WO2023169481A1 - Tetrahydroisoquinoline derivative as pan-kras inhibitor, preparation method therefor and use thereof - Google Patents

Tetrahydroisoquinoline derivative as pan-kras inhibitor, preparation method therefor and use thereof Download PDF

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WO2023169481A1
WO2023169481A1 PCT/CN2023/080353 CN2023080353W WO2023169481A1 WO 2023169481 A1 WO2023169481 A1 WO 2023169481A1 CN 2023080353 W CN2023080353 W CN 2023080353W WO 2023169481 A1 WO2023169481 A1 WO 2023169481A1
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alkyl
following group
heteroaryl
aryl
group
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PCT/CN2023/080353
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French (fr)
Chinese (zh)
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魏国平
林毅晖
丁长根
龚兆龙
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思路迪生物医药(上海)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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present application relates to a class of tetrahydroisoquinoline derivatives, their preparation methods, pharmaceutical compositions containing these compounds or salts thereof, and their medical use as pan-KRAS inhibitors in the treatment of different tumors.
  • RAS is the first discovered human tumor gene (Oncogene) and is one of the most common mutated genes in tumors. About 30% of tumors carry RAS mutations. If the regulatory factors of RAS and the upstream and downstream signaling pathways of RAS are combined, Mutations cover almost all tumors.
  • KRAS gene Kerrsten rat sarcoma viral oncogene homolog
  • the protein encoded by the KRAS gene is a GDP/GTP binding protein, a small GTPase enzyme, which belongs to the superprotein family.
  • the KRAS protein has 188 amino acids and a molecular weight of 21.6KD.
  • KRAS binds to GTP in an activated state (KRAS-GTP), and binds to GDP in a closed state (or inactive state) (KRAS-GDP). Subsequently, GTPase activating protein (GAP) can bind GTP on KRAS-GTP Hydrolysis to GDP promotes the formation of KRAS-GDP closed state, thus leaving KRAS in an inactive state.
  • GAP GTPase activating protein
  • KRAS protein is a "switch" between the KRAS-GTP activated state and the KRAS-GDP inactive state (off state).
  • KRAS can activate downstream signaling pathways, including MAPK signaling pathway, PI3K signaling pathway and Ral-GDS signaling. path.
  • the RAS protein switch controls its downstream signaling pathways, thereby promoting cell survival, proliferation and cytokine release, and plays an important role in life processes such as cell proliferation, differentiation and apoptosis.
  • KRAS can also be transiently activated by growth factors (such as EGFR). Activated KRAS can activate downstream signaling pathways such as the PI3K-AKT-mTOR signaling pathway that controls cell production, and the RAS-RAF-MEK-ERK signaling pathway that controls cell proliferation. Mutations KRAS will continue to be activated even without activation of kinases such as EGFR, leading to continued cell proliferation and eventual canceration.
  • KRAS mutations are highly expressed in a variety of tumors, and the most common ones found include lung cancer, intestinal cancer, pancreatic cancer, colon cancer, small intestine cancer, cholangiocarcinoma, etc. Structural studies have shown that most KRAS gene mutations interfere with KRAS's ability to hydrolyze GTP, ultimately causing KRAS to continue to be activated, making it unable to effectively regulate cell signal transduction, thus promoting the occurrence, development and metastasis of tumors.
  • KRAS mutations mutations in amino acid position 12 (G12) account for approximately 80%, while G12C mutations account for approximately 14% of all G12 mutations.
  • researchers have developed a series of covalent inhibitors of KRAS G12C mutations, but the development of KRAS G12D mutation inhibitors has encountered great challenges.
  • pan-KRAS inhibitors that are safe and effective for oral administration.
  • the purpose of the present invention is to provide a pan-KRAS inhibitor that is safe and effective for oral administration, especially an inhibitor for the treatment of tumors such as intestinal cancer, lung cancer, pancreatic cancer, cholangiocarcinoma, and gastric cancer.
  • a first aspect of the present invention provides a compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
  • the carbon atom marked * is a chiral center, and each chiral center can optionally be in R configuration or S configuration;
  • R 1 is selected from the following group:
  • A, B, C and D are each independently selected from the following group: CH, CF, C(OMe), CMe or N;
  • Each R' 1 is independently selected from the group consisting of halogen, OH, OCH 2 CH 2 NR a R b , SH, NH 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 - C 6 alkyl hydroxyl, S (C 1 -C 6 alkyl), allyl, vinyl, aryl (including monocyclic or fused ring aryl), heteroaryl (including monocyclic or fused ring heteroaryl ), COR a , CONH 2 , CONR a R b , NHR a , 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, (C 1 -C 4 alkyl) 3-7-membered heterocyclyl; wherein , when A, B, C or D is CH, each R' 1 can optionally be located on A, B, C or D, and at this time the H atom on A, B, C or D is replaced by
  • R a is selected from the following group: H, C 1 -C 5 alkyl
  • R b is selected from the following group: H, C 1 -C 5 alkyl or C 1 -C 5 haloalkyl;
  • n 0, 1, 2, 3, 4 or 5;
  • R 2 is selected from the following group: halogen, OH, NH 2 , NHR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy , allyl, vinyl, OCD 3 , OR c , 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, (C 1 -C 4 alkyl) 3-7-membered heterocyclyl, SR c , B(OH) 2 , or a heterocycle selected from the following group:
  • R 2 is selected from the following group: OMe, OCD 3 ;
  • R c is C 1 -C 6 alkyl or allyl
  • L is selected from the following group: single bond, O, S, NH, N (C 1 -C 6 alkyl), CH 2 , CF 2 ;
  • Q is selected from the following group: single bond, (CH 2 ) p ; where p is 1, 2, 3 or 4;
  • R 3 is selected from the following group: H,
  • Each R 3 ' can be independently located at any position on the ring, and each R 3' can be independently selected from the following group: halogen, OH, SH, NH 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl hydroxyl, S (C 1 -C 6 alkyl), allyl, vinyl, aryl (including monocyclic or fused ring aryl), heteroaryl (including monocyclic or fused ring Heteroaryl), piperidinyl, morpholinyl; n is 0, 1, 2 or 3;
  • X is selected from the following group: O, N, NH, S, CH, CH 2 , CF 2 , CFH, NR a ;
  • Y is selected from the following group: NH, CH, CO, CH 2 , CF 2 , CR a , OR a , S (C 1 -C 6 alkyl), C (NR a R b ), C (aryl), C (Heteroaryl), C (3-8 membered cycloalkyl), C (3-8 membered heterocyclyl);
  • Z, E and F are each independently selected from the following group: O, N, NH, S, CH, CH 2 , CF 2 , CFH, NR a ;
  • R 4 is selected from the following group: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylhydroxy, C 1 -C 6 alkoxy, C 2 -C 6 acyl, allyl Base, cycloalkyl, heterocyclyl, propargyl, C(O)NH 2 , CH 2 (aryl), CH 2 (heteroaryl), C(O)NH (C 1 -C 6 alkyl) , C(O)NH(aryl), C(O)NH(heteroaryl), C(O)NHCH 2 (aryl), C(O)NHCH 2 (heteroaryl), C(S)NH 2.
  • R 5 is selected from the following group: H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, cycloalkyl; preferably, R 5 is selected from the following group: Methyl, fluoromethyl, ethyl, fluoroethyl, deuterated methyl, isopropyl, cyclopropyl;
  • R 6 or R 7 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 deuterated alkyl, C 1 -C 6 deuterated alkoxy, C 2 -C 6 alkenyl, CH 2 O (C 1 -C 5 alkyl);
  • R 3 is selected from the following group:
  • the aryl group is a C 6 -C 14 aryl group
  • the heterocyclic group is a 3-12-membered heterocyclic group
  • the heteroaryl group is a 5-14-membered heteroaryl group (for example, 5- 6-membered heteroaryl or benzo 5-6 membered heteroaryl)
  • cycloalkyl is C 3 -C 12 cycloalkyl group (such as C 3 -C 6 cycloalkyl or C 3 -C 8 cycloalkyl)
  • the heterocyclic group or heteroaryl group includes 1-3 heteroatoms selected from the following group: N, S, O, P or B; and unless otherwise specified, the vinyl, allyl, propargyl, aryl, heteroaryl, cycloalkyl and heterocyclic groups may optionally have 1-3 selected from Substituents of the following group: halogen, deuterium atom, C 1 -C 6 alkyl;
  • the heterocyclyl group includes saturated or partially unsaturated aza, oxa or sulfur heterocycle
  • L is selected from the following group: O, S, NH, CF 2 ;
  • Q is selected from the following group: (CH 2 ) p ; wherein p is 1, 2 or 3.
  • R 4 is selected from the following group: C(O)NH (C 1 -C 6 alkyl), C(O)NH (aryl), C(O)NH (heteroaryl), C(O)NHCH 2 (aryl), C(O)NHCH 2 (heteroaryl), C(S)NH 2 , C(S)NH(C 1 -C 6 alkyl), C(S)NH (aryl), C(S)NH (heteroaryl), C(S)NHCH 2 (aryl), C(S)NHCH 2 (heteroaryl).
  • R 2 is selected from the following group: C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OCD 3 ,
  • R 5 is selected from the following group: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, cycloalkyl; preferably, R 5 is selected from the following group: methyl , fluoromethyl, ethyl, fluoroethyl, deuterated methyl, isopropyl, cyclopropyl;
  • R 6 or R 7 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1 -C 6 alkyl.
  • R 1 is selected from the following group:
  • R 3 is selected from the following group:
  • each R 3 ' is independently selected from the following group: halogen, OH, SH, NH 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl hydroxyl, S (C 1 -C 6 alkyl), allyl, vinyl, aryl (including monocyclic or fused ring aryl), heteroaryl (including monocyclic or fused ring heteroaryl), piperidyl, methyl phenylinyl;
  • X is selected from the following group: O, N, NH, S, CH, CH 2 , CF 2 , CFH, NR a ;
  • Y is selected from the following group: NH, CH, CO, CH 2 , CF 2 , CR a , OR a , S (C 1 -C 6 alkyl), C (NR a R b ), C (aryl), C (Heteroaryl), C (3-8 membered cycloalkyl), C (3-8 membered heterocyclyl);
  • Z is selected from the following group: O, N, NH, S, CH, CH 2 , CF 2 , CFH, NR a ;
  • E and F are each independently selected from the group consisting of: O, N, NH, or S.
  • R 3 is selected from the following group:
  • one of the X and Z is selected from the following group: O, S, NH, CH 2 ; and the other is selected from the following group: CH, N;
  • Y is selected from the following group: NH, CH, CO, CH 2 , CF 2 , CR a , OR a , S (C 1 -C 6 alkyl), C (NR a R b ), C (aryl), C (Heteroaryl), or a group selected from the following group:
  • the compound of formula I has a structure represented by the following formula (II), (III), (IV) or (IV-A):
  • R 2 is selected from the following group: halogen, OH, NH 2 , NHR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, allyl, vinyl, OCD 3 , OR c , 3-7 yuan Cycloalkyl, 3-7 membered heterocyclyl, (C 1 -C 4 alkyl) 3-7 membered heterocyclyl, SR c ; preferably, R 2 is selected from the following group: OMe, OCD 3 .
  • the compound of formula I has a structure represented by the following formula (II-A), (V), (VI) or (VI-A):
  • each R 3 ' is independently selected from the following group: halogen, OH, SH, NH 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl hydroxyl, S (C 1 -C 6 alkyl), allyl, vinyl.
  • the compound of formula I is selected from the following group:
  • the compound of formula I is selected from the following group:
  • the compound of formula I is selected from the following group:
  • a second aspect of the present invention provides the use of a compound as described in the first aspect of the present invention for the preparation of a medicament for treating diseases related to the activity or expression level of KRAS mutants.
  • the disease related to KRAS mutant activity or expression is a tumor, preferably a tumor selected from the following group: sarcoma, myxoma, rhabdomyomas, fibromas, lipomas, and teratomas.
  • tumour bronchial cancer, lung cancer, bronchial adenoma, lymphoma, enchondromatous hamartoma, mesothelioma, esophageal cancer, gastric cancer, pancreatic cancer, small intestine cancer, colorectal cancer, genitourinary tract tumors, kidney cancer, bladder cancer, urethra Cancer, prostate, testicular cancer, liver cancer, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary cancer, cholangiocarcinoma, bone cancer, brain cancer, uterine cancer, vaginal cancer, Hematoma, skin cancer, breast cancer.
  • the third aspect of the present invention provides a pharmaceutical composition, said pharmaceutical composition comprising: (i) a therapeutically effective amount of the compound of formula I as described in the first aspect of the present invention, or a pharmaceutically acceptable amount thereof a salt; and (ii) a pharmaceutically acceptable carrier.
  • the effective amount refers to a therapeutically effective amount or an inhibitory effective amount, preferably 0.01 to 99.99%.
  • the pharmaceutical composition is used to treat diseases related to KRAS mutant activity or expression.
  • the KRAS mutant is a KRAS G12D mutant, a KRAS G12V mutant, a KRAS G12S mutant or a KRAS G13D mutant.
  • C 1 -C 6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, or similar groups, Expressions such as “C 1 -C 3 alkyl” have similar definitions.
  • C 1 -C 6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, or the like.
  • Group, "C 1 -C 3 alkoxy” and other expressions have similar definitions.
  • the terms “comprises”, “comprises” or “includes” indicate that various ingredients can be used together in the mixture or composition of the present invention. Therefore, the terms “consisting essentially of” and “consisting of” are included in the term “comprising”.
  • the term "pharmaceutically acceptable” ingredients refers to substances that are suitable for humans and/or animals without excessive adverse side effects (such as toxicity, irritation and allergic reactions), that is, with a reasonable benefit/risk ratio.
  • the term "effective amount" refers to an amount of a therapeutic agent that treats, alleviates, or prevents a target disease or condition, or that exhibits a detectable therapeutic or preventive effect.
  • the precise effective amount for a given subject will depend on the size and health of the subject, the nature and extent of the condition, and the therapeutic agent and/or combination of therapeutic agents chosen to be administered. Therefore, it is useless to pre-specify the exact effective amount. However, routine experimentation can be used to determine the effective amount for a given condition and the clinician will be able to judge this.
  • substituted means that one or more hydrogen atoms on a group are replaced with a substituent selected from the group consisting of: halogen, unsubstituted or halogenated C 1 -C 6 alkyl , unsubstituted or halogenated C 2 -C 6 acyl, unsubstituted or halogenated C 1 -C 6 alkyl-hydroxy.
  • each chiral carbon atom may optionally be in R configuration or S configuration, or a mixture of R configuration and S configuration.
  • cycloalkyl includes saturated and partially unsaturated cycloalkyl groups having 3 to 12 carbons, such as 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl group optionally additionally replaced by one or more.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • cycloalkyl also includes bridged cycloalkyl groups, such as bicyclo[1.1.1]pentyl.
  • aryl group is a C6-C14 aromatic moiety containing one to three aromatic rings.
  • the aryl group is a C6-C10 aryl group.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.
  • Aryl also refers to a bicyclic or tricyclic ring system, wherein one or both rings of the aryl ring system, respectively, may be saturated or partially saturated, and wherein if the ring system includes two saturated rings, then The saturated ring may be fused or spiro, but its attachment position to the rest of the compound is on the aryl moiety.
  • a “heterocyclyl” or “heterocycle” group is a ring structure having 3 to 12 atoms, such as 4 to 8 atoms, in which one or more atoms are selected from the group consisting of N, O and S, wherein ring N atoms can be oxidized to NO, and the ring S atoms can be oxidized to SO or SO2 , the remaining ring atoms are carbon.
  • Heterocyclyl can be monocyclic, bicyclic, spirocyclic or bridged ring system.
  • heteroaryl refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9 or 10 ring atoms; and in addition to carbon atoms, each ring has one to three selected from N, O and Heteroatom of S, “heteroaryl” also refers to a bicyclic system with one to three heteroatoms selected from N, O and S in each ring in addition to carbon atoms, one of the ring systems may be saturated or partially saturated of.
  • halogen refers to F, Cl, Br and I.
  • the term "compound of the invention” refers to a compound of Formula I.
  • the term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
  • salts refers to salts of compounds of the invention with acids or bases suitable for use as pharmaceuticals.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • One preferred class of salts are the salts of the compounds of the invention with acids.
  • Acids suitable for forming salts include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid and other organic acids; as well as aspartic acid, glutamic acid and other acidic amino acids.
  • Step b
  • Step b
  • the reactant was washed three times with 2.0 molar NaOH aqueous solution (80 ml x 3) and sodium bisulfite aqueous solution (80 ml x 2).
  • Step f
  • Step g
  • Example 3 was prepared in a manner similar to Example 7. Using 2-(benzo[d]oxazol-5-yl)ethan-1- ol (30 mg) and Preparation 1 (69 mg) gave Example 3 (33.12 mg) as a white solid.
  • Step b
  • 6-Bromobenzothiophene 5-1 (1.10 g, 5.2 mmol) was added to dioxane (30 ml) and water (6 ml), followed by (E)-1-ethoxyethylene group -2-Pinacol borate (1.5 g, 7.7 mmol), 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (190 mg, 0.26 mmol), potassium carbonate (2.10 g, 15.2 millimole), then the mixture was replaced with argon three times, the system was heated to 80°C, and the reaction was carried out at 80°C for 3 hours under argon protection.
  • Step b
  • Step b
  • n-Butyllithium (7.31 mL, 11.7 mmol, 1.6 M/hexane) was slowly added to tetrahydrofuran (5 mL) and 1,4-dibromo-2(2bromoethoxy)benzene under nitrogen protection at -70°C. 6-2 (4.20 g, 11.7 mmol). After the dropping was completed, the reaction solution was stirred at -70°C for 1 hour, and then 5 ml of acetic acid was added to quench the reaction. Add 50 ml of water to dilute the reaction solution, and extract with ethyl acetate (50 ml x 2 times).
  • 6-Bromo-2,3-dihydrobenzofuran 6-3 (1.15 g, 5.84 mmol), (E)-1-ethoxyvinyl-2-boronic acid That ester (1.73 g, 8.76 mmol), potassium carbonate (2.42 g, 17.5 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (427 mg, 0.58 mmol)
  • Add to a mixture of 20 ml of dioxane and 5 ml of water replace the reaction system with argon three times, then raise the temperature to 80°C, and stir at this temperature for 2 hours.
  • Step f
  • Example 6 was prepared in a manner similar to Example 5. Using 6-6 (43.9 mg, 0.27 mmol) and Preparation 1 (100 mg) gave Example 6 (24.37 mg) as a white solid.
  • Step b
  • Step b
  • Example 8 (27.4 mg) was obtained as a white solid.
  • Example 9 was prepared in a manner similar to Example 8. The raw material 2-(benzo[d-]thiazol-6-)yl)ethanol-1 (200 mg, 1.116 mmol) was reacted with Preparation Example 1 (349 mg, 0.931 mmol) to obtain white solid Example 9 (151.26 mg).
  • Step b
  • Example 11 The preparation of Example 11 was obtained by a method similar to that of Example 10. Use 2-(benzo[d-]pyrazol-6-)yl)ethanol-1 (100 mg, 0.381 mmol) and Preparation Example 1 (142 mg, 0.379 mmol) to obtain a white solid intermediate (30 mg ).
  • Example 11 (6.67 mg) as a white solid.
  • Example 12 was prepared in a manner similar to Example 2. Using 2-(3,3-difluoro-2,3-dihydro-1H-inden-5-yl-5-yl)ethane-1-ethan-1-ol (53.0 mg) and Preparation Example 1 ( 100 mg) to give Example 12 (35.25 mg) as a white solid.
  • Example 13 was prepared in a manner similar to Example 6. The raw material 5-(2-hydroxyethyl)-2,3-dihydrobenzofuran (130 mg, 0.79 mmol) was reacted with Preparation Example 1 (296 mg) to obtain Example 13 (51.66 mg) as a white solid.
  • Example 14 The preparation of Example 14 was obtained by a method similar to that of Example 8. Using 2-(benzo[d][1,3]dioxol-5-yl]ethane-1-ethan-1-1-ol (300 mg, 1.81 mmol) and Preparation 1 (564 mg , 1.51 mmol) reacted to obtain white solid Example 14 (206.5 mg).
  • reaction solution was concentrated under reduced pressure, ice water (80 ml) was added, and extracted with ethyl acetate (60 ml ⁇ 2). The organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 15-2 (780 mg, yellow oil).
  • Step b
  • Example 15 was prepared in a manner similar to Example 8. Use 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-ylethan-1-ethan-1-ol (200 m mg, 1.11 mmol) 15-2 and Preparation Example 1 (349 mg, 0.93 mmol Er) reaction gave off-white solid Example 15 (100 mg).
  • Example 16 was prepared in a manner similar to Example 5. Starting from 2-(benzo[b]thiophen-5-yl]ethan-1-ol (200 mg, 1.12 mmol) and Preparation 1 (350 mg), Example 16 (62.55 mg) was obtained as a white solid.
  • Example 17 was prepared in a manner similar to Example 16. 2-(Benzofuran-5-yl)ethane-1-1-ol (150 mg, 0.926 mmol) was reacted with Preparation Example 1 (346 mg, 0.926 mmol) to obtain Example 17 (9.27 mg) as a white solid.
  • Step b
  • Step b
  • TFA solution (30 ml) was added dropwise to 4-(2-aminoethyl)-2-methoxyphenol 19-6 (2.5 g, 14.97 mmol) and 2,4-di Methyl benzaldehyde 19-7 (2.5 ml, 17.96 mmol) mixture.
  • the reaction solution was stirred at 100°C for 24 hours. After the reaction is completed, add an appropriate amount of water to quench, and then add ammonia solution to adjust the pH value of the mixed solution to 10.
  • the mixture was extracted three times with ethyl acetate (150ml*3), and the organic phases were combined.
  • Step f
  • Step g
  • LiAlH4 (4 mg, 0.09 mmol, 1 eq) was added to the tetrahydrofuran solution mixture of Example 19 (60 mg, 0.09 mmol, 1.0 eq) under nitrogen protection at 0°C. The mixture was stirred at 0°C for 1 hour. After the reaction was completed, the reaction mixture of LiAlH4 was quenched with water (0.5 ml), 15% sodium hydroxide solution (0.5 ml), and water (1 ml) under cooling at 0°C. After stirring for 30 minutes, the reaction mixture was stirred with ethyl acetate (3 ⁇ 10 ml) extraction.
  • Example 20 (3.35 mg) as a yellow solid.
  • PANC-1 G12D
  • H358 G12C
  • A549 G12S
  • HCT116 G13D
  • DMEM fetal calf serum
  • F12K McCoy's 5A
  • RPMI-1640 RPMI-1640
  • EMEM medium Gibco, ThermoFisher
  • the results of the proliferation inhibitory activity (IC50, ⁇ M) of the test compounds on 6 commercial tumor cell lines (PANC-1, H358, A549 and HCT116) are shown in Table 2 below.
  • This experiment uses the homogeneous time-resolved fluorescence (HTRF) method to detect the inhibitory activity of small molecule compounds on the interaction between the KRAS protein and the downstream RAF1 protein in the GTP-activated state.
  • the working concentration is optimized to ensure maximum signal generation.
  • Use DMSO solution to perform gradient dilutions of the compounds to be tested to obtain a series of compound action concentrations, and control the final concentration of DMSO to be 0.5%.
  • GTP-KRAS protein Add 4 ⁇ L of GTP-KRAS protein, 4 ⁇ L of RAF1 protein, and 2 ⁇ L of compound working solution to a 384-well white shallow-well plate (PerkinElmer). Appropriate controls (no compound wells and positive compound wells) are also included in the 384-well plate.
  • GTP-KRAS protein, RAF1 protein and compounds were pre-incubated in a 384-well plate for 15 minutes, and then 10 ⁇ L Anti-Tag1-Eu 3+ and Anti-Tag2-XL665 labeled antibody mixture diluted in HTRF detection buffer was added to start the reaction.
  • the plate was sealed and incubated at 4°C in the dark for 2 hours, and the TR-FRET signal value was measured using an EnVision microplate reader (PerkinElmer) (excitation wavelength: 320 nm, emission wavelength: 615 nm and 665nm).
  • RLU (665nm signal/615nm signal) x 10 4 ;
  • the compound % inhibition rate is calculated by calculating the signals of the set 0% inhibition rate hole and 100% inhibition rate hole, which are the maximum signal reaction hole (no compound hole, DMSO control well) and minimum signal reaction well (no KRAS protein well).

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Abstract

The present invention provides a tetrahydroisoquinoline derivative as a pan-KRAS inhibitor. Specifically, the present invention provides a tetrahydroisoquinoline derivative having a structural formula as shown in general formula (I) and a pharmaceutically acceptable salt thereof which have pan-KRAS inhibitory activity. The present invention also provides a preparation method for the derivative, a pharmaceutical composition thereof, a salt-forming compound thereof, and a use thereof in treating different types of tumors as a pan-KRAS inhibitor.

Description

一类作为泛-KRAS抑制剂的四氢异喹啉类衍生物及其制备方法和应用A class of tetrahydroisoquinoline derivatives as pan-KRAS inhibitors and their preparation methods and applications 技术领域Technical field
本申请涉及一类四氢异喹啉衍生物，其制备方法，含有这些化合物的药物组合物或其盐以及作为泛-KRAS抑制剂在治疗不同肿瘤中的医学用途。The present application relates to a class of tetrahydroisoquinoline derivatives, their preparation methods, pharmaceutical compositions containing these compounds or salts thereof, and their medical use as pan-KRAS inhibitors in the treatment of different tumors.
背景技术Background technique
RAS是首个被发现的人类肿瘤基因(Oncogene)，是肿瘤中最常见的突变基因之一，在约30％的肿瘤中均携带有RAS突变，如果结合RAS的调控因子和信号通路的上下游突变，则几乎覆盖所有肿瘤。KRAS基因(Kirsten rat sarcoma viral oncogene homolog)是RAS基因家族中的重要成员。KRAS基因编码的蛋白是GDP/GTP结合蛋白，是一种小GTPase酶，它属于超蛋白家族。KRAS蛋白有188个氨基酸，其分子量为21.6KD，其定位于细胞膜内侧，通过法尼酰基(Farnesyl)的修饰基因连接到细胞膜上。KRAS与GTP结合呈激活状态(KRAS-GTP)，与GDP结合呈关闭状态(或非活状态)(KRAS-GDP)，随后，GTP酶激活蛋白(GAP)可以将结合在KRAS-GTP上的GTP水解为GDP，促使KRAS-GDP关闭状态的形成，从而使KRAS处在失活态。KRAS蛋白是处在KRAS-GTP激活状态和KRAS-GDP非活状态(关闭状态)之间的“开关”，在激活状态可激活下游信号通路其中包括MAPK信号通路，PI3K信号通路和Ral-GDS信号通路。RAS蛋白开关控制着其下游信号通路，从而促进细胞生存，增殖和细胞因子释放，在细胞增殖，分化和凋亡等生命过程中发挥着重要作用。KRAS也可被生长因子(如EGFR)短暂激活，活化后的KRAS可激活下游如控制细胞生成的PI3K-AKT-mTOR信号通路，以及控制细胞增殖的RAS-RAF-MEK-ERK信号通路，而突变的KRAS即使没有EGFR等激酶激活的情况下却会发生持续活化，导致细胞持续增值，最终发生癌变。RAS is the first discovered human tumor gene (Oncogene) and is one of the most common mutated genes in tumors. About 30% of tumors carry RAS mutations. If the regulatory factors of RAS and the upstream and downstream signaling pathways of RAS are combined, Mutations cover almost all tumors. KRAS gene (Kirsten rat sarcoma viral oncogene homolog) is an important member of the RAS gene family. The protein encoded by the KRAS gene is a GDP/GTP binding protein, a small GTPase enzyme, which belongs to the superprotein family. The KRAS protein has 188 amino acids and a molecular weight of 21.6KD. It is located on the inside of the cell membrane and is connected to the cell membrane through a Farnesyl modified gene. KRAS binds to GTP in an activated state (KRAS-GTP), and binds to GDP in a closed state (or inactive state) (KRAS-GDP). Subsequently, GTPase activating protein (GAP) can bind GTP on KRAS-GTP Hydrolysis to GDP promotes the formation of KRAS-GDP closed state, thus leaving KRAS in an inactive state. KRAS protein is a "switch" between the KRAS-GTP activated state and the KRAS-GDP inactive state (off state). In the activated state, it can activate downstream signaling pathways, including MAPK signaling pathway, PI3K signaling pathway and Ral-GDS signaling. path. The RAS protein switch controls its downstream signaling pathways, thereby promoting cell survival, proliferation and cytokine release, and plays an important role in life processes such as cell proliferation, differentiation and apoptosis. KRAS can also be transiently activated by growth factors (such as EGFR). Activated KRAS can activate downstream signaling pathways such as the PI3K-AKT-mTOR signaling pathway that controls cell production, and the RAS-RAF-MEK-ERK signaling pathway that controls cell proliferation. Mutations KRAS will continue to be activated even without activation of kinases such as EGFR, leading to continued cell proliferation and eventual canceration.
KRAS突变在多种肿瘤中高表达，被发现到最常见的包括肺癌，肠癌，胰腺癌、结肠癌、小肠癌、胆管癌等。结构学研究表明，KRAS的基因突变大多干扰了KRAS水解GTP的能力，最终使KRAS持续激活，使之无法有效调控细胞信号转导，从而促进肿瘤的发生、发展以及转移。KRAS mutations are highly expressed in a variety of tumors, and the most common ones found include lung cancer, intestinal cancer, pancreatic cancer, colon cancer, small intestine cancer, cholangiocarcinoma, etc. Structural studies have shown that most KRAS gene mutations interfere with KRAS's ability to hydrolyze GTP, ultimately causing KRAS to continue to be activated, making it unable to effectively regulate cell signal transduction, thus promoting the occurrence, development and metastasis of tumors.
对于KRAS突变，12位氨基酸(G12)的突变约占80％，而G12C突变大约占G12全部突变的14％。近几年来，研究人员相继开发了一系列KRAS G12C突变共价抑制剂，但开发KRAS G12D突变抑制剂遇到了极大的挑战。For KRAS mutations, mutations in amino acid position 12 (G12) account for approximately 80%, while G12C mutations account for approximately 14% of all G12 mutations. In recent years, researchers have developed a series of covalent inhibitors of KRAS G12C mutations, but the development of KRAS G12D mutation inhibitors has encountered great challenges.
目前还没有开发出共价结合在天冬氨酸的方法。直接抑制KRAS G12D突变体难点不仅在于KRAS编码的蛋白表面光滑，缺少结合位点，且KRAS与GTP/GDP的结合力非常强，胞内GTP/GDP的浓度也很高，导致无法开发对GTP竞争性抑制剂。不仅KRAS膜定位受法尼基转移酶等调节，而且靶向KRAS下游信号分子(效应蛋白)，抑制生长所需的野生型信号通路的治疗窗口狭小，更由于补偿机制使无法完全而有效地抑 制KRAS突变体下游信号，从而使开发效应蛋白的激酶抑制剂对KRAS突变的疗效受到极大限制。No method of covalently binding aspartic acid has yet been developed. The difficulty in directly inhibiting the KRAS G12D mutant is not only that the protein encoded by KRAS has a smooth surface and lacks binding sites, but also the binding force between KRAS and GTP/GDP is very strong, and the concentration of intracellular GTP/GDP is also very high, making it impossible to develop competition for GTP. Sex inhibitors. Not only is KRAS membrane localization regulated by farnesyl transferase, but also targeting KRAS downstream signaling molecules (effector proteins). The therapeutic window for the wild-type signaling pathway required to inhibit growth is narrow, and due to the compensation mechanism, it cannot be completely and effectively inhibited. The downstream signaling of KRAS mutants is inhibited, thereby greatly limiting the efficacy of developing kinase inhibitors of effector proteins against KRAS mutations.
综上所述，对于开发具有口服安全有效性的泛-KRAS抑制剂仍然有很大的未能满足的临床需求。Taken together, there is still a large unmet clinical need for the development of pan-KRAS inhibitors that are safe and effective for oral administration.
发明内容Contents of the invention
本发明的目的是提供一种具有口服安全有效性的泛-KRAS抑制剂，特别是用于治疗肠癌、肺癌、胰腺癌、胆管癌、胃癌等肿瘤的治疗的抑制剂。The purpose of the present invention is to provide a pan-KRAS inhibitor that is safe and effective for oral administration, especially an inhibitor for the treatment of tumors such as intestinal cancer, lung cancer, pancreatic cancer, cholangiocarcinoma, and gastric cancer.
本发明的第一方面，提供了一种如下式(I)所示的化合物，或其药学上可接受的盐，或其立体异构体，
A first aspect of the present invention provides a compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
其中，*标记的碳原子为手性中心，且各个手性中心可任选地为R构型或S构型；Among them, the carbon atom marked * is a chiral center, and each chiral center can optionally be in R configuration or S configuration;
R1选自下组：
R 1 is selected from the following group:
式中，A、B、C和D各自独立地选自下组：CH、CF、C(OMe)、CMe或N；In the formula, A, B, C and D are each independently selected from the following group: CH, CF, C(OMe), CMe or N;
各个R'1各自独立地选自下组：卤素、OH、OCH2CH2NRaRb、SH、NH2、C1-C6烷基、C3-C8环烷基、C1-C6烷基羟基、S(C1-C6烷基)、烯丙基、乙烯基、芳基(包括单环或稠环芳基)、杂芳基(包括单环或稠环杂芳基)、CORa、CONH2、CONRaRb、NHRa、3-7元环烷基、3-7元杂环基、(C1-C4烷基)3-7元杂环基；其中，当A、B、C或D为CH时，各个R'1可任选地位于A、B、C或D上，且此时A、B、C或D上的H原子被R'1取代；Each R' 1 is independently selected from the group consisting of halogen, OH, OCH 2 CH 2 NR a R b , SH, NH 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 - C 6 alkyl hydroxyl, S (C 1 -C 6 alkyl), allyl, vinyl, aryl (including monocyclic or fused ring aryl), heteroaryl (including monocyclic or fused ring heteroaryl ), COR a , CONH 2 , CONR a R b , NHR a , 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, (C 1 -C 4 alkyl) 3-7-membered heterocyclyl; wherein , when A, B, C or D is CH, each R' 1 can optionally be located on A, B, C or D, and at this time the H atom on A, B, C or D is replaced by R'1;
Ra选自下组：H、C1-C5烷基；R a is selected from the following group: H, C 1 -C 5 alkyl;
Rb选自下组：H、C1-C5烷基或C1-C5卤代烷基；R b is selected from the following group: H, C 1 -C 5 alkyl or C 1 -C 5 haloalkyl;
m为0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;
R2选自下组：卤素、OH、NH2、NHRa、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、烯丙基、乙烯基、OCD3、ORc、3-7元环烷基、3-7元杂环基、(C1-C4烷基)3-7元杂环基、SRc、B(OH)2、或选自下组的杂环： 较佳地，R2选自下组：OMe、OCD3；R 2 is selected from the following group: halogen, OH, NH 2 , NHR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy , allyl, vinyl, OCD 3 , OR c , 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, (C 1 -C 4 alkyl) 3-7-membered heterocyclyl, SR c , B(OH) 2 , or a heterocycle selected from the following group: Preferably, R 2 is selected from the following group: OMe, OCD 3 ;
Rc为C1-C6烷基或烯丙基；R c is C 1 -C 6 alkyl or allyl;
L选自下组：单键、O、S、NH、N(C1-C6烷基)、CH2、CF2；L is selected from the following group: single bond, O, S, NH, N (C 1 -C 6 alkyl), CH 2 , CF 2 ;
Q选自下组：单键、(CH2)p；其中，p为1、2、3或4；Q is selected from the following group: single bond, (CH 2 ) p ; where p is 1, 2, 3 or 4;
R3选自下组：H、 R 3 is selected from the following group: H,
各个R3'可各自独立地位于环上的任意位置，且各自独立地选自下组：卤素、OH、SH、NH2、C1-C6烷基、C3-C8环烷基、C1-C6烷基羟基、S(C1-C6烷基)、烯丙基、乙烯基、芳基(包括单环或稠环芳基)、杂芳基(包括单环或稠环杂芳基)、哌啶基、吗啉基；n为0、1、2或3；Each R 3 ' can be independently located at any position on the ring, and each R 3' can be independently selected from the following group: halogen, OH, SH, NH 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl hydroxyl, S (C 1 -C 6 alkyl), allyl, vinyl, aryl (including monocyclic or fused ring aryl), heteroaryl (including monocyclic or fused ring Heteroaryl), piperidinyl, morpholinyl; n is 0, 1, 2 or 3;
X选自下组：O、N、NH、S、CH、CH2、CF2、CFH、NRa；X is selected from the following group: O, N, NH, S, CH, CH 2 , CF 2 , CFH, NR a ;
Y选自下组：NH、CH、CO、CH2、CF2、CRa、ORa、S(C1-C6烷基)、C(NRaRb)、C(芳基)、C(杂芳基)、C(3-8元环烷基)、C(3-8元杂环基)；Y is selected from the following group: NH, CH, CO, CH 2 , CF 2 , CR a , OR a , S (C 1 -C 6 alkyl), C (NR a R b ), C (aryl), C (Heteroaryl), C (3-8 membered cycloalkyl), C (3-8 membered heterocyclyl);
Z、E和F各自独立地选自下组：O、N、NH、S、CH、CH2、CF2、CFH、NRa；Z, E and F are each independently selected from the following group: O, N, NH, S, CH, CH 2 , CF 2 , CFH, NR a ;
R4选自下组：C1-C6烷基、C1-C6卤代烷基、C1-C6烷基羟基、C1-C6烷氧基、C2-C6酰基、烯丙基、环烷基、杂环基、炔丙基、C(O)NH2、CH2(芳基)、CH2(杂芳基)、C(O)NH(C1-C6烷基)、C(O)NH(芳基)、C(O)NH(杂芳基)、C(O)NHCH2(芳基)、C(O)NHCH2(杂芳基)、C(S)NH2、C(S)NH(C1-C6烷基)、C(S)NH(芳基)、C(S)NH(杂芳基)、C(S)NHCH2(芳基)、C(S)NHCH2(杂芳基)、芳基，杂芳基；R 4 is selected from the following group: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylhydroxy, C 1 -C 6 alkoxy, C 2 -C 6 acyl, allyl Base, cycloalkyl, heterocyclyl, propargyl, C(O)NH 2 , CH 2 (aryl), CH 2 (heteroaryl), C(O)NH (C 1 -C 6 alkyl) , C(O)NH(aryl), C(O)NH(heteroaryl), C(O)NHCH 2 (aryl), C(O)NHCH 2 (heteroaryl), C(S)NH 2. C(S)NH(C 1 -C 6 alkyl), C(S)NH(aryl), C(S)NH(heteroaryl), C(S)NHCH 2 (aryl), C (S)NHCH 2 (heteroaryl), aryl, heteroaryl;
R5选自下组：H、C1-C6烷基、C1-C6卤代烷基、C1-C6氘代烷基、环烷基；较佳地，R5选自下组：甲基、氟代甲基、乙基、氟代乙基、氘代甲基、异丙基、环丙基；R 5 is selected from the following group: H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, cycloalkyl; preferably, R 5 is selected from the following group: Methyl, fluoromethyl, ethyl, fluoroethyl, deuterated methyl, isopropyl, cyclopropyl;
R6或R7各自独立地选自下组：氢、氘、卤素、CN、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基，C1-C6氘代烷基、C1-C6氘代烷氧基、C2-C6烯基、CH2O(C1-C5烷基)；R 6 or R 7 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 deuterated alkyl, C 1 -C 6 deuterated alkoxy, C 2 -C 6 alkenyl, CH 2 O (C 1 -C 5 alkyl);
且当R5为H时，R3选自下组： And when R 5 is H, R 3 is selected from the following group:
上述各式中，除非特别说明，所述的芳基为C6-C14芳基、杂环基为3-12元杂环基、杂芳基为5-14元杂芳基(例如5-6元杂芳基或苯并5-6元杂芳基)、环烷基为C3-C12环烷 基(例如C3-C6环烷基或C3-C8环烷基)；所述的杂环基或杂芳基中包括1-3个选自下组的杂原子：N、S、O、P或B；且除非特别说明，所述的乙烯基、烯丙基、炔丙基、芳基、杂芳基、环烷基和杂环基可任选地具有1-3个选自下组的取代基：卤素、氘原子、C1-C6烷基；In the above formulas, unless otherwise specified, the aryl group is a C 6 -C 14 aryl group, the heterocyclic group is a 3-12-membered heterocyclic group, and the heteroaryl group is a 5-14-membered heteroaryl group (for example, 5- 6-membered heteroaryl or benzo 5-6 membered heteroaryl), cycloalkyl is C 3 -C 12 cycloalkyl group (such as C 3 -C 6 cycloalkyl or C 3 -C 8 cycloalkyl); the heterocyclic group or heteroaryl group includes 1-3 heteroatoms selected from the following group: N, S, O, P or B; and unless otherwise specified, the vinyl, allyl, propargyl, aryl, heteroaryl, cycloalkyl and heterocyclic groups may optionally have 1-3 selected from Substituents of the following group: halogen, deuterium atom, C 1 -C 6 alkyl;
所述的杂环基包括饱和或部分不饱和的氮杂、氧杂或硫杂环；The heterocyclyl group includes saturated or partially unsaturated aza, oxa or sulfur heterocycle;
为单键或双键。 be a single bond or a double bond.
在另一优选例中，L选自下组：O、S、NH、CF2；Q选自下组：(CH2)p；其中，p为1、2或3。In another preferred example, L is selected from the following group: O, S, NH, CF 2 ; Q is selected from the following group: (CH 2 ) p ; wherein p is 1, 2 or 3.
在另一优选例中，R4选自下组：C(O)NH(C1-C6烷基)、C(O)NH(芳基)、C(O)NH(杂芳基)、C(O)NHCH2(芳基)、C(O)NHCH2(杂芳基)、C(S)NH2、C(S)NH(C1-C6烷基)、C(S)NH(芳基)、C(S)NH(杂芳基)、C(S)NHCH2(芳基)、C(S)NHCH2(杂芳基)。In another preferred embodiment, R 4 is selected from the following group: C(O)NH (C 1 -C 6 alkyl), C(O)NH (aryl), C(O)NH (heteroaryl), C(O)NHCH 2 (aryl), C(O)NHCH 2 (heteroaryl), C(S)NH 2 , C(S)NH(C 1 -C 6 alkyl), C(S)NH (aryl), C(S)NH (heteroaryl), C(S)NHCH 2 (aryl), C(S)NHCH 2 (heteroaryl).
在另一优选例中，R2选自下组：C1-C6烷氧基、C1-C6卤代烷氧基、OCD3、 In another preferred embodiment, R 2 is selected from the following group: C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OCD 3 ,
R5选自下组：C1-C6烷基、C1-C6卤代烷基、C1-C6氘代烷基、环烷基；较佳地，R5选自下组：甲基、氟代甲基、乙基、氟代乙基、氘代甲基、异丙基、环丙基；R 5 is selected from the following group: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, cycloalkyl; preferably, R 5 is selected from the following group: methyl , fluoromethyl, ethyl, fluoroethyl, deuterated methyl, isopropyl, cyclopropyl;
R6或R7各自独立地选自下组：氢、氘、卤素、C1-C6烷基。R 6 or R 7 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1 -C 6 alkyl.
在另一优选例中，所述的R1选自下组：
In another preferred example, the R 1 is selected from the following group:
在另一优选例中，所述的R3选自下组：
In another preferred embodiment, the R 3 is selected from the following group:
其中，各个R3'各自独立地选自下组：卤素、OH、SH、NH2、C1-C6烷基、C3-C8环烷基、C1-C6烷基羟基、S(C1-C6烷基)、烯丙基、乙烯基、芳基(包括单环或稠环芳基)、杂芳基(包括单环或稠环杂芳基)、哌啶基、吗啉基；Wherein, each R 3 ' is independently selected from the following group: halogen, OH, SH, NH 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl hydroxyl, S (C 1 -C 6 alkyl), allyl, vinyl, aryl (including monocyclic or fused ring aryl), heteroaryl (including monocyclic or fused ring heteroaryl), piperidyl, methyl phenylinyl;
X选自下组：O、N、NH、S、CH、CH2、CF2、CFH、NRa；X is selected from the following group: O, N, NH, S, CH, CH 2 , CF 2 , CFH, NR a ;
Y选自下组：NH、CH、CO、CH2、CF2、CRa、ORa、S(C1-C6烷基)、C(NRaRb)、C(芳基)、C(杂芳基)、C(3-8元环烷基)、C(3-8元杂环基)；Y is selected from the following group: NH, CH, CO, CH 2 , CF 2 , CR a , OR a , S (C 1 -C 6 alkyl), C (NR a R b ), C (aryl), C (Heteroaryl), C (3-8 membered cycloalkyl), C (3-8 membered heterocyclyl);
Z选自下组：O、N、NH、S、CH、CH2、CF2、CFH、NRa；Z is selected from the following group: O, N, NH, S, CH, CH 2 , CF 2 , CFH, NR a ;
E和F各自独立地选自下组：O、N、NH或S。E and F are each independently selected from the group consisting of: O, N, NH, or S.
在另一优选例中，所述的R3选自下组：
In another preferred embodiment, the R 3 is selected from the following group:
或所述的R3为其中，所述的X和Z之一选自下组：O、S、NH、CH2；且另一个选自下组：CH、N；or the R 3 is Wherein, one of the X and Z is selected from the following group: O, S, NH, CH 2 ; and the other is selected from the following group: CH, N;
Y选自下组：NH、CH、CO、CH2、CF2、CRa、ORa、S(C1-C6烷基)、C(NRaRb)、C(芳基)、C(杂芳基)、或选自下组的基团：
Y is selected from the following group: NH, CH, CO, CH 2 , CF 2 , CR a , OR a , S (C 1 -C 6 alkyl), C (NR a R b ), C (aryl), C (Heteroaryl), or a group selected from the following group:
在另一优选例中，所述的式I化合物具有如下式(II)、(III)、(IV)或(IV-A)所示的结构：
In another preferred embodiment, the compound of formula I has a structure represented by the following formula (II), (III), (IV) or (IV-A):
其中：in:
R2选自下组：卤素、OH、NH2、NHRa、C1-C6烷基、C1-C6卤代烷基、烯丙基、乙烯基、OCD3、ORc、3-7元环烷基、3-7元杂环基、(C1-C4烷基)3-7元杂环基、SRc；较佳地，R2选自下组：OMe、OCD3。R 2 is selected from the following group: halogen, OH, NH 2 , NHR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, allyl, vinyl, OCD 3 , OR c , 3-7 yuan Cycloalkyl, 3-7 membered heterocyclyl, (C 1 -C 4 alkyl) 3-7 membered heterocyclyl, SR c ; preferably, R 2 is selected from the following group: OMe, OCD 3 .
在另一优选例中，所述的式I化合物具有如下式(II-A)、(V)、(VI)或(VI-A)所示的结构：
In another preferred embodiment, the compound of formula I has a structure represented by the following formula (II-A), (V), (VI) or (VI-A):
较佳地，所述的式(II-A)、(V)、(VI)或(VI-A)中，各个R3'各自独立地选自下组：卤素、OH、SH、NH2、C1-C6烷基、C3-C8环烷基、C1-C6烷基羟基、S(C1-C6烷基)、烯丙基、乙烯基。Preferably, in the formula (II-A), (V), (VI) or (VI-A), each R 3 ' is independently selected from the following group: halogen, OH, SH, NH 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl hydroxyl, S (C 1 -C 6 alkyl), allyl, vinyl.
在另一优选例中，所述的式I化合物选自下组：


In another preferred embodiment, the compound of formula I is selected from the following group:


在另一优选例中，所述的式I化合物选自下组：
In another preferred embodiment, the compound of formula I is selected from the following group:
在另一优选例中，所述的式I化合物选自下组：

In another preferred embodiment, the compound of formula I is selected from the following group:

本发明的第二方面，提供了如本发明第一方面所述的化合物的用途，其用于制备治疗与KRAS突变体活性或表达量相关的疾病的药物的用途。A second aspect of the present invention provides the use of a compound as described in the first aspect of the present invention for the preparation of a medicament for treating diseases related to the activity or expression level of KRAS mutants.
在另一优选例中，所述与KRAS突变体活性或表达量相关的疾病为肿瘤，较佳地为选自下组的肿瘤：肉瘤、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤、畸胎瘤、支气管癌、肺癌、支气管腺瘤、淋巴瘤、软骨瘤错构瘤、间皮瘤、食道癌、胃癌、胰腺癌、小肠癌、大肠癌、泌尿生殖道肿瘤、肾癌、膀胱癌、尿道癌、前列腺、睾丸癌、肝癌、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤、胆囊癌、壶腹癌、胆管癌、骨癌、脑癌、子宫癌、阴道癌、血液瘤、皮肤癌、乳腺癌。In another preferred embodiment, the disease related to KRAS mutant activity or expression is a tumor, preferably a tumor selected from the following group: sarcoma, myxoma, rhabdomyomas, fibromas, lipomas, and teratomas. tumour, bronchial cancer, lung cancer, bronchial adenoma, lymphoma, enchondromatous hamartoma, mesothelioma, esophageal cancer, gastric cancer, pancreatic cancer, small intestine cancer, colorectal cancer, genitourinary tract tumors, kidney cancer, bladder cancer, urethra Cancer, prostate, testicular cancer, liver cancer, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary cancer, cholangiocarcinoma, bone cancer, brain cancer, uterine cancer, vaginal cancer, Hematoma, skin cancer, breast cancer.
本发明的第三方面，提供了一种药物组合物，所述的药物组合物包括：(i)治疗有效量的如本发明第一方面所述的式I化合物，或其药学上可接受的盐；和(ii)药学上可接受的载体。The third aspect of the present invention provides a pharmaceutical composition, said pharmaceutical composition comprising: (i) a therapeutically effective amount of the compound of formula I as described in the first aspect of the present invention, or a pharmaceutically acceptable amount thereof a salt; and (ii) a pharmaceutically acceptable carrier.
在另一优选例中，所述的有效量是指治疗有效量或抑制有效量，较佳地为0.01～99.99％。In another preferred embodiment, the effective amount refers to a therapeutically effective amount or an inhibitory effective amount, preferably 0.01 to 99.99%.
在另一优选例中，所述的药物组合物用于治疗与KRAS突变体活性或表达量相关的疾病。In another preferred embodiment, the pharmaceutical composition is used to treat diseases related to KRAS mutant activity or expression.
在另一优选例中，所述KRAS突变体为KRAS G12D突变体、KRAS G12V突变体、KRAS G12S突变体或KRAS G13D突变体。In another preferred embodiment, the KRAS mutant is a KRAS G12D mutant, a KRAS G12V mutant, a KRAS G12S mutant or a KRAS G13D mutant.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇 幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Limited to articles Each of them will not be described one by one here.
具体实施方式Detailed ways
本发明人经过长期而深入的研究，制备了一类具有式I所示结构的化合物，并发现其具有抑制KRAS-effector蛋白-蛋白相互作用的活性，是一种泛-KRAS抑制剂。基于上述发现，发明人完成了本发明。After long-term and in-depth research, the inventor has prepared a class of compounds with the structure shown in Formula I, and found that it has the activity of inhibiting KRAS-effector protein-protein interaction and is a pan-KRAS inhibitor. Based on the above findings, the inventor completed the present invention.
术语the term
如本文所用，术语“C1-C6烷基”指具有1～6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基，或类似基团，“C1-C3烷基”等表述具有类似的定义。As used herein, the term "C 1 -C 6 alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, or similar groups, Expressions such as "C 1 -C 3 alkyl" have similar definitions.
术语“C1-C6烷氧基”指具有1～6个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基，或类似基团，“C1-C3烷氧基”等表述具有类似的定义。The term "C 1 -C 6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, or the like. Group, "C 1 -C 3 alkoxy" and other expressions have similar definitions.
本发明中，术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。In the present invention, the terms "comprises", "comprises" or "includes" indicate that various ingredients can be used together in the mixture or composition of the present invention. Therefore, the terms "consisting essentially of" and "consisting of" are included in the term "comprising".
本发明中，术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)，即有合理的效益/风险比的物质。In the present invention, the term "pharmaceutically acceptable" ingredients refers to substances that are suitable for humans and/or animals without excessive adverse side effects (such as toxicity, irritation and allergic reactions), that is, with a reasonable benefit/risk ratio.
本发明中，术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量，或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此，预先指定准确的有效量是没用的。然而，对于某给定的状况而言，可以用常规实验来确定该有效量，临床医师是能够判断出来的。As used herein, the term "effective amount" refers to an amount of a therapeutic agent that treats, alleviates, or prevents a target disease or condition, or that exhibits a detectable therapeutic or preventive effect. The precise effective amount for a given subject will depend on the size and health of the subject, the nature and extent of the condition, and the therapeutic agent and/or combination of therapeutic agents chosen to be administered. Therefore, it is useless to pre-specify the exact effective amount. However, routine experimentation can be used to determine the effective amount for a given condition and the clinician will be able to judge this.
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C2-C6酰基、未取代或卤代的C1-C6烷基-羟基。As used herein, unless otherwise stated, the term "substituted" means that one or more hydrogen atoms on a group are replaced with a substituent selected from the group consisting of: halogen, unsubstituted or halogenated C 1 -C 6 alkyl , unsubstituted or halogenated C 2 -C 6 acyl, unsubstituted or halogenated C 1 -C 6 alkyl-hydroxy.
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的光学异构体，如单一手性的化合物，或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。Unless otherwise specified, all compounds appearing in the present invention are intended to include all possible optical isomers, such as single chiral compounds, or mixtures of various chiral compounds (i.e., racemates). In all compounds of the present invention, each chiral carbon atom may optionally be in R configuration or S configuration, or a mixture of R configuration and S configuration.
术语“环烷基”包括具有3至12个碳，例如3至8个碳，并且作为进一步实例3至6个碳的饱和和部分不饱和的环烃基，其中所述环烷基另外任选地被一个或多个取代。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基和环辛基。术语“环烷基”还包括桥连环烷基，例如双环[1.1.1]戊基。The term "cycloalkyl" includes saturated and partially unsaturated cycloalkyl groups having 3 to 12 carbons, such as 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl group optionally additionally replaced by one or more. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "cycloalkyl" also includes bridged cycloalkyl groups, such as bicyclo[1.1.1]pentyl.
如本文所用，术语“芳基”基团是包含一到三个芳环的C6-C14芳族部分。作为一个实施例，芳基是C6-C10芳基。芳基的实例包括但不限于苯基、萘基、蒽基、芴基和二氢苯并呋喃基。“芳基”还指二环或三环环系统，其中所述芳环系统的一个或两个环分别可以是饱和或部分饱和的，并且其中如果所述环系统包括两个饱和环，则所述饱和环可以是稠合的或螺环，但其与化合物的其他部分的连接位置在芳基部分上。As used herein, the term "aryl" group is a C6-C14 aromatic moiety containing one to three aromatic rings. As an example, the aryl group is a C6-C10 aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. "Aryl" also refers to a bicyclic or tricyclic ring system, wherein one or both rings of the aryl ring system, respectively, may be saturated or partially saturated, and wherein if the ring system includes two saturated rings, then The saturated ring may be fused or spiro, but its attachment position to the rest of the compound is on the aryl moiety.
“杂环基”或“杂环”基团是具有3至12个原子，例如4至8个原子的环结构，其中一个或多个原子选自由N、O和S组成的组，其中环N原子可以被氧化成NO，并且环S原子可以被氧化成SO或SO2，其余的环原子是碳。杂环基可以是单环、双环、螺环或桥 环系统。A "heterocyclyl" or "heterocycle" group is a ring structure having 3 to 12 atoms, such as 4 to 8 atoms, in which one or more atoms are selected from the group consisting of N, O and S, wherein ring N atoms can be oxidized to NO, and the ring S atoms can be oxidized to SO or SO2 , the remaining ring atoms are carbon. Heterocyclyl can be monocyclic, bicyclic, spirocyclic or bridged ring system.
术语“杂芳基”是指具有5至14个环原子，优选5、6、9或10个环原子的基团；并且除碳原子外，每个环具有一至三个选自N、O和S的杂原子，“杂芳基”还指除碳原子外，每个环具有一到三个选自N、O和S的杂原子的双环系统，其中一个环系统可以是饱和的或部分饱和的。The term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9 or 10 ring atoms; and in addition to carbon atoms, each ring has one to three selected from N, O and Heteroatom of S, "heteroaryl" also refers to a bicyclic system with one to three heteroatoms selected from N, O and S in each ring in addition to carbon atoms, one of the ring systems may be saturated or partially saturated of.
术语“卤素”指F、Cl、Br和I。The term "halogen" refers to F, Cl, Br and I.
如本文所用，术语“本发明化合物”指式I所示的化合物。该术语还包括及式I化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。As used herein, the term "compound of the invention" refers to a compound of Formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。As used herein, the term "pharmaceutically acceptable salts" refers to salts of compounds of the invention with acids or bases suitable for use as pharmaceuticals. Pharmaceutically acceptable salts include inorganic salts and organic salts. One preferred class of salts are the salts of the compounds of the invention with acids. Acids suitable for forming salts include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid and other organic acids; as well as aspartic acid, glutamic acid and other acidic amino acids.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.
制备例1
Preparation Example 1
实验步骤：Experimental steps:
步骤a：Step a:
室温条件下，将原料1-1(30.0克),1-2(47.0克),三氟乙酸126mL混合后，反应液在80℃搅拌16小时。LCMS显示检测到反应完毕，反应液在真空中蒸发得到粗产品。添加200毫升冰水液体，然后加入NaOH,将液体中和到PH值为8-9，并用DCM(500毫升*2)萃取。合并后的有机相经饱和食盐水(300毫升)洗涤。将有机层在无水Na2SO4结晶干燥，过滤后在真空中蒸发得到粗产品，通过硅胶过柱纯化(MeOH:DCM:＝0.5-2.5％)得到白色固体1-3(24.1克)。At room temperature, raw materials 1-1 (30.0 g), 1-2 (47.0 g), and 126 mL of trifluoroacetic acid were mixed, and the reaction solution was stirred at 80°C for 16 hours. LCMS showed that the reaction was completed, and the reaction solution was evaporated in vacuum to obtain a crude product. Add 200 ml of ice-water liquid, then add NaOH, neutralize the liquid to a pH of 8-9, and extract with DCM (500 ml*2). The combined organic phases were washed with saturated brine (300 ml). The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated in vacuo to obtain the crude product, which was purified through silica gel column (MeOH:DCM:=0.5-2.5%) to obtain white solid 1-3 (24.1 g).
LCMS：(ESI)m/z 304.1(M+H)+. LCMS: (ESI)m/z 304.1(M+H) + .
步骤b:Step b:
室温条件下，将1-3(20.0克),TEA(18.40毫升)溶于THF(200毫升),滴加乙基异氰酸酯(7.83毫升)。反应液在25℃搅拌1小时。过滤后在真空中蒸发得到粗产品。粗品用硅胶柱层析纯化(乙酸乙酯：石油醚＝5％-10％)，得到白色固体制备例1(7.0克)。Dissolve 1-3 (20.0 g) and TEA (18.40 ml) in THF (200 ml) at room temperature, and add ethyl isocyanate (7.83 ml) dropwise. The reaction solution was stirred at 25°C for 1 hour. After filtration and evaporation in vacuo the crude product was obtained. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 5%-10%) to obtain Preparation Example 1 (7.0 g) as a white solid.
MS(ESI)m/z:375.3[M+H]+。MS(ESI)m/z:375.3[M+H] + .
实施例1
Example 1
实验步骤：Experimental steps:
步骤a：Step a:
0度温度条件下，将2-氨基-5-溴苯酚1-1(1.0克)和碳酸氢钠(1.34克)溶于1,2-二甲氧基乙烷(25毫升)和水(2毫升中)后搅拌下滴加2-氯乙酰氯(902毫克)。添加后的反应混合物在同样温度下搅拌30分钟后，在80度加热搅拌16小时。冷却到室温后，将反应混合物倒入冰水(100毫升)，所得固体经过滤收集，冻干后得到浅棕色 固体1-2(1.05克)。Dissolve 2-amino-5-bromophenol 1-1 (1.0 g) and sodium bicarbonate (1.34 g) in 1,2-dimethoxyethane (25 ml) and water (2 ml), then 2-chloroacetyl chloride (902 mg) was added dropwise with stirring. After the addition, the reaction mixture was stirred at the same temperature for 30 minutes, and then heated and stirred at 80 degrees Celsius for 16 hours. After cooling to room temperature, the reaction mixture was poured into ice water (100 ml). The solid obtained was collected by filtration and lyophilized to obtain a light brown color. Solid 1-2 (1.05 g).
1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.17-7.12(m,2H),6.83(d,J＝8.4Hz,1H),4.60(s,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.81 (s, 1H), 7.17-7.12 (m, 2H), 6.83 (d, J = 8.4Hz, 1H), 4.60 (s, 2H).
步骤bStep b
在0度下将硼烷的四氢呋喃溶液(17.5毫升，浓度为1.0摩尔)滴加到原料1-2(2.0克)的THF(10毫升)溶液中。反应混合物在70度搅拌3小时。反应物冷却后在0度搅拌下滴加甲醇(2毫升)。反应混合物减压浓缩后粗品用硅胶柱层析纯化(乙酸乙酯：石油醚＝3/1)，得到浅棕色固体1-3(1。81克)。A solution of borane in tetrahydrofuran (17.5 ml, concentration 1.0 mol) was added dropwise to a solution of starting material 1-2 (2.0 g) in THF (10 ml) at 0°C. The reaction mixture was stirred at 70 degrees for 3 hours. After the reaction was cooled, methanol (2 ml) was added dropwise with stirring at 0°C. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 3/1) to obtain light brown solid 1-3 (1.81 g).
MS:m/z 214.1[M+H]+.MS:m/z 214.1[M+H] + .
步骤cStep c
将原料1-3(1.8克)，三乙基胺(1.7可)和二碳酸二叔丁酯(2.75克)溶于二氯甲烷(50毫升)，反应液在25℃搅拌16小时。反应完全后减压浓缩后粗品用硅胶柱层析纯化(乙酸乙酯：石油醚＝5/1)，得到白色固体1-4(2.40克)。Raw material 1-3 (1.8g), triethylamine (1.7g) and di-tert-butyl dicarbonate (2.75g) were dissolved in dichloromethane (50ml), and the reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, the crude product was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 5/1) to obtain white solid 1-4 (2.40 g).
LCMS:m/z 213.9[M+H-100]+.LCMS:m/z 213.9[M+H-100] + .
步骤dStep d
氩气保护下将1-4(1.78克,5.69毫摩尔)，(E)-1-乙氧乙烯基-2-硼酸频那醇酯(1.69克，8.53毫摩尔)，1,1'-双(二苯基膦)二茂铁二氯化钯((416毫克,0.569毫摩尔)，碳酸钾(2.35克,17.06毫摩尔)，1,4-二氧六环(40毫升)和水(10毫升)的混合物加热至90℃搅拌2小时。将反应液冷却至室温后经过滤后加水(10毫升)并用乙酸乙酯(3X 20毫升)萃取。合并后的有机相经干燥并过滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯20/1-21)，得到浅黄色固体1-5(1.70克)。Under argon protection, 1-4 (1.78 g, 5.69 mmol), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (1.69 g, 8.53 mmol), 1,1'-bis (Diphenylphosphine)ferrocene palladium dichloride (416 mg, 0.569 mmol), potassium carbonate (2.35 g, 17.06 mmol), 1,4-dioxane (40 ml) and water (10 ml) mixture was heated to 90°C and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, water (10 ml) was added and extracted with ethyl acetate (3×20 ml). The combined organic phases were dried and filtered. The filtrate was concentrated , the obtained residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 20/1-21) to obtain light yellow solid 1-5 (1.70 g).
LCMS:m/z 250.0[M+H-56]+.LCMS:m/z 250.0[M+H-56] + .
步骤e和f：Steps e and f:
将中间体1-5(500毫克)溶于二氯甲烷(10毫升)，加入甲酸(1毫升)。反应液在40℃搅拌16小时。薄层硅胶柱层析检测反应完全后，混合物用饱和碳酸氢钠水溶液(50毫升)中和，用乙酸乙酯(50毫升)萃取三次。结合有机层，加入饱和食盐水(30毫升)洗涤，有机层用无水硫酸钠干燥。处理后反应液经减压浓缩得到粗产品中间体，不经分离直接用于下一步反应。Intermediate 1-5 (500 mg) was dissolved in dichloromethane (10 mL) and formic acid (1 mL) was added. The reaction solution was stirred at 40°C for 16 hours. After the completion of the reaction was detected by thin-layer silica gel column chromatography, the mixture was neutralized with saturated aqueous sodium bicarbonate solution (50 ml) and extracted three times with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (30 ml), and the organic layer was dried over anhydrous sodium sulfate. After treatment, the reaction solution was concentrated under reduced pressure to obtain a crude product intermediate, which was directly used in the next step of the reaction without separation.
在0度下将硼氢化钠(125毫克，3.28毫摩尔)加入到上述粗产品中间体(1.0克)的甲醇(20毫升)溶液中。反应混合物室温搅拌3小时。反应结束后加水(50毫升)，用乙酸乙酯(50毫升)萃取三次。结合有机层，加入饱和食盐水(30毫升)洗涤，有机层用无水硫酸钠干燥。处理后反应液经减压浓缩得到粗产品中间体，反应混合物减压浓缩后粗品用硅胶柱层析纯化(乙酸乙酯：石油醚＝3/1)，得到黄色油状物1-6(304毫克)。Sodium borohydride (125 mg, 3.28 mmol) was added to a solution of the above crude intermediate product (1.0 g) in methanol (20 ml) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. After the reaction, water (50 ml) was added, and the mixture was extracted three times with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (30 ml), and the organic layer was dried over anhydrous sodium sulfate. After treatment, the reaction solution was concentrated under reduced pressure to obtain a crude product intermediate. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 3/1) to obtain yellow oil 1-6 (304 mg ).
1H NMR(400MHz,CDCl3):δ7.71(s,1H),6.75-6.73(m,2H),4.23(d,J＝4.6Hz,2H),3.84(d,J＝4.6Hz,4H),2.78(d,J＝6.6Hz,2H),1.54(s,9H). 1 H NMR (400MHz, CDCl 3 ): δ7.71 (s, 1H), 6.75-6.73 (m, 2H), 4.23 (d, J = 4.6Hz, 2H), 3.84 (d, J = 4.6Hz, 4H) ), 2.78 (d, J = 6.6Hz, 2H), 1.54 (s, 9H).
步骤gStep g
室温下将1-6(150毫克,0.53毫摩尔)，三苯基膦(182mg,0.7毫摩尔)，制备例1(200mg,0.53毫摩尔)的甲苯(10mL)溶液氩气抽换气三次，氩气保护下加热至120℃搅拌10分钟。随后逐滴加入偶氮二甲酸二异丙酯(0.14mL,0.70毫摩尔)。反应液随后120℃并且氩气保护下搅拌2小时。反应液冷却至室温后加水(50mL)，所得混合物用乙酸乙酯(3X 50毫升)萃取。合并后的有机相经饱和食盐水(30毫升)洗涤，无水硫酸钠 干燥并过滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯1/1)得到白色固体1-7(196毫克)。A solution of 1-6 (150 mg, 0.53 mmol), triphenylphosphine (182 mg, 0.7 mmol) and Preparation Example 1 (200 mg, 0.53 mmol) in toluene (10 mL) was purged with argon three times at room temperature. Heat to 120°C under argon protection and stir for 10 minutes. Then diisopropyl azodicarboxylate (0.14 mL, 0.70 mmol) was added dropwise. The reaction solution was then stirred at 120°C for 2 hours under argon protection. After the reaction solution was cooled to room temperature, water (50 mL) was added, and the resulting mixture was extracted with ethyl acetate (3X 50 mL). The combined organic phases were washed with saturated brine (30 ml) and anhydrous sodium sulfate. Dry and filter. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1/1) to obtain white solid 1-7 (196 mg).
LCMS:m/z 636.3[M+H]+.LCMS:m/z 636.3[M+H] + .
步骤hStep h
将中间体1-7(196毫克，0.31毫摩尔)溶于二氯甲烷(10毫升)，加入三氟乙酸(1毫升)。反应液在25℃搅拌16小时。反应完全后，混合物加入碳酸氢钠水溶液(20毫升)中和，用乙酸乙酯(50毫升)萃取三次。结合有机层，加入饱和食盐水(30毫升)洗涤，有机层用无水硫酸钠干燥。处理后反应液经减压浓缩得到粗产品，用制备色谱柱(Waters 2767/2545/2489/Qda,Inertsil ODS-3 10um 20*250nm,流动相A:0.1％甲酸水溶液,流动相B:乙腈,流速:20毫升/m分钟:柱温:室温)分离得到白色固体实施例1(63.56毫克)。Intermediate 1-7 (196 mg, 0.31 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at 25°C for 16 hours. After the reaction was complete, the mixture was neutralized by adding aqueous sodium bicarbonate solution (20 ml), and extracted three times with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (30 ml), and the organic layer was dried over anhydrous sodium sulfate. After treatment, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was used with a preparative chromatography column (Waters 2767/2545/2489/Qda, Inertsil ODS-3 10um 20*250nm, mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: acetonitrile, Flow rate: 20 ml/m (minute: column temperature: room temperature) was separated to obtain white solid Example 1 (63.56 mg).
MS(ESI)m/z:536.3[M+H]+；MS(ESI)m/z:536.3[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ7.25(d,J＝2.0Hz,1H),7.08(dd,J＝8.4Hz,1H),6.76(s,1H),6.67(t,J＝5.4Hz,1H),6.54–6.49(m,5H),6.44(d,J＝7.6Hz,1H),6.54(s,1H),4.07(t,J＝4.2Hz,2H),3.96–3.90(m,1H),3.83–3.76(m,1H),3.75(s,3H),3.73–3.69(m,1H),3.22(t,J＝4.0Hz,2H),3.10–3.08(m,2H),2.97–2.80(m,2H),2.74(t,J＝7.4Hz,2H),2.57–2.54(m,1H),2.40(s,3H),1.01(t,J＝7.2Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.25 (d, J＝2.0Hz, 1H), 7.08 (dd, J＝8.4Hz, 1H), 6.76 (s, 1H), 6.67 (t, J＝ 5.4Hz,1H),6.54–6.49(m,5H),6.44(d,J＝7.6Hz,1H),6.54(s,1H),4.07(t,J＝4.2Hz,2H),3.96–3.90( m,1H),3.83–3.76(m,1H),3.75(s,3H),3.73–3.69(m,1H),3.22(t,J＝4.0Hz,2H),3.10–3.08(m,2H) ,2.97–2.80(m,2H),2.74(t,J＝7.4Hz,2H),2.57–2.54(m,1H),2.40(s,3H),1.01(t,J＝7.2Hz,3H).
实施例2

Example 2

步骤a:Step a:
在氩气保护下，将2-1(10.0克)，1,2-2硫代羟基乙烷(4.5克)加入无水甲苯(450)毫升)，然后加入对甲基苯磺酸(200毫克)。在120℃搅拌24小时。反应完全后，反应液浓缩干，减压浓缩得粗品，粗品用硅胶柱纯化(石油醚/乙＝20：1)，得淡黄色固体2-2(12.0克)。Under argon protection, add 2-1 (10.0 g), 1,2-2 thiol ethane (4.5 g) to anhydrous toluene (450 ml), and then add p-toluenesulfonic acid (200 mg ). Stir at 120°C for 24 hours. After the reaction was completed, the reaction solution was concentrated to dryness and concentrated under reduced pressure to obtain a crude product. The crude product was purified with a silica gel column (petroleum ether/ethyl alcohol = 20:1) to obtain a light yellow solid 2-2 (12.0 g).
1H NMR(400MHz,CDCl3)δ7.42-7.40(m,1H),7.37-7.32(m,2H),3.57-3.49(m,2H),3.46-3.39(m,2H),2.85(t,J＝6.8Hz,2H),2.67(t,J＝6.8Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.42-7.40(m,1H),7.37-7.32(m,2H),3.57-3.49(m,2H),3.46-3.39(m,2H),2.85(t ,J＝6.8Hz,2H),2.67(t,J＝6.8Hz,2H).
步骤b:Step b:
在-70度氩气保护条件下，将氟化氢吡啶(130克，0.94摩尔，70％重量/重量)加入到1,3-二溴-5,5-二甲基咪唑啉-2,4-二酮(24克)的二氯甲烷(200毫升)溶液，然后2-2(6.0克)的二氯甲烷(40毫升)溶液在-60度条件下滴加到上述溶液中。在同一温度下搅拌4小时，然后升至室温后继续搅拌12小时。反应物用2.0摩尔浓度的NaOH水溶液洗涤三次(80毫升x3),亚硫酸氢钠水溶液洗涤(80毫升x2).有机相用饱和食盐水洗涤(30毫升)，然后用无水硫酸钠干燥，减压浓缩得粗品，粗品用硅胶柱纯化(石油醚/乙酸乙酯＝20/1)，得油状物2-3(5.2克)。Under argon protection at -70 degrees, hydrogen fluoride pyridine (130 g, 0.94 mol, 70% weight/weight) was added to 1,3-dibromo-5,5-dimethylimidazoline-2,4-di A solution of ketone (24 g) in methylene chloride (200 ml), and then a solution of 2-2 (6.0 g) in methylene chloride (40 ml) was added dropwise to the above solution at -60°C. Stir at the same temperature for 4 hours, then rise to room temperature and continue stirring for 12 hours. The reactant was washed three times with 2.0 molar NaOH aqueous solution (80 ml x 3) and sodium bisulfite aqueous solution (80 ml x 2). The organic phase was washed with saturated brine (30 ml), then dried over anhydrous sodium sulfate, and reduced to Concentrate under pressure to obtain a crude product, which was purified with a silica gel column (petroleum ether/ethyl acetate = 20/1) to obtain oily substance 2-3 (5.2 g).
1H NMR(CDCl3,400MHz):δ7.72(s,1H),7.59(d,J＝8.4Hz,1H),7.16(d,J＝8.0Hz,1H),4.61–4.51(m,1H),3.52–3.48(m,1H),3.23–3.15(m,1H). 1 H NMR (CDCl 3 , 400MHz): δ7.72 (s, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.16 (d, J = 8.0Hz, 1H), 4.61–4.51 (m, 1H ),3.52–3.48(m,1H),3.23–3.15(m,1H).
步骤c:Step c:
0度条件下，将中间体2-3(5.4克)溶于二氯甲烷(200毫升)，然后滴加1,8-二氮杂二环十一碳-7-烯(DBU)(3.95克)。反应到在室温下搅拌16小时。反应完全后，反应液浓缩干，粗品用硅胶柱纯化(石油醚/乙酸乙酯＝20/1)，得油状物2-4(2.90克)。Under 0°C conditions, intermediate 2-3 (5.4 g) was dissolved in dichloromethane (200 ml), and then 1,8-diazabicyclounde-7-ene (DBU) (3.95 g) was added dropwise. ). The reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was purified with a silica gel column (petroleum ether/ethyl acetate = 20/1) to obtain oily substance 2-4 (2.90 g).
步骤d：Step d:
0℃下向搅拌着的粗品2-4(2.9克,12.6毫摩尔)和磷酸钾(0.530克，2.51毫摩尔) 的乙腈(20mL)溶液中加入2-硝基磺酰氯(2.78克,12.6毫摩尔)和水合肼(1.48克，25.1毫摩尔)。反应液随后60度下搅拌16小时。冷却后向反应液中加水(20毫升)。所得混合物用乙酸乙酯(3X 20毫升)萃取。合并后的有机相经饱和食盐水(20毫升)洗涤，无水硫酸钠干燥并过滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:石油醚)，得到无色油状物2-5(2.5克)。To the stirring crude product 2-4 (2.9 g, 12.6 mmol) and potassium phosphate (0.530 g, 2.51 mmol) at 0°C To a solution of acetonitrile (20 mL) were added 2-nitrosulfonyl chloride (2.78 g, 12.6 mmol) and hydrazine hydrate (1.48 g, 25.1 mmol). The reaction solution was then stirred at 60°C for 16 hours. After cooling, water (20 ml) was added to the reaction solution. The resulting mixture was extracted with ethyl acetate (3X 20 mL). The combined organic phases were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography (eluent: petroleum ether) to obtain colorless oily substance 2-5 (2.5 g).
1H NMR(CDCl3,400MHz):δ7.66(s,1H),7.58(d,J＝10.0Hz,1H),7.50(d,J＝8.4Hz,1H),3.07-3.20(m,2H),2.64-2.54(m,2H). 1 H NMR (CDCl 3 , 400MHz): δ7.66 (s, 1H), 7.58 (d, J = 10.0Hz, 1H), 7.50 (d, J = 8.4Hz, 1H), 3.07-3.20 (m, 2H ),2.64-2.54(m,2H).
步骤e：Step e:
氩气保护下将2-5(1克,4.29毫摩尔)，(E)-1-乙氧乙烯基-2-硼酸频那醇酯(1.27克6.44毫摩尔)，1,1'-双(二苯基膦)二茂铁二氯化钯(314毫克,0.43毫摩尔)，碳酸钾(1.78克,12.88毫摩尔)，1,4-二氧六环(15毫升)和水(5毫升)的混合物加热至90℃搅拌5小时。将反应液冷却至室温后经过滤后加水(50毫升)并用乙酸乙酯(3X 50毫升)萃取。合并有机层，用盐水(30mL)洗涤，无水硫酸钠干燥，过滤并减压浓缩，所得残渣经硅胶柱层析分离(洗脱剂:石油醚)，得到黄色固体2-6(614毫克)。Under argon protection, 2-5 (1 g, 4.29 mmol), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (1.27 g, 6.44 mmol), 1,1'-bis( Diphenylphosphine) ferrocene palladium dichloride (314 mg, 0.43 mmol), potassium carbonate (1.78 g, 12.88 mmol), 1,4-dioxane (15 mL) and water (5 mL) The mixture was heated to 90°C and stirred for 5 hours. The reaction solution was cooled to room temperature, filtered, water (50 ml) was added and extracted with ethyl acetate (3×50 ml). The organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (eluent: petroleum ether) to obtain yellow solid 2-6 (614 mg) .
1H NMR(CDCl3,400MHz):δ7.42(d,J＝8.0Hz,1H),7.18(d,J＝8.0Hz,1H),7.12(s,1H),7.03(d,J＝12.8Hz,1H),5.85(d,J＝12.8Hz,1H),3.94-3.89(m,2H),3.01-2.97(m,2H),2.59-2.55(m,2H),1.36(t,J＝3.4Hz,3H). 1 H NMR (CDCl 3 , 400MHz): δ7.42 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.03 (d, J = 12.8 Hz,1H),5.85(d,J＝12.8Hz,1H),3.94-3.89(m,2H),3.01-2.97(m,2H),2.59-2.55(m,2H),1.36(t,J＝ 3.4Hz,3H).
步骤f:Step f:
将浓盐酸(1.5毫升)在0度下加到2-6(324毫克,1.45毫摩尔)的四氢呋喃(10毫升)溶液中。于0度下搅拌3小时。所得混合物加水(50毫升)后用乙酸乙酯(3X 50毫升)萃取。合并后的有机相经饱和食盐水(30毫升)洗涤，无水硫酸钠干燥并过滤。滤液浓缩，得到粗品黄色油状物中间体(520mg)。可以直接用于下一步反应。Concentrated hydrochloric acid (1.5 ml) was added to a solution of 2-6 (324 mg, 1.45 mmol) in tetrahydrofuran (10 ml) at 0°C. Stir at 0 degrees for 3 hours. The resulting mixture was added with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain crude yellow oily intermediate (520 mg). It can be used directly for the next reaction.
步骤g:Step g:
0℃下向搅拌着的粗品中间体(520mg,1.321毫摩尔)的干燥的四氢呋喃(20mL)溶液中加入硼氢化钠(60mg,1.59毫摩尔)。反应液随后同温下搅拌3小时。向反应液中加入水(50毫升)。混合物用乙酸乙酯(3X 50毫升)萃取。合并后的有机相经饱和食盐水(30毫升)洗涤，无水硫酸钠干燥并过滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯3/1，体积/体积)，得到棕色油状物2-7(112毫克)。To a stirred solution of the crude intermediate (520 mg, 1.321 mmol) in dry tetrahydrofuran (20 mL) at 0 °C was added sodium borohydride (60 mg, 1.59 mmol). The reaction solution was then stirred at the same temperature for 3 hours. Water (50 ml) was added to the reaction solution. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3/1, volume/volume) to obtain brown oil 2-7 (112 mg).
1H NMR(CDCl3,400MHz):δ7.49(d,J＝7.6Hz,1H),7.24-7.20(m,2H),7.17(s,1H),3.90-3.86(m,2H),3.04-3.00(m,2H)，2.92-2.86(m,2H)，2.64-2.53(m,2H). 1 H NMR (CDCl 3 , 400MHz): δ7.49 (d, J = 7.6Hz, 1H), 7.24-7.20 (m, 2H), 7.17 (s, 1H), 3.90-3.86 (m, 2H), 3.04 -3.00(m,2H), 2.92-2.86(m,2H), 2.64-2.53(m,2H).
步骤h:Step h:
室温下将制备例1(100毫克0.26毫摩尔)，三苯基膦(100mg,0.38毫摩尔)，2-7(50mg,0.26毫摩尔)的甲苯(5mL)溶液氩气抽换气三次，氩气保护下加热至120℃搅拌10分钟。随后逐滴加入偶氮二甲酸二异丙酯(0.07mL,0.38毫摩尔)。反应液随后120℃并且氩气保护下搅拌2小时。反应液冷却至室温后加水(50mL)，所得混合物用乙酸乙酯(3X 50毫升)萃取。合并后的有机相经饱和食盐水(30毫升)洗涤，无水硫酸钠干燥并过滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯1/1)，得到白色固体实施例2(20.78毫克)。A solution of Preparation Example 1 (100 mg, 0.26 mmol), triphenylphosphine (100 mg, 0.38 mmol), and 2-7 (50 mg, 0.26 mmol) in toluene (5 mL) was purged and replaced with argon three times at room temperature. Heat to 120°C under air protection and stir for 10 minutes. Then diisopropyl azodicarboxylate (0.07 mL, 0.38 mmol) was added dropwise. The reaction solution was then stirred at 120°C for 2 hours under argon protection. After the reaction solution was cooled to room temperature, water (50 mL) was added, and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1/1) to obtain white solid Example 2 (20.78 mg).
1H NMR(400MHz,DMSO-d6)δ7.44(d,J＝8.0Hz,1H),7.29–7.26(m,2H),7.09(d,J＝8.0Hz,1H),6.77(s,1H),6.68(t,J＝5.4Hz,3H),6.53(t,J＝9.2Hz,3H),4.08–4.06(m,1H),3.96–3.94(m,1H),3.76(s,3H),3.73–3.71(m,1H),3.10–3.08(m,2H),3.03–2.93(m,6H),2.85–2.52(m,2H),2.40(s,3H),1.01(t,J＝6.0Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.44 (d, J = 8.0 Hz, 1H), 7.29–7.26 (m, 2H), 7.09 (d, J = 8.0 Hz, 1H), 6.77 (s, 1H),6.68(t,J＝5.4Hz,3H),6.53(t,J＝9.2Hz,3H),4.08–4.06(m,1H),3.96–3.94(m,1H),3.76(s,3H ),3.73–3.71(m,1H),3.10–3.08(m,2H),3.03–2.93(m,6H),2.85–2.52(m,2H),2.40(s,3H),1.01(t,J =6.0Hz,3H).
MS(ESI)m/z:555.2[M+H]+；MS(ESI)m/z:555.2[M+H] + ;
实施例3
Example 3
实施例3的制备按照类似实施例7的方法得到。用2-(苯并[d]恶唑-5-基)乙烷-1- 醇(30mg)和制备例1(69毫克)得到白色固体实施例3(33.12毫克)。Example 3 was prepared in a manner similar to Example 7. Using 2-(benzo[d]oxazol-5-yl)ethan-1- ol (30 mg) and Preparation 1 (69 mg) gave Example 3 (33.12 mg) as a white solid.
MS(ESI):m/z 520.2[M+H]+.MS(ESI):m/z 520.2[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),7.72(s,1H),7.65(d,J＝8.0Hz,1H),7.35–7.33(m,1H),7.23(d,J＝2.0Hz,1H),7.10–7.07(m,1H),6.77(s,1H),6.69–6.66(m,1H),6.54–6.48(m,3H),4.11–4.06(m,1H),4.01–3.97(m,1H),3.76(s,3H),3.74–3.69(m,1H),3.11–3.04(m,4H),2.95–2.78(m,2H),2.57–2.56(m,1H),2.39(s,3H),1.00(t,J＝7.2Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.69 (s, 1H), 7.72 (s, 1H), 7.65 (d, J = 8.0Hz, 1H), 7.35–7.33 (m, 1H), 7.23 ( d,J＝2.0Hz,1H),7.10–7.07(m,1H),6.77(s,1H),6.69–6.66(m,1H),6.54–6.48(m,3H),4.11–4.06(m, 1H),4.01–3.97(m,1H),3.76(s,3H),3.74–3.69(m,1H),3.11–3.04(m,4H),2.95–2.78(m,2H),2.57–2.56( m,1H),2.39(s,3H),1.00(t,J=7.2Hz,3H).
实施例4
Example 4
步骤a: Step a:
将2-(3-氨基-4-羟基苯基)乙酸甲酯4-1(2.00克，11.0毫摩尔)溶于乙酸乙酯(4毫升)和水(4毫升)中,0度下加入碳酸氢钠(1.00克，12.1毫摩尔)和氯乙酰氯(1.42毫升，11.0毫摩尔)，室温下搅拌反应3小时。TLC监测反应结束后，反应液用乙酸乙酯(20毫升)和盐水(20毫升)稀释。分离有机层，无水硫酸钠干燥，过滤并浓缩。所得残渣溶于N,N-二甲基甲酰胺(50毫升)，加入碳酸钾(3.36克，22.0毫升)。反应加热至80度，继续搅拌反应3小时。TLC监测反应结束后，反应冷却至室温，用水(100毫升)稀释，乙酸乙酯(100毫升*3)萃取，合并有机相，用盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到2-(3-氧代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)乙酸甲酯4-2(1,7克，黄色油状产品)。Dissolve 2-(3-amino-4-hydroxyphenyl)methyl acetate 4-1 (2.00 g, 11.0 mmol) in ethyl acetate (4 ml) and water (4 ml), add carbonic acid at 0°C Sodium hydrogen (1.00 g, 12.1 mmol) and chloroacetyl chloride (1.42 ml, 11.0 mmol) were stirred and reacted at room temperature for 3 hours. After the reaction was monitored by TLC, the reaction solution was diluted with ethyl acetate (20 ml) and brine (20 ml). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was dissolved in N,N-dimethylformamide (50 ml), and potassium carbonate (3.36 g, 22.0 ml) was added. The reaction was heated to 80 degrees and the reaction was continued with stirring for 3 hours. After the reaction was monitored by TLC, the reaction was cooled to room temperature, diluted with water (100 ml), extracted with ethyl acetate (100 ml*3), combined the organic phases, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate under reduced pressure to obtain 2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)acetic acid methyl ester 4-2 (1,7 g, yellow oily product).
MS(ESI):m/z 222.1[M+H]+ MS(ESI):m/z 222.1[M+H] +
步骤b:Step b:
在0度下，向2-(3-氧代-3,4-二氢-2H-苯并[b-[1,4]恶嗪-6-基)乙酸酯4-2(1.70克，7.70毫摩尔)的四氢呋喃(20毫升)溶液中分批加入氢化铝锂(0.73克，19.3毫摩尔)，室温下搅拌反应过夜。LC-MS监测反应结束后，将所得混合物用水(0.8毫升)淬灭，然后0度下加入氢氧化钠水溶液(0.8毫升，3.0摩尔浓度)和水(2.4毫升)，所得混合物用硅藻土过滤，滤液浓缩，所得残余物用硅胶柱层析法(二氯甲烷/甲醇＝100/1至20/1)纯化得到2-(3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)乙-1-醇4-3(500mg，黄色油状物)。To 2-(3-oxo-3,4-dihydro-2H-benzo[b-[1,4]oxazin-6-yl)acetate 4-2 (1.70 g, Lithium aluminum hydride (0.73 g, 19.3 mmol) was added in portions to a solution of 7.70 mmol) in tetrahydrofuran (20 ml), and the reaction was stirred at room temperature overnight. After the reaction was monitored by LC-MS, the resulting mixture was quenched with water (0.8 ml), then aqueous sodium hydroxide solution (0.8 ml, 3.0 molar concentration) and water (2.4 ml) were added at 0°C, and the resulting mixture was filtered through diatomaceous earth. , the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 20/1) to obtain 2-(3,4-dihydro-2H-benzo[b][1, 4]oxazin-6-yl)ethan-1-ol 4-3 (500 mg, yellow oil).
MS(ESI):m/z 180.1[M+H]+ MS(ESI):m/z 180.1[M+H] +
步骤c:Step c:
向2-(3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)乙-1-醇4-3(500毫克，2.79毫摩尔)的二氯甲烷(20毫升)溶液中加入三乙胺(1.10毫升，8.40毫摩尔)，二碳酸二叔丁酯(730毫克，3.38毫摩尔)和4-二甲氨基吡啶(100毫克，0.820毫摩尔)，室温搅拌反应过夜。LC-MS监测反应结束后，反应液真空浓缩，所得残余物用硅胶柱层析法(石油醚/乙酸乙酯＝4/1-1/1)纯化得到6-(2-羟乙基)-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯4-4(80mg，白色固体)，产率：10.2％。To 2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethan-1-ol 4-3 (500 mg, 2.79 mmol) in dichloromethane (20 ml) solution was added triethylamine (1.10 ml, 8.40 mmol), di-tert-butyl dicarbonate (730 mg, 3.38 mmol) and 4-dimethylaminopyridine (100 mg, 0.820 mmol) at room temperature. The reaction was stirred overnight. After the reaction was monitored by LC-MS, the reaction solution was concentrated in vacuum, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1-1/1) to obtain 6-(2-hydroxyethyl)- 2,3-Dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl ester 4-4 (80 mg, white solid), yield: 10.2%.
MS(ESI):m/z 180.1[M-Boc+H]+ MS(ESI):m/z 180.1[M-Boc+H] +
步骤d:Step d:
向6-(2-羟乙基)-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯4-4(80毫克，0.286毫摩尔)的甲苯(5毫升)溶液中依次加入制备例1(107毫升，0.286毫摩尔)和三苯基膦(90毫克，0.343毫摩尔)。氩气保护下，反应混合物加热至105度，搅拌30分钟，加入偶氮二甲酸二异丙酯(70毫克，0.343毫摩尔)，继续搅拌反应3小时。LC-MS监测反应结束后，反应冷却至室温，盐水(20毫升)稀释，乙酸乙酯(20毫升×3)萃取,无水硫酸钠干燥，过滤并减压浓缩，所得残余物用硅胶柱(石油醚/乙酸乙酯＝1/1)纯化得到6-(2-((1-(4-氯-2-甲基苯基)-2-(乙基氨基甲酰基)-6-甲氧基-1,2-四氢异喹啉-7-基)氧基)乙基)-2,3-二氢-4H-苯并[b][1,4]恶嗪-4-羧酸叔丁酯4-5(150mg，黄色油状物)。To 6-(2-hydroxyethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl ester 4-4 (80 mg, 0.286 mmol ) to a solution of toluene (5 ml) was added Preparation Example 1 (107 ml, 0.286 mmol) and triphenylphosphine (90 mg, 0.343 mmol) in sequence. Under argon protection, the reaction mixture was heated to 105 degrees, stirred for 30 minutes, added diisopropyl azodicarboxylate (70 mg, 0.343 mmol), and continued to stir for 3 hours. After the reaction was monitored by LC-MS, the reaction was cooled to room temperature, diluted with brine (20 ml), extracted with ethyl acetate (20 ml × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified with a silica gel column ( Petroleum ether/ethyl acetate=1/1) was purified to obtain 6-(2-((1-(4-chloro-2-methylphenyl))-2-(ethylcarbamoyl)-6-methoxy -1,2-Tetrahydroisoquinolin-7-yl)oxy)ethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl Ester 4-5 (150 mg, yellow oil).
MS(ESI):m/z 658.3[M+Na]+ MS(ESI):m/z 658.3[M+Na] +
步骤e:Step e:
将4-5(150毫克，0.236毫摩尔)和盐酸/二氧六环(5毫升，4.0摩尔浓度)的混合物在室温下搅拌2小时。LC-MS监测反应结束后，反应液真空浓缩，所得残余物通过高效液相制备(NH 4HCO 3)纯化得到实施例4(13.83mg，白色固体). A mixture of 4-5 (150 mg, 0.236 mmol) and hydrochloric acid/dioxane (5 mL, 4.0 molar) was stirred at room temperature for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was concentrated in vacuum, and the resulting residue was purified by high-performance liquid phase preparation (NH 4HCO 3) to obtain Example 4 (13.83 mg, white solid).
MS(ESI):m/z 536.3[M+H]+ MS(ESI):m/z 536.3[M+H] +
1H NMR(400MHz,CDCl3)δ7.17(d,J＝1.8Hz,1H),6.97(dd,J＝8.3,1.9Hz,1H),6.91–6.76(m,3H),6.63(s,1H),6.56(d,J＝8.3Hz,1H),6.27(d,J＝51.4Hz,3H),4.35(d,J＝4.7Hz,2H),4.20–4.04(m,2H),3.85(s,3H),3.59–3.43(m,3H),3.33–3.20(m,3H),3.05–2.85(m,3H),2.62(dd,J＝16.7,3.3Hz,1H),2.40(s,3H),1.30–1.24(m,1H),1.11(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.17 (d, J＝1.8Hz, 1H), 6.97 (dd, J＝8.3, 1.9Hz, 1H), 6.91–6.76 (m, 3H), 6.63 (s, 1H),6.56(d,J＝8.3Hz,1H),6.27(d,J＝51.4Hz,3H),4.35(d,J＝4.7Hz,2H),4.20–4.04(m,2H),3.85( s,3H),3.59–3.43(m,3H),3.33–3.20(m,3H),3.05–2.85(m,3H),2.62(dd,J＝16.7,3.3Hz,1H),2.40(s, 3H),1.30–1.24(m,1H),1.11(t,J=7.2Hz,3H).
实施列5
Implement column 5
步骤a:Step a:
将6-溴代苯并噻吩5-1(1.10克，5.2毫摩尔)加入至二氧六环(30毫升)和水(6毫升)中，然后依次添加(E)-1-乙氧乙烯基-2-硼酸频那醇酯(1.5克，7.7毫摩尔)，1,1'-双二苯基膦二茂铁二氯化钯(190毫克，0.26毫摩尔)，碳酸钾(2.10可，15.2毫摩尔)，之后将混合物氩气置换三次，体系升温至80℃，氩气保护下80℃反应3小时。反应完全后将混合物冷却至室温，用水(30毫升)稀释并用乙酸乙酯(30毫升×3)萃取。有机层合并后用无水硫酸钠干燥，过滤并浓缩得到残留物，残留物过硅胶柱(洗脱剂：石油醚/乙酸乙酯＝100/1-20/1)纯化得到目标化合物(E)-6-(2-乙氧基乙烯基)苯并[b]噻吩5-2(900毫克)，为淡黄色固体。6-Bromobenzothiophene 5-1 (1.10 g, 5.2 mmol) was added to dioxane (30 ml) and water (6 ml), followed by (E)-1-ethoxyethylene group -2-Pinacol borate (1.5 g, 7.7 mmol), 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (190 mg, 0.26 mmol), potassium carbonate (2.10 g, 15.2 millimole), then the mixture was replaced with argon three times, the system was heated to 80°C, and the reaction was carried out at 80°C for 3 hours under argon protection. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (30 ml) and extracted with ethyl acetate (30 ml × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified through a silica gel column (eluent: petroleum ether/ethyl acetate = 100/1-20/1) to obtain the target compound (E). -6-(2-ethoxyvinyl)benzo[b]thiophene 5-2 (900 mg), as a light yellow solid.
步骤b:Step b:
将中间体5-2(900毫克，4.41毫摩尔)溶于5毫升四氢呋喃溶液中，并在0℃下加 入1.5毫升浓盐酸，之后所得混合物在0℃下搅拌4小时，反应完全后用水(30毫升)稀释再用乙酸乙酯(30毫升×3)萃取，有机层合并后用盐水(30毫升)洗涤，用无水硫酸钠干燥，过滤并浓缩，2-(苯并[b]噻吩-6-基)乙醛粗品5-3(700毫克)，为淡黄色油状物，粗品直接用于下一步。Intermediate 5-2 (900 mg, 4.41 mmol) was dissolved in 5 ml of tetrahydrofuran solution and added at 0°C. 1.5 ml of concentrated hydrochloric acid was added, and the resulting mixture was stirred at 0°C for 4 hours. After the reaction was complete, it was diluted with water (30 ml) and extracted with ethyl acetate (30 ml × 3). The organic layers were combined and washed with brine (30 ml). , dried over anhydrous sodium sulfate, filtered and concentrated, the crude product 2-(benzo[b]thiophen-6-yl)acetaldehyde 5-3 (700 mg) was a light yellow oil, and the crude product was used directly in the next step.
步骤c:Step c:
将5-3(700毫克)溶于甲醇(5毫升)中，并在0℃下添加硼氢化钠(151毫克，3.98毫摩尔)，之后混合物在室温下搅拌1小时。反应完全后用稀盐酸调反应液pH＝5，然后用乙酸乙酯(50毫升×2)萃取。合并后有机层，用饱和食盐水(50毫升)洗涤，再用无水硫酸钠干燥，过滤和浓缩得到残留物。残留物过硅胶柱柱纯化(洗脱剂：石油醚/乙酸乙酯＝20/1-2/1)得到目标化合物2-(苯并[b]噻吩-6-基)乙烷-1-醇5-4(290毫克)，为淡黄色油状物。5-3 (700 mg) was dissolved in methanol (5 mL) and sodium borohydride (151 mg, 3.98 mmol) was added at 0°C, after which the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid, and then extracted with ethyl acetate (50 ml × 2). The organic layers were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified through a silica gel column (eluent: petroleum ether/ethyl acetate = 20/1-2/1) to obtain the target compound 2-(benzo[b]thiophen-6-yl)ethane-1-ol. 5-4 (290 mg), light yellow oily substance.
1H NMR(400MHz,CDCl3)δ7.75(t,J＝6.6Hz,2H),7.39(d,J＝5.6Hz,1H),7.30(t,J＝2.8Hz,1H),7.22–7.25(m,1H),3.90(t,J＝6.6Hz,2H),2.96(t,J＝6.4Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.75 (t, J = 6.6 Hz, 2H), 7.39 (d, J = 5.6 Hz, 1H), 7.30 (t, J = 2.8 Hz, 1H), 7.22–7.25 (m,1H),3.90(t,J＝6.6Hz,2H),2.96(t,J＝6.4Hz,2H).
步骤d:Step d:
将化合物1-(4-氯-2-甲基苯基)-N-乙基-7-羟基-6-甲氧基-3,4-二氢异喹啉-2(1H)-甲酰胺制备例1(80毫克，0.21毫摩尔)加入至5毫升甲苯中，再依次添加三苯基膦(73毫克，0.28毫摩尔)，5-4(38.0毫克，0.21毫摩尔)，之后将混合物用氩气换气三次。将所得的混合物在120℃下加热10分钟，然后逐滴添加偶氮二甲酸二异丙酯(0.05毫升，0.28毫摩尔)。滴毕，反应混合物在120℃下再搅拌3小时。反应完全后将所得混合物冷却至室温，然后加入10毫升水稀释，再用乙酸乙酯(30毫升×2)萃取体系。合并后有机层用20毫升饱和食盐水洗涤，再用无水硫酸钠干燥，有机相过滤浓缩的残留物，残留物通过制备板(二氯甲烷/甲醇＝42/1)纯化得到实施例5(25.75毫克)，为白色固体。Preparation of compound 1-(4-chloro-2-methylphenyl)-N-ethyl-7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxamide Example 1 (80 mg, 0.21 mmol) was added to 5 ml of toluene, then triphenylphosphine (73 mg, 0.28 mmol), 5-4 (38.0 mg, 0.21 mmol) were added successively, and then the mixture was purged with argon Breathe air three times. The resulting mixture was heated at 120°C for 10 minutes, then diisopropyl azodicarboxylate (0.05 mL, 0.28 mmol) was added dropwise. After completion of the dropping, the reaction mixture was stirred at 120°C for another 3 hours. After the reaction was complete, the resulting mixture was cooled to room temperature, then 10 ml of water was added to dilute it, and the system was extracted with ethyl acetate (30 ml × 2). The combined organic layer was washed with 20 ml of saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was filtered to concentrate the residue, and the residue was purified through a preparation plate (dichloromethane/methanol=42/1) to obtain Example 5 ( 25.75 mg), as a white solid.
MS(ESI):m/z 535.3[M+H]+.MS(ESI):m/z 535.3[M+H] + .
H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.77(d,J＝8.0Hz,1H),7.67(d,J＝5.2Hz,1H),7.39(d,J＝5.6Hz,1H),7.29–7.27(m,1H),7.24(d,J＝2.4Hz,1H),7.09–7.06(m,1H),6.76(s,1H),6.66(t,J＝5.2Hz,1H),6.53(t,J＝4.2Hz,2H),6.48(s,1H),4.11–4.07(m,1H),4.02–3.97(m,1H),3.75(s,3H),3.72–3.68(m,1H),3.10–3.03(m,4H),2.92–2.79(m,2H),2.67–2.56(m,1H),2.33(s,3H),1.00(t,J＝7.2Hz,3H).H NMR (400MHz, DMSO-d 6 ) δ7.86 (s, 1H), 7.77 (d, J = 8.0Hz, 1H), 7.67 (d, J = 5.2Hz, 1H), 7.39 (d, J = 5.6 Hz,1H),7.29–7.27(m,1H),7.24(d,J＝2.4Hz,1H),7.09–7.06(m,1H),6.76(s,1H),6.66(t,J＝5.2Hz ,1H),6.53(t,J＝4.2Hz,2H),6.48(s,1H),4.11–4.07(m,1H),4.02–3.97(m,1H),3.75(s,3H),3.72– 3.68(m,1H),3.10–3.03(m,4H),2.92–2.79(m,2H),2.67–2.56(m,1H),2.33(s,3H),1.00(t,J＝7.2Hz, 3H).
实施例6

Example 6

步骤a:Step a:
室温下向1,2-二溴乙烷(7.55毫升,87.3毫摩尔),碳酸钾(24.1克,175毫摩尔)和100毫升乙腈的混合液中加入2，5-二溴苯酚6-1(11.0克,43.6毫摩尔)。将反应体系在80℃下搅拌18小时。反应毕混合液冷却至室温，加入200毫升水，再用乙酸乙酯(100毫升*2次)萃取。有机层合并后用饱和食盐水(100毫升)洗涤，再用无水硫酸钠干燥，过滤并减压浓缩得残留物，残留物用硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝100/1-50/1)得到1,4-二溴-2(2溴乙氧基)苯6-2(4.00克)，为无色油状物。To a mixture of 1,2-dibromoethane (7.55 ml, 87.3 mmol), potassium carbonate (24.1 g, 175 mmol) and 100 ml acetonitrile was added 2,5-dibromophenol 6-1 ( 11.0 g, 43.6 mmol). The reaction system was stirred at 80°C for 18 hours. After the reaction, the mixture was cooled to room temperature, 200 ml of water was added, and then extracted with ethyl acetate (100 ml x 2 times). The organic layers were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue, which was purified with a silica gel column (eluent: petroleum ether/ethyl acetate = 100 /1-50/1) to obtain 1,4-dibromo-2(2bromoethoxy)benzene 6-2 (4.00 g) as a colorless oil.
1H NMR(400MHz,DMSO-d6)δ7.54(d,J＝8.4Hz,1H),7.35(d,J＝2.1Hz,1H),7.12(dd,J＝8.4,2.1Hz,1H),4.48–4.43(m,2H),3.84–3.79(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.54(d,J＝8.4Hz,1H),7.35(d,J＝2.1Hz,1H),7.12(dd,J＝8.4,2.1Hz,1H) ,4.48–4.43(m,2H),3.84–3.79(m,2H).
步骤b:Step b:
将正丁基锂(7.31毫升，11.7毫摩尔，1.6M/己烷)缓慢添加到氮气保护-70℃下四氢呋喃(5毫升)和1,4-二溴-2(2溴乙氧基)苯6-2(4.20克，11.7毫摩尔)的溶液中。滴毕，反应液在-70℃下搅拌1小时，然后加入5毫升乙酸淬灭反应。再加入50毫升水稀释反应液，用乙酸乙酯(50毫升*2次)萃取。有机层合并后用50毫升饱和食盐水洗涤，再用无水硫酸钠干燥，有机相过滤并减压浓缩残留物，残留物用硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝1/0-100/1)得6-溴-2,3-二氢苯并呋喃6-3(1.20g)，为白色固体。n-Butyllithium (7.31 mL, 11.7 mmol, 1.6 M/hexane) was slowly added to tetrahydrofuran (5 mL) and 1,4-dibromo-2(2bromoethoxy)benzene under nitrogen protection at -70°C. 6-2 (4.20 g, 11.7 mmol). After the dropping was completed, the reaction solution was stirred at -70°C for 1 hour, and then 5 ml of acetic acid was added to quench the reaction. Add 50 ml of water to dilute the reaction solution, and extract with ethyl acetate (50 ml x 2 times). The organic layers were combined, washed with 50 ml of saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and the residue was concentrated under reduced pressure. The residue was purified with a silica gel column (eluent: petroleum ether/ethyl acetate = 1/ 0-100/1) to obtain 6-bromo-2,3-dihydrobenzofuran 6-3 (1.20g) as a white solid.
1H NMR(400MHz,CDCl3)δ7.03(d,J＝7.8Hz,1H),6.98–6.92(m,2H),4.58(t,J＝8.7Hz,2H),3.15(t,J＝8.5Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.03 (d, J＝7.8Hz, 1H), 6.98–6.92 (m, 2H), 4.58 (t, J＝8.7Hz, 2H), 3.15 (t, J＝ 8.5Hz,2H).
步骤c:Step c:
将6-溴-2,3-二氢苯并呋喃6-3(1.15克，5.84毫摩尔)，(E)-1-乙氧乙烯基-2-硼酸频 那醇酯(1.73克，8.76毫摩尔)、碳酸钾(2.42克，17.5毫摩尔)和1,1'-双(二苯基膦)二茂铁二氯化钯(427毫克，0.58毫摩尔)加入至20毫升二氧六环和5毫升水的混合液中，反应体系氩气置换三次再升温至80℃，并在此温度下搅拌2小时。加入50毫升水50毫升稀释反应液，再用乙酸乙酯(50毫升*2次)萃取。有机层合并后用50毫升饱和食盐水洗涤，再用无水硫酸钠干燥，有机相过滤并减压浓缩得残留物，残留物用硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝20/1-1/1)得6-4(1.00克)，为淡黄色固体。6-Bromo-2,3-dihydrobenzofuran 6-3 (1.15 g, 5.84 mmol), (E)-1-ethoxyvinyl-2-boronic acid That ester (1.73 g, 8.76 mmol), potassium carbonate (2.42 g, 17.5 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (427 mg, 0.58 mmol) Add to a mixture of 20 ml of dioxane and 5 ml of water, replace the reaction system with argon three times, then raise the temperature to 80°C, and stir at this temperature for 2 hours. Add 50 ml of water to dilute the reaction solution, and then extract with ethyl acetate (50 ml x 2 times). The organic layers were combined and washed with 50 ml of saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified with a silica gel column (eluent: petroleum ether/ethyl acetate = 20 /1-1/1) to obtain 6-4 (1.00 g) as a light yellow solid.
MS(ESI):m/z 191.2[M+H]+.MS(ESI):m/z 191.2[M+H] + .
步骤d:Step d:
0℃下，向(E)-6-(2-乙氧基乙烯基)-2,3-二氢苯并呋喃6-4(200毫克，1.06毫摩尔)和5毫升四氢呋喃的溶液中加入1.1毫升浓盐酸,体系在0℃下搅拌3小时，然后加入20毫升水，再用乙酸乙酯(20毫升*2次)萃取。有机层合并，用20毫升饱和食盐水洗涤，再用无水硫酸钠干燥，过滤并减压浓缩得到2-(2,3-二氢苯并呋喃-6-基)乙醛粗品6-5(554毫克),为黄色油状物，直接用于下一步反应。To a solution of (E)-6-(2-ethoxyvinyl)-2,3-dihydrobenzofuran 6-4 (200 mg, 1.06 mmol) and 5 ml of tetrahydrofuran was added 1.1 ml of concentrated hydrochloric acid, the system was stirred at 0°C for 3 hours, then 20 ml of water was added, and then extracted with ethyl acetate (20 ml * 2 times). The organic layers were combined, washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude 2-(2,3-dihydrobenzofuran-6-yl)acetaldehyde 6-5( 554 mg), as a yellow oil, which was directly used in the next reaction.
步骤e:Step e:
0℃下，向中间体6-5(554毫克,3.42毫摩尔)和甲醇(10毫升)的溶液中加入硼氢化钠(51毫克，1.06毫摩尔)。混合物在室温下搅拌1小时。用1当量(1N))稀盐酸调体系pH＝5，然后用乙酸乙酯(50毫升*2)萃取。有机层合并后用50毫升饱和食盐水洗涤，再用无水硫酸钠干燥，有机相过滤并减压浓缩得残留物，残留物用硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-3/1)得到6-6(230毫克)，为浅棕色油状物。To a solution of intermediate 6-5 (554 mg, 3.42 mmol) and methanol (10 mL) was added sodium borohydride (51 mg, 1.06 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour. Use 1 equivalent (1N)) dilute hydrochloric acid to adjust the system pH to 5, and then extract with ethyl acetate (50 ml*2). The organic layers were combined, washed with 50 ml of saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified with a silica gel column (eluent: petroleum ether/ethyl acetate = 10 /1-3/1) to obtain 6-6 (230 mg) as light brown oil.
1H NMR(400MHz,CDCl3)δ7.12(d,J＝7.6Hz,1H),6.70–6.72(m,1H),6.67(s,1H),4.56(t,J＝8.8Hz,2H),3.83–3.84(m,2H),3.18(t,J＝8.6Hz,2H),2.82(t,J＝6.4Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.12 (d, J＝7.6Hz, 1H), 6.70–6.72 (m, 1H), 6.67 (s, 1H), 4.56 (t, J＝8.8Hz, 2H) ,3.83–3.84(m,2H),3.18(t,J＝8.6Hz,2H),2.82(t,J＝6.4Hz,2H).
步骤f:Step f:
实施例6的制备按照类似实施例5的方法得到。用6-6(43.9毫克，0.27毫摩尔)和制备例1(100毫克)得到白色固体实施例6(24.37毫克)。Example 6 was prepared in a manner similar to Example 5. Using 6-6 (43.9 mg, 0.27 mmol) and Preparation 1 (100 mg) gave Example 6 (24.37 mg) as a white solid.
MS(ESI):m/z 521.3[M+H]+.MS(ESI):m/z 521.3[M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.24(d,J＝2.0Hz,1H),7.06–7.09(m,2H),6.76(s,1H),6.65–6.69(m,3H),6.48–6.53(m,3H),4.47(t,J＝8.6Hz,2H),3.98–4.00(m,1H),3.86–3.88(m,1H),3.76(s,3H),3.68–3.75(m,1H),3.05–3.11(m,4H),2.83–2.92(m,4H),2.56–2.80(m,1H),2.39(s,3H),1.00(t,J＝7.0Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.24 (d, J＝2.0Hz, 1H), 7.06–7.09 (m, 2H), 6.76 (s, 1H), 6.65–6.69 (m, 3H), 6.48–6.53(m,3H),4.47(t,J＝8.6Hz,2H),3.98–4.00(m,1H),3.86–3.88(m,1H),3.76(s,3H),3.68–3.75( m,1H),3.05–3.11(m,4H),2.83–2.92(m,4H),2.56–2.80(m,1H),2.39(s,3H),1.00(t,J＝7.0Hz,3H) .
实施例7

Example 7

步骤a:Step a:
氩气保护下将7-1(1.4克,7.1毫摩尔)，(E)-1-乙氧乙烯基-2-硼酸频那醇酯(2.10克10.6毫摩尔)，1,1'-双(二苯基膦)二茂铁二氯化钯(260毫克,0.36毫摩尔)，碳酸钾(2.00克,14.5毫摩尔)，1,4-二氧六环(30毫升)和水(6毫升)的混合物加热至80℃搅拌3小时。将反应液冷却至室温后经过滤后加水(20毫升)并用乙酸乙酯(3X 30毫升)萃取。合并后的有机相经干燥并过滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯20/1～10/1)，得到浅黄色固体7-2(1.10克)。Under argon protection, 7-1 (1.4 g, 7.1 mmol), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (2.10 g, 10.6 mmol), 1,1'-bis( Diphenylphosphine) ferrocene palladium dichloride (260 mg, 0.36 mmol), potassium carbonate (2.00 g, 14.5 mmol), 1,4-dioxane (30 ml) and water (6 ml) The mixture was heated to 80°C and stirred for 3 hours. The reaction solution was cooled to room temperature, filtered, water (20 ml) was added and extracted with ethyl acetate (3×30 ml). The combined organic phases were dried and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 20/1 to 10/1) to obtain light yellow solid 7-2 (1.10 g).
1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.64(d,J＝8.4Hz,1H),7.40(s,1H),7.27-7.23(m,1H),7.03(d,J＝12.8Hz,1H),5.95(d,J＝13.2Hz,1H),3.93(q,J＝7.1Hz,2H),1.36(t,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.01 (s, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.40 (s, 1H), 7.27-7.23 (m, 1H), 7.03 (d, J＝12.8Hz,1H),5.95(d,J＝13.2Hz,1H),3.93(q,J＝7.1Hz,2H),1.36(t,J＝7.0Hz,3H).
步骤b:Step b:
将7-2(250毫克,1.321毫摩尔)的甲酸(3.5毫升)溶液于室温下搅拌3小时。所得混合物加饱和碳酸氢钠水溶液(30毫升)后用乙酸乙酯(2X 30毫升)萃取。合并后的有机相经饱和食盐水(20毫升)洗涤，无水硫酸钠干燥并过滤。滤液浓缩，得到粗品黄色油状物7-3(213mg)。可以直接用于下一步反应。A solution of 7-2 (250 mg, 1.321 mmol) in formic acid (3.5 mL) was stirred at room temperature for 3 hours. The resulting mixture was added with saturated aqueous sodium bicarbonate solution (30 ml) and extracted with ethyl acetate (2×30 ml). The combined organic phases were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain crude yellow oil 7-3 (213 mg). It can be used directly for the next reaction.
步骤c:Step c:
0℃下向搅拌着的粗品7-3(213mg,1.321毫摩尔)的甲醇(10mL)溶液中加入硼氢化钠(50mg,1.321毫摩尔)。反应液随后同温下搅拌1小时。向反应液中加入稀盐酸(1.0M)淬灭反应，直至pH＝5。所得混合物用乙酸乙酯(2X 50毫升)萃取。合并后的有机相经饱和食盐水(50毫升)洗涤，无水硫酸钠干燥并过滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯10/1～1/1)，得到7-4(60毫克(棕色油状物)。To a stirred solution of crude product 7-3 (213 mg, 1.321 mmol) in methanol (10 mL) was added sodium borohydride (50 mg, 1.321 mmol) at 0°C. The reaction solution was then stirred at the same temperature for 1 hour. Dilute hydrochloric acid (1.0M) was added to the reaction solution to quench the reaction until pH=5. The resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with saturated brine (50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 10/1 to 1/1) to obtain 7-4 (60 mg (brown oil)).
1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.72(d,J＝8.0Hz,1H),7.48(d,J＝0.4Hz,1H),7.25(dd,J＝8.4,1.2Hz,1H),3.93(t,J＝6.4Hz,2H),3.02(t,J＝6.4Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.06 (s, 1H), 7.72 (d, J = 8.0Hz, 1H), 7.48 (d, J = 0.4Hz, 1H), 7.25 (dd, J = 8.4, 1.2Hz,1H),3.93(t,J＝6.4Hz,2H),3.02(t,J＝6.4Hz,2H).
步骤d:Step d:
室温下将制备例1(168毫克0.448毫摩尔)，三苯基膦(126mg,0.4785毫摩尔)，7-4(60mg,0.368毫摩尔)的甲苯(5mL)溶液氩气抽换气三次，氩气保护下加热至120℃搅拌10分钟。随后逐滴加入偶氮二甲酸二异丙酯(0.08mL,0.4785毫摩尔)。反应液随后120℃并且氩气保护下搅拌3小时。反应液冷却至室温后加水(10mL)，所得混合物 用乙酸乙酯(2X 30毫升)萃取。合并后的有机相经饱和食盐水(20毫升)洗涤，无水硫酸钠干燥并过滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯10/1～1/2)，再经薄层制备色谱分离(展开剂:二氯甲烷/甲醇＝40/1)，得到白色固体实施例7(35.23毫克)。A solution of Preparation Example 1 (168 mg, 0.448 mmol), triphenylphosphine (126 mg, 0.4785 mmol), and 7-4 (60 mg, 0.368 mmol) in toluene (5 mL) was purged and ventilated with argon three times at room temperature. Heat to 120°C under air protection and stir for 10 minutes. Then diisopropyl azodicarboxylate (0.08 mL, 0.4785 mmol) was added dropwise. The reaction solution was then stirred at 120°C for 3 hours under argon protection. After the reaction solution was cooled to room temperature, water (10 mL) was added, and the resulting mixture Extract with ethyl acetate (2X 30 mL). The combined organic phases were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 10/1~1/2), and then separated by thin layer preparative chromatography (developing agent: dichloromethane/methanol=40/ 1), white solid Example 7 (35.23 mg) was obtained.
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),7.69-7.66(m,2H),7.30(dd,J＝8.2,1.4Hz,1H),7.24(d,J＝2.4Hz,1H),7.07(dd,J＝8.4,2.4Hz,1H),6.76(s,1H),6.66(t,J＝5.4Hz,1H),6.53-6.48(m,3H),4.11-4.08(m,1H),4.07-3.97(m,1H),3.75(s,3H),3.72-3.68(m,1H),3.12-3.04(m,4H),2.95-2.75(m,2H),2.56-2.55(m,1H),2.39(s,3H),1.00(t,J＝7.2Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.66 (s, 1H), 7.69-7.66 (m, 2H), 7.30 (dd, J = 8.2, 1.4Hz, 1H), 7.24 (d, J = 2.4 Hz,1H),7.07(dd,J＝8.4,2.4Hz,1H),6.76(s,1H),6.66(t,J＝5.4Hz,1H),6.53-6.48(m,3H),4.11-4.08 (m,1H),4.07-3.97(m,1H),3.75(s,3H),3.72-3.68(m,1H),3.12-3.04(m,4H),2.95-2.75(m,2H),2.56 -2.55(m,1H),2.39(s,3H),1.00(t,J=7.2Hz,3H).
LC-MS(ESI):m/z 520.2[M+H]+.LC-MS(ESI):m/z 520.2[M+H] + .
实施例8
Example 8
步骤a:Step a:
将8-1(2.3克,10.74毫摩尔)，乙烯三氟硼酸钾(2.16克,16.12毫摩尔)，双(三苯基膦)二氯化钯(754毫克,1.07毫摩尔)，碳酸钾(4.45克,32.2毫摩尔)，1,4-二氧六环(100毫升)和水(20毫升)的混合物加热至90℃并且氩气保护下搅拌5小时。将反应液冷却至室温后加水(100毫升)，所得混合物用乙酸乙酯(3X 100毫升)萃取。合并后的有机相经饱和食盐水(100毫升)洗涤，无水硫酸钠干燥并过滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯＝20/1)，得到8-2(1.30克)，为无色油状 物。Combine 8-1 (2.3 g, 10.74 mmol), potassium ethylene trifluoroborate (2.16 g, 16.12 mmol), bis(triphenylphosphine)palladium dichloride (754 mg, 1.07 mmol), potassium carbonate ( A mixture of 4.45 g, 32.2 mmol), 1,4-dioxane (100 ml) and water (20 ml) was heated to 90°C and stirred under argon for 5 hours. The reaction solution was cooled to room temperature, water (100 ml) was added, and the resulting mixture was extracted with ethyl acetate (3X 100 ml). The combined organic phases were washed with saturated brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1) to obtain 8-2 (1.30 g) as a colorless oil. things.
LC-MS(ESI):m/z 162.0[M+H]+.LC-MS(ESI):m/z 162.0[M+H] + .
步骤b:Step b:
室温并且氩气保护下向搅拌着的8-2(1.3克,8.06毫摩尔)的四氢呋喃(100毫升)溶液中逐滴加入9-BBN的四氢呋喃溶液(0.5摩尔浓度,24.2毫升L,12.1毫摩尔)。反应液随后加热至80℃并且氩气保护下搅拌4小时。将反应液冷却至室温，搅拌下逐滴加入双氧水(30％水溶液,4.57克,40.32毫摩尔)。所得混合物加热至80℃并且搅拌1小时。反应液冷却至室温后加乙酸乙酯(2X 100毫升)萃取。合并后的有机相经水(2X 100毫升)洗涤，亚硫酸钠水溶液(50毫升)洗涤，无水硫酸钠干燥并过滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯＝2/1)，得到8-3(620毫克)，为浅黄色油状物。To a stirring solution of 8-2 (1.3 g, 8.06 mmol) in tetrahydrofuran (100 ml) at room temperature and under argon protection, 9-BBN in tetrahydrofuran (0.5 molar concentration, 24.2 ml L, 12.1 mmol) was added dropwise. ). The reaction solution was then heated to 80°C and stirred under argon protection for 4 hours. The reaction solution was cooled to room temperature, and hydrogen peroxide (30% aqueous solution, 4.57 g, 40.32 mmol) was added dropwise with stirring. The resulting mixture was heated to 80°C and stirred for 1 hour. The reaction solution was cooled to room temperature and extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with water (2×100 ml), aqueous sodium sulfite solution (50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 2/1) to obtain 8-3 (620 mg) as a light yellow oil.
LC-MS(ESI):m/z 180.1[M+H]+.LC-MS(ESI):m/z 180.1[M+H] + .
步骤c:Step c:
室温下将8-3(150毫克,0.837毫摩尔)，制备例1(313毫克,0.835毫摩尔)和三苯基膦(263毫克，1.00毫摩尔)的干燥四氢呋喃(10毫升)溶液氩气抽换气三次，氩气保护下冷却至0℃并且搅拌下逐滴加入偶氮二甲酸二异丙酯(0.199毫升,1.00毫摩尔)的四氢呋喃(3毫升)溶液。反应液随后恢复至室温并且氩气保护下搅拌2小时。将反应液浓缩，所得残渣经高效液相制备色谱分离(Waters 2767/2545/2489/Qda,Inertsil ODS-3 10um 20*250nm,流动相A:0.1％甲酸水溶液,流动相B:乙腈,流速:20毫升/分钟:柱温:室温)，得到实施例8(27.4毫克)，为白色固体。A solution of 8-3 (150 mg, 0.837 mmol), Preparation 1 (313 mg, 0.835 mmol) and triphenylphosphine (263 mg, 1.00 mmol) in dry tetrahydrofuran (10 ml) was purged with argon at room temperature. The mixture was ventilated three times, cooled to 0°C under argon protection, and a solution of diisopropyl azodicarboxylate (0.199 ml, 1.00 mmol) in tetrahydrofuran (3 ml) was added dropwise with stirring. The reaction solution was then returned to room temperature and stirred under argon protection for 2 hours. The reaction solution was concentrated, and the resulting residue was separated by high performance liquid phase preparative chromatography (Waters 2767/2545/2489/Qda, Inertsil ODS-3 10um 20*250nm, mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: acetonitrile, flow rate: 20 ml/min: column temperature: room temperature), Example 8 (27.4 mg) was obtained as a white solid.
LC-MS(ESI):m/z 536.3[M+H]+.LC-MS(ESI):m/z 536.3[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.15-7.97(m,2H),7.45-7.37(m,1H),7.24(d,J＝2.1Hz,1H),7.07(dd,J＝8.3,2.2Hz,1H),6.76(s,1H),6.67(t,J＝5.4Hz,1H),6.58-6.42(m,3H),4.14-4.08(m,1H),4.05-3.98(m,1H),3.74(s,3H),3.73-3.65(m,1H),3.16-3.05(m,4H),2.95-2.70(m,2H),2.58-2.53(m,1H),2.38(s,3H),1.00(t,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.35 (s, 1H), 8.15-7.97 (m, 2H), 7.45-7.37 (m, 1H), 7.24 (d, J = 2.1Hz, 1H), 7.07(dd,J＝8.3,2.2Hz,1H),6.76(s,1H),6.67(t,J＝5.4Hz,1H),6.58-6.42(m,3H),4.14-4.08(m,1H) ,4.05-3.98(m,1H),3.74(s,3H),3.73-3.65(m,1H),3.16-3.05(m,4H),2.95-2.70(m,2H),2.58-2.53(m, 1H),2.38(s,3H),1.00(t,J=7.1Hz,3H).
实施例9
Example 9
实施例9的制备按照类似实施例8的方法得到。用原料2-(苯并【d-】噻唑-6-)基)乙醇-1(200毫克，1.116毫摩尔)和制备例1(349毫克,0.931毫摩尔)反应得到白色固体实施例9(151.26毫克)。Example 9 was prepared in a manner similar to Example 8. The raw material 2-(benzo[d-]thiazol-6-)yl)ethanol-1 (200 mg, 1.116 mmol) was reacted with Preparation Example 1 (349 mg, 0.931 mmol) to obtain white solid Example 9 (151.26 mg).
LC-MS(ESI):m/z 536.1[M+H]+.LC-MS(ESI):m/z 536.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.03(d,J＝1.2Hz,1H),7.98(d,J＝8.4Hz,1H),7.45(dd,J＝8.4,1.6Hz,1H),7.24(d,J＝2.0Hz,1H),7.08(dd,J＝8.2,2.2Hz,1H),6.77(s,1H),6.67(t,J＝5.4Hz,1H),6.55-6.50(m,2H),6.49(s,1H),4.15-4.08(m,1H),4.04-3.96(m,1H),3.75(s,3H),3.74-3.67(m,1H),3.14-3.03(m,4H),2.97- 2.87(m,1H),2.86-2.75(m,1H),2.58-2.52(m,1H),2.39(s,3H),1.00(t,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.32 (s, 1H), 8.03 (d, J = 1.2Hz, 1H), 7.98 (d, J = 8.4Hz, 1H), 7.45 (dd, J = 8.4,1.6Hz,1H),7.24(d,J＝2.0Hz,1H),7.08(dd,J＝8.2,2.2Hz,1H),6.77(s,1H),6.67(t,J＝5.4Hz, 1H),6.55-6.50(m,2H),6.49(s,1H),4.15-4.08(m,1H),4.04-3.96(m,1H),3.75(s,3H),3.74-3.67(m, 1H),3.14-3.03(m,4H),2.97- 2.87(m,1H),2.86-2.75(m,1H),2.58-2.52(m,1H),2.39(s,3H),1.00(t,J=7.1Hz,3H).
实施例10
Example 10
步骤a:Step a:
室温并且氩气保护下向10-1(8.00克,40.6毫摩尔)，1,4-二氧六环(150毫升)和水(50毫升)的混合物中加入乙烯三氟硼酸钾(8.16克,60.9毫摩尔)，1,1'-双(二苯基膦)二茂铁二氯化钯(1.48克,2.03毫摩尔)和碳酸铯(39.7克，122毫摩尔)。反应液随后加热至100℃并且氩气保护下搅拌16小时。反应液冷却至室温后抽滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯＝4/1)，得到10-2(4.30克)，为黄色固体。To a mixture of 10-1 (8.00 g, 40.6 mmol), 1,4-dioxane (150 ml) and water (50 ml) was added potassium ethylene trifluoroborate (8.16 g, 50 ml) at room temperature under argon protection. 60.9 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (1.48 g, 2.03 mmol) and cesium carbonate (39.7 g, 122 mmol). The reaction solution was then heated to 100°C and stirred under argon for 16 hours. The reaction solution was cooled to room temperature and then filtered with suction. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 4/1) to obtain 10-2 (4.30 g) as a yellow solid.
LC-MS(ESI):m/z 145.1[M+H]+.LC-MS(ESI):m/z 145.1[M+H] + .
步骤b:Step b:
室温下向搅拌着的10-2(1.00克,6.94毫摩尔)的四氢呋喃(10毫升)溶液中加入二碳酸二叔丁酯(4.45毫升,20.8毫摩尔)和4-二甲氨基吡啶(0.42克,3.47毫摩尔。反应液随后室温下搅拌3小时。反应液加水(100毫升)稀释后用二氯甲烷(2X 100毫升)萃取。合并后的有机相经饱和食盐水(100毫升)洗涤，无水硫酸钠干燥并过滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯＝100/1～80/1)，得到10-3(1.10克)，为黄色固体。To a stirred solution of 10-2 (1.00 g, 6.94 mmol) in tetrahydrofuran (10 ml) at room temperature were added di-tert-butyl dicarbonate (4.45 ml, 20.8 mmol) and 4-dimethylaminopyridine (0.42 g , 3.47 mmol. The reaction solution was then stirred at room temperature for 3 hours. The reaction solution was diluted with water (100 ml) and extracted with dichloromethane (2×100 ml). The combined organic phases were washed with saturated brine (100 ml). Dry over sodium sulfate and filter. The filtrate is concentrated, and the resulting residue is separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1 ~ 80/1) to obtain 10-3 (1.10 g), which is yellow solid.
LC-MS(ESI):m/z 189.1[M-t-Bu+2H]+.LC-MS(ESI):m/z 189.1[Mt-Bu+2H] + .
步骤c:Step c:
0℃并且氩气保护下向搅拌着的硼烷四氢呋喃溶液(1.0M,4.91毫升,4.91毫摩 尔)和干燥四氢呋喃(20毫升)混合物中逐滴加入10-3(800毫克,3.28毫摩尔)的四氢呋喃(30毫升)溶液。反应液随后恢复至室温并且氩气保护下搅拌过夜。逐滴加入氢氧化钠水溶液(3.0M,1.64毫升,4.92毫摩尔)和双氧水(30％水溶液,0.493毫升,4.91毫摩尔)。所得混合物加热至80℃并且搅拌5小时。反应液冷却至室温后加水(40毫升)稀释，所得混合物用二氯甲烷(2X 100毫升)萃取。合并后的有机相经饱和食盐水(30毫升)洗涤，无水硫酸钠干燥并过滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇＝40/1)，得到10-4(500mg)，为黄色固体。To a stirring solution of borane in tetrahydrofuran (1.0 M, 4.91 ml, 4.91 mmol) at 0°C under argon protection A solution of 10-3 (800 mg, 3.28 mmol) in tetrahydrofuran (30 ml) was added dropwise to a mixture of (e) and dry tetrahydrofuran (20 ml). The reaction solution was then returned to room temperature and stirred overnight under argon protection. Aqueous sodium hydroxide solution (3.0 M, 1.64 mL, 4.92 mmol) and hydrogen peroxide (30% aqueous solution, 0.493 mL, 4.91 mmol) were added dropwise. The resulting mixture was heated to 80°C and stirred for 5 hours. The reaction solution was cooled to room temperature and diluted with water (40 ml), and the resulting mixture was extracted with dichloromethane (2X 100 ml). The combined organic phases were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol=40/1) to obtain 10-4 (500 mg) as a yellow solid.
LC-MS(ESI):m/z 263.0[M+H]+.LC-MS(ESI):m/z 263.0[M+H] + .
步骤d:Step d:
室温下将10-4(200毫克,0.762毫摩尔)，30-3(239毫克,0.635毫摩尔)和三苯基膦(200毫克,0.762毫摩尔)的干燥四氢呋喃(10毫升)溶液氩气抽换气三次，氩气保护下冷却至0℃并且搅拌下逐滴加入偶氮二甲酸二异丙酯(0.151毫升,0.762毫摩尔)的四氢呋喃(10毫升)溶液。反应液随后恢复至室温并且氩气保护下搅拌3小时。将反应液浓缩，所得残渣加水(50毫升)稀释后用二氯甲烷(2X 100毫升)萃取。合并后的有机相经饱和食盐水(100毫升)洗涤，无水硫酸钠干燥并过滤。滤液浓缩，所得残渣经硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇＝50/1～10/1)，得到10-5(210毫升)，为黄色固体。A solution of 10-4 (200 mg, 0.762 mmol), 30-3 (239 mg, 0.635 mmol) and triphenylphosphine (200 mg, 0.762 mmol) in dry tetrahydrofuran (10 ml) was evaporated under argon at room temperature. The mixture was ventilated three times, cooled to 0°C under argon protection, and a solution of diisopropyl azodicarboxylate (0.151 ml, 0.762 mmol) in tetrahydrofuran (10 ml) was added dropwise with stirring. The reaction solution was then returned to room temperature and stirred under argon protection for 3 hours. The reaction solution was concentrated, and the resulting residue was diluted with water (50 ml) and extracted with dichloromethane (2×100 ml). The combined organic phases were washed with saturated brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol=50/1~10/1) to obtain 10-5 (210 ml) as a yellow solid.
LC-MS(ESI):m/z 619.2[M+H]+.LC-MS(ESI):m/z 619.2[M+H] + .
步骤e:Step e:
将10-5(150毫克,0.242毫摩尔)和氯化氢/1,4-二氧六环溶液(4.0M,10毫升,40毫摩尔)的混合物在室温下搅拌4小时。反应液浓缩，所得残渣经高效液相制备色谱分离(Waters 2767/2545/2489/Qda,Inertsil ODS-3 10um 20*250nm,流动相A:0.1％甲酸溶液,流动相B:CH3CN,流速:20毫升/分钟:柱温:室温)，得到实施例10(33.16毫克)，为白色固体。A mixture of 10-5 (150 mg, 0.242 mmol) and hydrogen chloride/1,4-dioxane solution (4.0 M, 10 mL, 40 mmol) was stirred at room temperature for 4 h. The reaction solution was concentrated, and the resulting residue was separated by high performance liquid phase preparative chromatography (Waters 2767/2545/2489/Qda, Inertsil ODS-3 10um 20*250nm, mobile phase A: 0.1% formic acid solution, mobile phase B: CH 3 CN, flow rate :20 ml/min: column temperature: room temperature) to obtain Example 10 (33.16 mg) as a white solid.
LC-MS(ESI):m/z 519.3[M+H]+.LC-MS(ESI):m/z 519.3[M+H] + .
1H NMR(400MHz,DMSO-d6)δ12.93(s,1H),7.96(s,1H),7.58(s,1H),7.43(d,J＝8.5Hz,1H),7.29-7.17(m,2H),7.08(dd,J＝8.3,2.1Hz,1H),6.76(s,1H),6.66(t,J＝5.3Hz,1H),6.55-6.47(m,3H),4.10-4.04(m,1H),3.96-3.92(m,1H),3.75(s,3H)3.74-3.66(m,1H),3.13-2.98(m,4H),2.96-2.72(m,2H),2.56-2.51(m,1H),2.39(s,3H),1.00(t,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.93 (s, 1H), 7.96 (s, 1H), 7.58 (s, 1H), 7.43 (d, J = 8.5Hz, 1H), 7.29-7.17 ( m,2H),7.08(dd,J＝8.3,2.1Hz,1H),6.76(s,1H),6.66(t,J＝5.3Hz,1H),6.55-6.47(m,3H),4.10-4.04 (m,1H),3.96-3.92(m,1H),3.75(s,3H)3.74-3.66(m,1H),3.13-2.98(m,4H),2.96-2.72(m,2H),2.56- 2.51(m,1H),2.39(s,3H),1.00(t,J＝7.1Hz,3H).
实施例11
Example 11
实施11的制备按照类似实施例10的方法得到。用2-(苯并【d-】吡唑-6-)基)乙醇-1(100毫克，0.381毫摩尔)和制备例1(142毫克,0.379毫摩尔)反应得到白色固体中间体(30毫克)。The preparation of Example 11 was obtained by a method similar to that of Example 10. Use 2-(benzo[d-]pyrazol-6-)yl)ethanol-1 (100 mg, 0.381 mmol) and Preparation Example 1 (142 mg, 0.379 mmol) to obtain a white solid intermediate (30 mg ).
将中间体(30毫克,0.048毫摩尔)和氯化氢/1,4-二氧六环溶液(4.0M,3毫升,12毫摩尔)的混合物在室温下搅拌2小时。反应液浓缩，所得残渣经高效液相制备色谱分离(流动相含碳酸氢铵)，得到实施例11(6.67mg)，为白色固体。 A mixture of the intermediate (30 mg, 0.048 mmol) and hydrogen chloride/1,4-dioxane solution (4.0 M, 3 mL, 12 mmol) was stirred at room temperature for 2 h. The reaction solution was concentrated, and the resulting residue was separated by high-performance liquid phase preparative chromatography (the mobile phase contained ammonium bicarbonate) to obtain Example 11 (6.67 mg) as a white solid.
LC-MS(ESI):m/z 519.3[M+H]+.LC-MS(ESI):m/z 519.3[M+H] + .
1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),7.98(s,1H),7.63(d,J＝8.0Hz,1H),7.40(s,1H),7.24(d,J＝2.0Hz,1H),7.09-7.00(m,2H),6.76(s,1H),6.67(t,J＝5.2Hz,1H),6.54-6.48(m,3H),4.11-4.04(m,1H),4.00-3.92(m,1H),3.74(s,3H),3.74-3.69(m,1H),3.10-3.04(m,4H),2.96-2.65(m,2H),2.60-2.52(m,1H),2.39(s,3H),1.00(t,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.91 (s, 1H), 7.98 (s, 1H), 7.63 (d, J = 8.0Hz, 1H), 7.40 (s, 1H), 7.24 (d, J＝2.0Hz,1H),7.09-7.00(m,2H),6.76(s,1H),6.67(t,J＝5.2Hz,1H),6.54-6.48(m,3H),4.11-4.04(m ,1H),4.00-3.92(m,1H),3.74(s,3H),3.74-3.69(m,1H),3.10-3.04(m,4H),2.96-2.65(m,2H),2.60-2.52 (m,1H),2.39(s,3H),1.00(t,J＝7.1Hz,3H).
实施例12
Example 12
实施例12的制备按照类似实施例2的方法得到。用2-(3,3-二氟-2,3-二氢-1H-茚-5-基-5-基)乙烷-1-乙烷-1-醇(53.0mg)和制备例1(100毫克)得到白色固体实施例12(35.25毫克)。Example 12 was prepared in a manner similar to Example 2. Using 2-(3,3-difluoro-2,3-dihydro-1H-inden-5-yl-5-yl)ethane-1-ethan-1-ol (53.0 mg) and Preparation Example 1 ( 100 mg) to give Example 12 (35.25 mg) as a white solid.
1H NMR(400MHz,DMSO-d6)δ7.47(s,1H),7.39(d,J＝8.0Hz,1H),7.28(d,J＝8.0Hz,1H),7.24(s,1H),7.07(d,J＝8.0Hz,1H),6.76(s,1H),6.66(s,1H),6.51(t,J＝10.0Hz,3H),4.08–4.02(m,1H),3.96–3.90(m,1H),3.74(s,3H),3.69–3.67(m,1H),3.08–3.05(m,2H),3.03–2.75(m,6H),2.57–2.52(m,2H),2.39(s,3H),2.28–2.25(m,1H),1.00(t,J＝6.0Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.47 (s, 1H), 7.39 (d, J = 8.0Hz, 1H), 7.28 (d, J = 8.0Hz, 1H), 7.24 (s, 1H) ,7.07(d,J＝8.0Hz,1H),6.76(s,1H),6.66(s,1H),6.51(t,J＝10.0Hz,3H),4.08–4.02(m,1H),3.96– 3.90(m,1H),3.74(s,3H),3.69–3.67(m,1H),3.08–3.05(m,2H),3.03–2.75(m,6H),2.57–2.52(m,2H), 2.39(s,3H),2.28–2.25(m,1H),1.00(t,J＝6.0Hz,3H).
MS(ESI)m/z:555.2[M+H]+；MS(ESI)m/z:555.2[M+H] + ;
实施列13
Implement column 13
实施例13的制备按照类似实施例6的方法得到。用原料5-(2-羟乙基)-2,3-二氢苯并呋喃(130毫克，0.79毫摩尔)和制备例1(296毫克)反应得到白色固体实施例13(51.66毫克)。Example 13 was prepared in a manner similar to Example 6. The raw material 5-(2-hydroxyethyl)-2,3-dihydrobenzofuran (130 mg, 0.79 mmol) was reacted with Preparation Example 1 (296 mg) to obtain Example 13 (51.66 mg) as a white solid.
MS(ESI):m/z 521.2[M+H]+ MS(ESI):m/z 521.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ7.25(d,J＝2.1Hz,1H),7.10–7.06(m,2H),6.93(d,J＝8.1Hz,1H),6.76(s,1H),6.67(t,J＝5.4Hz,1H),6.62(d,J＝8.1Hz,1H),6.53(d,J＝8.3Hz,1H),6.49(d,J＝3.0Hz,2H),4.46(t,J＝8.7Hz,2H),3.97(dd,J＝16.4,7.5Hz,1H),3.85(dd,J＝16.8,7.3Hz,1H),3.75(s,3H),3.72–3.66(m,1H),3.10–3.00(m,4H),2.96–2.74(m,4H),2.56(d,J＝3.2Hz,1H),2.39(s,3H),1.00(t,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.25 (d, J = 2.1 Hz, 1H), 7.10–7.06 (m, 2H), 6.93 (d, J = 8.1 Hz, 1H), 6.76 (s, 1H),6.67(t,J＝5.4Hz,1H),6.62(d,J＝8.1Hz,1H),6.53(d,J＝8.3Hz,1H),6.49(d,J＝3.0Hz,2H) ,4.46(t,J＝8.7Hz,2H),3.97(dd,J＝16.4,7.5Hz,1H),3.85(dd,J＝16.8,7.3Hz,1H),3.75(s,3H),3.72– 3.66(m,1H),3.10–3.00(m,4H),2.96–2.74(m,4H),2.56(d,J＝3.2Hz,1H),2.39(s,3H),1.00(t,J＝ 7.1Hz,3H).
实施例14
Example 14
实施14的制备按照类似实施例8的方法得到。用2-(苯并[d][1,3]二氧醇-5-基]乙烷-1-乙烷-1-1-醇(300毫克，1.81毫摩尔)和制备例1(564毫克,1.51毫摩尔)反应得到白色固体实施例14(206.5毫克)。The preparation of Example 14 was obtained by a method similar to that of Example 8. Using 2-(benzo[d][1,3]dioxol-5-yl]ethane-1-ethan-1-1-ol (300 mg, 1.81 mmol) and Preparation 1 (564 mg , 1.51 mmol) reacted to obtain white solid Example 14 (206.5 mg).
MS(ESI):m/z 523.2[M+H]+ MS(ESI):m/z 523.2[M+H] +
1H NMR(400MHz,DMSO-d6))δ7.24(d,J＝1.2Hz,1H),7.10–7.05(m,1H),6.79(s,1H),6.78–6.75(m,2H),6.74–6.65(m,2H),6.52–6.48(m,3H),5.93(s,2H),4.01–3.95(m,1H),3.89–3.85(m,1H),3.88–3.74(m,4H),3.15–3.00(m,2H),2.90–2.75(m,4H),2.39(s,3H),1.25(s,1H),1.00(t,J＝7.2Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )) δ7.24 (d, J＝1.2Hz, 1H), 7.10–7.05 (m, 1H), 6.79 (s, 1H), 6.78–6.75 (m, 2H) ,6.74–6.65(m,2H),6.52–6.48(m,3H),5.93(s,2H),4.01–3.95(m,1H),3.89–3.85(m,1H),3.88–3.74(m, 4H),3.15–3.00(m,2H),2.90–2.75(m,4H),2.39(s,3H),1.25(s,1H),1.00(t,J＝7.2Hz,3H).
实施例15
Example 15
步骤a:Step a:
在干燥的250毫升三口烧瓶中依次加入化合物2-(2,3-二氢苯并[b][1,4]二恶英-6-基)乙酸15-1(1.00克，5.15毫摩尔)和无水四氢呋喃溶液(30毫升)，0度下滴加硼烷(8.0毫升，8.0毫摩尔，1.0M)的四氢呋喃(30毫升)溶液，然后升至室温，搅拌反应4小时。薄板层析(TLC)监测反应结束后，反应液减压浓缩，加入冰水(80毫升)，乙酸乙酯(60毫升×2)萃取。有机层合并，用盐水(30毫升)洗涤，无水硫酸钠干燥，过滤并浓缩以得到15-2(780毫克，黄色油状)。In a dry 250 ml three-necked flask, compound 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetic acid 15-1 (1.00 g, 5.15 mmol) was added successively. and anhydrous tetrahydrofuran solution (30 ml), a solution of borane (8.0 ml, 8.0 mmol, 1.0 M) in tetrahydrofuran (30 ml) was added dropwise at 0°C, then raised to room temperature, and the reaction was stirred for 4 hours. After the reaction was monitored by thin plate chromatography (TLC), the reaction solution was concentrated under reduced pressure, ice water (80 ml) was added, and extracted with ethyl acetate (60 ml × 2). The organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 15-2 (780 mg, yellow oil).
LC-MS(ESI):m/z 163.0[M-OH]+.LC-MS(ESI):m/z 163.0[M-OH] + .
步骤b:Step b:
实施例15的制备按照类似实施例8的方法得到。用2-(2,3-二氢苯并[b][1,4]二恶英-6-基乙烷-1-乙烷-1-醇(200m毫克，1.11毫摩尔)15-2和制备例1(349毫克,0.93毫摩 尔)反应得到灰白色固体实施例15(100毫克)。Example 15 was prepared in a manner similar to Example 8. Use 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-ylethan-1-ethan-1-ol (200 m mg, 1.11 mmol) 15-2 and Preparation Example 1 (349 mg, 0.93 mmol Er) reaction gave off-white solid Example 15 (100 mg).
MS(ESI):m/z 537.2[M+H]+ MS(ESI):m/z 537.2[M+H] +
1H NMR(400MHz,CDCl3)δ7.19(d,J＝2.1Hz,1H),6.99(dd,J＝8.2,2.5Hz,1H),6.76(d,J＝8.2Hz,1H),6.72(d,J＝2.0Hz,1H),6.68–6.61(m,3H),6.48(s,1H),6.36(s,1H),4.22(s,4H),4.06–3.90(m,2H),3.86(s,3H),3.57–3.47(m,1H),3.33–3.22(m,3H),3.04–2.89(m,3H),2.64(d,J＝15.4Hz,1H),2.48(s,3H),1.63(s,1H),1.12(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.19 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 8.2, 2.5 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.72 (d,J＝2.0Hz,1H),6.68–6.61(m,3H),6.48(s,1H),6.36(s,1H),4.22(s,4H),4.06–3.90(m,2H), 3.86(s,3H),3.57–3.47(m,1H),3.33–3.22(m,3H),3.04–2.89(m,3H),2.64(d,J＝15.4Hz,1H),2.48(s, 3H),1.63(s,1H),1.12(t,J=7.2Hz,3H).
实施例16
Example 16
实施例16的制备按照类似实施例5的方法得到。用原料2-(苯并[b]噻吩-5-基]乙烷-1-醇(200毫克，1.12毫摩尔)和制备例1(350毫克)得到白色固体实施例16(62.55毫克)。Example 16 was prepared in a manner similar to Example 5. Starting from 2-(benzo[b]thiophen-5-yl]ethan-1-ol (200 mg, 1.12 mmol) and Preparation 1 (350 mg), Example 16 (62.55 mg) was obtained as a white solid.
MS(ESI):m/z 535.2[M+H]+.MS(ESI):m/z 535.2[M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.88(d,J＝8.2Hz,1H),7.76–7.70(m,2H),7.37(d,J＝5.5Hz,1H),7.27(d,J＝8.4Hz,1H),7.24(d,J＝1.9Hz,1H),7.09–7.06(m,1H),6.76(s,1H),6.67(t,J＝5.2Hz,1H),6.52(t,J＝4.1Hz,2H),6.48(s,1H),4.11–4.06(m,1H),4.02–3.95(m,1H),3.75(s,3H),3.70(s,1H),3.06(t,J＝6.4Hz,4H),2.96–2.75(m,2H),2.56(s,1H),2.38(s,3H),1.00(t,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.88 (d, J = 8.2 Hz, 1H), 7.76–7.70 (m, 2H), 7.37 (d, J = 5.5 Hz, 1H), 7.27 (d, J＝8.4Hz,1H),7.24(d,J＝1.9Hz,1H),7.09–7.06(m,1H),6.76(s,1H),6.67(t,J＝5.2Hz,1H),6.52( t,J＝4.1Hz,2H),6.48(s,1H),4.11–4.06(m,1H),4.02–3.95(m,1H),3.75(s,3H),3.70(s,1H),3.06 (t,J＝6.4Hz,4H),2.96–2.75(m,2H),2.56(s,1H),2.38(s,3H),1.00(t,J＝7.1Hz,3H).
实施例17
Example 17
实施例17的制备按照类似实施例16的方法得到。用2-(苯并呋喃-5-基)乙烷-1-1-醇(150mg，0.926mmol)和制备例1(346毫克,0.926毫摩尔)反应得到白色固体实施例17(9.27毫克)。Example 17 was prepared in a manner similar to Example 16. 2-(Benzofuran-5-yl)ethane-1-1-ol (150 mg, 0.926 mmol) was reacted with Preparation Example 1 (346 mg, 0.926 mmol) to obtain Example 17 (9.27 mg) as a white solid.
MS(ESI):m/z 519.2[M+H]+ MS(ESI):m/z 519.2[M+H] +
1H NMR(400MHz,DMSO-d6))δ7.93(d,J＝2.4Hz,1H),7.51(s,1H),7.46(d,J＝8.4Hz,1H),7.24(d,J＝2.4Hz,1H),7.20(dd,J＝8.4,1.6Hz,1H),7.07(dd,J＝8.0,1.5Hz,1H),6.87(dd,J＝2.4,1.2Hz,1H),6.76(s,1H),6.67(t,J＝5.4Hz,1H),6.54–6.51(m,2H),6.48(s,1H),4.10–4.04(m,1H),3.98–3.91(m,1H),3.75(s,3H),3.74–3.68(m,1H),3.12–3.00(m,4H),2.96–2.74(m,2H),2.56–2.51(m,1H),2.38(s,3H),1.00(t,J＝7.2Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )) δ7.93 (d, J = 2.4Hz, 1H), 7.51 (s, 1H), 7.46 (d, J = 8.4Hz, 1H), 7.24 (d, J ＝2.4Hz,1H),7.20(dd,J＝8.4,1.6Hz,1H),7.07(dd,J＝8.0,1.5Hz,1H),6.87(dd,J＝2.4,1.2Hz,1H),6.76 (s,1H),6.67(t,J＝5.4Hz,1H),6.54–6.51(m,2H),6.48(s,1H),4.10–4.04(m,1H),3.98–3.91(m,1H ),3.75(s,3H),3.74–3.68(m,1H),3.12–3.00(m,4H),2.96–2.74(m,2H),2.56–2.51(m,1H),2.38(s,3H ),1.00(t,J＝7.2Hz,3H).
实施例18
Example 18
步骤a:Step a:
将5-溴-1,3-二氢-2H-茚-2-酮18-1(900.0毫克，0.476毫摩尔)溶解在无水二氯甲烷(20.00毫升)中,-60℃氮气保护下加入二乙氨基三氟化硫(DAST)(1.414克，0.976毫摩尔)，将混合物在下在氮气气氛中搅拌至室温16小时。反应完成后向反应混合物中加入水(20毫升)。然后，用二氯甲烷(5毫升x2)萃取混合物。用饱和盐水(20毫升)洗涤有机相，用无水硫酸钠干燥，过滤并减压浓缩。粗产物经硅胶柱层析纯化，得到18-2(501毫克)无色油状化合物。Dissolve 5-bromo-1,3-dihydro-2H-inden-2-one 18-1 (900.0 mg, 0.476 mmol) in anhydrous dichloromethane (20.00 ml), and add it under nitrogen protection at -60°C Diethylaminosulfur trifluoride (DAST) (1.414 g, 0.976 mmol) and the mixture was stirred to room temperature under nitrogen atmosphere for 16 hours. After the reaction was completed, water (20 ml) was added to the reaction mixture. Then, the mixture was extracted with dichloromethane (5 ml x 2). The organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 18-2 (501 mg) as a colorless oily compound.
1H NMR(400MHz,CDCl3)δ7.37-7.35(m,2H),7.09(d,J＝8.8Hz,1H),3.45-3.33(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ7.37-7.35 (m, 2H), 7.09 (d, J = 8.8Hz, 1H), 3.45-3.33 (m, 4H).
步骤b:Step b:
在室温氮气保护下，将18-2(200毫克g,0.86毫摩尔)加入到1,4-二氧六环(5毫升)中然后加入乙烯氧基甲基-苯18-3(121毫克,0.49毫摩尔)、四(三苯基膦)钯(50毫克,0.024毫摩尔)和碳酸钾(119毫克,0.47毫摩尔)，氮气保护下，100℃的搅拌10小时。反应结束后冷却经过滤，减压下浓缩混合物。粗产物通过硅胶柱(石油醚中：乙酸乙酯＝20:1洗脱)纯化，得到无色油状物18-4(70毫克)。Under nitrogen protection at room temperature, 18-2 (200 mg g, 0.86 mmol) was added to 1,4-dioxane (5 ml) and then vinyloxymethyl-benzene 18-3 (121 mg, 0.49 mmol), tetrakis(triphenylphosphine)palladium (50 mg, 0.024 mmol) and potassium carbonate (119 mg, 0.47 mmol), stir at 100°C for 10 hours under nitrogen protection. After the reaction was completed, the mixture was cooled and filtered, and the mixture was concentrated under reduced pressure. The crude product was purified through a silica gel column (elution with petroleum ether: ethyl acetate = 20:1) to obtain colorless oil 18-4 (70 mg).
1H NMR(400MHz,CDCl3)δ7.40-7.35(m,5H),7.12-7.06(m,3H),7.05(d,J＝12.8Hz,1H),5.94(d,J＝12.8Hz,1H),4.89(s,2H),3.38(t,J＝14.4Hz,4H). 1 H NMR (400MHz, CDCl 3 ) δ7.40-7.35 (m, 5H), 7.12-7.06 (m, 3H), 7.05 (d, J = 12.8Hz, 1H), 5.94 (d, J = 12.8Hz, 1H), 4.89 (s, 2H), 3.38 (t, J = 14.4Hz, 4H).
步骤c:Step c:
将18-4(60毫克，0.21毫摩尔)溶在甲醇(5毫升)中，在氮气保护中依次添加10％Pd/C(10毫克)。所得混合物在氢气下搅拌12小时。将反应混合物冷却至室温，通过硅藻土垫过滤，并用甲醇(2x5毫升)清洗滤饼。滤液合减压下浓缩，以无色油的形式得到黄色油状物18-5(40毫克).18-4 (60 mg, 0.21 mmol) was dissolved in methanol (5 ml), and 10% Pd/C (10 mg) was added sequentially under nitrogen protection. The resulting mixture was stirred under hydrogen for 12 hours. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and the filter cake was washed with methanol (2x5 mL). The filtrate was concentrated under reduced pressure to obtain yellow oil 18-5 (40 mg) as a colorless oil.
1H NMR(400MHz,CDCl3)δ7.17-7.15(m,1H),7.11-7.09(m,2H),3.84(t,J＝6.4Hz,2H),3.43–3.36(m,4H),2.84(t,J＝6.4Hz,2H)，1.75-1.65(br.s,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.17-7.15 (m, 1H), 7.11-7.09 (m, 2H), 3.84 (t, J = 6.4Hz, 2H), 3.43–3.36 (m, 4H), 2.84(t,J=6.4Hz,2H), 1.75-1.65(br.s,1H).
步骤d:Step d:
在室温下，向DCM(5mL)中的18-5(3毫克，0.015毫摩尔)和三乙胺(1.5毫克，0.03 毫摩尔)的搅拌混合物中添加MsCl(3毫克，0.03毫摩尔)。将所得混合物搅拌2h并浓缩，得到粗品白色固体18-6(5毫克)，无需进一步纯化，直接用于下步反应。To 18-5 (3 mg, 0.015 mmol) and triethylamine (1.5 mg, 0.03 To the stirred mixture (0.03 mmol) was added MsCl (3 mg, 0.03 mmol). The resulting mixture was stirred for 2 h and concentrated to obtain crude white solid 18-6 (5 mg), which was directly used in the next reaction without further purification.
步骤e:Step e:
将上述粗品18-6(5毫克，0.018毫摩尔)、制备例1(6毫克，0.016毫摩尔)和碳酸铯(18毫克，0.054毫摩尔)在DMF(2毫升)中的混合物在80℃下搅拌16h。反应完毕后，冷却减压下浓缩得粗产品，通过反相制备HPLC纯化，得到白色固体实施例18(3毫克)。A mixture of the above crude product 18-6 (5 mg, 0.018 mmol), Preparation 1 (6 mg, 0.016 mmol) and cesium carbonate (18 mg, 0.054 mmol) in DMF (2 ml) was heated at 80°C. Stir for 16h. After the reaction was completed, the product was cooled and concentrated under reduced pressure to obtain a crude product, which was purified by reverse-phase preparative HPLC to obtain Example 18 (3 mg) as a white solid.
MS(ESI):m/z 555.0[M+H]+ MS(ESI):m/z 555.0[M+H] +
1H NMR(400MHz,CD3OD-d4)δ7.21(d,J＝2.0Hz,1H),7.12–7.07(m,3H),7.02–7.00(m,1H),6.77(s,1H),6.58(d,J＝8.4Hz,1H),6.46(s,1H),6.43(s,1H),4.10–4.01(m,2H),3.80(s,3H),3.75–3.70(m,1H),3.37–3.30(m,3H),3.24–2.94(m,4H),2.96–2.72(m,3H),2.62–2.58(m,1H),2.43(s,3H),1.10(t,J＝6.8Hz,3H). 1 H NMR (400MHz, CD3OD-d 4 ) δ7.21 (d, J = 2.0Hz, 1H), 7.12–7.07 (m, 3H), 7.02–7.00 (m, 1H), 6.77 (s, 1H), 6.58(d,J＝8.4Hz,1H),6.46(s,1H),6.43(s,1H),4.10–4.01(m,2H),3.80(s,3H),3.75–3.70(m,1H) ,3.37–3.30(m,3H),3.24–2.94(m,4H),2.96–2.72(m,3H),2.62–2.58(m,1H),2.43(s,3H),1.10(t,J＝ 6.8Hz,3H).
19F NMR(376MHz,CD3OD-d4):δ-95.80ppm。 19 F NMR (376MHz, CD3OD-d 4 ): δ-95.80ppm.
实施例19和实施例20
Example 19 and Example 20
步骤a:Step a:
在氮气保护下，向2-溴-4-碘苯甲酸甲酯19-1(2.5克，7.33毫摩尔)，硼酸酯19-2(1.52克，7.7毫摩尔)和K2CO3(2.03克，14.66毫摩尔)在1,4-二氧六环(25毫升)和H2O(2.5毫升)中的溶液中添加PdCl2(dppf)(360毫克，0.49毫摩尔)。然后在100℃下加热过夜。停止反应并冷却后过滤，减压浓缩获得粗产物，其通过硅胶柱(PE/EA＝20％的洗脱液)进一步纯化获得黄色油状的(E)-2-溴-4-(2-乙氧基乙烯基)苯甲酸甲酯19-3(1.668克)。Under nitrogen protection, 2-bromo-4-iodobenzoic acid methyl ester 19-1 (2.5 g, 7.33 mmol), borate ester 19-2 (1.52 g, 7.7 mmol) and K2CO3 (2.03 g, 14.66 To a solution of 1,4-dioxane (25 mL) and H2O (2.5 mL) was added PdCl2(dppf) (360 mg, 0.49 mmol). Then heat at 100°C overnight. Stop the reaction, cool, filter, and concentrate under reduced pressure to obtain a crude product, which is further purified through a silica gel column (PE/EA=20% eluent) to obtain (E)-2-bromo-4-(2-ethyl) as a yellow oil. Oxyvinyl)benzoic acid methyl ester 19-3 (1.668 g).
MS(ESI):m/z 285.0[M+H]+。MS(ESI): m/z 285.0[M+H] + .
步骤b:Step b:
在室温下，向(E)-2-溴-4-(2-乙氧基乙烯基)苯甲酸甲酯19-3(1.6克，5.63毫摩尔)在盐酸(4N在EtOAc中，15毫升)中的溶液中添加5-6滴水。然后在室温下搅拌一夜。LCMS监测到反应完毕。停止反应后，在低温下直接去减压旋转浓缩，得到黄色油状的粗产物2-溴-4-(2-氧乙基)苯甲酸甲酯19-4。19-4直接用于下步反应。(E)-Methyl 2-bromo-4-(2-ethoxyvinyl)benzoate 19-3 (1.6 g, 5.63 mmol) was dissolved in hydrochloric acid (4N in EtOAc, 15 mL) at room temperature. Add 5-6 drops of water to the solution. Then stir at room temperature overnight. LCMS monitored the reaction to completion. After stopping the reaction, directly depressurize and concentrate at low temperature to obtain the crude product 2-bromo-4-(2-oxyethyl)benzoic acid methyl ester 19-4 as a yellow oil. 19-4 is directly used in the next reaction. .
MS(ESI):m/z 257.0[M+H]+。MS(ESI): m/z 257.0[M+H] + .
步骤c:Step c:
将上述粗产物19-4溶解在THF(10毫升)中，加入NaBH4(1.3克)，然后在室温下搅拌2小时。反应结束后，添加水(15毫升)并用乙酸乙酯(150ml*3)萃取，用盐水洗涤并干燥。加压浓缩得到粗品，然后通过柱层析方法(PE/EtOAc＝50％的洗脱液)进一步纯化，得到黄色油状2-溴-4-(2-羟乙基)苯甲酸甲酯19-5(695毫克，两步产率48％)。The above crude product 19-4 was dissolved in THF (10 ml), NaBH4 (1.3 g) was added, and then stirred at room temperature for 2 hours. After the reaction was completed, water (15 ml) was added and extracted with ethyl acetate (150 ml*3), washed with brine and dried. Concentrate under pressure to obtain a crude product, which is then further purified by column chromatography (PE/EtOAc = 50% eluent) to obtain 2-bromo-4-(2-hydroxyethyl)benzoic acid methyl ester 19-5 as a yellow oil. (695 mg, 48% yield over two steps).
MS(ESI):m/z 259.0[M+H]+。MS(ESI): m/z 259.0[M+H] + .
步骤d:Step d:
在0℃条件下，将TFA溶液(30毫升)逐滴加到4-(2-氨基乙基)-2-甲氧基苯酚19-6(2.5克，14.97毫摩尔)和2,4-二甲基苯甲醛19-7(2.5毫升，17.96毫摩尔)混合液中。反应液在100℃下搅拌24小时。反应结束后，加适量水淬灭，后加入氨水溶液将混合液酸碱度pH值调至10。混合液用乙酸乙酯(150ml*3)萃取三次，合并有机相，有机相用饱和氯化钠水溶液洗涤，然后用无水硫酸钠干燥，过滤，经减压浓缩所得残余物用硅胶柱层析纯化(洗脱剂:二氯甲烷/甲醇＝10/1)纯化得到棕色固体1-(2,4-二甲基苯基)-6-甲氧基-1,2,3,4-四氢异喹啉-7-醇19-8(1.9克)。TFA solution (30 ml) was added dropwise to 4-(2-aminoethyl)-2-methoxyphenol 19-6 (2.5 g, 14.97 mmol) and 2,4-di Methyl benzaldehyde 19-7 (2.5 ml, 17.96 mmol) mixture. The reaction solution was stirred at 100°C for 24 hours. After the reaction is completed, add an appropriate amount of water to quench, and then add ammonia solution to adjust the pH value of the mixed solution to 10. The mixture was extracted three times with ethyl acetate (150ml*3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride aqueous solution, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography. Purification (eluent: dichloromethane/methanol = 10/1) purification gave a brown solid 1-(2,4-dimethylphenyl)-6-methoxy-1,2,3,4-tetrahydro Isoquinolin-7-ol 19-8 (1.9 g).
MS(ESI):m/z 284.0[M+H]+。MS(ESI): m/z 284.0[M+H] + .
步骤e:Step e:
在室温下，向DMF(2毫升)中的噁唑-4-基甲酰胺盐酸盐19-9(464毫克，3.44毫摩尔)溶液中添加三乙胺(1克，9.92毫摩尔)。然后在这个温度下搅拌10分钟。然后加入CDI(382mg，2.36mmol)并持续搅拌1小时。之后，向上述溶液中加入1-(2,4-二甲基苯基)-6-甲氧基-1,2,3,4-四氢异喹啉-7-醇19-8(350毫克，1.24毫摩尔)(预溶于5毫升DMF)并在室温下持续搅拌过夜。LCMS监测反应。反应结束后，添加20毫升水并用EtOAc(100ml*3)萃取，用NH4Cl(aq.)和盐水洗涤，干燥过滤后，减压浓缩获得粗产物，进一步在EtOAc(5毫升)中重新溶解，并收集固体并干燥,得到黄色固体的1-(2,4-二甲基苯基)-7-羟基-6-甲氧基-N-(噁唑-4-基甲基)-3,4-二氢异喹啉-2(1H)-羧酰胺19-10(376毫克)。To a solution of oxazol-4-ylcarboxamide hydrochloride 19-9 (464 mg, 3.44 mmol) in DMF (2 mL) was added triethylamine (1 g, 9.92 mmol) at room temperature. Then stir at this temperature for 10 minutes. Then CDI (382 mg, 2.36 mmol) was added and stirring was continued for 1 hour. After that, 1-(2,4-dimethylphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol 19-8 (350 mg , 1.24 mmol) (pre-dissolved in 5 ml DMF) and continued stirring at room temperature overnight. The reaction was monitored by LCMS. After the reaction, 20 ml of water was added and extracted with EtOAc (100 ml*3), washed with NH4Cl (aq.) and brine, dried and filtered, and concentrated under reduced pressure to obtain the crude product, which was further redissolved in EtOAc (5 ml) and The solid was collected and dried to obtain 1-(2,4-dimethylphenyl)-7-hydroxy-6-methoxy-N-(oxazol-4-ylmethyl)-3,4- as a yellow solid Dihydroisoquinoline-2(1H)-carboxamide 19-10 (376 mg).
MS(ESI):m/z 408.0[M+H]+。MS(ESI):m/z 408.0[M+H] + .
步骤f: Step f:
在氮气保护下，将1-(2,4-二甲基苯基)-7-羟基-6-甲氧基-N-(噁唑-4-基甲基)-3,4-二氢异喹啉-2(1H)-羧酰胺19-10(30毫克，0.074毫摩尔)、2-溴-4-(2-羟基乙基)苯甲酸甲酯19-5(29毫克，0.011毫摩尔)、PPh3(29毫克，0.11毫摩尔)和甲苯(2毫升)的混合物在110℃下回流10分钟。待反应液变澄清后，在该温度下缓慢滴加DIAD(22毫克，0.11毫摩尔)(预溶于1毫升甲苯中)。之后，它在110℃下搅拌了一夜。LCMS显示所需产品已形成。部分19-10仍然存在。反应停止并冷却后，在减压下浓缩并干燥以获得粗产物，其在碱性条件下通过碱性Pre-HPLC进一步纯化，得到白色固体2-溴-4-(2-((1-(2,4-二甲基苯基)-6-甲氧基-2-((噁唑-4-基甲基)氨甲酰)-1,2,3,4-四氢异喹啉-7-基)氧基)乙基)苯甲酸甲酯实施例19(10毫克)。Under nitrogen protection, 1-(2,4-dimethylphenyl)-7-hydroxy-6-methoxy-N-(oxazol-4-ylmethyl)-3,4-dihydroiso Quinoline-2(1H)-carboxamide 19-10 (30 mg, 0.074 mmol), methyl 2-bromo-4-(2-hydroxyethyl)benzoate 19-5 (29 mg, 0.011 mmol) A mixture of PPh3 (29 mg, 0.11 mmol) and toluene (2 ml) was refluxed at 110°C for 10 minutes. After the reaction solution became clear, DIAD (22 mg, 0.11 mmol) (pre-dissolved in 1 ml of toluene) was slowly added dropwise at this temperature. After that, it was stirred at 110°C overnight. LCMS showed the desired product had formed. Parts 19-10 still exist. After the reaction was stopped and cooled, it was concentrated and dried under reduced pressure to obtain the crude product, which was further purified by alkaline Pre-HPLC under alkaline conditions to obtain a white solid 2-bromo-4-(2-((1-( 2,4-Dimethylphenyl)-6-methoxy-2-((oxazol-4-ylmethyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7 -methyl)oxy)ethyl)benzoate Example 19 (10 mg).
MS(ESI):m/z 648.0[M+H]+。MS(ESI): m/z 648.0[M+H] + .
1H NMR(400MHz,MeOD)δ8.10(s,1H),7.65(dd,J＝7.8,4.8Hz,3H),7.30(dd,J＝8.0,1.5Hz,1H),7.00(s,1H),6.82(d,J＝7.5Hz,1H),6.76(s,1H),6.47(dd,J＝14.8,6.1Hz,3H),4.29(q,J＝16.0Hz,2H),4.15–4.03(m,2H),3.88(s,3H),3.81(s,3H),3.75(dd,J＝14.5,5.9Hz,1H),3.24–3.16(m,1H),2.97(dt,J＝12.8,6.1Hz,3H),2.61(dd,J＝16.6,3.4Hz,1H),2.37(s,3H),2.24(s,3H).1H NMR(400MHz,MeOD)δ8.10(s,1H),7.65(dd,J＝7.8,4.8Hz,3H),7.30(dd,J＝8.0,1.5Hz,1H),7.00(s,1H) ,6.82(d,J＝7.5Hz,1H),6.76(s,1H),6.47(dd,J＝14.8,6.1Hz,3H),4.29(q,J＝16.0Hz,2H),4.15–4.03( m,2H),3.88(s,3H),3.81(s,3H),3.75(dd,J＝14.5,5.9Hz,1H),3.24–3.16(m,1H),2.97(dt,J＝12.8, 6.1Hz, 3H), 2.61 (dd, J = 16.6, 3.4Hz, 1H), 2.37 (s, 3H), 2.24 (s, 3H).
MS(ESI):m/z 648.0[M+H]+。MS(ESI): m/z 648.0[M+H] + .
步骤g:Step g:
在氮气保护，温度为0℃下向实施例19(60毫克，0.09毫摩尔，1.0eq)的四氢呋喃溶液混合物中添加LiAlH4(4毫克，0.09毫摩尔，1eq)。将混合物在0℃下搅拌1小时。反应完成后0℃冷却下，用水(0.5毫升)、15％氢氧化钠溶液(0.5毫升)、水(1毫升)淬灭LiAlH4的反应混合物，搅拌30分钟后，用乙酸乙酯(3×10毫升)萃取。用饱和盐水(10毫升)清洗合并的有机层，用无水硫酸钠干燥，再过滤后，减压浓缩得到残渣。通过Pre-HPLC纯化得到黄色固体实施例20(3.35毫克)。LiAlH4 (4 mg, 0.09 mmol, 1 eq) was added to the tetrahydrofuran solution mixture of Example 19 (60 mg, 0.09 mmol, 1.0 eq) under nitrogen protection at 0°C. The mixture was stirred at 0°C for 1 hour. After the reaction was completed, the reaction mixture of LiAlH4 was quenched with water (0.5 ml), 15% sodium hydroxide solution (0.5 ml), and water (1 ml) under cooling at 0°C. After stirring for 30 minutes, the reaction mixture was stirred with ethyl acetate (3×10 ml) extraction. The combined organic layers were washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Purification by Pre-HPLC gave Example 20 (3.35 mg) as a yellow solid.
MS(ESI):m/z 620.0[M+H]+。MS(ESI): m/z 620.0[M+H] + .
1H NMR(400MHz,DMSO)δ8.27(s,1H),7.74(s,1H),7.50(s,1H),7.40(d,J＝7.9Hz,1H),7.26(d,J＝8.4Hz,1H),7.11(t,J＝5.5Hz,1H),6.98(s,1H),6.81(d,J＝7.9Hz,1H),6.75(s,1H),6.47(s,2H),6.41(d,J＝7.8Hz,1H),5.33(t,J＝5.6Hz,1H),4.46(d,J＝5.6Hz,2H),4.16(qd,J＝15.6,5.5Hz,2H),4.03(dd,J＝16.1,6.6Hz,1H),3.90(dd,J＝16.3,7.0Hz,1H),3.75(s,4H),3.29(s,1H),3.03–2.77(m,4H),2.34(s,3H),2.20(s,3H),0.00(s,3H).1H NMR (400MHz, DMSO) δ8.27(s,1H),7.74(s,1H),7.50(s,1H),7.40(d,J＝7.9Hz,1H),7.26(d,J＝8.4Hz ,1H),7.11(t,J＝5.5Hz,1H),6.98(s,1H),6.81(d,J＝7.9Hz,1H),6.75(s,1H),6.47(s,2H),6.41 (d,J＝7.8Hz,1H),5.33(t,J＝5.6Hz,1H),4.46(d,J＝5.6Hz,2H),4.16(qd,J＝15.6,5.5Hz,2H),4.03 (dd,J＝16.1,6.6Hz,1H),3.90(dd,J＝16.3,7.0Hz,1H),3.75(s,4H),3.29(s,1H),3.03–2.77(m,4H), 2.34(s,3H),2.20(s,3H),0.00(s,3H).
测试例1：细胞增殖抑制实验Test Example 1: Cell Proliferation Inhibition Experiment
选取商业化来源的4株肿瘤细胞系PANC-1(G12D)、H358(G12C)、A549(G12S)、HCT116(G13D)开展细胞增殖抑制实验，分别培养在含10％胎牛血清的DMEM、DMEM、F12K、McCoy's 5A、RPMI-1640和EMEM培养基(Gibco,ThermoFisher)中，放置于37℃、5％的CO2培养箱中孵育。细胞均呈贴壁状态生长，在倒置显微镜下观察生长状况，待细胞数量适量时传代培养。Four commercially derived tumor cell lines, PANC-1 (G12D), H358 (G12C), A549 (G12S), and HCT116 (G13D), were selected to conduct cell proliferation inhibition experiments and were cultured in DMEM and DMEM containing 10% fetal calf serum respectively. , F12K, McCoy's 5A, RPMI-1640 and EMEM medium (Gibco, ThermoFisher), and incubated in a 37°C, 5% CO 2 incubator. The cells all grew in an adherent state, and the growth status was observed under an inverted microscope. When the number of cells reached an appropriate level, they were subcultured.
取对数生长期的PANC-1、H358、A549、HCT116细胞，以合适的细胞密度接种于96孔细胞培养板中(Corning)，在含5％CO2的细胞培养箱中37℃培养24h后，每孔分别加入10μL待测化合物或阳性药物。同时设置阳性对照组(100％抑制孔)及阴性对照组(0％抑制孔)，药物组每浓度重复2孔，阳性对照组和阴性对照组重复6孔，培养箱中继续培养5天后，接后续AlamarBlue测试操作；Take PANC-1, H358, A549, and HCT116 cells in the logarithmic growth phase, seed them in a 96-well cell culture plate (Corning) at an appropriate cell density, and culture them in a cell culture incubator containing 5% CO2 at 37°C for 24 hours. , add 10 μL of the test compound or positive drug to each well. At the same time, a positive control group (100% inhibition well) and a negative control group (0% inhibition well) were set up. The drug group repeated 2 wells for each concentration, and the positive control group and negative control group repeated 6 wells. After continuing to culture in the incubator for 5 days, the Subsequent AlamarBlue test operations;
AlamarBlue测试操作：每孔加10μL AlamarBlue试剂(ThermoFisher)孵育1-4h，振 荡1-2min，MD酶标仪EX:560nm,EM:590nm波长测得荧光值，记录结果，通过计算药物对细胞抑制率(％)＝(A0％抑制－A药物)/(A0％抑制－A100％抑制)×100％，再利用MATILAB软件采用非线性回归的方法(常采用四参数拟合曲线方程，4-parameter logistic model))作图得到药物剂量反应曲线，从而获得化合物的IC50值及其他相关参数。测试化合物对6株商业化肿瘤细胞系(PANC-1、H358、A549和HCT116)的增殖抑制活性(IC50,μM)结果如下表2所示。AlamarBlue test operation: Add 10 μL AlamarBlue reagent (ThermoFisher) to each well, incubate for 1-4 hours, shake Swirl for 1-2 minutes, measure the fluorescence value with MD microplate reader at EX: 560nm, EM: 590nm wavelength, record the results, and calculate the drug's inhibition rate on cells (%) = (A 0% inhibition - A drug )/(A 0% Inhibition -A 100% inhibition ) × 100%, and then use MATILAB software to use nonlinear regression method (often using four-parameter fitting curve equation, 4-parameter logistic model)) to draw the drug dose response curve, thereby obtaining the compound's IC50 value and other related parameters. The results of the proliferation inhibitory activity (IC50, μM) of the test compounds on 6 commercial tumor cell lines (PANC-1, H358, A549 and HCT116) are shown in Table 2 below.
化合物生物活性数据Compound bioactivity data
表1：细胞增殖抑制(IC50:μM)
Table 1: Cell proliferation inhibition (IC 50 : μM)
测试例2：KRAS蛋白相互作用(PPI)实验Test Example 2: KRAS protein interaction (PPI) experiment
本实验使用均相时间分辨荧光(HTRF)的方法检测小分子化合物对GTP活化状态下的KRAS蛋白与下游RAF1蛋白相互作用的抑制活性。用TR-FRET缓冲液100倍稀释纯化好的Tag1-RAF1蛋白储液，同理，用缓冲液100倍稀释纯化好的Tag2-KRAS蛋白和GTP混合液,保证GTP的终浓度为10μM，这些蛋白的工作浓度经过优化以保证最大信号的产生。使用DMSO溶液对待测化合物进行梯度倍比稀释，得到一系列化合物作用浓度，控制DMSO的终浓度为0.5％。向384孔白色浅孔板中(PerkinElmer)加入4μL GTP-KRAS蛋白，4μL RAF1蛋白以及2μL化合物工作液，合适的对照(无化合物孔和阳性化合物孔)也包含在384孔板上。将GTP-KRAS蛋白，RAF1蛋白与化合物在384孔板中预孵育15分钟，随后加入HTRF检测缓冲液稀释的10μL Anti-Tag1-Eu3+和Anti-Tag2-XL665标记抗体混合液来启动反应。封板，4℃避光孵育2小时后，使用EnVision酶标仪(PerkinElmer)测定TR-FRET信号值(激发波长：320nm，发射波长：615nm和 665nm)。计算荧光信号比RLU＝(665nm信号/615nm信号)x 104；化合物％抑制率通过设置的0％抑制率孔和100％抑制率孔信号计算获得，分别为最大信号反应孔(无化合物孔，DMSO对照孔)和最小信号反应孔(无KRAS蛋白孔)。
化合物抑制率IR(％)公式＝(RLU0％抑制-RLU化合物)/(RLU0％抑制-RLU100％抑制)x 100％，
使用四参数法(4-parameter logistic model)拟合化合物梯度稀释浓度和对应的抑制率，计算出IC50值。测试化合物对KRAS G12D蛋白的抑制活性(IC50，μM)结果如下表1所示。This experiment uses the homogeneous time-resolved fluorescence (HTRF) method to detect the inhibitory activity of small molecule compounds on the interaction between the KRAS protein and the downstream RAF1 protein in the GTP-activated state. Dilute the purified Tag1-RAF1 protein stock solution 100 times with TR-FRET buffer. In the same way, dilute the purified Tag2-KRAS protein and GTP mixture 100 times with buffer to ensure that the final concentration of GTP is 10 μM. These proteins The working concentration is optimized to ensure maximum signal generation. Use DMSO solution to perform gradient dilutions of the compounds to be tested to obtain a series of compound action concentrations, and control the final concentration of DMSO to be 0.5%. Add 4 μL of GTP-KRAS protein, 4 μL of RAF1 protein, and 2 μL of compound working solution to a 384-well white shallow-well plate (PerkinElmer). Appropriate controls (no compound wells and positive compound wells) are also included in the 384-well plate. GTP-KRAS protein, RAF1 protein and compounds were pre-incubated in a 384-well plate for 15 minutes, and then 10 μL Anti-Tag1-Eu 3+ and Anti-Tag2-XL665 labeled antibody mixture diluted in HTRF detection buffer was added to start the reaction. The plate was sealed and incubated at 4°C in the dark for 2 hours, and the TR-FRET signal value was measured using an EnVision microplate reader (PerkinElmer) (excitation wavelength: 320 nm, emission wavelength: 615 nm and 665nm). Calculate the fluorescence signal ratio RLU = (665nm signal/615nm signal) x 10 4 ; the compound % inhibition rate is calculated by calculating the signals of the set 0% inhibition rate hole and 100% inhibition rate hole, which are the maximum signal reaction hole (no compound hole, DMSO control well) and minimum signal reaction well (no KRAS protein well).
The formula of compound inhibition rate IR (%) = (RLU 0% inhibition -RLU compound )/(RLU 0% inhibition -RLU 100% inhibition ) x 100%,
Use the four-parameter logistic model to fit the gradient dilution concentration of the compound and the corresponding inhibition rate, and calculate the IC50 value. The results of the inhibitory activity (IC 50 , μM) of the test compounds against KRAS G12D protein are shown in Table 1 below.
化合物生物活性数据Compound bioactivity data
表2 KRRAS G12D蛋白抑制活性(IC50:μM)
Table 2 KRRAS G12D protein inhibitory activity (IC 50 : μM)
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。 All documents mentioned in this application are incorporated by reference in this application to the same extent as if each individual document was individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims (14)

  1. 一种如下式(I)所示的化合物，或其药学上可接受的盐，或其立体异构体，
    A compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
    其中，*标记的碳原子为手性中心，且各个手性中心可任选地为R构型或S构型；Among them, the carbon atom marked * is a chiral center, and each chiral center can optionally be in R configuration or S configuration;
    R1选自下组：
    R 1 is selected from the following group:
    式中，A、B、C和D各自独立地选自下组：CH、CF、C(OMe)、CMe或N；In the formula, A, B, C and D are each independently selected from the following group: CH, CF, C(OMe), CMe or N;
    各个R'1各自独立地选自下组：卤素、OH、OCH2CH2NRaRb、SH、NH2、C1-C6烷基、C3-C8环烷基、C1-C6烷基羟基、S(C1-C6烷基)、烯丙基、乙烯基、芳基(包括单环或稠环芳基)、杂芳基(包括单环或稠环杂芳基)、CORa、CONH2、CONRaRb、NHRa、3-7元环烷基、3-7元杂环基、(C1-C4烷基)3-7元杂环基；其中，当A、B、C或D为CH时，各个R'1可任选地位于A、B、C或D上，且此时A、B、C或D上的H原子被R'1取代；Each R' 1 is independently selected from the group consisting of halogen, OH, OCH 2 CH 2 NR a R b , SH, NH 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 - C 6 alkyl hydroxyl, S (C 1 -C 6 alkyl), allyl, vinyl, aryl (including monocyclic or fused ring aryl), heteroaryl (including monocyclic or fused ring heteroaryl ), COR a , CONH 2 , CONR a R b , NHR a , 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, (C 1 -C 4 alkyl) 3-7-membered heterocyclyl; wherein , when A, B, C or D is CH, each R' 1 can optionally be located on A, B, C or D, and at this time the H atom on A, B, C or D is replaced by R'1;
    Ra选自下组：H、C1-C5烷基；R a is selected from the following group: H, C 1 -C 5 alkyl;
    Rb选自下组：H、C1-C5烷基或C1-C5卤代烷基；R b is selected from the following group: H, C 1 -C 5 alkyl or C 1 -C 5 haloalkyl;
    m为0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;
    R2选自下组：卤素、OH、NH2、NHRa、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、烯丙基、乙烯基、OCD3、ORc、3-7元环烷基、3-7元杂环基、(C1-C4烷基)3-7元杂环基、SRc、B(OH)2、或选自下组的杂环：较佳地，R2选自下组：OMe、OCD3；R 2 is selected from the following group: halogen, OH, NH 2 , NHR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy , allyl, vinyl, OCD 3 , OR c , 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, (C 1 -C 4 alkyl) 3-7-membered heterocyclyl, SR c , B(OH) 2 , or a heterocycle selected from the following group: Preferably, R 2 is selected from the following group: OMe, OCD 3 ;
    Rc为C1-C6烷基或烯丙基；R c is C 1 -C 6 alkyl or allyl;
    L选自下组：单键、O、S、NH、N(C1-C6烷基)、CH2、CF2；L is selected from the following group: single bond, O, S, NH, N (C 1 -C 6 alkyl), CH 2 , CF 2 ;
    Q选自下组：单键、(CH2)p；其中，p为1、2、3或4； Q is selected from the following group: single bond, (CH 2 ) p ; where p is 1, 2, 3 or 4;
    R3选自下组：H、 R 3 is selected from the following group: H,
    各个R3'可各自独立地位于环上的任意位置，且各自独立地选自下组：卤素、OH、SH、NH2、C1-C6烷基、C3-C8环烷基、C1-C6烷基羟基、S(C1-C6烷基)、烯丙基、乙烯基、芳基(包括单环或稠环芳基)、杂芳基(包括单环或稠环杂芳基)、哌啶基、吗啉基；n为0、1、2或3；Each R 3 ' can be independently located at any position on the ring, and each R 3' can be independently selected from the following group: halogen, OH, SH, NH 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl hydroxyl, S (C 1 -C 6 alkyl), allyl, vinyl, aryl (including monocyclic or fused ring aryl), heteroaryl (including monocyclic or fused ring Heteroaryl), piperidinyl, morpholinyl; n is 0, 1, 2 or 3;
    X选自下组：O、N、NH、S、CH、CH2、CF2、CFH、NRa；X is selected from the following group: O, N, NH, S, CH, CH 2 , CF 2 , CFH, NR a ;
    Y选自下组：NH、CH、CO、CH2、CF2、CRa、ORa、S(C1-C6烷基)、C(NRaRb)、C(芳基)、C(杂芳基)、C(3-8元环烷基)、C(3-8元杂环基)；Y is selected from the following group: NH, CH, CO, CH 2 , CF 2 , CR a , OR a , S (C 1 -C 6 alkyl), C (NR a R b ), C (aryl), C (Heteroaryl), C (3-8 membered cycloalkyl), C (3-8 membered heterocyclyl);
    Z、E和F各自独立地选自下组：O、N、NH、S、CH、CH2、CF2、CFH、NRa；Z, E and F are each independently selected from the following group: O, N, NH, S, CH, CH 2 , CF 2 , CFH, NR a ;
    R4选自下组：C1-C6烷基、C1-C6卤代烷基、C1-C6烷基羟基、C1-C6烷氧基、C2-C6酰基、烯丙基、环烷基、杂环基、炔丙基、C(O)NH2、CH2(芳基)、CH2(杂芳基)、C(O)NH(C1-C6烷基)、C(O)NH(芳基)、C(O)NH(杂芳基)、C(O)NHCH2(芳基)、C(O)NHCH2(杂芳基)、C(S)NH2、C(S)NH(C1-C6烷基)、C(S)NH(芳基)、C(S)NH(杂芳基)、C(S)NHCH2(芳基)、C(S)NHCH2(杂芳基)、芳基，杂芳基；R 4 is selected from the following group: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylhydroxy, C 1 -C 6 alkoxy, C 2 -C 6 acyl, allyl Base, cycloalkyl, heterocyclyl, propargyl, C(O)NH 2 , CH 2 (aryl), CH 2 (heteroaryl), C(O)NH (C 1 -C 6 alkyl) , C(O)NH(aryl), C(O)NH(heteroaryl), C(O)NHCH 2 (aryl), C(O)NHCH 2 (heteroaryl), C(S)NH 2. C(S)NH(C 1 -C 6 alkyl), C(S)NH(aryl), C(S)NH(heteroaryl), C(S)NHCH 2 (aryl), C (S)NHCH 2 (heteroaryl), aryl, heteroaryl;
    R5选自下组：H、C1-C6烷基、C1-C6卤代烷基、C1-C6氘代烷基、环烷基；较佳地，R5选自下组：甲基、氟代甲基、乙基、氟代乙基、氘代甲基、异丙基、环丙基；R 5 is selected from the following group: H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, cycloalkyl; preferably, R 5 is selected from the following group: Methyl, fluoromethyl, ethyl, fluoroethyl, deuterated methyl, isopropyl, cyclopropyl;
    R6或R7各自独立地选自下组：氢、氘、卤素、CN、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基，C1-C6氘代烷基、C1-C6氘代烷氧基、C2-C6烯基、CH2O(C1-C5烷基)；R 6 or R 7 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 deuterated alkyl, C 1 -C 6 deuterated alkoxy, C 2 -C 6 alkenyl, CH 2 O (C 1 -C 5 alkyl);
    且当R5为H时，R3选自下组： And when R 5 is H, R 3 is selected from the following group:
    上述各式中，除非特别说明，所述的芳基为C6-C14芳基、杂环基为3-12元杂环基、杂芳基为5-14元杂芳基(例如5-6元杂芳基或苯并5-6元杂芳基)、环烷基为C3-C12环烷基(例如C3-C6环烷基或C3-C8环烷基)；所述的杂环基或杂芳基中包括1-3个选自下组的杂原子：N、S、O、P或B；且除非特别说明，所述的乙烯基、烯丙基、炔丙基、芳基、杂芳基、环烷基和杂环基可任选地具有1-3个选自下组的取代基：卤素、氘原子、C1-C6烷基；In the above formulas, unless otherwise specified, the aryl group is a C 6 -C 14 aryl group, the heterocyclic group is a 3-12-membered heterocyclic group, and the heteroaryl group is a 5-14-membered heteroaryl group (for example, 5- 6-membered heteroaryl or benzo 5-6 membered heteroaryl), cycloalkyl is C 3 -C 12 cycloalkyl (such as C 3 -C 6 cycloalkyl or C 3 -C 8 cycloalkyl); The heterocyclyl or heteroaryl group includes 1-3 heteroatoms selected from the following group: N, S, O, P or B; and unless otherwise specified, the vinyl, allyl, alkyne Propyl, aryl, heteroaryl, cycloalkyl and heterocyclyl may optionally have 1 to 3 substituents selected from the group consisting of: halogen, deuterium atom, C 1 -C 6 alkyl;
    所述的杂环基包括饱和或部分不饱和的氮杂、氧杂或硫杂环；The heterocyclyl group includes saturated or partially unsaturated aza, oxa or sulfur heterocycle;
    为单键或双键。 be a single bond or a double bond.
  2. 如权利要求1所述的化合物，或其药学上可接受的盐，或其立体异构体，其特征在于，L选自下组：O、S、NH、CF2；Q选自下组：(CH2)p；其中，p为1、2或3。The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein L is selected from the following group: O, S, NH, CF 2 ; Q is selected from the following group: (CH 2 ) p ; where p is 1, 2 or 3.
  3. 如权利要求1所述的化合物，或其药学上可接受的盐，或其立体异构体，其特征在于，R4选自下组：C(O)NH(C1-C6烷基)、C(O)NH(芳基)、C(O)NH(杂芳基)、C(O)NHCH2(芳基)、C(O)NHCH2(杂芳基)、C(S)NH2、C(S)NH(C1-C6烷基)、C(S)NH(芳基)、C(S)NH(杂芳基)、C(S)NHCH2(芳基)、C(S)NHCH2(杂芳基)。The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 4 is selected from the following group: C(O)NH (C 1 -C 6 alkyl) , C(O)NH(aryl), C(O)NH(heteroaryl), C(O)NHCH 2 (aryl), C(O)NHCH 2 (heteroaryl), C(S)NH 2. C(S)NH(C 1 -C 6 alkyl), C(S)NH(aryl), C(S)NH(heteroaryl), C(S)NHCH 2 (aryl), C (S)NHCH 2 (heteroaryl).
  4. 如权利要求1所述的化合物，或其药学上可接受的盐，或其立体异构体，其特征在于：The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that:
    R2选自下组：C1-C6烷氧基、C1-C6卤代烷氧基、OCD3、 R 2 is selected from the following group: C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OCD 3 ,
    R5选自下组：C1-C6烷基、C1-C6卤代烷基、C1-C6氘代烷基、环烷基；较佳地，R5选自下组：甲基、氟代甲基、乙基、氟代乙基、氘代甲基、异丙基、环丙基；R 5 is selected from the following group: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, cycloalkyl; preferably, R 5 is selected from the following group: methyl , fluoromethyl, ethyl, fluoroethyl, deuterated methyl, isopropyl, cyclopropyl;
    R6或R7各自独立地选自下组：氢、氘、卤素、C1-C6烷基。R 6 or R 7 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1 -C 6 alkyl.
  5. 如权利要求1所述的化合物，或其药学上可接受的盐，或其立体异构体，其特征在于，所述的R1选自下组：
    The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that said R 1 is selected from the following group:
  6. 如权利要求1所述的化合物，或其药学上可接受的盐，或其立体异构体，其特征在于，所述的R3选自下组：
    The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that said R 3 is selected from the following group:
    其中，各个R3'各自独立地选自下组：卤素、OH、SH、NH2、C1-C6烷基、C3-C8环烷基、C1-C6烷基羟基、S(C1-C6烷基)、烯丙基、乙烯基、芳基(包括单环或稠环芳基)、杂芳基(包括单环或稠环杂芳基)、哌啶基、吗啉基；Wherein, each R 3 ' is independently selected from the following group: halogen, OH, SH, NH 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl hydroxyl, S (C 1 -C 6 alkyl), allyl, vinyl, aryl (including monocyclic or fused ring aryl), heteroaryl (including monocyclic or fused ring heteroaryl), piperidyl, methyl phenylinyl;
    X选自下组：O、N、NH、S、CH、CH2、CF2、CFH、NRa；X is selected from the following group: O, N, NH, S, CH, CH 2 , CF 2 , CFH, NR a ;
    Y选自下组：NH、CH、CO、CH2、CF2、CRa、ORa、S(C1-C6烷基)、C(NRaRb)、C(芳基)、C(杂芳基)、C(3-8元环烷基)、C(3-8元杂环基)；Y is selected from the following group: NH, CH, CO, CH 2 , CF 2 , CR a , OR a , S (C 1 -C 6 alkyl), C (NR a R b ), C (aryl), C (Heteroaryl), C (3-8 membered cycloalkyl), C (3-8 membered heterocyclyl);
    Z选自下组：O、N、NH、S、CH、CH2、CF2、CFH、NRa；Z is selected from the following group: O, N, NH, S, CH, CH 2 , CF 2 , CFH, NR a ;
    E和F各自独立地选自下组：O、N、NH或S。E and F are each independently selected from the group consisting of: O, N, NH, or S.
  7. 如权利要求1所述的化合物，或其药学上可接受的盐，或其立体异构体，其特征在于，所述的R3选自下组：
    The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that said R 3 is selected from the following group:
    或所述的R3为其中，所述的X和Z之一选自下组：O、S、NH、CH2；且另一个选自下组：CH、N；or the R 3 is Wherein, one of the X and Z is selected from the following group: O, S, NH, CH 2 ; and the other is selected from the following group: CH, N;
    Y选自下组：NH、CH、CO、CH2、CF2、CRa、ORa、S(C1-C6烷基)、C(NRaRb)、C(芳基)、C(杂芳基)、或选自下组的基团：
    Y is selected from the following group: NH, CH, CO, CH 2 , CF 2 , CR a , OR a , S (C 1 -C 6 alkyl), C (NR a R b ), C (aryl), C (Heteroaryl), or a group selected from the following group:
  8. 如权利要求1所述的化合物，或其药学上可接受的盐，或其立体异构体，其特征在于，所述的式I化合物具有如下式(II)、(III)、(IV)或(IV-A)所示的结构：
    The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound of formula I has the following formula (II), (III), (IV) or The structure shown in (IV-A):
    其中：in:
    R2选自下组：卤素、OH、NH2、NHRa、C1-C6烷基、C1-C6卤代烷基、烯丙基、乙烯基、OCD3、ORc、3-7元环烷基、3-7元杂环基、(C1-C4烷基)3-7元杂环基、SRc；较佳地，R2选自下组：OMe、OCD3。R 2 is selected from the following group: halogen, OH, NH 2 , NHR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, allyl, vinyl, OCD 3 , OR c , 3-7 yuan Cycloalkyl, 3-7 membered heterocyclyl, (C 1 -C 4 alkyl) 3-7 membered heterocyclyl, SR c ; preferably, R 2 is selected from the following group: OMe, OCD 3 .
  9. 如权利要求1所述的化合物，或其药学上可接受的盐，或其立体异构体，其特征在于，所述的式I化合物具有如下式(II-A)、(V)、(VI)或(VI-A)所示的结构：
    The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the compound of formula I has the following formula (II-A), (V), (VI ) or the structure shown in (VI-A):
    较佳地，所述的式(II-A)、(V)、(VI)或(VI-A)中，各个R3'各自独立地选自下组：卤素、OH、SH、NH2、C1-C6烷基、C3-C8环烷基、C1-C6烷基羟基、S(C1-C6烷基)、烯丙基、乙烯基。Preferably, in the formula (II-A), (V), (VI) or (VI-A), each R 3 ' is independently selected from the following group: halogen, OH, SH, NH 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl hydroxyl, S (C 1 -C 6 alkyl), allyl, vinyl.
  10. 如权利要求1所述的化合物，或其药学上可接受的盐，或其立体异构体，其 特征在于，所述的式I化合物选自下组：


    The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, It is characterized in that the compound of formula I is selected from the following group:


    较佳地，所述的式I化合物选自下组：

    Preferably, the compound of formula I is selected from the following group:

  11. 如权利要求1所述的化合物和前体化合物，或其药学上可接受的盐，或其立体异构体，其特征在于，所述的式I化合物选自下组：
    The compound and precursor compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the compound of formula I is selected from the following group:
  12. 如权利要求1所述的化合物或其前体化合物，或其药学上可接受的盐，或其立体异构体，其特征在于，所述的式I化合物选自下组：

    The compound of claim 1 or its precursor compound, or its pharmaceutically acceptable salt, or its stereoisomer, characterized in that the compound of formula I is selected from the following group:

  13. 如权利要求1-12任一所述的化合物的用途，其特征在于，用于制备治疗与KRAS突变体活性或表达量相关的疾病的药物的用途；较佳地，所述与KRAS突变体活性或表达量相关的疾病为肿瘤，较佳地为选自下组的肿瘤：肉瘤、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤、畸胎瘤、支气管癌、肺癌、支气管腺瘤、淋巴瘤、软骨瘤错构瘤、间皮瘤、食道癌、胃癌、胰腺癌、小肠癌、大肠癌、泌尿生殖道肿瘤、肾癌、膀胱癌、尿道癌、前列腺、睾丸癌、肝癌、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤、胆囊癌、壶腹癌、胆管癌、骨癌、脑癌、子宫癌、阴道癌、血液瘤、皮肤癌、乳腺癌。The use of the compound according to any one of claims 1 to 12, characterized in that it is used for the preparation of drugs for the treatment of diseases related to the activity or expression of KRAS mutants; preferably, the activity or expression of the KRAS mutants is Or the disease related to the expression level is a tumor, preferably a tumor selected from the following group: sarcoma, myxoma, rhabdomyomas, fibroma, lipoma, teratoma, bronchial carcinoma, lung cancer, bronchial adenoma, lymphoma, Chondromatous hamartoma, mesothelioma, esophageal cancer, gastric cancer, pancreatic cancer, small bowel cancer, colorectal cancer, urogenital tract cancer, kidney cancer, bladder cancer, urethra cancer, prostate, testicular cancer, liver cancer, cholangiocarcinoma, hepatocellular carcinoma Cytoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary cancer, cholangiocarcinoma, bone cancer, brain cancer, uterine cancer, vaginal cancer, hematoma, skin cancer, breast cancer.
  14. 一种药物组合物，所述的药物组合物包括：(i)治疗有效量的如权利要求1-12任一所述的式I化合物，或其药学上可接受的盐；和(ii)药学上可接受的载体。 A pharmaceutical composition, said pharmaceutical composition comprising: (i) a therapeutically effective amount of the compound of formula I according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutical acceptable carrier.
PCT/CN2023/080353 2022-03-09 2023-03-08 Tetrahydroisoquinoline derivative as pan-kras inhibitor, preparation method therefor and use thereof WO2023169481A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021005165A1 (en) * 2019-07-09 2021-01-14 Allinky Biopharma Tetrahydroisoquinoline compounds
CN112262137A (en) * 2018-01-10 2021-01-22 阿林齐生物制药公司 Tetrahydroisoquinoline compounds
WO2021216770A1 (en) * 2020-04-22 2021-10-28 Accutar Biotechnology Inc. Substituted tetrahydroquinazoline compounds as kras inhibitors
CN114874201A (en) * 2022-04-08 2022-08-09 思路迪生物医药(上海)有限公司 Pan-KRAS inhibitor and preparation and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112262137A (en) * 2018-01-10 2021-01-22 阿林齐生物制药公司 Tetrahydroisoquinoline compounds
WO2021005165A1 (en) * 2019-07-09 2021-01-14 Allinky Biopharma Tetrahydroisoquinoline compounds
WO2021216770A1 (en) * 2020-04-22 2021-10-28 Accutar Biotechnology Inc. Substituted tetrahydroquinazoline compounds as kras inhibitors
CN114874201A (en) * 2022-04-08 2022-08-09 思路迪生物医药(上海)有限公司 Pan-KRAS inhibitor and preparation and application thereof

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