是指通过本领域已知的方法或本文教导的方法可化学得到，并且不产生过度不稳定的分子的所述基团上的任何位置。当在任何基团上有两个或多个取代基时，每个取代基独立于任何其它取代基而定义，因此可以是相同或不同的。
在本说明书的各个位置，本发明化合物的取代基以基团或范围的形式进行公开。这具体意味着本发明包括这样的基团和范围的每个成员或成员中的每个个体的亚组合。如术语“C 1-4烷基”具体意味着单独公开了甲基、乙基、C 3烷基和C 4烷基。
“本发明化合物”(除非另有具体指明)在本文中是指式(I)化合物及其所有纯的和混合的立体异构体、几何异构体、互变异构体、消旋体、对映异构体、非对映异构体、N-氧化物、S-氧化物、溶剂合物、代谢物、前药及同位素标记的化合物和任何药学上可接受的盐。
“溶剂合物”指本发明所述化合物与化学上常用的溶剂以共价键、氢键、离子键、范德华力、络合、包合等形成的稳定物质，所述的溶剂可以为：甲醇、乙醇、丙醇、丁醇、乙二醇、丙二醇、聚乙二醇、丙酮、乙腈、乙醚、甲基叔丁醚、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺等。
“水合物”指溶剂合物，其中的溶剂为水。
“药学上可接受”表示化合物或组合物在化学上、药理学上和/或毒理学上必须与构成制剂的其它成分和/或用其治疗的哺乳动物相容。
“前药”指通过化学合成或物理的方法将本发明中的化合物转化为另一种化合物，并将该化合物给予哺乳动物后，在动物体内被转化成本发明所述的化合物。利用“前药”方法通常是为了克服药物分子本身不良或欠佳的物理化学性质或成药性。
“消旋体(racemates or racemic mixtures)”、“对映异构体(enantiomers)”、“非对映异构体(diasteromers)”、“顺反异构体(cis/trans isomers or E-/Z-isomers)”或别的“立体异构体(stero isomers)”指化合物具有相同的分子式及分子量，然而由于原子之间的不同键合方式及/或空间安排顺序而形成不同的化合物，这样的化合物叫异构体或称立体异构体。当这些立体异构体互为镜像关系，即看起来很像，却不能完全重合，就如左手与右手，这些化合物叫对映异构体。对映异构体的绝对构型通常用(R)-及(S)-或R-及S-来标示。具体确定对映异构体的绝对构型的规则见Chapter 4 of“Advanced Organic Chemistry,”4 th edition(by J.March,John Wiley and Sons,New York,1992)。(R)-及(S)-对映异构体对偏振光具有相反的旋转作用，即左旋和右旋。当(R)-及(S)-对映异构体按1:1的比例混合或存在时，该混合物对偏振光没有旋转作用，这时该混合物称为消旋体。当化合物分子中有两个或者两个以上的手性中心，就有可能存在非对映异构体的情况，即分子中的所有手性中心，至少有一个绝对构型相同，但也至少有一个得绝对构型不相同。
“互变异构体(tautomers)”在本文中是指具有不同能量的结构同分异构体可以越过低能垒，从而互相转化。诸如质子互变异构体包括通过质子迁移进行互变，如烯醇-酮互变异构体和亚胺-烯胺互变异构体，或者含有连接到环-NH-部分和环＝N-部分的环原子的杂芳基基团的互变异构形式，如吡唑、咪唑、苯并咪唑、三唑和四唑。化合价互变异构体包括一些成键电子重组而进行互变。
本发明所述化合物可能存在互变异构体(tautomers)、旋转异构体(rotamers)、顺反异构体等，这些概念都可在J.March的“Advanced Organic Chemistry,”4 th edition中找到并得到理解。只要这些异构体具有与本发明所述化合物相同或类似的抑制KRAS活性的作用，这些异构体也涵盖于本发明中。
本发明中的化合物被给予哺乳动物(例如人)后，据本领域的常识，有可能在动物体内被不同的酶代谢成各种代谢产物(metabolites)，只要这些代谢产物具有与本发明所述化合物类似的抑制KRAS活性的作用，这些代谢产物也涵盖于本发明中。
“药物组合物”指将本发明所述化合物中的一个、多个、药学上可接受的盐或溶剂合物或水合物或前药与别的化学成分(例如药学上可接受的载体或稀释剂)混合制得的制剂。药物组合物的目的是促进给动物给药的过程。上述的药物组合物中，除了包括药学上可接受的载体外，还可以包括在药(剂)学上常用的辅剂，例如：抗细菌剂、抗真菌剂、抗微生物剂、保质剂、调色剂、增溶剂、增稠剂、表面活性剂、络合剂、蛋白质、氨基酸、脂肪、糖类、维生素、矿物质、微量元素、甜味剂、色素、香精或它们的结合等。
“药学上可接受的载体”或”稀释剂”指药物组合物中的非活性成分，包括但不限于：碳酸钙、磷酸钙、碳酸镁、硅胶、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、丙烯酸聚合物、甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油、氢化蓖麻油、多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
“药学上可接受的盐”指本发明所述化合物与无机酸、有机酸、无机碱、或有机碱通过化学反应形成的盐，这种盐保留本发明所述化合物的生物活性及有效性。所述的无机酸或有机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硫酸、硝酸、碳酸、磷酸、高氯酸、醋酸、柠檬酸、草酸、乳酸、苹果酸、水杨酸、酒石酸、甲磺酸、乙磺酸、苯磺酸、取代的苯磺酸(例如，对甲基苯磺酸)、樟脑磺酸、异烟酸、油酸、鞣酸、泛酸、抗坏血酸、丁二酸、马来酸、龙胆酸、富马酸、葡萄糖酸、糖醛酸、葡萄糖二酸或蔗糖酸、甲酸、苯甲酸、谷氨酸、双羟萘酸、山梨酸等；所述的无机碱或有机碱包括但不限于氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铁、氢氧化钙、氢氧化钡、氢氧化铝、氢氧化镁、氢氧化锌、氨水、氢氧化有机季铵盐、碳酸钠、碳酸钾、碳酸锂、碳酸钙、碳酸钡、碳酸镁、碳酸化有机季铵盐、碳酸氢钠、碳酸氢钾、碳酸氢锂、碳酸氢钙、碳酸氢钡、碳酸氢镁、碳酸氢化有机季铵盐等。
“烷基”指具有指定数目碳原子的直链或支链的饱和碳氢化合物基团，例如C 1-12烷基指含最少1个，最多12个碳原子的直链或支链基团。C 0烷基代表一个共价单键。本发明所述的烷基包括但不限于：甲基、乙基、丙基、丁基、异丙基、新戊基、2-甲基-1-己基等。本发明所述的烷基有时也指“亚烷基”，亚烷基是指烷基失去一个氢原子形成的基团。烷基或亚烷基中的一个或全部氢原子可任选地被下列基团取代：环烷基、芳基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NR aR b，其中，R a及R b分别选自：氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且R a及R b连同氮原子可形成5-或6-元杂脂环。
“环烷基”或“环烷”指具有指定数目碳原子的单、双或多环的碳氢化合物基团，双环或多环时，可以以“稠环”(两个环或多个环共用两个相邻的碳原子)、“螺环”(两个环或多个环共用一个碳原子)或“桥环”(两个环或多个环共用两个或多个不相邻的碳原子)的形式结合，例如C 1-12环烷基指含最少1个，最多12个的单、双或多环的碳氢化合物基团。C 0环烷基代表一个共价单键。环烷基中可以含有双键或三键，但不具有完全共轭的π电子体系。本发明所述的环烷基 有时也指亚环烷基，即环烷基失去一个氢原子形成的基团。本发明所述的环烷基包括但不限于：环丙基、环丁基、环己基、环戊烯基、环庚三烯基、金刚烷等(举例如表A)：
表A
Figure PCTCN2020111031-appb-000033
环烷基或环烷中的一个或全部氢原子可被下列基团取代：烷基、芳基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NR aR b，其中，R a及R b分别选自：氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且R a及R b连同氮原子可形成5-或6-元杂脂环。
“杂脂环基(heteroalicyclyl或heterocycloalkyl)”或“杂脂环(heteroalicycle或heterocycloalkane)”或“杂脂环烷(heteroalicycle或heterocycloalkane)”指由3至18个非氢环原子组成的单环、双环或多环体系，其中至少一个环原子为选自O、N、S或P的杂原子，其余环原子为碳原子，例如，C 8杂脂环基指的是由8个非氢环原子构成的单环、双环或多环基团，其中至少一个环原子选自O、N、S或P。这里的C 8不是指8个碳原子，而是指8个由碳原子、O、N、S或P构成的环原子。这种环中除单键外，还可含有双键或叁键，但这些双键或叁键不构成全部共轭的芳香结构。这些单环、双环或多环体系可以以稠环、桥环或螺环的形式存在。本发明所述的杂脂环基有时也指亚杂脂环基，即杂脂环基失去一个氢原子形成的基团。本发明中的杂脂环基或杂脂环包括但不限于：哌啶、吗啉、哌嗪、吡咯烷、吲哚啉、四氢吡啶、四氢呋喃、托品醇等(举例如表B)：
表B
Figure PCTCN2020111031-appb-000034
杂脂环基或杂脂环中的一个或全部氢原子可被下列基团取代：烷基、环烷基、芳基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NR aR b，其中，R a及R b分别选自：氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且R a及R b连同氮原子可形成5-或6-元杂脂环。
“烯基”指含有至少两个碳原子及至少一个双键的直链或支链碳氢化合物基团，例如C 2-12烯基指含最少2个，最多12个碳原子的直链或支链含至少一个双键的不饱和基团。本发明中的烯基包括但不限于：乙烯基、2-丙烯基、1-戊烯基等。
“炔基”指含有至少两个碳原子及至少一个三键的直链或支链碳氢化合物基团，例如C 2-12炔基指含最少2个，最多12个碳原子的直链或支链含至少一个三键的不饱和基团。本发明中的炔基包括但不限于：乙烯基、2-丙烯基、1-戊烯基等。
“卤素”指氟、氯、溴或碘。
“烷氧基”指具有指定数目碳原子的烷基通过氧原子与其他基团相连。本发明中的烷氧基包括但不限于：甲氧基、乙氧基、丙氧基、丁氧基、环戊氧基、环己氧基、异丙氧基、新戊氧基、2-甲基-1-己氧基等。
“环烷氧基”指具有指定数目碳原子的环烷基通过氧原子与其他基团相连。本发明中的环烷氧基包括但不限于：环丙烷氧基、环丁烷氧基、环己烷氧基等。
“杂脂环氧基”指杂脂环基通过氧原子与其他基团相连。本发明中的杂脂环氧基包括但不限于：哌啶-4基氧基、氧杂环丁烷-3-基氧基等。
“芳基”指由指定数目碳原子组成的单环、双环或多环基团，其中至少一个环具有完全共轭的π电子体系并符合N+2规则，即具有芳香性，但整个基团不必全部共轭。例如，C 6芳基指苯基。芳基也可以以亚芳基的形式出现，即芳基结构中与其他基团有两个或以上的连接点。本发明中的芳基包括但不限于：苯基、萘基、茚基、二氢化茚基、四氢化萘等。芳基中的一个或全部氢原子可被下列基团取代：烷基、环烷基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NR aR b，其中，R a及R b分别选自：氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且R a及R b连同氮原子可形成5-或6-元杂脂环。
“杂芳基”指由指定数目非氢环原子组成的单环、双环或多环基团，其中至少一个环原子为选自O、N、S或P的杂原子，其余环原子为碳原子，并且，其中至少一个环具有完全共轭的π电子体系并符合N+2规则，即具有芳香性，但整个基团不必全部共轭，例如，C 5杂芳基指的是由5个非氢环原子构成的芳香环基团，其中至少一个环原子选自O、N、S或P，其余环原子为碳原子。杂芳基也可以以亚杂芳基的形式出现，即杂芳基结构中与其他基团有两个或以上的连接点。本发明中的杂芳基包括但不限于：砒啶、砒碇酮、四氢砒碇酮、咪啶、吡嗪、哒嗪、咪唑、噻唑、噻吩、呋喃、吲哚、氮杂吲哚、苯并咪唑、吲哚啉、吲哚酮、喹咛等(举例如表C)：
表C
Figure PCTCN2020111031-appb-000035
杂芳基中的一个或全部氢原子可被下列基团取代：烷基、环烷基、芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NR aR b，其中，R a及R b分别选自氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等，并且R a及R b连同氮原子可形成5-或6-元杂脂环。
“含氮原子杂芳基”指杂芳基，但是该杂芳基中包含至少一个氮原子。本发明中的含氮原子杂芳基包括但不限于：吡啶基、喹啉基、吡嗪基、哒嗪基等。
“芳氧基”指芳基通过氧原子与其他基团相连。本发明中的芳氧基包括但不限于：苯氧基、萘氧基等。
“杂芳氧基”指杂芳基通过氧原子与其他基团相连。本发明中的杂芳氧基包括但不限于：4-砒啶氧基、2-噻吩氧基等。
“N-氧化物”指分子中的N原子与O原子通过双键相连，形成N＝O或N +-O -结构。
“氨基”指H 2N-或其中氢原子被取代的H 2N-，即R aHN-及R aR bN-。
“oxo”或“氧基”指＝O或-O-，即氧原子通过双键或单键与碳或N、S、P等杂原子相连接。被氧基取代的例子包括但不限于表D中所示物质：
表D
Figure PCTCN2020111031-appb-000036
“羟基”指-OH。
“硝基”指-NO 2。
“羧基”指-CO 2H。
“巯基”指-SH。
“烷基巯基”指烷基-S-。
“芳基巯基”指芳基-S-。
“羰基”指-C(＝O)-。
“硫羰基”指-C(＝S)-。
“C-酰胺基”指-C(＝O)NR aR b。
“N-酰胺基”指C(＝O)NR a-。
“O-氨羰氧基”指-O-C(＝O)NR aR b。
“N-氨羰氧基”指O-C(＝O)NR a-。
“O-硫代氨羰氧基”指-O-C(＝S)NR aR b。
“N-硫代氨羰氧基”指O-C(＝S)NR a-。
“C-酯基”指-C(＝O)OR a。
“N-酯基”指C(＝O)O-。
“乙酰基”指CH 3C(＝O)-。
“磺酰基”指-SO 2R a。
“三氟甲磺酰基”指CF 3SO 2-。
“哌嗪环”指
Figure PCTCN2020111031-appb-000037
附图说明
图1为三种人类RAS基因(KRAS，HRAS和NRAS)的突变发生率。
图2为实施例二十二中溶媒对照组、治疗组1和治疗组2的肿瘤生长抑制。
图3为实施例二十二中溶媒对照组、治疗组1和治疗组2的小鼠体重变化。
图4为实施例十六中制备的2-((S)-1-丙烯酰基-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)哌嗪-2-基)乙腈 甲酸盐(Ex.16)与AMG-510进行抗肿瘤实验的结果对比。
具体实施方式
以下结合具体实施例对本发明作进一步详细说明，但不用来限制本发明的范围。
下面列出在实施例中出现的英文缩写及相应的中文含义。如果实施例中出现没有列于此的缩写，则代表普遍接受的含义。
HPLC：高效液相色谱
g：克
mg：毫克
mol：摩尔
mmol：毫摩尔
nM：纳摩尔(浓度单位)
μM：微摩尔(浓度单位)
M：摩尔(浓度单位)
N：当量浓度
L：升
μL：微升
[M+H] +：质谱中的分子离子峰
m/z：质荷比
δ：化学位移
DMSO-d 6：六氘代二甲基亚砜
CDCl 3：氘代氯仿
CD 3OD：氘代甲醇
TMS：四甲基硅烷
DMSO：二甲基亚砜
MeOH：甲醇
EtOH：乙醇
THF：四氢呋喃
EtOAc：乙酸乙酯
DCM：二氯甲烷
Dioxane：二氧六环
DMA：二甲基乙酰胺
HCl：氯化氢或盐酸
MeONa：甲醇钠
Et 3N：三乙胺
Na 2CO 3：碳酸钠
[RhCl(C 2H 4) 2] 2：二(乙烯)氯化铑(I)二聚体
Ti(OEt) 4：四乙氧基钛
NaCN：氰化钠
K 3PO 4：磷酸钾
NaBH 4：硼氢化钠
Pd/C：钯碳
Pd(PPh 3) 2Cl 2：双(三苯基膦)二氯化钯(II)
POCl 3：三氯氧磷
Urea：尿素
Thiourea：硫脲
CBZ：苄氧基羰基
CBZ-Cl：氯甲酸苄基酯
Ms-Cl：甲磺酰氯
LDA：二异丙基氨基锂
DIPEA或DIEA：二异丙基乙基胺
RuPhos Pd G3：RuPhos-G3-Palladacycle(CAS#1445085-77-7)
LiHMDS：双(三甲基甲硅烷基)氨基锂
Boc 2O：二碳酸二叔丁酯
BBr 3：三溴化硼
TEA：三乙胺
AcOK：乙酸钾
t-BuONa：叔丁醇钠
t-BuOK：叔丁醇钾
Tf 2O：三氟甲磺酸酐
2,6-Lutidine：2,6-二甲基吡啶
TFA：三氟乙酸
一般实验条件：
核磁共振氢谱及碳谱于Varian 300或400MHz或Bruker 300或400MHz仪器上获得(氘代二甲基亚砜，氘代氯仿，氘代甲醇等为溶剂，使用或不使用四甲基硅烷为内标)。质谱由液相色谱-质谱联用仪获得(美国Waters或者Agilent公司仪器)。高效液相色谱使用Waters公司或者Agilent公司高效液相色谱仪，除非另外说明。
起始原料、试剂及溶剂从下列供应商购买：Sigma-Aldrich,Milwaukee,WI,USA；Acros,Morris Plains,NJ,USA；Frontier Scientific,Logan,Utah,USA；Alfa Aesar,Ward Hill,MA,USA；Shanghai Aladdin Bio-Chem Technology Co.,Ltd,Shanghai,China；Shanghai Macklin Bio-Chemical Co.,Ltd.,Shanghai,China；WuXi LabNetwork,Shanghai,China等或利用文献报道的方法合成。除非特别指出，溶剂一般不经干燥，而直接使用供应商的产品或经过分子筛干燥。
中间体1：2-氧代环己-3-烯羧酸乙酯(Int-1)的制备：
Figure PCTCN2020111031-appb-000038
在-78℃下，在10分钟内向环己-2-烯酮(P1-1,15.1mL,156mmol)的THF(450mL)溶液中滴加二异丙基胺基锂的THF溶液(LDA，2M，85.8mL,171.6mmol)，所得混合物在此温度下搅拌45分钟后，滴加入氰基甲酸乙酯(P1-2,18.3mL,187mmol)，加完后，在-78℃下搅拌4小时，TLC显示反应完成。反应用饱和氯化铵水溶液(450mL)淬灭，并用乙酸乙酯(150mL×3)萃取，合并有机相，用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到残余物，通过硅胶柱色谱纯化(洗脱液：0-20％乙酸乙酯/石油醚梯度)得到2-氧代环己-3-烯羧酸乙酯(Int-1,11.2g,66.5mmol,产率：42.7％)，为黄色油状物。分析数据： 1H-NMR(400MHz,CDCl 3)：δ＝7.00(dt,J＝3.6,7.2Hz,1H),6.07(dd,J＝2.0,8.0Hz,1H),4.24-4.20(m,2H),3.42-3.38(m,1H),2.43-2.36(m,4H),1.30-1.24(m,3H)。
中间体2：(R)-N-肉桂基2-甲基丙烷-2-亚磺酰胺(Int-2)的制备：
Figure PCTCN2020111031-appb-000039
往肉桂醛(P2-1,9.5mL,75.5mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(P2-2,6.13g,50.5mmol)的THF(130mL)溶液中加入四乙氧基钛(Ti(OEt) 4,20.9mL,101mmol)，所得混合物在80℃下搅拌4小时，然后将反应混合物冷却至25℃， 分批加入硼氢化钠(7.62g,201mmol)，加完后，在25℃搅拌另外2小时，TLC显示反应完成。往反应混合物中缓慢滴加甲醇直至没有气泡产生，将反应混合物倒入饱和食盐水(120mL)中，搅拌5分钟，过滤，将滤液用乙酸乙酯(150mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱纯化(洗脱液：0-10％乙酸乙酯/石油醚)得到(R)-N-肉桂基2-甲基丙烷-2-亚磺酰胺(Int-2,10.5g,44.2mmol,产率：58.6％)，浅黄色固体。分析数据：质谱(ESI)m/z：238.2[M+H] +。
中间体3：(S)-2-(氰基甲基)哌嗪-1-羧酸苄酯盐酸盐(Int-3)的制备：
Figure PCTCN2020111031-appb-000040
第一步：1-苄基-4-叔丁基(R)-2-(羟甲基)哌嗪-1,4-二羧酸二酯(P3-3)的制备：在0℃下，往(R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(P3-1,7.50g,34.6mmol)和Na 2CO 3(11.0g,104mmol)的乙酸乙酯(70.0mL)和水(70.0mL)溶液中滴加氯甲酸苄酯(P3-2,7.39mL,52.0mmol)，所得反应混合物在25℃下搅拌12小时，TLC显示反应完成。将反应混合物用乙酸乙酯(80.0mL)稀释，并用乙酸乙酯(80.0mL×2)萃取，合并有机相，用饱和食盐水(80.0mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到残余物为1-苄基-4-叔丁基(R)-2-(羟甲基)哌嗪-1,4-二羧酸二酯(P3-3，14.5g,粗品)，为无色油状物。无需纯化，直接用于下一步反应。分析数据：质谱(ESI)m/z：251.2[M+H-Boc] +。
第二步：1-苄基-4-叔丁基(R)-2-(((甲基磺酰基)氧基)甲基)哌嗪-1,4-二羧酸二酯(P3-4)的制备：在0℃下，往1-苄基-4-叔丁基(R)-2-(羟甲基)哌嗪-1,4-二羧酸二酯(P3-3,14.5g,41.4mmol)和三乙胺(8.64mL,62.1mmol)的二氯甲烷(150mL)溶液中滴加甲基磺酰氯(4.8mL,62.1mmol)，所得反应混合物在25℃下搅拌15分钟，TLC显示反应完成。将反应混合物用乙酸乙酯(250mL)稀释，依次用1M盐酸(150mL)，水(150mL)，饱和碳酸氢钠水溶液(150mL)和饱和食盐水(150mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到1-苄基-4-叔丁基(R)-2-(((甲基磺酰基)氧基)甲基)哌嗪-1,4-二羧酸二酯(P3-4,20.0g,粗品)，为黄色油状物。无需纯化，直接用于下一步反应。
第三步：1-苄基-4-叔丁基(S)-2-(氰基甲基)哌嗪-1,4-二羧酸二酯(P3-5)的 制备：往1-苄基-4-叔丁基(R)-2-(((甲基磺酰基)氧基)甲基)哌嗪-1,4-二羧酸二酯(P3-4,20.0g,46.7mmol)的二甲基乙酰胺(500mL)溶液中加入氰化钠(4.57g,93.4mmol)，所得混合物在55℃下搅拌24小时，TLC显示反应完成。冷却至室温后，加入乙酸乙酯(150mL)和饱和食盐水(150mL)，分离有机相，用饱和食盐水(150mL×3)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到残余物，用硅胶柱色谱纯化(洗脱液：石油醚:乙酸乙酯＝1:0至5:1)得到1-苄基-4-叔丁基(S)-2-(氰基甲基)哌嗪-1,4-二羧酸二酯(P3-5,10.0g,27.8mmol,三步总产率：80.3％)，为浅黄色固体。分析数据：质谱(ESI)m/z：360.3[M+H] +。
第四步：(S)-2-(氰基甲基)哌嗪-1-羧酸苄酯盐酸盐(Int-3)的制备：往1-苄基-4-叔丁基(S)-2-(氰基甲基)哌嗪-1,4-二羧酸二酯(P3-5,10.0g,27.8mmol)的二氯甲烷(50mL)溶液中加入4M HCl的二恶烷溶液(34.8mL,139.2mmol)，所得混合物在25℃下搅拌24小时，TLC显示反应完成。溶剂减压浓缩得到(S)-2-(氰基甲基)哌嗪-1-羧酸苄酯盐酸盐(Int-3,8.222g,27.8mmol,产率：100％)。分析数据：质谱(ESI)m/z：260.1[M+H] +。
实施例一：2-((S)-1-丙烯酰基-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈(Ex.1)的制备：
Figure PCTCN2020111031-appb-000041
第一步：(4S)-4-(萘-1-基)-2-氧代环己烷羧酸乙酯(I-2)的制备：在氮气下，萘-1-基硼酸(I-1,11.5g,66.8mmol)，二(乙烯)氯铑二聚体([RhCl(C 2H 4) 2] 2,184mg,0.473mmol)和(R)-N-肉桂基-2-甲基丙烷-2-亚磺酰胺(Int-2,207mg,0.872mmol)的二恶烷(60.0mL)溶液在40℃下搅拌30分钟，加入2-氧代环己-3-烯羧酸乙酯(Int-1,11.2g,66.6mmol)，然后加入1.5M K 3PO 4水溶液(9.32mL, 13.98mmol)，所得混合物继续在40℃搅拌1小时，TLC显示反应完成。将反应混合物减压浓缩，残留物使用硅胶柱色谱纯化(洗脱液：0-5％乙酸乙酯/石油醚)得到产物(4S)-4-(萘-1-基)-2-氧代环己烷羧酸乙酯(I-2,17.8g，57.6mmol，产率：86.2％)，为白色固体。分析数据： 1H-NMR(400MHz,CDCl 3)：δ＝12.36(s,1H),8.15-8.07(m,1H),7.93-7.87(m,1H),7.80-7.73(m,1H),7.59-7.44(m,3H),7.41-7.36(m,1H),4.35-4.24(m,2H),3.83-3.73(m,1H),2.82-2.72(m,1H),2.64-2.39(m,3H),2.20-2.11(m,1H),1.96-1.83(m,1H),1.57(s,1H),1.39-1.32(m,3H)。
第二步：(S)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-2,4(1H,3H)-二酮(I-3)的制备：往(4S)-4-(萘-1-基)-2-氧代环己烷羧酸乙酯(I-2,21.0g,70.9mmol)的乙醇(250mL)溶液中加入尿素(5.57g,92.6mmol)，在25℃下搅拌15分钟，加入NaOMe(7.67g,141mmol)的MeOH(200mL)溶液，所得混合物在80℃下搅拌12小时，TLC显示反应完成。将反应混合物冷却至室温后，过滤，固体产物用甲基叔丁基醚(MTBE)洗涤(50mL×2)得到(S)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-2,4(1H,3H)-二酮(I-3,11.5g,36.9mmol,产率：52.1％，纯度：93.8％)，为白色固体。分析数据：质谱(ESI)m/z：293.1[M+H] +。无需进一步纯化，直接用于下一步反应。
第三步：(S)-2,4-二氯-7-(萘-1-基)-5,6,7,8-四氢喹唑啉(I-4)的制备：将(S)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-2,4(1H,3H)-二酮(I-3,10.0g,34.21mmol)在三氯氧磷(POCl 3,80mL,860mmol)中的悬浮液在120℃下搅拌2小时，所得反应混合物减压浓缩，残余物溶于三氯氧磷(POCl 3,80mL,860mmol)中，并在120℃搅拌2小时，TLC显示反应完成。将反应混合物减压浓缩，残余物用乙酸乙酯(80.0mL)稀释，然后，缓慢地倒入冷至0℃的饱和碳酸氢钠水溶液(80.0mL)中，分离有机相，水相用乙酸乙酯(80.0mL×3)萃取。合并有机相，用饱和食盐水(80.0mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到残余物使用硅胶柱色谱纯化(洗脱液：石油醚:乙酸乙酯＝1/0至5/1)得到(S)-2,4-二氯-7-(萘-1-基)-5,6,7,8-四氢喹唑啉(I-4,6.90g,20.6mmol,产率：60.3％。纯度：98.4％)，为白色固体。分析数据： 1H-NMR(400MHz,CDCl 3)：δ＝8.09-8.03(m,1H),7.95-7.88(m,1H),7.83-7.77(m,1H),7.59-7.44(m,3H),7.36-7.30(m,1H),3.99-3.85(m,1H),3.47-3.35(m,1H),3.21-3.07(m,1H),3.06-2.84(m,2H),2.48-2.34(m,1H),2.21-2.04(m,1H)。质谱(ESI)m/z：329.1[M+H, 35Cl, 35Cl] +,331.1[M+H, 35Cl, 37Cl] +。
第四步：(S)-4-((S)-2-氯-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(I-5)的制备：往(S)-2,4-二氯-7-(萘-1-基)-5,6,7,8-四氢喹唑啉 (I-4,6.90g,20.9mmol)和(S)-2-(氰基甲基)哌嗪-1-羧酸苄酯盐酸盐(Int-3,6.21g,21.0mmol)的DMSO(250mL)溶液中加入二异丙基乙基胺(DIPEA,10.95mL,62.88mmol)，所得混合物在50℃下搅拌12小时，TLC显示反应完全。冷却至室温后，反应混合物用水(150mL)稀释，用乙酸乙酯(150mL×3)萃取，合并有机相，用饱和食盐水(150mL×3)洗涤，用无水硫酸钠干燥，过滤，将滤液减压浓缩得到残余物，用硅胶柱色谱纯化(洗脱液：石油醚:乙酸乙酯＝1/0至10/1)得到(S)-4-((S)-2-氯-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(I-5,7.23g,12.8mmol,产率：61.2％。纯度：97.9％)，为浅黄色固体。分析数据： 1H-NMR(400MHz,CDCl 3)：δ＝8.14-8.06(m,1H),7.93-7.88(m,1H),7.81-7.75(m,1H),7.58-7.45(m,3H),7.44-7.34(m,6H),5.26(s,2H),4.72-4.64(m,1H),4.04(d,br,J＝12.3Hz,3H),3.51-3.36(m,3H),3.09-3.00(m,2H),2.94-2.83(m,1H),2.79-2.66(m,3H),2.37-2.30(m,1H),2.07-2.04(m,1H),2.04-1.94(m,1H)。质谱(ESI)m/z：552.2[M+H, 35Cl, 35Cl] +,554.2[M+H, 35Cl, 37Cl] +。
第五步：(S)-2-(氰基甲基)-4((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-1-羧酸苄酯(I-7)的制备：在氮气下，往(S)-4-((S)-2-氯-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)-2-(氰基甲基)哌嗪-1-羧酸苄酯(I-5,1.35g，2.45mmol)的二恶烷(60.0mL)溶液中加入(S)-(1-甲基吡咯烷-2-基)甲醇(I-6,864mg,7.50mmol)，碳酸铯(2.40g,7.38mmol)和(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯)[2-(2'-氨基-1,1'-联苯基)]]钯(II)甲磺酸盐,RuPhos-G3-Palladacycle(RuPhos Pd G3,CAS#1445085-77-7,216mg,0.258mmol)，所得混合物在100℃下搅拌12小时，LC-MS显示反应完成。冷却至室温后，将反应混合物用乙酸乙酯(100mL)稀释，并用饱和食盐水(100mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到淡黄色油状物，用制备型HPLC纯化(柱:Waters Xbridge 150*50 10u；流动相:[水(0.05％氨水v/v)-乙腈]；B％:58％-88％,11.5分钟)得到(S)-2-(氰基甲基)-4((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-1-羧酸苄酯(I-7,300mg,0.475mmol,产率：19.5％)，为淡黄色固体。分析数据： 1H-NMR(400MHz,CDCl 3)：δ＝8.15-8.11(m,1H),7.92-7.88(m,1H),7.80-7.75(m,1H),7.56-7.45(m,3H),7.43-7.34(m,6H),5.25(s,2H),4.63(s,1H),4.43-4.34(m,1H),4.19-4.09(m,2H),3.96-3.83(m,3H),3.44-3.28(m,3H),3.13-3.05(m,1H),3.02-2.61(m,8H),2.44(s,3H),2.37-2.23(m,2H),2.11-1.94(m,2H),1.89-1.72(m,3H)。质谱(ESI)m/z：631.3[M+H] +。
第六步：2-((S)-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8- 四氢喹唑啉-4-基)哌嗪-2-基)乙腈(I-8)的制备：在氮气下，往(S)-2-(氰基甲基)-4((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-1-羧酸苄酯(I-7,0.548g,0.868mmol)的甲醇(6mL)和四氢呋喃(6mL)溶液中加入10％Pd/C(50.0mg,0.0868mmol)，将所得混合物脱气，然后在25℃下搅拌氢化(15psi(＝103.42kpa))2小时。LC-MS显示反应完成。将反应混合物过滤，滤液浓缩至干得到2-((S)-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈(I-8,356mg,0.716mmol,产率：82.5％)，为白色固体。分析数据：质谱(ESI)m/z：497.3[M+H] +。无需进一步纯化，直接用于下一步反应。
第七步：2-((S)-1-丙烯酰基-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈(Ex.1)的制备：在0℃下，往2-((S)-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈(I-8,0.457g,0.92mmol)和二异丙基乙基胺(DIPEA,0.8mL,4.60mmol)的二氯甲烷(10.0mL)溶液中滴加丙烯酰氯(0.226mL,2.78mmol)，所得混合物在25℃搅拌15分钟,LC-MS显示反应完成。往反应混合物中依次加入乙酸乙酯(1.0mL)，2M碳酸钾水溶液(1.0mL)和饱和食盐水(1.0mL)，分离有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用制备型HPLC纯化(碱性条件：柱:Waters Xbridge 150*50 10u；流动相:[水(10mM碳酸氢铵)-乙腈]；B％:43％-73％,11.5min)得到2-((S)-1-丙烯酰基-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈(Ex.1,0.240g,0.435mmol,产率：47.3％，纯度：99.9％)，为白色固体。分析数据： 1H-NMR(400MHz,CDCl 3)：δ＝8.13(d,J＝8.0Hz,1H),7.91-7.89(m,1H),7.78(d,J＝8.4Hz,1H),7.53-7.46(m,3H),7.40-7.37(m,1H),6.64-6.55(m,1H),6.40(dd,J＝1.6,16.8Hz,1H),5.83(d,J＝11.2Hz,1H),5.07(m,1H),4.42(m,1H),4.16(m,1H),4.04-3.55(m,5H),3.36-3.31(m,2H),3.01-2.71(m,8H),2.50(s,3H),2.34-2.31(m,2H),2.02-1.95(m,2H),1.78-1.75(m,3H)。质谱(ESI)m/z：551.4[M+H] +。
实施例二：2-((S)-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)-1-(2,3,3-三氘代丙-2-烯酰基)哌嗪-2-基)乙腈 甲酸盐(Ex.2)的制备：
Figure PCTCN2020111031-appb-000042
按照实施例一相同的方法制备，经中间体I-8与氘代丙烯酸(CAS#285138-82-1)反应得到Ex.2，为灰黄色固体。分析数据：质谱(ESI)m/z：554.4[M+H] +。
实施例三：2-((S)-1-((E)-3-环丙基丙烯酰基)-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈 甲酸盐(Ex.3)的制备：
Figure PCTCN2020111031-appb-000043
按照实施例一相同的方法制备，经中间体I-8与(E)-3-环丙基丙烯酸(CAS#60129-33-1。按照文献方法制备：G.Wang et al.Chem.Eur.J.2017,23,554-557)反应得到Ex.3，为灰白色固体。分析数据：质谱(ESI)m/z：591.3[M+H] +。
实施例四：(E)-4-((S)-2-(氰甲基)-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-1-基)-4-氧代丁-2-烯腈 甲酸盐(Ex.4)的制备：
Figure PCTCN2020111031-appb-000044
按照实施例一相同的方法制备，经中间体I-8与(E)-3-氰基丙烯酸(CAS#:42356-32-1。按照文献方法制备：WO2014068527)反应得到Ex.4，为黄色固体。分析数据：质谱(ESI)m/z：576.3[M+H] +。
实施例五：2-((S)-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)-1-((E)-3-(吡啶-4-基)丙烯酰基)哌嗪-2-基)乙腈 甲酸盐(Ex.5)的制备：
Figure PCTCN2020111031-appb-000045
按照实施例一相同的方法制备，经中间体I-8与(E)-3-(吡啶-4-基)丙烯酸(CAS#84228-93-3)反应得到Ex.5，为浅黄色固体。分析数据：质谱(ESI)m/z：628.2[M+H] +。
实施例六：(E)-4-((S)-2-(腈甲基)-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-1-基)-4-氧代丁-2-烯酰胺甲酸盐(Ex.6)的制备：
Figure PCTCN2020111031-appb-000046
按照实施例一相同的方法制备，经中间体I-8与(E)-4-氨基-4-氧代丁-2-烯酸(CAS#2987-87-3。按照文献方法制备：WO2016154998)反应得到Ex.6，为浅黄色固体。分析数据：质谱(ESI)m/z：594.3[M+H] +。
实施例七：2-((S)-1-((E)-4-(1H-吡唑-1-基)丁-2-烯酰基)-4-((S)-2-(((S)-1-甲基吡咯烷酮)-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈(Ex.7)的制备：
Figure PCTCN2020111031-appb-000047
按照实施例一相同的方法制备，经中间体I-8与(E)-4-(1H-吡唑-1-基)丁-2-烯酸(CAS#2326524-70-1。按照文献方法制备：WO2020101736)反应得到Ex.7，为浅黄色固体。分析数据：质谱(ESI)m/z：631.3[M+H] +。
实施例八：2-((S)-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)-1-((E)-3-(吡啶-3-基)丙烯酰基)哌嗪-2-基)乙腈 甲酸盐(Ex.8)的制备：
Figure PCTCN2020111031-appb-000048
按照实施例一相同的方法制备，经中间体I-8与(E)-3-(吡啶-3-基)丙烯酸(CAS#19337-97-4)反应得到Ex.8，为浅黄色固体。分析数据：质谱(ESI)m/z：628.3[M+H] +。
实施例九：2-((S)-1-(3-环丙基丙酰基)-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈 甲酸盐(Ex.9)的制备：
Figure PCTCN2020111031-appb-000049
按照实施例一相同的方法制备，经中间体I-8与3-环丙基丙炔酸(CAS# 7358-93-2)反应得到Ex.9，为浅黄色固体。分析数据：质谱(ESI)m/z：589.4[M+H] +。
实施例十：2-((S)-1-(2-环丙亚基乙酰基)-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈 甲酸盐(Ex.10)的制备：
Figure PCTCN2020111031-appb-000050
按照实施例一相同的方法制备，经中间体I-8与2-环丙亚基乙酸((2-cyclopropylideneacetic acid)：CAS#:5687-73-0。按照文献方法制备：Henderson,J.R.；Parvez,M.；Keay,B.A.Org.Lett.2007,9,5167-5170)反应得到Ex.10，为浅棕色固体。分析数据：质谱(ESI)m/z：577.5[M+H] +。
实施例十一：2-((S)-1-((氯甲基)磺酰基)-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈 甲酸盐(Ex.11)的制备：
Figure PCTCN2020111031-appb-000051
按照实施例一相同的方法制备，经中间体I-8与氯甲基磺酰胺(CAS#:3518-65-8)反应得到Ex.11，为白色固体。分析数据：质谱(ESI)m/z：609.2[M+H, 35Cl] +，611.2[M+H, 37Cl] +。
实施例十二：2-((2S)-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)-1-(环氧乙烷-2-羰基)哌嗪-2-基)乙腈 甲酸盐(Ex.12)的制备：
Figure PCTCN2020111031-appb-000052
按照实施例一相同的方法制备，经中间体I-8与环氧乙烷-2-羧酸钾(CAS#:51877-54-4)反应得到Ex.12，为灰白色固体。分析数据：质谱(ESI)m/z：567.3[M+H] +。
实施例十三：2-((S)-1-丙烯酰基-4-(7-(2-氟-6-羟基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)哌嗪-2-基)乙腈(Ex.13)的制备：
Figure PCTCN2020111031-appb-000053
第一步：2'-氟-6'-甲氧基-5,6-二氢-[1,1'-联苯]-3(4H)-酮(XIII-3)的制备：在N 2下，往(2-氟-6-甲氧基苯基)硼酸(XIII-1,20.0g,81.9mmol,1.00eq)的THF(200mL)溶液中加入3-氧代环己-1-烯-1-
Figure PCTCN2020111031-appb-000054
三氟甲磺酸酯(XIII-2,CAS#109459-28-1。按照文献方法制备：M.T.Burger et al.J.Med.Chem.2015,58,8373-8386,15.3g,90.0mmol,1.10eq)，Na 2CO 3(2.00M,115mL,2.80eq)和Pd(PPh 3) 2Cl 2(1.15g,1.64mmol,0.02eq)，将所得混合物在N 2和60℃下搅拌2小时。LC-MS显示反应完成。将反应混合物倒入水(100mL)中，并用乙酸乙酯(100mL)萃取，合并的有机相用饱和盐水(50.0mL×2)洗涤，用无水Na 2SO 4干燥，过滤，滤液真空浓缩得到残余物，将残余物用硅胶硅胶柱色谱法(洗脱液： 石油醚/乙酸乙酯＝1:0至10:1)纯化得到产物XIII(23.0g,粗品)，为黄色油。直接用于下一步。
第二步：2'-氟-6'-甲氧基-5-氧代-2,3,4,5-四氢-[1,1'-联苯]-4-羧酸乙酯(XIII-4)的制备：在-70℃下，往2'-氟-6'-甲氧基-5,6-二氢-[1,1'-联苯]-3(4H)-酮(XIII-3,21.0g,95.3mmol,1.00eq)的THF(210mL)溶液中滴加LiHMDS(1.00M,191mL,191mmol,2.00eq)，然后将混合物在0℃下搅拌2小时，然后将反应混合物冷却至-70℃，加入氰基甲酸乙酯(P1-2,11.2mL，114mmol,1.20eq)，所得混合物并在25℃下搅拌3小时，LC-MS显示反应完成。将反应混合物倒入饱和NH 4Cl溶液(300mL)中，并用乙酸乙酯(300mL×2)萃取，合并的有机相用饱和盐水(300mL×2)洗涤，用无水Na 2SO 4干燥，过滤，滤液真空浓缩得到残余物，将残余物通过硅胶柱色谱法(洗脱液：石油醚/乙酸乙酯＝1:0至20:1)纯化，得到化合物XIII-4(25.5g,粗品)，为黄色油。直接用于下一步。
第三步：7-(2-氟-6-甲氧基苯基)-5,6-二氢喹唑啉-2,4-二醇(XIII-5)的制备：将2'-氟-6'-甲氧基-5-氧代-2,3,4,5-四氢-[1,1'-联苯]-4-羧酸乙酯(XIII-4,25.5g,87.2mmol,1.00eq)和尿素(41.9g,698mmol,8.00eq)的混合物在170℃下搅拌2小时，LC-MS显示反应完成。将反应混合物冷却至100℃下用水缓慢淬灭，然后用乙酸乙酯(20.0mL×3)萃取，合并的有机相用饱和盐水(10.0mL×2)洗涤，用无水Na 2SO 4干燥，过滤，滤液真空浓缩得到残余物，用异丙醇(120mL)重结晶的到化合物XIII-5(15.0g,52.0mmol,产率：59％)，为浅黄色固体。
第四步：2,4-二氯-7-(2-氟-6-甲氧基苯基)-5,6-二氢喹唑啉(XIII-6)的制备：在25℃下，往7-(2-氟-6-甲氧基苯基)-5,6-二氢喹唑啉-2,4-二醇(XIII-5,9.00g,31.2mmol,1.00eq)中加入POCl 3(100mL,1.08mol,34.6eq)，将所得混合物在110℃下搅拌3小时，LC-MS显示反应完成。将反应混合物冷至室温，并缓慢倒入水(200mL)中，并用乙酸乙酯(80.0mL×3)萃取，合并的有机相用饱和盐水(100mL×2)洗涤，用无水Na 2SO 4干燥，过滤，滤液真空浓缩得到产物XIII-6(6.00g,18.5mmol,产率：59.1％)，为黄色固体，无需进一步纯化，直接用于下一步。
第五步：(S)-4-(2-氯-7-(2-氟-6-甲氧基苯基)-5,6-二氢喹唑啉-4-基)-2-(氰基甲基)哌嗪-1-甲酸叔丁酯(XIII-8)的制备：往2,4-二氯-7-(2-氟-6-甲氧基苯基)-5,6-二氢喹唑啉(XIII-6,1.40g,4.31mmol,1.00eq)和(S)-2-(哌嗪-2-基)乙腈二盐酸盐(XIII-7,CAS#2158301-19-8。按照文献方法制备：WO201720161,835mg,5.17mmol,1.20eq)的DMF(10.0mL)中加入DIEA(3.75mL,21.5mmol,5.00eq)，将所得混合物在40℃下搅拌6小时，加入Boc 2O(1.88g，8.61mmol，2.00eq)，继续在25℃下搅拌10小时，LC-MS显示反应完成。将反应混合物倒入水(50.0mL)中，并用乙酸乙酯(20.0mL×2)萃取，合并的有机相用饱和盐水(30.0mL×2) 洗涤，用无水Na 2SO 4干燥，过滤，滤液真空浓缩得到残余物，通过硅胶柱色谱法(洗脱液：石油醚/乙酸乙酯＝1:1至1:5)纯化残余物得到化合物XIII-8(1.5g,2.92mmol,产率：67.8％)，为黄色固体。
第六步：(S)-2-(氰甲基)-4-(7-(2-氟-6-甲氧基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)哌嗪-1-甲酸叔丁酯(XIII-9)的制备：在N 2下，将(S)-4-(2-氯-7-(2-氟-6-甲氧基苯基)-5,6-二氢喹唑啉-4-基)-2-(氰基甲基)哌嗪-1-甲酸叔丁酯(XIII-8,1.20g,2.33mmol,1.00eq)，(S)-(1-甲基吡咯烷-2-基)甲醇(I-6,807mg,7.00mmol,3.00eq)，Cs 2CO 3(2.28g,7.00mmol,3.00eq)和(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯)[2-(2'-氨基-1,1'-联苯基)]]钯(II)甲磺酸盐,RuPhos-G3-Palladacycle(RuPhos Pd G3,CAS#1445085-77-7,97.6mg,0.117mmol.0.05eq)二恶烷(20.0mL)在100℃下搅拌8小时，LC-MS显示反应完成。将反应混合物过滤，固体用DCM(20.0mL×3)洗涤，将合并的有机相减压浓缩得到残余物，通过硅胶柱色谱法(洗脱液：石油醚/乙酸乙酯＝1:1至1:5)纯化得到化合物XIII-9(1.0g,1.69mmol,产率：72.3％)，为黄色固体。
第七步：2-((S)-4-(7-(2-氟-6-羟基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基 哌嗪-2-基)乙腈(XIII-10)的制备：在0℃下，往(S)-2-(氰甲基)-4-(7-(2-氟-6-甲氧基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)哌嗪-1-甲酸叔丁酯(XIII-9,800mg,1.35mmol,1.00eq)的DCM(1.00mL)溶液中加入BBr 3(0.39mL,4.05mmol,3.00eq)，将所得混合物在0℃下搅拌0.5小时，LC-MS显示反应完成。在0℃下，将甲基叔丁基醚(2.00mL)加入到反应混合物中，然后用饱和NaHCO 3调节pH至7。混合物用乙酸乙酯(10.0mL×3)萃取，合并的有机相用饱和盐水(10.0mL×2)洗涤，用无水Na 2SO 4干燥，过滤，滤液真空浓缩得到粗产物XIII-10(600，粗品)为浅黄色固体，无需进一步纯化直接用于下一步。
第八步：2-((S)-1-丙烯酰基-4-(7-(2-氟-6-羟基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)哌嗪-2-基)乙腈(Ex.13)的制备：在0℃下，往2-((S)-4-(7-(2-氟-6-羟基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基 哌嗪-2-基)乙腈(XIII-10,300mg,0.627mmol,1.00eq)和TEA(95.9μL,0.689mmol,1.10eq)的THF(1.00mL)溶液中加入丙烯酰氯(I-9,25.6μL,0.313mmol,0.50eq)，将所得混合物在0℃下搅拌0.5小时，LC-MS显示反应完成。往反应混合物中加入水(0.50mL)，并减压浓缩得到粗产物，通过制备型HPLC纯化(柱：Waters Xbridge C18 150*50mm*10um；流动相：[水(10mM NH 4HCO 3)-乙腈]；B％：28％-58％,10min)，得到产物2-((S)-1-丙烯酰基-4-(7-(2-氟-6-羟基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)哌嗪-2-基)乙腈(Ex. 13,60.6mg,0.114mmol,产率：18.1％)，为浅黄色固体。分析数据： 1H-NMR(400MHz,CDCl 3)：δ＝7.13(td,J＝8.40,6.63Hz,1H),6.85(m,1H),6.60-6.69(m,2H),6.48(d,J＝1.20Hz,1H),6.28(d,J＝16.00Hz,1H),5.83(d,J＝10.80Hz,1H),5.10(m,1H),4.57(m,1H),4.42(d,J＝6.00Hz,2H),3.99-4.18(m,2H),3.95(m,1H),3.65(m,1H),3.18-3.29(m,3H),2.95-3.12(m,4H),2.85-2.93(m,2H),2.68(s,1H),2.66(s,3H),2.56(m,1H),2.16(m,1H),1.76-1.95(m,3H)。质谱(ESI)m/z：533.2[M+H] +。
实施例十四：2-((S)-1-丙烯酰基-4-(2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6-二氢喹唑啉-4-基)哌嗪-2-基)乙腈 甲酸盐(Ex.14)的制备：
Figure PCTCN2020111031-appb-000055
第一步：4-(萘-1-基)-2-氧代环己基-3-烯甲酸乙酯(XIV-2)的制备：在N 2及-70℃下，往3-(萘-1-基)环己-2-烯酮(2,CAS#42160-94-1,按照文献方法制备：Y.Fall et al.Tetrahedron 2009,65,489-495,9.00g,40.5mmol,1.00eq)的THF(100mL)溶液中加入LiHMDS(1.0M,44.5mL,44.5mmol,1.10eq)，加完以后将温度升至0℃，并在此温度下搅拌30分钟，然后冷却至-70℃，加入氰基甲酸乙酯(P1-2,4.77mL,48.6mmol,1.20eq)，加完以后将温度升至25℃，并在此温度下将反应混合物搅拌30分钟。TLC显示反应完成，将反应用饱和NH 4Cl水溶液(500mL)淬灭并用乙酸乙酯稀释。过滤收集有机层，用盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩得到残余物，残余物通过硅胶柱色谱法纯化(洗脱液：石油醚/乙酸乙酯＝100/1至1/1)得到4-(萘-1-基)-2-氧代环己基-3-烯甲酸乙酯(XIV-2,8.30g,11.4mmol,产率：28％,纯度：40.4％)，为黄色油状物。
第二步：2-巯基-7-(萘-1-基)-5,6-二氢喹唑啉-4-醇(XIV-3)的制备：往XIV-2 (4.85g,16.48mmol,1.00eq)的EtOH(40mL)溶液中加入硫脲(6.27g,82.4mmol,5.00eq)和t-BuOK(1.85g,16.5mmol,1.00eq)，所得混合物于80℃搅拌2小时。TLC显示反应完成，将反应混合物冷至室温后倒入150mL水中，过滤收集产物，干燥后得到化合物XIV-3(4.30g,10.6mmol,产率：64％,纯度：75.6％)为黄色固体。质谱(ESI)m/z：307.1[M+H] +。
第三步：2-(甲硫基)-7-(萘-1-基)-5,6-二氢喹唑啉-4-醇(XIV-4)的制备：在0℃下，往XIV-3(4.30g,14.0mmol,1.00eq)的DMF(40mL)溶液中加入乙酸钾(4.13g,42.1mmol,3.00eq)，然后在加入MeI(873.7μL,14.0mmol,1.00eq)，所得混合物在0℃下搅拌0.5小时。TLC显示反应完成，将反应混合物倒入30mL水中，过滤收集产物，干燥后得到化合物XIV-4(4.30g,6.0mmol,产率：42.7％,纯度：44.7％)，为黄色固体。质谱(ESI)m/z：321.2[M+H] +。
第四步：2-(甲硫基)-7-(萘-1-基)-5,6-二氢喹唑啉-4-基 三氟甲磺酸酯(XIV-5)的制备：在0℃下，往化合物XIV-4(2.90g,9.05mmol,1.00eq)的DCM(30mL)溶液中加入2,6-二甲基吡啶(2.91g,27.2mmol,3.16mL,3.00eq)，然后加入三氟甲磺酸酐(Tf 2O,3.1g,10.8mmol,1.79mL,1.20eq)，将所得混合物在0℃下搅拌2小时。TLC显示反应完成，将反应混合物倒入水(100mL)中，并用乙酸乙酯(2×200mL)萃取。合并有机相，用饱和盐水(2×100mL)洗涤，无水Na 2SO 4干燥，过滤，滤液减压浓缩得到残留物，通过硅胶柱色谱法纯化(洗脱液：石油醚/乙酸乙酯＝1/0至1/1)得到化合物XIV-5(2.0g,4.3mmol,产率：47％,纯度：96.6％)，为黄色油。质谱(ESI)m/z：453.1[M+H] +。
第五步：(S)-2-(氰甲基)-4-(2-(甲硫基)-7-(萘-1-基)-5,6-二氢喹唑啉-4-基)哌嗪-1-甲酸叔丁酯(XIV-6)的制备：往化合物XIV-5(2.00g,4.40mmol,1.00eq)和(S)-2-(哌嗪-2-基)乙腈二盐酸盐(XIII-7,964.5mg,5.80mmol,1.35eq)的DMF(20mL)溶液中加入DIEA(4.62mL,26.5mmol,6.00eq)，所得混合物在25℃下搅拌5小时，然后加入Boc 2O(1.93g,8.84mmol,2.00eq)，将混合物在25℃下继续搅拌12小时，LC-MS显示反应完成。将反应混合物倒入水(100mL)中，用乙酸乙酯(200mL×2)萃取，合并的有机相用饱和盐水(200mL×2)洗涤，用无水Na 2SO 4干燥，过滤，滤液真空浓缩得到化合物XIV-6(2.00g,3.79mmol,产率：85.7％)，为黄色油，质谱(ESI)m/z：529.1[M+H] +。直接用于下一步。
第六步：(2S)-2-(氰甲基)-4-(2-(甲基亚磺酰基)-7-(萘-1-基)-5,6-二氢喹唑啉-4-基)哌嗪-1-羧酸叔丁酯(XIV-7)的制备：在0℃下，往化合物XIV-6(2.00g,3.79mmol,1.00eq)的乙酸乙酯(60mL)溶液中加入间氯过氧苯甲酸(m-CPBA,731.0mg,3.60mmol,纯度：80.9％,0.95eq)，所得混合物在0℃下搅拌30分钟，LC-MS显示反应完成。将反应混合物用乙酸乙酯(200mL)稀释，用100mL饱和NaHCO 3 溶液(50mL×2)洗涤，用Na 2SO 4干燥，过滤，滤液减压浓缩得到粗产物，用硅胶柱色谱法(洗脱液：石油醚/乙酸乙酯＝50:1至0:1)纯化得到化合物XIV-7(1.20g,1.88mmol,产率：49.7％,纯度：85.4％)，为白色固体。质谱(ESI)m/z：544.1[M+H] +。
第七步：(S)-2-(氰甲基)-4-(2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6-二氢喹唑啉-4-基)哌嗪-1-羧酸叔丁酯(XIV-8)的制备：在0℃下，往化合物XIV-7(0.500g,0.92mmol,1.00eq)和(S)-(1-甲基吡咯烷-2-基)甲醇(211.8mg,218.4μL,1.84mmol,2.00eq)的甲苯(2mL)溶液中加入t-BuONa(176.8mg,1.84mmol,2.00eq)，将所得混合物在0℃下搅拌0.5小时，LC-MS显示反应完成。往反应混合物中加入饱和NH 4Cl水溶液(100mL)，并用乙酸乙酯(200mL×2)萃取，合并的有机层用Na 2SO 4干燥，过滤，滤液减压浓缩得到残余物，用制备型HPLC纯化(甲酸条件)得到化合物XIV-8(0.15g,0.22mmol,产率：24％，纯度：88％)为白色固体。质谱(ESI)m/z：595.3[M+H] +。
第八步：2-((S)-4-(2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6-二氢喹唑啉-4-基)哌嗪-2-基)乙腈 三氟乙酸盐(XIV-9)的制备：在25℃下，往化合物XIV-8(0.15g,0.25mmol,1.00eq)的DCM(1.0mL)溶液中加入TFA(0.3mL,4.05mmol,16.1eq)，所得混合物在25℃下搅拌1小时。LC-MS显示反应完成。将反应混合物减压浓缩得到化合物XIV-9(50mg,0.10mmol,产率：40.1％)，为黄色固体。质谱(ESI)m/z：495.3[M+H] +。直接用于下一步。
第九步：2-((S)-1-丙烯酰基-4-(2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6-二氢喹唑啉-4-基)哌嗪-2-基)乙腈 甲酸盐(Ex.14)的制备：在-78℃下，往化合物XIV-9(50.0mg,0.10mmol,1.00eq)的DCM(1mL)溶液中加入丙烯酰氯(24.7μL,0.30mmol,3.00eq)和DIEA(88.0μL,0.505mmol,5.00eq)，所得混合物在-78℃下搅拌1小时，LC-MS显示反应完成。将反应混合物倒入水(100mL)中，用DCM(100mL×2)萃取，合并的有机相用饱和盐水(100mL×2)洗涤，用无水Na 2SO 4干燥，过滤，滤液真空浓缩得到残余物，残余物用反相HPLC纯化(柱：Shim-pack C18 150x25x10um；流动相：[水(0.225％甲酸)-乙腈]；B％：24％-44％，9min)得到2-((S)-1-丙烯酰基-4-(2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6-二氢喹唑啉-4-基)哌嗪-2-基)乙腈 甲酸盐(Ex.14,6.2mg,10.2μmol,产率：10.1％,纯度：97.7％)，为白色固体。分析数据： 1H-NMR(400MHz,CDCl 3)：δ＝8.45(s,1H),8.1(d,J＝8.0Hz,1H),7.89-7.96(m,2H),7.49-7.53(m,3H),7.44(d,J＝9.6Hz,1H),6.68(s,1H),6.64(m,1H),6.40(d,J＝17.2Hz,1H),5.84(d,J＝10.0Hz,1H),4.55(m,1H),4.29(m,1H),3.97-4.00(d,J＝14.8Hz,1H),3.85(m,1H),3.76(m,1H),3.54(m,1H),3.30(d,J＝8.0Hz,2H), 3.06-3.12(m,2H),2.92-2.96(m,4H),2.76-2.80(m,2H),2.62(s,3H),2.45-2.46(m,2H),1.82-2.05(m,4H)。质谱(ESI)m/z：549.3[M+H] +。
实施例十五：2-((S)-1-丙烯酰基-4-(7-(8-甲基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)哌嗪-2-基)乙腈 甲酸盐(Ex.15)的制备：
Figure PCTCN2020111031-appb-000056
从(8-甲基萘-1-基)硼酸(CAS#948592-91-4，按照文献方法制备：W.H.Miles et al.J.Org.Chem.2016,81,10791-10801)出发，按照实施例十四相同的方法合成Ex.15，为白色固体。分析数据：质谱(ESI)m/z：563.3[M+H] +。
实施例十六：2-((S)-1-丙烯酰基-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)哌嗪-2-基)乙腈 甲酸盐(Ex.16)的制备：
Figure PCTCN2020111031-appb-000057
从(8-氯萘-1-基)硼酸(CAS#2305022-53-9)出发，按照实施例十四相同的方法合成Ex.16，为白色固体。分析数据：质谱(ESI)m/z：583.2[M+H, 35Cl] +，585.2[M+H, 37Cl] +。
实施例十七：2-((S)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)-1-(2,3,3-三氘代丙-2-烯酰基)哌嗪-2-基)乙腈 甲酸盐(Ex.17)的制备：
Figure PCTCN2020111031-appb-000058
从(8-氯萘-1-基)硼酸(CAS#2305022-53-9)出发，利用氘代丙烯酸(CAS# 204259-63-2)，按照实施例十四相同的方法合成Ex.17，为灰白色固体。分析数据：质谱(ESI)m/z：586.3[M+H, 35Cl] +，588.3[M+H, 37Cl] +。
实施例十八：2-((S)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈 甲酸盐(Ex.18)的制备：
Figure PCTCN2020111031-appb-000059
从(8-氯萘-1-基)硼酸(CAS#2305022-53-9)出发，利用2-氟丙烯酸(CAS#430-99-9)，按照实施例十四相同的方法合成Ex.18，为白色固体。分析数据：质谱(ESI)m/z：601.2[M+H, 35Cl] +，603.2[M+H, 37Cl] +。
实施例十九：2-((S)-1-(丁-2-炔酰基)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)哌嗪-2-基)乙腈 甲酸盐(Ex.19)的制备：
Figure PCTCN2020111031-appb-000060
从(8-氯萘-1-基)硼酸(CAS#2305022-53-9)出发，利用2-丁炔酸(CAS#590-93-2)，按照实施例十四相同的方法合成Ex.19，为白色固体。分析数据：质谱(ESI)m/z：595.4[M+H, 35Cl] +，597.4[M+H, 37Cl] +。
实施例二十：(E)-4-((S)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)-2-(氰基甲基)哌嗪-1-基)-4-氧丁-2-烯腈 甲酸盐(Ex.20)的制备：
Figure PCTCN2020111031-appb-000061
从(8-氯萘-1-基)硼酸(CAS#2305022-53-9)出发，利用(E)-3-氰基丙烯酸(CAS#:42356-32-1。按照文献方法制备：WO2014068527)，按照实施例十四相同的方法合成Ex.20，为白色固体。分析数据：质谱(ESI)m/z：608.4[M+H, 35Cl] +，610.4[M+H, 37Cl] +。
实施例二十一：2-((S)-1-((E)-丁-2-烯酰基)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)哌嗪-2-基)乙腈 三氟乙酸盐(Ex.21)的制备：
Figure PCTCN2020111031-appb-000062
从(8-氯萘-1-基)硼酸(CAS#2305022-53-9)出发，利用(E)-2-丁烯酸(CAS#:107-93-7)，按照实施例十四相同的方法合成Ex.21，为浅黄色固体。分析数据：质谱(ESI)m/z：597.3[M+H, 35Cl] +，599.3[M+H, 37Cl] +。
实施例二十二、体内抗肿瘤实验
采用实施例一中制备的2-((S)-1-丙烯酰基-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈(Ex.1)在MIA PaCa-2人胰腺癌细胞异种移植裸鼠动物模型中进行抗肿瘤实验：
1.实验材料
7～8周龄SPF级雌性BALB/c-nu/nu小鼠，体重16～18g，购自浙江维通利华实验动物技术有限公司，合格证编号：1903040007；
MIA PaCa-2人胰腺癌细胞购自American Type Culture Collection(ATCC,Manassas,VA,USA)；
RPMI-1640培养基和胎牛血清(FBS)均购自GIBCO公司(Grand Island,NY,USA)；
基质胶(Matrigel)购自BD公司(Franklin lake,NJ,USA)。
2.实验方法
2.1模型建立
MIA PaCa-2细胞培养于含10％FBS的RPMI-1640培养基，维持在5％CO 2的37℃饱和湿度培养箱中。
收集对数生长期MIA PaCa-2细胞，重悬于含50％Matrigel的RPMI-1640基础培养基中，调整细胞浓度至3×10 7/mL，得到细胞悬液。无菌条件下，分别 在80只7～8周龄SPF级雌性BALB/c-nu/nu小鼠右侧背部皮下接种0.1mL细胞悬液，接种浓度为3×10 6/0.1mL/mouse。
2.2分组及给药观察
当接种后的小鼠体内肿瘤体积达到200mm 3左右时，从中选取24只小鼠按肿瘤体积随机分为3组(溶媒对照(vehicle：10％Tween-80+40％PEG400+10％(5％w/v)柠檬酸水溶液+40％水)组、治疗组1和治疗组2)，每组8只，使各组肿瘤体积差异小于均值的10％。分组当日记为Day 0，并按照小鼠体重开始给药，每天1次口服给药，连续给药2周，给药结束后延长观察1周，Day 21天处死动物，取瘤称重并拍照记录，其中，溶媒对照组为每只小鼠每日口服与治疗组1和治疗组2相同体积的溶媒(0.2mL)，治疗组1为每只小鼠每日口服3mg/kg(Ex.1重量/体重)实施例一制备的2-((S)-1-丙烯酰基-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈(Ex.1)，治疗组2为每只小鼠每日口服10mg/kg(Ex.1重量/体重)实施例一制备的2-((S)-1-丙烯酰基-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈(Ex.1)。给药期间，如果个别小鼠体重与Day 0相比下降超过15％(BWL≥15％)，将做停药处理，直至动物体重恢复后(BWL<15％)，恢复给药，给药结束后延长观察1周。
实验期间每周2次测定小鼠体重和肿瘤体积，每日观察记录动物临床症状。
2.3实验终点说明
根据动物福利相关规定，实验期间如果个别实验小鼠符合以下任一条件，该小鼠将从实验组中移除并施以安乐死。1、小鼠体重与Day 0相比下降超过20％(BWL≥20％)；2、小鼠出现严重不良反应，如失明、瘫痪等；3、肿瘤体积大于2000mm 3；4、肿瘤表面形成开放式溃疡。
实验周期为21天，实验终点最后一次称量结束后，用CO 2安乐死处死剩余小鼠，取瘤称重并拍照记录后结束实验。
3. 评价指标
肿瘤体积(Tumor volume，TV)计算公式为：TV＝1/2×a×b 2，其中a、b分别为肿瘤测量的长和宽；
相对肿瘤体积(Relative tumor volume，RTV)计算公式为：RTV＝Vt/V 0，其中V 0为分组时的肿瘤体积，Vt为测量时的肿瘤体积；
相对肿瘤增值率％T/C RTV计算公式为：％T/C RTV＝T RTV/C RTV×100％，其中T RTV为治疗组RTV，C RTV为溶媒对照组RTV；
抑瘤率％TGI TW计算公式为：％TGI TW＝(TW C-TW T)/TW C×100％，TW C为溶媒对照组平均肿瘤重量，TW T为治疗组平均肿瘤重量；
动物体重变化(％)计算公式为：BWC％＝(BW t-BW 0)/BW 0×100％，BW t为测量时动物体重，BW 0为分组时动物体重。
根据中国NMPA《细胞毒类抗肿瘤药物非临床研究技术指导原则》(2006年11月)，％T/C RTV≤40％并经统计学分析P<0.05为有效。药物相关动物死亡数超过20％，则认为该药物剂量具有严重毒性。
4.统计分析
本研究中，实验数据均以Mean±SEM表示。
以时间点为X轴，肿瘤平均体积(mm 3)为Y轴绘制肿瘤生长曲线，结果如图2所示；以时间点为X轴，小鼠体重(g)为Y轴绘制小鼠体重变化曲线，结果如图3所示。组间比较采用双尾t-检验，P<0.05为显著性差异，P<0.01为极显著差异(Microsoft Excel 2007,Redmond,WA,USA)。
5.实验结果
5.1抑瘤率
实验结束后，溶媒对照组、治疗组1和治疗组2中小鼠的平均肿瘤重量及抑瘤率(Tumor Growth Inhibition:TGI)结果如表1所示。
表1平均肿瘤重量及抑瘤率
实施例 平均肿瘤重量(mg) 抑瘤率(％)
溶媒对照组 438 0
治疗组1 283 64.6
治疗组2 66 84.9
5.2肿瘤生长曲线
由图2可知，治疗开始后，溶媒对照组和治疗组1中小鼠的肿瘤体积均继续生长，但与溶媒对照组相比，治疗组1中肿瘤体积的生长速度明显更加缓慢，进一步的，在治疗组2中，不仅肿瘤生长得到完全抑制，与初始肿瘤体积相比，还出现肿瘤消退(Tumor Regression,TR＝5％)。肿瘤消退TR的计算公式为：TR＝(V treatment day0-V treatment day21)/V treatment day0×100％(V treatment day0：治疗组2给药前小鼠肿瘤平均体积；V treatment day21：治疗组2给药14天然后停药7天后小鼠肿瘤平均体积)。
5.3小鼠体重变化
由图3可知，治疗14天，然后停药观察7天以后，治疗组1和治疗组2中小鼠的体重变化<10％，体重没有明显减轻，说明药物没有明显的毒性。
从上述实验结果可以得出，实施例一制备的2-((S)-1-丙烯酰基-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈(Ex.1)在MIA PaCa-2人胰腺癌异种移植裸鼠动物模型(xenograft  models)中显示出显著的、剂量依赖性的肿瘤抑制作用。治疗组的动物体重没有明显减轻，说明药物没有明显的毒性。
实施例二十三、体内抗肿瘤实验
利用与实施例二十二相同的方法，将实施例十六中制备的2-((S)-1-丙烯酰基-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢喹唑啉-4-基)哌嗪-2-基)乙腈 甲酸盐(Ex.16)在MIA PaCa-2人胰腺癌细胞异种移植裸鼠动物模型中进行抗肿瘤实验，并与AMG-510进行比较，实验结果见图4。实验证明Ex.16在该动物模型中显示与AMG-510类似的抗肿瘤活性。
实施例二十四、肿瘤细胞中Phospho-ERK抑制活性的测定
实施例一制备的2-((S)-1-丙烯酰基-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈(Ex.1)抑制MIA PaCa-2胰腺癌细胞中磷酸化ERK(Phospho-ERK)的IC 50值委托Reaction Biology Corporation公司(地址：1Great Valley Parkway,Suite 2,Malvern,PA 19355,USA.www.reactionbiology.com)测定。
材料：
对照化合物Staurosporine从Sigma-Aldrich公司购买(地址：PO Box 14508,St.Louis,MO 63178,USA)；
Phospho(Thr202/Tyr204；Thr185/Tyr187)/Total ERK1/2 MSD试剂盒从Meso Scale Diagnostics公司购买(地址：1601 Research Blvd,Rockville,MD 20850,USA)；
MIA PaCa-2细胞株从American Type Culture Collection(ATCC，地址：10801University Blvd,Manassas,VA 20110,USA)购买；
MIA PaCa-2在含2.5％马血清的Dulbecco's Modified Eagle's Medium中培养，所有培养基补充有(supplemented with)10％胎牛血清、100μg/mL青霉素和100μg/mL链霉素。将培养物(cultures)保持在37℃，5％CO 2和95％的空气潮湿气氛中。
试验步骤：
1)将MIA PaCa-2细胞以1×10 4个细胞/孔接种在96孔板中的100μL完全培养基中，然后在37℃，5％CO 2下孵育过夜；
2)分别用实施例一制备的2-((S)-1-丙烯酰基-4-((S)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(萘-1-基)-5,6,7,8-四氢喹唑啉-4-基)哌嗪-2-基)乙腈(Ex.1)(起始浓度10μM,10个剂量，3倍稀释，一式两份(in duplicate))和参照化合物 Staurosporine(起始浓度25μM，10个剂量，3倍稀释，一式两份(in duplicate))预处理细胞2小时；
3)将细胞离心并吸出培养基，用75μL的1X Complete Lysis Buffer裂解细胞；
4)将37.5μL细胞裂解物用于MSD测定；
5)MSD phosphor-ERK和total ERK测定按照试剂盒使用手册进行；
6)绘制IC 50曲线，并使用GraphPad Prism 4基于S形剂量反应方程(sigmoidal dose-response equation)计算IC 50值，结果如表2所示。
采用上述相同的方法，对实施例二至实施例二十一制备的化合物进行测试，并与AMG-510进行比较，结果总结于表2中。
表2、实施例一至实施例二十一制备的化合物和参照化合物Staurosporine和AMG-510的IC 50值
实施例 IC 50值(nM)
Staurosporine 86.2
AMG-510 55.8
Ex.1 2.35
Ex.2 7.19
Ex.3 6920
Ex.4 5.23
Ex.5 471
Ex.6 244
Ex.7 >10,000
Ex.8 7870
Ex.9 450
Ex.10 108
Ex.11 >10,000
Ex.12 607
Ex.13 320
Ex.14 51.5
Ex.15 39.4
Ex.16 18.6
Ex.17 20.2
Ex.18 27.6
Ex.19 243
Ex.20 6.7
Ex.21 28.3
由表2可知，本发明实施例制备的化合物的IC 50值最低可达个位数nM级别，对细胞中的磷酸化ERK显示了比较强的抑制活性，因此可以用于治疗因KRAS的异常活性引起的疾病，例如，肿瘤等。
虽然，上文中已经用一般性说明、具体实施方式及试验，对本发明作了详尽的描述，但在本发明基础上，可以对其作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
工业实用性
本发明提供了一类如式(I)所示的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，同时还公开了用于合成该化合物的中间体化合物及其制备方法，以及包含该化合物的药物组合物及其应用。该化合物是KRAS G12C抑制剂，可用于治疗因KRAS异常活性所引起的疾病，例如肿瘤等，具有较好的经济价值和应用前景。
Figure PCTCN2020111031-appb-000063

Claims (20)

  1. 一种二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，该化合物分子结构式如式(I)所示：
    Figure PCTCN2020111031-appb-100001
    式中：
    Cy为C 3-12环烷基或C 3-12杂脂环基；
    X为C＝O、C＝S或S(＝O) m；
    Y为O、NRR’或S(＝O) m；
    R 1为C 2-12烯基或C 2-12炔基，且所述R 1中的一个或多个氢可任选地被相同或不同的G 1取代；
    R 2选自氢、C 1-12烷基、C 3-12环烷基、C 2-12烯基，C 2-12炔基，C 6-12芳基、C 5-12杂芳基或C 3-12杂脂环基，且所述R 2中的一个或多个氢可任选地被相同或不同的G 2取代；
    R 3和R 4相同或者不同，各自独立地代表一个或多个相同或不同的氢、氘、卤素、OH、CN、NO 2、CO 2H、CONH 2、SH、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2OH、CH 2CH 2OH、OCH 2F、OCHF 2、OCF 3、NRR’、C 1-12烷基、C 3-12环烷基、C 3-12杂脂环基、C 1-12烷氧基、C 3-12环烷氧基或C 3-12杂脂环氧基；
    当存在两个或多个相同或者不同的R 3时，在化学上可行的情况下，其中任意两个相邻或不相邻的R 3可以彼此键合，并且通过与其相连的Cy上的原子一起形成环，所形成的环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子；
    Ar为C 6-12芳基或C 5-12杂芳基，且所述Ar中的一个或多个氢可任选地被相同或不同的G 3取代；
    Figure PCTCN2020111031-appb-100002
    代表单键或者双键；当
    Figure PCTCN2020111031-appb-100003
    代表单键时，*代表所示碳原子为手性碳原子，可以以R-构型、S-构型或者R-构型和S-构型任意比例的混合形式存在；
    其中：
    R和R’相同或不同，各自独立地选自氢、氘、OH、CN、C 1-12烷基、C 3-12环烷基、C 3-12杂脂环基、C 1-12烷氧基、C 3-12环烷氧基或C 3-12杂脂环氧基；
    G 1、G 2和G 3相同或不同，各自独立地选自一个或多个相同或不同的氘、卤素、OH、CN、NO 2、CO 2H、SH、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、OCH 2F、OCHF 2、OCF 3、C 1-12烷基、C 3-12环烷基、C 2-12烯基、C 2-12炔基、C 6-12芳基、C 5-12杂芳基或C 3-12杂脂环基，其中所述C 1-12烷基、C 3-12环烷基、C 2-12烯基、C 2-12炔基、C 6-12芳基、C 5-12杂芳基或C 3-12杂脂环基中的一个或多个氢可任选地被相同或不同的氘、卤素、CN、NO 2、C 1-12烷基、C 3-12环烷基、C 2-12烯基、C 2-12炔基、C 6-12芳基、C 5-12杂芳基、C 3-12杂脂环基、R 5O-、R 6R 7N-、R 5S(＝O) m-、R 6R 7NS(＝O) m-、R 5C(＝O)-、R 6R 7NC(＝O)-、R 5OC(＝O)-、R 5C(＝O)O-、R 6R 7NC(＝O)O-、R 5C(＝O)NR 8-、R 6R 7NC(＝O)NR 8-、R 5OC(＝O)NR 8-、R 5S(＝O) mNR 8-、R 6R 7NS(＝O) mNR 8-、R 6R 7NC(＝NR 9)NR 8-、R 6R 7NC(＝CHNO 2)NR 8-、R 6R 7NC(＝N-CN)NR 8-、R 6R 7NC(＝NR 9)-、R 5S(＝O)(＝NR 9)NR 8-或R 6R 7NS(＝O)(＝NR 9)-取代；
    R 5、R 6、R 7、R 8和R 9相同或不同，各自独立地选自氢、氘、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 3-12环烷基、C 6-12芳基、C 5-12杂芳基或C 3-12杂脂环基；当R 6和R 7连接在同一氮原子上时，可通过彼此连接与该氮原子一起形成一个杂脂环，所述杂脂环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子；且R 5、R 6、R 7、R 8和R 9中的一个或多个氢可任选地被相同或不同的氘、卤素、OH、OCH 3、CN、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、OCH 2F、OCHF 2、OCF 3、C 1-12烷基或C 3-12环烷基取代；
    G 1、G 2和G 3中的一个或多个氢可任选地进一步被相同或不同的氘、卤素、OH、OCH 3、CN、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、OCH 2F、OCHF 2、OCF 3、C 1-12烷基或C 3-12环烷基取代；
    m＝0、1或2。
  2. 根据权利要求1所述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，其中，R 1还可以为-CH 2-卤素、
    Figure PCTCN2020111031-appb-100004
  3. 根据权利要求1或2所述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，其中，所述化合物的结构式为(Ia)：
    Figure PCTCN2020111031-appb-100005
    式中所述，
    Cy1为包含两个N原子的C 3-12杂脂环基，优选的，选自Cy1-1至Cy1-9中的任意一种：
    Figure PCTCN2020111031-appb-100006
    X、R 2-R 4、Ar、*、
    Figure PCTCN2020111031-appb-100007
    是如权利要求1所定义的，R 1是如权利要求1或2所定义的。
  4. 根据权利要求1-3任一项所述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，其中，所述化合物的结构式为(Ib)或(Ic)：
    Figure PCTCN2020111031-appb-100008
    式中所述，
    X 1为C＝O或S(＝O) m；
    R 2-R 3、Ar、*、
    Figure PCTCN2020111031-appb-100009
    m是如权利要求1所定义的，R 1是如权利要求1或2所定义的。
  5. 根据权利要求1-4任一项所述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，其中，所述化合物的结构式为(Id)、(Ie)、If)、(Ig)、(Ih)或(Ii)：
    Figure PCTCN2020111031-appb-100010
    式中所述，
    R 3a代表一个或多个相同或不同的氢、氘、卤素、OH、CN、NO 2、CO 2H、CONH 2、SH、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2OH、CH 2CH 2OH、OCH 2F、OCHF 2、OCF 3、NRR’、C 1-12烷基、C 3-12环烷基、C 3-12杂脂环基、C 1-12烷氧基、C 3-12环烷氧基或C 3-12杂脂环氧基；
    当R 3a代表至少两个相同或不同的C 1-12烷基时，所述两个相同或不同的C 1-12烷基可以彼此连接，并且通过与其相连的哌嗪环上的一个或两个原子与哌嗪环一起形成一个5-18元的螺环、稠环或桥环，所述的螺环、稠环或桥环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子；
    R 1a、R 1b和R 1c相同或不同，各自独立地选自氢、氘、卤素、CN、NO 2、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3或C 1-12烷基，其中所述C 1-12烷基中的一个或多个氢可任选地被相同或不同的氘、卤素、CN、NO 2、R 5O-、R 6R 7N-、R 5S(＝O) m-、R 6R 7NS(＝O) m-、R 5C(＝O)-、R 6R 7NC(＝O)-、R 5OC(＝O)-、R 5C(＝O)O-、R 6R 7NC(＝O)O-、R 5C(＝O)NR 8-、R 6R 7NC(＝O)NR 8-、R 5OC(＝O)NR 8-、R 5S(＝O) mNR 8-或R 6R 7NS(＝O) mNR 8-取代；
    R 2、Ar、*、
    Figure PCTCN2020111031-appb-100011
    m、R、R’、R 5、R 6、R 7、R 8是如权利要求1所定义的。
  6. 根据权利要求1-5任一项所述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，其中，所述化合物的结构式为(Ij)、(Ik)、(Il)、(Im)、(In)、(Io)、(Ip)、(Iq)、(Ir)、(Is)、(It)或(Iu)：
    Figure PCTCN2020111031-appb-100012
    Figure PCTCN2020111031-appb-100013
    式中所述，
    R 3b代表一个或多个相同或不同的氢、氘、卤素、CN、CO 2H、CONH 2、CH 2CN、CH 2F、CHF 2、CF 3、CH 2CH 2CN、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2OH、CH 2CH 2OH或C 1-12烷基；
    当R 3b代表至少两个相同或不同的C 1-12烷基时，所述两个相同或不同的C 1-12烷基可以彼此连接，并且通过与其相连的哌嗪环上的一个或两个原子与哌嗪环一起形成一个5-18元的螺环、稠环或桥环，所述的螺环、稠环或桥环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子；
    R 2、Ar、*、m是如权利要求1所定义的；R 1a、R 1b和R 1c是如权利要求5所定义的。
  7. 根据权利要求1-6任一项所述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，其中，所述化合物的结构式是下面任意一种：
    Figure PCTCN2020111031-appb-100014
    Figure PCTCN2020111031-appb-100015
    Figure PCTCN2020111031-appb-100016
    Figure PCTCN2020111031-appb-100017
    Figure PCTCN2020111031-appb-100018
    Figure PCTCN2020111031-appb-100019
    Figure PCTCN2020111031-appb-100020
    Figure PCTCN2020111031-appb-100021
    Figure PCTCN2020111031-appb-100022
    式中所示，*是如权利要求1所定义的。
  8. 根据权利要求1或2所述的二氢或四氢喹唑啉类化合物、其消旋体、对 映异构体、非对映异构体、药学上可接受的盐或溶剂合物，其中，所述化合物的结构式是下面任意一种：
    Figure PCTCN2020111031-appb-100023
  9. 根据权利要求1所述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，其中，所述化合物的结构式是下面任意一种：
    Figure PCTCN2020111031-appb-100024
  10. 包含至少一种权利要求1-9任一项所述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物的药物组合物。
  11. 根据权利要求10所述的药物组合物，其中，还包含至少一种药学上可接受的载体或稀释剂。
  12. 根据权利要求10或11所述的药物组合物，其中，所述药物组合物的制剂形式包括：口服剂、注射剂、肛塞剂、鼻孔吸入剂、滴眼剂或皮肤贴剂。
  13. 权利要求1-9任一项所述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，或权利要求10-12任一项所述的药物组合物在治疗因KRAS异常活性所引起的疾病中的应用，优选的，所述KRAS为KRAS G12C突变体。
  14. 根据权利要求13所述的应用，其中，所述疾病为肿瘤，所述肿瘤选自实体瘤和液体瘤，优选的，所述肿瘤选自肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、结直肠癌、肛门区癌、胃癌、结肠癌、乳腺癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、阴户癌、何 杰金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、膀胱癌、肾或输尿管癌、肾癌、肾上腺癌、肾细胞癌、肾盂癌、脑胶质瘤、脑干神经胶质瘤、神经内分泌胶质肿瘤、神经胶质瘤、中枢神经中枢系统(CNS)赘生物、脊柱轴肿瘤、垂体腺瘤、胃肠间质肿瘤、结肠直肠癌、非小细胞肺癌、小细胞肺癌、肥大细胞增多症、胶质瘤、肉瘤、淋巴瘤中的一种或任意几种的组合。
  15. 一种治疗因KRAS异常活性所引起的疾病的方法，其特征在于，所述方法包括对需要的受试者通过口服或非口服途径给予有效剂量的权利要求1-9任一项所述的二氢或四氢喹唑啉类化合物、其消旋体、对映异构体、非对映异构体、药学上可接受的盐或溶剂合物，或权利要求10-12任一项所述的药物组合物；优选的，所述KRAS为KRAS G12C突变体。
  16. 根据权利要求15所述的方法，其特征在于，所述疾病为肿瘤，所述肿瘤选自实体瘤和液体瘤，优选的，所述肿瘤选自肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、结直肠癌、肛门区癌、胃癌、结肠癌、乳腺癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、阴户癌、何杰金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、膀胱癌、肾或输尿管癌、肾癌、肾上腺癌、肾细胞癌、肾盂癌、脑胶质瘤、脑干神经胶质瘤、神经内分泌胶质肿瘤、神经胶质瘤、中枢神经中枢系统(CNS)赘生物、脊柱轴肿瘤、垂体腺瘤、胃肠间质肿瘤、结肠直肠癌、非小细胞肺癌、小细胞肺癌、肥大细胞增多症、胶质瘤、肉瘤、淋巴瘤中的一种或任意几种的组合。
  17. 用于合成权利要求1-9任一项所述的二氢或四氢喹唑啉类化合物的中间体化合物，其特征在于，所述中间体化合物的结构式为(IIa)或(IIb)：
    Figure PCTCN2020111031-appb-100025
    式中：
    Ar’为C 6-12芳基或C 5-12杂芳基，且所述Ar’中的一个或多个氢可任选地被相同或不同的G 4取代；
    每一个Z独立地代表相同或者不同的卤素；
    #代表所示碳原子是手性碳原子，可以以R-构型、S-构型或者R-构型和S-构型任意比例的混合形式存在；
    其中：
    G 4选自一个或多个相同或不同的氘、卤素、OH、CN、NO 2、C 1-12烷基、C 2-12烯基、C 2-12炔基、C 3-12环烷基、C 6-12芳基、C 5-12杂芳基、C 3-12杂脂环基、R 55O-、R 66R 77N-、R 55S(＝O) m-、R 66R 77NS(＝O) m-、R 55C(＝O)-、R 66R 77NC(＝O)-或R 55OC(＝O)-，其中所述C 1-12烷基、C 2-12烯基、C 2-12炔基、C 3-12环烷基、C 6-12芳基、C 5-12杂芳基、C 3-12杂脂环基、R 55O-、R 66R 77N-、R 55S(＝O) m-、R 66R 77NS(＝O) m-、R 55C(＝O)-、R 66R 77NC(＝O)-或R 55OC(＝O)-中的一个或多个氢可任选地被相同或不同的氘、卤素、OH、CN、NO 2、OCH 3、OCH 2F、OCHF 2、CH 2F、CHF 2、CF 3、OCF 3或C 1-12烷基取代；
    R 55、R 66和R 77相同或不同，各自独立地选自氢、氘、C 1-12烷基、C 3-12环烷基、C 6-12芳基、C 5-12杂芳基或C 3-12杂脂环基，且R 55、R 66和R 77中的一个或多个氢可任选地被相同或不同的氘、OH、OCH 3、CN、NO 2、CH 2F、CHF 2、CF 3、OCH 2F、OCHF 2、OCF 3或C 1-12烷基取代；当R 66和R 77连接在同一氮原子上时，可通过彼此连接与该氮原子一起形成一个杂脂环，所述杂脂环可任选地包含一个或多个额外的O、N或S(＝O) m杂原子；
    m是如权利要求1所定义的；
    优选的，所述Ar’选自苯基、萘基、咪唑基、噻唑基、恶唑基、呋喃基、噻酚基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、三嗪基、哒嗪基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、吲哚基、吲唑基、氮杂吲哚基、氮杂吲唑基、苯并咪唑基、苯并噻唑基、苯并恶唑基、氮杂苯并咪唑基、氮杂苯并噻唑基、氮杂苯并恶唑基、咪唑并吡嗪基、咪唑并吡啶基、咪唑并哒嗪基、噻唑并吡嗪基、噻唑并吡啶基、噻唑并哒嗪基、恶唑并吡嗪基、恶唑并吡啶基、恶唑并哒嗪基、吡咯并吡嗪基、噻酚并吡啶基或呋喃并哒嗪基。
  18. 用于合成权利要求1-9任一项所述的二氢或四氢喹唑啉类化合物的中间体化合物，其特征在于，所述中间体化合物的结构式为(IIc)：
    Figure PCTCN2020111031-appb-100026
    式中：
    Ar’是如权利要求17所定义的；
    Z 1和Z 2相同或者不同，各自独立地代表卤素、OH、CF 3SO 3、SH、CH 3S、CH 3S(O)或CH 3S(O) 2。
  19. 一种如Scheme A所示的制备权利要求17所述的中间体化合物的方法，其特征在于，包括步骤1至步骤2或步骤1至步骤3，
    Figure PCTCN2020111031-appb-100027
    其中：
    Ar’、#和Z是如权利要求17所定义的；
    W代表C 1-12烷基、C 2-12烯基、C 2-12炔基、C 3-12环烷基、C 6-12芳基、C 5-12杂芳基或C 3-12杂脂环基；优选C 1-12烷基或C 3-12环烷基；更进一步优选甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基或环己基；
    步骤1：式II-1化合物与式II-2化合物反应得到式II-3化合物；
    步骤2：式II-3化合物与式II-4化合物发生缩合反应得到如式IIa所示的中间体化合物；
    步骤3：式IIa中间体化合物与卤化试剂Halogenating Reagent反应得到式IIb中间体化合物；
    优选的，
    步骤1:在铑催化剂Rh catalyst、配体L和碱Base-1的条件下，式II-1化合物与式II-2化合物在溶剂Solvent-1中反应得到式II-3化合物；
    步骤2:在碱Base-1存在的条件下，式II-3化合物与式II-4化合物在溶剂Solvent-1中发生缩合反应得到式IIa中间体化合物；
    更优选的，
    所述铑催化剂Rh catalyst选自二(乙烯)氯化铑(I)二聚体、二乙烯(乙酰基丙酮)铑(I)、(乙酰基丙酮)(1,5-环辛二烯)铑(I)、(乙酰基丙酮)二羰基铑(I)、(乙酰基丙酮)(降冰片)铑(I)、(2,5-降冰片)氯化铑(I)二聚体、二(乙氰)(1,5-环辛二烯)铑(I)四氟硼酸盐或二(降冰片)铑(I)四氟硼酸盐；
    配体L具有如下结构：
    Figure PCTCN2020111031-appb-100028
    其中，W 1选自C 6-12芳基、 C 5-12杂芳基或C 3-12环烷基；W 2选自C 1-12烷基或C 3-12环烷基；所述W 1和W 2中的一个或多个氢可任选地被相同或不同的氘、卤素、甲基、乙基、正丙基、异丙基、环丙基、正丁基、叔丁基、甲氧基、乙氧基、三氟甲氧基、三氟甲基或二甲基氨基取代；
    所述步骤1和步骤2中的任意一个碱Base-1独立地选自K 3PO 4、K 2HPO 4、Na 3PO 4、Na 2HPO 4、Li 2CO 3、Na 2CO 3、NaHCO 3、K 2CO 3、KHCO 3、Cs 2CO 3、CsF、LiOH、NaOH、KOH、CsOH、Ca(OH) 2、Ba(OH) 2、氢化钠、氢化钾、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、LiN(SiMe 3) 2、NaN(SiMe 3) 2或KN(SiMe 3) 2；
    所述步骤1和步骤2中的任意一个溶剂Solvent-1独立地选自乙醚、甲基叔丁基醚、四氢呋喃、甲基四氢呋喃、二恶烷、二氯甲烷、二氯乙烷、甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、水、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、乙酸乙酯或它们两种或多种的混合物；
    所述卤化试剂Halogenating Reagent选自POCl 3、POBr 3、SOCl 2、PCl 3、PCl 5、PBr 3、PPh 3+CCl 4、PPh 3+CBr 4、PPh 3+Cl 2、PPh 3+Br 2、PPh 3+I 2、氰尿酰氯或草酰氯。
  20. 一种如Scheme B所示的制备权利要求18所述的中间体化合物的方法，其特征在于，包括步骤1至步骤4，
    Figure PCTCN2020111031-appb-100029
    其中，Ar’是如权利要求15所定义的，W是如权利要求17所定义的；
    步骤1：式II-10化合物与式II-11化合物反应得到式II-12化合物；
    步骤2：式II-12化合物与式II-13化合物发生缩合反应得到如式II-14化合物；
    步骤3：式II-14化合物与碘甲烷反应得到式II-15化合物；
    步骤4：三氟甲磺酰化式II-10化合物得到式(IIc)所示的中间体化合物；
    优选的，
    步骤1：式II-10化合物与式II-11化合物在碱Base-1存在下反应得到式II-12化合物；
    步骤3：式II-14化合物与碘甲烷在碱Base-1存在下反应得到式II-15化合物；
    所述碱Base-1是如权利要求19所定义的。
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