WO2019174533A1 - Small molecule pd-1/pd-l1 inhibitor and use thereof in drugs - Google Patents

Small molecule pd-1/pd-l1 inhibitor and use thereof in drugs Download PDF

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WO2019174533A1
WO2019174533A1 PCT/CN2019/077582 CN2019077582W WO2019174533A1 WO 2019174533 A1 WO2019174533 A1 WO 2019174533A1 CN 2019077582 W CN2019077582 W CN 2019077582W WO 2019174533 A1 WO2019174533 A1 WO 2019174533A1
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cancer
mmol
methoxy
etoac
disease
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PCT/CN2019/077582
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French (fr)
Chinese (zh)
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刘兵
杨悌平
喻性龙
孙丹丹
张英俊
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广东东阳光药业有限公司
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Priority to CN201980016053.3A priority Critical patent/CN111788193B/en
Publication of WO2019174533A1 publication Critical patent/WO2019174533A1/en

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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention discloses a small molecule compound used as an inhibitor of PD-1/PD-L1 protein interaction, a preparation method thereof and a pharmaceutical composition and use thereof, and belongs to the field of medicine.
  • immunotherapy can provide long-lasting efficacy and has been gradually transformed from the initial non-specific immunotherapy to specific immunotargeting therapy.
  • the success of immunological checkpoint inhibitors and chimeric antigen receptor T cell therapy has promoted tumor immunity as another effective cancer treatment after surgery, radiotherapy, chemotherapy and targeted therapy.
  • T cell activation mainly refers to "dual signal" intervention, that is, the first signal is provided by antigen peptide-major histocompatibility complex and T cell antigen receptor complex, and co-stimulatory molecules such as CD 28 and B7 provide T cell activation.
  • Second messenger In the absence of costimulatory molecules, it is easy to trigger an imbalance of T cell responses, allowing tumors to escape immune surveillance.
  • PD-1 programmed death receptor-1
  • PD-L1 signaling pathway can inhibit the body.
  • Anti-tumor immune response thereby blocking the pathway by drugs can significantly inhibit tumor growth.
  • PD-1 also known as CD279, is an immunosuppressive molecule found in apoptotic T cell hybridomas by subtractive hybridization. It is a type I transmembrane protein composed of 268 amino acids and belongs to the CD 28 family. PD-1 is structurally composed mainly of extracellular Ig V-like domain, hydrophobic transmembrane domain and cytoplasmic region. The cytoplasmic region retains immunoreceptor tyrosine inhibition motif (ITIM) and immunoreceptor cheese. Amino acid conversion motif (ITSM).
  • ITIM immunoreceptor tyrosine inhibition motif
  • ITSM Amino acid conversion motif
  • PD-1 is expressed not only in activated T lymphocytes, B lymphocytes, natural killer (NK) cells, but also in immune cells such as monocytes, and can also be expressed on the surface of some tumor cell lines or tumor cells.
  • PD-L1 is a natural ligand of PD-1.
  • the negative signal generated by the interaction between PD-1 and PD-L1 is a “brake” mechanism, mainly to prevent additional damage caused by excessive immune response.
  • PD-1 of peripheral autoreactive T cells interacts with PD-L1 on the surface of non-hematopoietic cells in tissues to inhibit proliferation and cytokine secretion of the T cell population, thereby achieving an immune tolerance effect.
  • the tumor immune process mainly occurs in the periphery.
  • the T cells have been stimulated and matured by the antigen presenting cells in the primary lymphatic system, showing high expression of PD-1.
  • Tumor cells up-regulate the expression of PD-L1 by stimulation with higher levels of extracellular cytokines or by continuous activation of certain pathways.
  • TCR T cell receptor
  • Monoclonal antibodies targeting PD-1 were introduced in 2014, Merck's Pembrolizumab and Bristol-Myers Squibb (BMS) Navumab (Nivolumab) ) for the treatment of metastatic melanoma.
  • BMS Bristol-Myers Squibb
  • Navumab Navolumab
  • the PD-L1 monoclonal antibody Atezolizumab developed by Roche's Genentech was approved by the US FDA for bladder cancer, and was approved for the treatment of lung cancer in November of the same year.
  • the development of small molecule immunoassay blockers has not shown a blowout pattern.
  • the small molecule inhibitors reported in the past include the benzenesulfonamides of the Harvard Sharpe group, the 2,6-disubstituted toluene immunomodulators disclosed by Bristol-Myers Squibb, and the peptidomimetic molecules jointly developed by Curis/Aurigene. Only the peptide-like small molecule developed by Curis/Aurigene was approved by the US FDA in June 2016 and is currently in clinical stage.
  • small molecule inhibitors Compared with antibody drugs, small molecule inhibitors have controllable pharmacokinetic behavior and are relatively inexpensive, which makes up for the clinical defects of macromolecular drugs. Therefore, it is of practical significance to design and synthesize a small molecule inhibitor having a blocking effect against PD-1/PD-L1.
  • the technical problem to be solved by the present invention is to provide a small molecule inhibitor having an inhibitory effect on PD-1/PD-L1, which is a compound represented by formula (I) or a compound represented by formula (I).
  • Isomers, geometric isomers, tautomers, oxynitrides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs, and compounds of formula (I) A preparation method, a pharmaceutical composition and use thereof for the preparation of a medicament for preventing or treating a disease associated with the PD-1/PD-L1 signaling pathway.
  • the present invention provides the following technical solutions:
  • a first aspect of the technical solution of the present invention is to provide a compound of the PD-1/PD-L1 type small molecule inhibitor, which is a structure represented by the formula (I) or a stereoscopic structure of the structure represented by the formula (I) Constructs, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
  • R 1 is -(CH 2 ) n Ar, wherein Ar is a C 6-12 aryl group or a C 5-12 heteroaryl group; the Ar is optionally substituted with 1, 2, 3 or 4 substituents, The substituents are each independently H, D, cyano, halogen, amino, methylsulfonyl, acetylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1 -6 alkoxy; n is 1, 2, 3 or 4;
  • A is -CH 2 O-, -OCH 2 -, -CH 2 -CH 2 -, -C(O)NH- or -NHC(O)-;
  • R 5 and R 6 are each independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; Z is CH or N;
  • R 7 is q is 1, 2, 3 or 4;
  • R 3 is a C 1-8 alkylamino group or a C 3-9 heterocyclic group, wherein the C 3-9 heterocyclic group contains at least one N atom; the C 1-8 alkylamino group or C 3 ⁇
  • P is 0, 1, 2 or 3;
  • X and Y are each independently H, D, C 1-6 alkyl, C 1-6 alkoxy, halogen or cyano.
  • Ar according to the invention is phenyl, pyridyl, pyrimidinyl, indenyl or quinolinyl; said Ar is optionally substituted by 1, 2, 3 or 4 substituents,
  • the substituents are each independently H, D, cyano, halogen, amino, methylsulfonyl, acetylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1- 6 alkoxy.
  • R v according to the invention is one of the groups formed by the following structural formula:
  • R v according to the invention is one of the groups formed by the following structural formula:
  • R 5 and R 6 of the invention are each independently H, D, fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl Base, n-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy or ethoxy.
  • R 3 of the invention is one of the groups formed by the structure:
  • the invention provides a small molecule inhibitor having an inhibitory effect on PD-1/PD-L1, which is a compound of formula (II), or a stereoisomer thereof, geometrically isomerized , tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
  • R 1 is -(CH 2 ) n Ar, wherein Ar is phenyl, pyridyl, pyrimidinyl, indenyl or quinolyl; said Ar is optionally substituted by 1, 2, 3 or 4 substituents , the substituents are each independently H, cyano, halogen, amino, methylsulfonyl, acetylamino, C 1-6 alkyl or C 1-6 alkoxy; n is 1, 2, 3 or 4;
  • R 2 , R 3 , R 5 , R 6 , R v , X, Y, Z and p have the meanings indicated in the present invention.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or formula (II) of the invention, or a stereoisomer, geometric isomer, tautomer thereof, Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable excipients or combinations thereof.
  • the invention relates to a compound of formula (I) or (II) or a pharmaceutical composition thereof for use in the manufacture of a medicament for use in the protection, treatment, treatment or alleviation of a disease associated with a PD-1/PD-L1 signaling pathway in a patient use.
  • the disease associated with the PD-1/PD-L1 signaling pathway of the invention is a cancer, an infectious disease, or an autoimmune disease.
  • the cancer of the present invention is a disease in which an immortalized cell exists in an organ or a body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; the autoimmune Sexual diseases are organ-specific autoimmune diseases or systemic autoimmune diseases.
  • the diseases in which the cells in the organ or body tissue of the present invention are immortalized are bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer.
  • the viral infectious diseases of the invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection, and influenza.
  • the organ-specific immune disease of the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic Vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.
  • the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention, thereby modulating the subject Immune response.
  • the invention features a method of protecting, treating, treating or ameliorating a disease associated with a PD-1/PD-L1 signaling pathway in a patient, the method comprising administering to the patient a therapeutically effective amount of the invention described in the present invention A compound or pharmaceutical composition.
  • the disease associated with the PD-1/PD-L1 signaling pathway of the invention is a cancer, an infectious disease, or an autoimmune disease.
  • the cancer of the present invention is a disease in which an immortalized cell exists in an organ or a body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; the autoimmune Sexual diseases are organ-specific autoimmune diseases or systemic autoimmune diseases.
  • the diseases in which the cells in the organ or body tissue of the present invention are immortalized are bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer.
  • the viral infectious diseases of the invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection, and influenza.
  • the organ-specific immune disease of the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic Vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.
  • the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention, thereby modulating the subject Immune response.
  • the compounds or pharmaceutical compositions described herein are used to protect, treat, treat, or ameliorate a disease associated with a PD-1/PD-L1 signaling pathway in a patient.
  • the disease associated with the PD-1/PD-L1 signaling pathway of the invention is a cancer, an infectious disease, or an autoimmune disease.
  • the cancer of the present invention is a disease in which an immortalized cell exists in an organ or a body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; the autoimmune Sexual diseases are organ-specific autoimmune diseases or systemic autoimmune diseases.
  • the diseases in which the cells in the organ or body tissue of the present invention are immortalized are bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer.
  • the viral infectious diseases of the invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection, and influenza.
  • the organ-specific immune disease of the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis;
  • the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic Vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.
  • the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention, thereby modulating the subject Immune response.
  • the invention relates to a process for the preparation, isolation and purification of a compound comprised by formula (I) or (II).
  • the articles used herein are used to refer to the articles of one or more than one (ie, at least one).
  • a component refers to one or more components, that is, there may be more than one component contemplated for use or use in embodiments of the embodiments.
  • subject refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (eg, humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
  • primates eg, humans, males or females
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient refers to a person (including adults and children) or other animal. In some embodiments, “patient” refers to a human.
  • Stereoisomer refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • “Chirality” is a molecule that has properties that cannot overlap with its mirror image; “non-chiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomer refers to two isomers of a compound that are not superimposable but are mirror images of each other.
  • Diastereomer refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers.
  • the prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence.
  • each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
  • racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert) E.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
  • the compounds of the invention may be independently and optionally substituted by one or more substituents, such as the compounds of the above formula, or as in the examples, subclasses, and the invention. a class of compounds.
  • substituents such as the compounds of the above formula, or as in the examples, subclasses, and the invention. a class of compounds.
  • substituents such as the compounds of the above formula, or as in the examples, subclasses, and the invention. a class of compounds.
  • substituents such as the compounds of the above formula, or as in the examples, subclasses, and the invention. a class of compounds.
  • an optional substituent group may have a substituent 1 substituted at each substitutable position of the group.
  • substituents 1 selected from a particular group the substituents may be substituted at the various positions, either identically or differently.
  • the substituent 1 can be further independently, optionally, monosubstituted by the substituent 2 or substituted by the same or different.
  • C 1 - 6-alkyl refers particularly disclosed independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 and C 6 alkyl group.
  • linking substituents are described.
  • the Markush variable recited for that group is understood to be a linking group.
  • the definition of the Markush group for the variable is "alkyl” or "aryl”
  • the “alkyl” or “aryl” respectively represent the attached An alkylene group or an arylene group.
  • alkyl as used herein, includes a straight or branched chain monovalent hydrocarbon radical of from 1 to 20 carbon atoms, wherein the alkyl radical can be independently and optionally substituted with one or more substituents as described herein.
  • the alkyl group contains 1-10 carbon atoms; in other embodiments, the alkyl group contains 1-8 carbon atoms; in other embodiments, the alkyl group contains 1-6 A further carbon atom, in other embodiments, the alkyl group contains from 1 to 4 carbon atoms; in other embodiments, the alkyl group contains from 1 to 3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu) , -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ),
  • haloalkyl denotes the case where the alkyl group may be substituted by one or more of the same or different halogen atoms. Wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 3,3 , 3-trifluoropropyl and the like.
  • the haloalkyl group may be substituted with a substituent as described herein.
  • amino refers to a group having the formula -NH 2.
  • alkylamino refers to "N-alkylamino" or "N,N-alkylamino” wherein the hydrogen atom of the amino group is held by one or two independent alkyl groups. Substituted wherein the alkyl group has the meaning as described herein.
  • the alkylamino group is a lower alkylamino group having a C1-8 alkyl group attached to the nitrogen atom.
  • the alkylamino group is a lower alkylamino group of C1-3 . Examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, and the like.
  • Alkylamino or “alkylamino” may be substituted by the substituents described herein.
  • C 1-8 alkylamino means that each of the individual alkyl groups in the alkylamino group has from 1 to 8 carbon atoms, and the alkylamino group has the definition as described above.
  • alkoxy denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein.
  • C1-6 alkoxy means that an alkyl group having from 1 to 6 carbon atoms is bonded to the other moiety of the molecule through an oxygen atom.
  • the alkoxy group contains from 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains from 1 to 4 carbon atoms; in still other embodiments, the alkoxy group The group contains 1-3 carbon atoms.
  • the alkoxy group can be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propyloxy, -OCH 2 CH 2 CH 3 ), and the like.
  • alkanoylamino or “alkanoylamino” denotes that the alkanoyl group is attached to the other part of the molecule via a group (-NH-), wherein the alkanoyl group has the meaning as described herein.
  • the alkoxyacyl, alkanoyl, or aminoacyl group may be optionally substituted with one or more substituents described herein.
  • alkyl sulfonyl denotes an alkyl group, an alkoxy group, an alkylamino group or an amino group (-NH 2) group bonded through a sulfonyl group (-SO 2 -) is attached to the remainder of the molecule wherein the alkyl, alkoxy, alkylamino group has the meaning as described herein.
  • the alkylsulfonyl, alkoxysulfonyl, alkylaminosulfonyl, aminosulfonyl group may be optionally substituted with one or more substituents described herein. Examples of alkylsulfonyl groups include, but are not limited to, methylsulfonyl (-SO 2 CH 3 ), ethylsulfonyl (-SO 2 CH 2 CH 3 ), and the like.
  • aryl may be a monocyclic, bicyclic, and tricyclic carbocyclic ring system in which at least one ring system is aromatic, wherein each ring system contains from 3 to 7 atoms and has only one point of attachment to the molecule The rest of the connection is connected.
  • aryl may be used interchangeably with the term “aromatic ring”, such as an aromatic ring which may include phenyl, naphthyl and anthracene.
  • the aryl group may be substituted with a substituent as described herein.
  • C 6-12 aryl means that the number of carbon atoms in the aryl group is from 6 to 12, and the aryl group has the above definition.
  • heteroaryl and “heteroaryl” are used interchangeably herein to refer to a monocyclic, bicyclic, tricyclic or tetracyclic ring system wherein a bicyclic heteroaryl ring, a tricyclic heteroaryl ring or a tetracyclic ring is used.
  • the aromatic ring system is fused in a fused form.
  • the heteroaromatic ring system is aromatic in its entirety, and one or more atoms on the ring are independently and independently substituted by a hetero atom (the hetero atom is selected from N, O, P, S, and S or P is independently optional herein)
  • the ground is replaced by one or more oxygen atoms to give groups like SO, SO 2 , PO, PO 2 ).
  • the heteroaryl system can be attached to the main structure at any heteroatom or carbon atom to form a stable compound.
  • the heteroaryl system group may be a single ring of 3-7 atoms, or a double ring of 7-10 atoms, or a tricyclic ring of 10-15 atoms.
  • a bicyclic ring having 7 to 10 atoms may be a bicyclo[4,5], [5,5], [5,6] or [6,6] system, and a tricyclic ring having 10 to 15 atoms may be a tricyclic ring. [5,5,6], [5,7,6] or [6,5,6] system.
  • C 5-12 heteroaryl means that the heteroaryl group has 5 to 12 carbon atoms, and the heteroaryl group has the above definition.
  • heteroaromatic systems include the following examples, but are not limited to these examples: furan-2-yl, furan-3-yl, N-imidazolyl, imidazole-2 -yl, imidazol-4-yl, imidazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, oxazol-2-yl, oxazole-4 -yl,oxazol-5-yl, 4-methylisoxazole-5-yl, N-pyrrolyl, pyrrol-2-yl, pyrrol-3-yl, pyridin-2-yl, pyridin-3-yl , pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazinyl (eg pyridazin-3-yl),
  • heterocyclyl refers to a monocyclic, bicyclic, tricyclic or tetracyclic ring system wherein one ring Or the plurality of atoms are independently optionally substituted by a heteroatom, the ring may be fully saturated or contain one or more unsaturations, but are by no means aromatic, and the heterocyclic system as a whole has no aromaticity.
  • a bicyclic heterocyclic group wherein one ring is aromatic and the other ring is not aromatic at all.
  • the heterocyclic ring system can be attached to the main structure at any heteroatom or carbon atom to form a stable compound.
  • C 3-9 heterocyclic group means that the heterocyclic group has 3 to 9 carbon atoms
  • heterocyclic group may be a carbon atom group or a hetero atom group.
  • Heterocyclyl also includes groups formed by the union of a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic ring.
  • heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Thioxazyl, azetidinyl, oxetanyl, thioheterobutyl, piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxetan, sulfur Heterocyclic heptyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazine , 1,2,3,6-tetrahydropyridin-1-yl, oxazepine, diazepine, thiaze
  • a heterocyclic group is a heterocyclic group of 4 to 12 atoms, and refers to a saturated or partially unsaturated monocyclic or polycyclic ring containing 4 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen. , sulfur and oxygen atoms.
  • heterocyclic group consisting of 4 to 12 atoms include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrroline, 3-pyrroline , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine Base, dioxoalkyl, dithiaalkyl, thiamethane, homopiperazin
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group, a thiomorpholino 1,1-dioxide, and the like.
  • the heterocyclic group consisting of 4-7 atoms is optionally substituted by one or more substituents described herein.
  • heteroatom refers to O, S, N, P, and Si, including any form of oxidation states of N, S, and P; forms of primary, secondary, tertiary, and quaternary ammonium salts; or nitrogen atoms in heterocycles. a form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).
  • halogen means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • spirocyclyl means that one ring originates from a particular cyclic carbon on the other ring.
  • a saturated bridged ring system (rings D and B') is referred to as a "fused bicyclic ring”, whereas ring A' and ring D share a carbon atom in two saturated ring systems, It is called a "spiral ring.”
  • Each ring in the spiro ring is either a carbon ring or a heterocyclic ring.
  • Such examples include, but are not limited to, 4-azaspiro[2.4]heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane -5-yl, spiro[2.4]heptanyl, spiro[4.4]decylalkyl, 7-hydroxy-5-azaspiro[2.4]heptane-5-yl and the like.
  • spirobicyclo means that one ring originates from a particular cyclic carbon on the other ring.
  • a saturated bridged ring system (rings D and B') is referred to as a "fused bicyclic ring", whereas ring A' and ring D share a carbon atom in two saturated ring systems, It is called a "spiral ring.”
  • at least one ring system comprises one or more heteroatoms, wherein each ring system comprises from 3 to 7 atoms, ie from 1 to 6 carbon atoms and from 1 to 3 heteroatoms selected from N, O, P, S Wherein N, S or P is independently substituted by one or more oxygen atoms to give a group like NO, NO 2 , SO, SO 2 , PO, PO 2 , and the —CH 2 — group may be independently
  • fused bicyclic means a saturated or unsaturated fused ring system involving a non-aromatic bicyclic system, at least one of which is non-aromatic of. Such a system may contain an independent or conjugated unsaturated state, but its core structure does not contain an aromatic ring or an aromatic heterocyclic ring (but an aromatic may serve as a substituent thereon).
  • Each of the fused bicyclic rings is either a carbocyclic ring or a heteroalicyclic group, and such examples include, but are not limited to, hexahydro-furan [3,2-b]furanyl, 2,3,3a,4 , 7,7a-hexahydro-1H-indenyl, 7-azabicyclo[2.2.1]heptyl, fused bicyclo[3.3.0]octyl, fused bicyclo[3.1.0]hexane 1,2,3,4,4a,5,8,8a-octahydronaphthyl, these are all contained within the fused bicyclic system.
  • fused heterobicyclic means a saturated or unsaturated fused ring system involving a non-aromatic bicyclic system, at least one of which is non-aromatic. Such a system may contain an independent or conjugated unsaturated state, but its core structure does not contain an aromatic ring or an aromatic heterocyclic ring (but an aromatic may serve as a substituent thereon).
  • a substituent forming a ring to form a ring system formed on the ring means that the substituent can be substituted at any substitutable position on the ring.
  • formula (a) represents that p substituents R may be substituted at any position on the pyridine ring that may be substituted.
  • a ring linkage to a ring system formed on the ring means that the linker can be attached to the remainder of the molecule at any linkable position on the ring system.
  • Formula b represents the position of any possible linkage on the octahydrocyclopentenopyrrole ring to the remainder of the molecule.
  • the attachment points can be joined to the remainder of the molecule at any connectable position on the ring, while the ends of the linkage can be interchanged.
  • the formula d represents that any position on the ring that may be connected can be used as a connection point, and both ends of the connection point can be interchanged.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable when administered to a human and generally do not produce an allergic or similar inappropriate response, such as gastrointestinal upset, dizziness, and the like.
  • pharmaceutically acceptable refers to an animal, more particularly a human body, approved by a federal or national government or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia.
  • carrier refers to a diluent, adjuvant, excipient or matrix with which the compound is administered.
  • These pharmaceutical carriers may be sterile liquids such as water and oils including petroleum, animal, vegetable or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Aqueous solutions of water and aqueous solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, in particular injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin.
  • the "hydrate” of the present invention refers to a compound provided by the present invention or a salt thereof, which further comprises a chemical amount or a non-chemical equivalent of water bound by a non-covalent intermolecular force, or a solvent molecule formed by water. Association.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, MeOH, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.
  • esters of the present invention means that the compound of the formula (I)-formula (II) containing a hydroxyl group forms an in vivo hydrolysable ester.
  • esters are, for example, pharmaceutically acceptable esters which are hydrolyzed in a human or animal body to yield the parent alcohol.
  • the group of the in vivo hydrolysable ester of the compound of the formula (I)-formula (II) containing a hydroxyl group includes, but is not limited to, a phosphate group, an acetoxymethoxy group, and a 2,2-dimethylpropionyloxy group.
  • the "nitrogen oxide” of the present invention means that when the compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form an N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid such as peroxycarboxylic acid to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • the N-oxide can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514) wherein the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as DCM.
  • MCPBA m-chloroperoxybenzoic acid
  • prodrug denotes a compound which is converted in vivo to a compound of formula (I)-formula (II). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • the prodrug-like compound of the present invention may be an ester.
  • the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C 1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters.
  • a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug.
  • Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent.
  • the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.
  • the present invention includes isotopically-labeled compounds which are equivalent to the compounds of formula (I)-formula (II), but one or more of the atoms are different in atomic mass or mass from atoms of atomic mass or mass number which are common in nature. instead.
  • isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18, respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically labeled compounds of the formula (I)-formula (II) of the present invention and prodrugs thereof can generally be prepared as described above, and are readily available when carrying out the processes disclosed in the following schemes and/or examples and preparations. Isotopically labeled reagents replace non-isotopically labeled reagents.
  • Metal product refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • compositions can be prepared by the active ingredient together with a pharmaceutically acceptable carrier.
  • the "pharmaceutically acceptable salt” as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, Nitrate, etc., and organic acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, tannic acid Salt, benzoate, mandelate, methanesulfonate, ethanesulfonate, tosylate, sulfosalicylate, etc., or by other methods described in the literature, such as ion exchange These salts.
  • salts include adipate, malate, 2-hydroxypropionic acid, alginate, ascorbate, aspartate, besylate, benzoate, heavy sulfate, Borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumaric acid Salt, glucoheptonate, glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate , laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, Pectate, persul
  • the present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N.
  • Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • the alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • Amine salts such as, but not limited to, N, N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methyl reduced glucose Amine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine And tris(hydroxymethyl)aminomethane; alkaline earth metal salts such as, but not limited to, barium, calcium and magnesium; transition metal salts such as, but not limited to, zinc.
  • alkaline earth metal salts such as, but not limited to, barium, calcium and magnesium
  • transition metal salts such as, but not limited to, zinc.
  • protecting group refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups.
  • protecting group of an amino group refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl. (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc).
  • a “hydroxy protecting group” refers to a substituent used to block or protect a hydroxyl group, and suitable protecting groups include acetyl and silyl groups.
  • Carboxy protecting group means a substituent of a carboxy group used to block or protect the functionality of a carboxy group.
  • Typical carboxy protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenyl Phosphine) ethyl, nitroethyl, and the like.
  • a general description of protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • Room temperature in the present invention means that the temperature is from 10 ° C to 40 ° C. In some embodiments, “room temperature” refers to a temperature of from 20 °C to 30 °C; in other embodiments, “room temperature” refers to 25 °C.
  • the present invention provides a compound or a pharmaceutical composition thereof which is useful as an inhibitor of PD-1/PD-L1.
  • the invention further relates to the use of said compound or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of a disease and/or condition by inhibiting PD-1 activity with said compound.
  • the invention further describes a method of synthesizing the compound.
  • the compounds of the invention exhibit improved biological activity and pharmacokinetic properties.
  • the present invention provides a compound of the PD-1/PD-L1 type small molecule inhibitor, which is a structure represented by the formula (I) or a stereoisomer of the structure represented by the formula (I), geometrically different a construct, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug,
  • A, X, R 1 , R 2 , R 3 and p have the meanings described in the present invention.
  • R 1 according to the invention is -(CH 2 ) n Ar, wherein Ar is C 6-12 aryl or C 5-12 heteroaryl; the Ar is optionally 1 2, 3 or 4 substituents, each of which is independently H, D, cyano, halogen, amino, methylsulfonyl, acetylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy; n is 1, 2, 3 or 4.
  • R 1 according to the invention is -(CH 2 ) n Ar, wherein said Ar is phenyl, pyridyl, pyrimidinyl, indenyl or quinolyl; Ar is optionally Substituting 1, 2, 3 or 4 substituents, each independently being H, cyano, halogen, amino, methylsulfonyl, acetylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy; n is 1.
  • the present invention is A is -CH 2 O -, - OCH 2 -, - CH 2 -CH 2 -, - C (O) NH- or -NHC (O) -.
  • A is according to the present invention is -CH 2 O-.
  • the R 2 of the present invention is
  • R 5 and R 6 are each independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; Z is CH or N;
  • R 7 is q is 1, 2, 3 or 4;
  • W 1 , W 3 and W 5 are each independently CH 2 , S, O, S(O) 2 or NH, W 2 and W 4 are each independently CH or N;
  • m1, m2, m3, m4, m5, m6, m7 and m8 are each independently 0, 1, 2 or 3;
  • X and Y are H, C 1-6 alkyl, C 1-6 alkoxy, halogen or cyano.
  • R 5 or R 6 according to the invention are each independently H, D, fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl Base, n-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy or ethoxy.
  • the R 7 of the present invention is q is 1.
  • R v according to the invention is one of the groups formed by the following structural formula:
  • W 1 , W 3 and W 5 are each independently CH 2 , S, O, S(O) 2 or NH, and W 2 and W 4 are each independently CH or CH or N; m1, m2 M3, m4, m5, m6, m7 and m8 are each independently 0, 1, 2 or 3;
  • R v according to the invention is one of the groups formed by the following structural formula:
  • Y of the invention is methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl or isobutyl; preferably, Y is methyl.
  • R 3 of the present invention is a C 1-8 alkylamino group or a C 3-9 heterocyclic group, wherein the C 3-9 heterocyclic group contains at least one N atom;
  • R 3 of the invention is one of the groups formed by the structure:
  • the p described herein is 0, 1, 2 or 3.
  • the X of the present invention is H, C 1-6 alkyl, C 1-6 alkoxy, halogen or cyano; preferably, X is fluoro, chloro, bromo, methyl, B.
  • Base n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • the compound of the present invention is a structure represented by formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen as shown in formula (II).
  • R 1 , R 2 , R 3 , R 5 , R 6 , R v , X, Y, Z and p have the meanings indicated in the present invention.
  • the invention comprises a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolism of a compound of one of the following or a compound of one of the following Product, pharmaceutically acceptable salt or prodrug:
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or formula (II) of the invention, or a stereoisomer, geometric isomer, tautomer thereof, Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable excipients or combinations thereof.
  • the invention relates to a compound of formula (I) or (II) or a pharmaceutical composition thereof for use in the manufacture of a medicament for use in the protection, treatment, treatment or alleviation of a disease associated with a PD-1/PD-L1 signaling pathway in a patient use.
  • the disease associated with the PD-1/PD-L1 signaling pathway of the invention is a cancer, an infectious disease, or an autoimmune disease.
  • the cancer of the present invention is selected from the group consisting of diseases in which an immortalized cell is present in an organ or body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; Autoimmune diseases are organ-specific autoimmune diseases or systemic autoimmune diseases.
  • the diseases in which the cells in the organ or body tissue of the present invention are immortalized are bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area.
  • Cancer gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid Cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, solid tumor of children, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) Tumor, primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmentally induced a combination of cancer or a disease as described above; wherein the chronic or acute leukemia comprises acute mye
  • the viral infectious diseases of the invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection, and influenza.
  • the organ-specific autoimmune disease of the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic Atrophic gastritis, pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis;
  • the systemic autoimmune disease is rheumatoid arthritis, systemic erythema Lupus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.
  • the invention features a method of protecting, treating, treating or ameliorating a disease associated with a PD-1/PD-L1 signaling pathway in a patient, the method comprising administering to the patient a therapeutically effective amount of the invention described in the present invention A compound or pharmaceutical composition.
  • the disease associated with the PD-1/PD-L1 signaling pathway of the invention is a cancer, an infectious disease, or an autoimmune disease.
  • the cancer of the present invention is a disease in which an immortalized cell exists in an organ or a body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; the autoimmune Sexual diseases are organ-specific autoimmune diseases or systemic autoimmune diseases.
  • the diseases in which the cells in the organ or body tissue of the present invention are immortalized are bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer.
  • the viral infectious diseases of the invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection, and influenza.
  • the organ-specific immune disease of the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic Vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.
  • the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention, thereby modulating the subject Immune response.
  • the compounds or pharmaceutical compositions described herein are used to protect, treat, treat, or ameliorate a disease associated with a PD-1/PD-L1 signaling pathway in a patient.
  • the disease associated with the PD-1/PD-L1 signaling pathway of the invention is a cancer, an infectious disease, or an autoimmune disease.
  • the cancer of the present invention is a disease in which an immortalized cell exists in an organ or a body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; the autoimmune Sexual diseases are organ-specific autoimmune diseases or systemic autoimmune diseases.
  • the diseases in which the cells in the organ or body tissue of the present invention are immortalized are bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer.
  • the viral infectious diseases of the invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection, and influenza.
  • the organ-specific immune disease of the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis;
  • the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic Vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.
  • the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention, thereby modulating the subject Immune response.
  • the invention relates to a process for the preparation, isolation and purification of a compound comprised by formula (I) or (II).
  • the pharmaceutical composition of the present invention comprises any one of the compounds of the formula (I) or (II) of the present invention, further comprising a pharmaceutically acceptable adjuvant, such as, for example, as applied in the present invention.
  • a pharmaceutically acceptable adjuvant such as, for example, as applied in the present invention.
  • a pharmaceutically acceptable adjuvant such as, for example, as applied in the present invention.
  • solvent solid excipient, diluent, binder, disintegrating agent, or other liquid excipient, dispersing agent, flavoring or suspending agent, surfactant, isotonic agent, thickening agent, Emulsifiers, preservative
  • Substances which may be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins such as human serum proteins; buffer substances such as phosphate; glycine; sorbic acid; Potassium acid; a partial glyceride mixture of saturated vegetable fatty acids; water; salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt; colloidal silicon; magnesium trisilicate; Pyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-blocking polymer; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Cellulose sodium, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talcum powder; excipients such as cocoa butter and
  • the compound of the present invention When the compound of the present invention is administered in a form of a medicament to a mammal such as a human, it may be administered as the compound itself or may contain, for example, 0.1 to 99.5%, more preferably 0.5 to 90%, of the active ingredient and pharmaceutically acceptable.
  • the form of the pharmaceutical composition of the carrier is administered.
  • “Therapeutically effective amount” or “effective amount” means that one or more compounds of the invention treat or prevent a particular disease, disorder or syndrome from alleviating, ameliorating or eliminating one or more symptoms of a particular disease, disorder or syndrome or A sufficient amount to prevent or delay the onset of one or more symptoms of a particular disease, disorder, or syndrome described herein.
  • a therapeutically effective amount of the drug can reduce the number of cancer cells; reduce the size of the cancer; inhibit (ie, slow down to some extent or alternatively terminate) the infiltration of cancer cells into the surrounding organs; suppression (ie, slowing down) To some extent or alternatively termination) tumor metastasis; to some extent tumor growth; and/or to some extent alleviate one or more symptoms associated with cancer.
  • the therapeutically effective amount is an amount sufficient to reduce or alleviate the infectious disease (symptoms of infection caused by bacteria, viruses and fungi).
  • infectious disease symptoms of infection caused by bacteria, viruses and fungi.
  • One of ordinary skill in the art will be able to study the factors contained herein and determine the effective amount of a compound of the invention without undue experimentation.
  • the administration regimen can affect the composition of the effective amount.
  • the compounds of the invention can be administered to an individual before or after the onset of a condition associated with the PD-1/PD-L1 signaling pathway.
  • multiple divided doses and staggered doses may be administered daily or sequentially, or may be administered as a continuous infusion, or may be administered by bolus injection.
  • the dose of the compound of the present invention may be increased or decreased as appropriate according to the urgency of the situation of treatment or prevention.
  • the compounds of the invention are useful in the treatment of the conditions, disorders or diseases described herein, or in the preparation of pharmaceutical compositions for the treatment of such diseases.
  • “Pharmaceutically acceptable carrier” is recognized in the art and includes pharmaceutically acceptable materials, compositions or carriers suitable for administration of a compound of the invention to a mammal.
  • the carrier includes a liquid or solid filler, diluent, excipient, solvent or encapsulating material that is involved in carrying the subject substance or transferring it from one part of the organ or body to another part of the body or body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
  • materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, Ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil , olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffer Agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphated
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring agents and fragrances may also be present in the compositions. , preservatives and antioxidants.
  • antioxidants examples include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium hydrogen sulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxybenzene Methyl ether (BHA), butylated hydroxytoluene (BHT), lecithin, propyl citrate, alpha-tocopherol, etc.; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid , phosphoric acid, etc.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium hydrogen sulfate, sodium metabisulfite, sodium sulfite, etc.
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxybenzene Methyl ether (BHA), butylated hydroxyto
  • Formulations of the invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods known in the art.
  • the amount of active ingredient which may be combined with the carrier materials in the preparation of a single dosage form is generally the amount of the compound which produces a therapeutic effect. Generally, the amount is from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10 to about 30%, in units of one percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with a carrier, optionally, optionally with one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately combining the compound of the present invention with a liquid carrier or a very fine solid carrier or both, and then shaping the product if desired.
  • Formulations of the invention suitable for oral administration may be capsules, cachets, pills, tablets, lozenges (using a flavoring base, typically sucrose and acacia or tragacanth), powders, granules, Or a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion, or an elixir or syrup, or a soft lozenge (using an inert base such as gelatin and glycerin, or Forms of sucrose and gum arabic) and/or mouthwashes, each containing as an active ingredient a predetermined amount of a compound of the invention.
  • the compounds of the invention may also be administered in the form of a bolus, electuary or paste.
  • a solid dosage form (capsule, tablet, pill, dragee, powder, granule, etc.) of the present invention for oral administration
  • the active ingredient is combined with one or more pharmaceutically acceptable carriers such as sodium citrate or Dicalcium phosphate and/or any of the following: fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; binders, for example, carboxymethylcellulose, alginate Class, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; humectants such as glycerin; disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicic acid and sodium carbonate; Solution retarding agent such as paraffin; absorption enhancer such as quaternary ammonium compound; wetting agent such as cetyl alcohol and glyceryl monostearate; adsorbent such as kaolin and bentonite
  • compositions may also contain buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • the compressed tablet may be coated with a binder (for example, gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (for example, sodium starch glycolate or croscarmellose sodium). ), a surfactant or a dispersant to prepare.
  • Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • Tablets and other solid dosage forms of the pharmaceutical compositions of the invention may optionally be scored or coated with a shell and shell such as enteric coatings and other coatings known in the pharmaceutical arts. preparation. They may also be formulated with various ratios of hydroxypropyl methylcellulose, other polymer matrices, liposomes and/or microspheres to provide the desired release properties to provide slow release or control of the active ingredients therein. freed. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation into a sterilizing agent in the form of a sterile solid composition which is soluble in sterile water or some other injectable sterile vehicle immediately prior to use.
  • compositions may also optionally contain opacifying agents and may be compositions which release the active ingredient(s) only, or preferentially, in a portion of the gastrointestinal tract, optionally in a delayed manner.
  • opacifying agents may also be used.
  • embedding compositions include polymeric materials and waxes.
  • the active ingredient may also be in microencapsulated form, if appropriate, using one or more of the above-mentioned excipients.
  • Liquid dosage forms of the compounds of the invention for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain, in addition to the active ingredient, inert diluents such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, which are commonly used in the art.
  • Ester propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and Fatty acid esters of sorbitol and mixtures thereof.
  • the oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservatives.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservatives.
  • the suspension may contain admixtures such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydrate, soap Soil, agar and tragacanth and mixtures thereof.
  • admixtures such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydrate, soap Soil, agar and tragacanth and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository by combining one or more compounds of the invention with one or more suitable non-irritating excipients or
  • the carrier including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate
  • the carrier is prepared by mixing, and it is solid at room temperature, but liquid at body temperature, and thus will melt and release in the rectum or vaginal cavity
  • the active compound is obtained.
  • Formulations of the invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art.
  • Dosage forms for topical or transdermal administration of the compounds of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • the active ingredient may be mixed under sterile conditions with apharmaceutically acceptable carrier and any preservatives, buffers or propellants which may be required.
  • Ointments, pastes, creams and gels may contain excipients, such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, fiber, in addition to the active compounds of the present invention.
  • excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, fiber, in addition to the active compounds of the present invention.
  • Powders and sprays can contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these materials.
  • Sprays can also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.
  • Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the invention to the body.
  • dosage forms can be prepared by dissolving or dispersing the compound in a suitable vehicle.
  • Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate of such flow can be controlled by providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
  • Ophthalmic formulations are also included within the scope of the invention.
  • compositions of the invention suitable for parenteral administration comprise one or more compounds of the invention together with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions
  • sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions An agent or emulsion, or a sterile powder which can be reconstituted into a sterile injectable solution or dispersion immediately prior to use, which may contain an antioxidant, a buffer, a bacteriostatic agent, such that the formulation and the recipient's blood are invigorating Solute or suspending agent or thickener.
  • aqueous and nonaqueous vehicles examples include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like) as well as suitable mixtures thereof, vegetable oils such as olive oil, and Injectable organic esters such as ethyl oleate.
  • polyols e.g., glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • Injectable organic esters such as ethyl oleate.
  • the proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of materials which delay absorption, such as aluminum monostearate and gelatin.
  • the rate of absorption of the drug will depend on its rate of dissolution, which in turn may depend on crystal size and crystalline form.
  • prolonged absorption of the parenterally administered drug form is accomplished by dissolving or suspending the drug in an oily base.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular compound employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by encapsulating the drug in liposomes or microemulsions which are compatible with body tissues.
  • the formulations of the invention may be administered orally, parenterally, topically or rectally. They are of course given in a form suitable for each route of administration. For example, they are administered in the form of tablets or capsules, administered by injection, inhalation, ophthalmic lotion, ointment, suppository, etc., by injection, infusion or inhalation; by lotion or ointment Topical application; administered rectally by suppository. Preferred is oral and/or intravenous administration.
  • parenteral administration means a mode of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, sputum.
  • Intra intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injections and infusions.
  • systemic administration and “peripheral administration” mean the administration of a compound, drug or other material other than direct administration to the central nervous system, such that it enters the patient's system and thus undergoes metabolism and other similar processes, For example, subcutaneous administration.
  • These compounds can be administered to humans and other animals by any suitable route of administration, including oral, nasal (eg, in the form of a spray), rectal, intravaginal, parenteral, intracisternal, and topical (as a powder, ointment). Administration in the form of a dose or drop, including topical and sublingual administration.
  • the compounds of the invention and/or pharmaceutical compositions of the invention which may be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.
  • the actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to achieve an amount of active ingredient that is effective to achieve the desired therapeutic response, non-toxic to the patient for a particular patient, composition, and mode of administration.
  • the selected dosage level will depend on a variety of factors, including the particular compound of the invention or its ester, salt or amide activity employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of treatment, Other drugs, compounds and/or materials used in combination with the particular compound employed, age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and formulate an effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can begin doses of the compounds of the invention used in the pharmaceutical compositions at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be the lowest amount of the compound effective to produce a therapeutic effect.
  • Such effective doses will generally depend on the above factors.
  • the intravenous and subcutaneous doses of the compounds of the invention for use in a subject are from about 0.0001 to about 100 mg/kg body weight per day, more preferably from about 0.01 to about 50 mg/kg/ Still more preferably, it is from about 1.0 to about 100 mg/kg/day.
  • An effective amount is an amount that treats a condition associated with a protein kinase.
  • an effective daily dose of the active compound can be administered in divided doses of two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, the sub-dose is a unit Dosage form.
  • the pharmaceutical composition or combination of the invention may be a unit dose of from about 1 to 1000 mg of the active ingredient, or from about 1 to 500 mg or from about 1 to 250 mg or from about 1 to 150 mg or from about 0.5 to 100 mg or about 1-50 mg of active ingredient.
  • the therapeutically effective dose of a compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and individual condition of the individual, the disorder or disease being treated, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a disorder or disease.
  • the above dosage properties can be illustrated by the use of advantageous mammals in in vitro and in vivo assays, such as mice, rats, dogs, monkeys or related organs, tissues or preparations.
  • the compounds of the present invention can be used in the form of a solution such as an aqueous solution in vitro, and can be administered enterally, parenterally, advantageously intravenously, for example, as a suspension or aqueous solution in vivo.
  • the in vitro dosage range can be between about 10-3 moles and 10-9 molar concentrations.
  • the therapeutically effective amount in vivo may range from about 0.1 to 500 mg/kg or from about 1 to 100 mg/kg, depending on the route of administration.
  • the term "individual” as used herein means an animal. Usually, the animal is a mammal. An individual also means, for example, a primate (eg, human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the individual is a primate. In other embodiments, the individual is a human.
  • a primate eg, human, male or female
  • the individual is a primate.
  • the individual is a human.
  • the compounds of the invention may be administered alone, it is preferred to administer the compounds in the form of a pharmaceutical composition.
  • One or more compounds or compositions provided herein, or a pharmaceutically acceptable derivative thereof, in combination with other pharmaceutically active agents, are used in combination therapy for the treatment of the diseases and conditions described herein.
  • An effective amount of a compound or a composition comprising a therapeutically effective concentration of a compound for oral, systemic delivery, including parenteral or intravenous delivery, or for topical or topical administration, is administered to an individual in need of treatment for a disease or condition .
  • the amount is effective to treat, control or ameliorate one or more symptoms of the disease or condition.
  • the compounds, isomers, prodrugs, and pharmaceutically acceptable derivatives provided by the present invention are widely used in combination therapy to treat the present invention.
  • the discomfort and disease described in the invention contemplates the use of the compounds, isomers, prodrugs, and pharmaceutically acceptable derivatives provided herein in combination with other active agents for the treatment of the diseases/discomforts described herein.
  • the compounds of the invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for the compounds of formula (I)-(II).
  • the following reaction schemes and examples are provided to further illustrate the contents of the present invention.
  • the reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated.
  • the general reagents were purchased from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.
  • Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal.
  • Anhydrous DCM and chloroform were obtained by reflux drying of calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.
  • reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe.
  • the glassware is dry.
  • the column is a silica gel column.
  • Silica gel 300-400 mesh
  • the nuclear magnetic resonance spectrum was measured by CDC1 3 , d 6 -DMSO, CD 3 OD or d 6 -acetone (reported in ppm) using TMS (0 ppm) or chloroform (7.25 ppm) as a reference standard.
  • TMS 0.25 ppm
  • s sensinglet, unimodal
  • d doublet, bimodal
  • t triplet, triplet
  • m multiplet, multiplet
  • br broadened, wide
  • Peak dd (doublet of doublets), dt (doublet of triplets).
  • Coupling constant expressed in Hertz (Hz).
  • MS data was measured with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C) Agilent 6320 Series LC-MS spectrometer, G1329A autosampler and G1315B DAD detector applied For analysis, the ESI source was applied to an LC-MS spectrometer.
  • MS mass spectrometry
  • Both spectrometers are equipped with an Agilent Zorbax SB-C18 column measuring 2.1 x 30 mm, 5 ⁇ m.
  • the injection volume was determined by sample concentration; the flow rate was 0.6 mL/min; the peak of HPLC was recorded by UV-Vis wavelengths at 210 nm and 254 nm.
  • the mobile phase was a 0.1% formic acid acetonitrile solution (Phase A) and a 0.1% formic acid ultrapure aqueous solution (Phase B).
  • the gradient elution conditions are shown in Table 1:
  • the compound intermediate (3a) of the present invention can be obtained by the synthesis method of the synthesis intermediate scheme 1: the compound (1a) and the compound (2a) are heated under basic conditions to form the compound (3a).
  • Z, q and R 6 have the meanings as described herein.
  • the intermediate compound (3b) of the present invention can be obtained by the synthesis method of the intermediate scheme 2: the compound (1b) and (pin) 2 B 2 are reacted under a base to form a compound (2b); the compound (2b) is alkaline.
  • the compound (3b) is obtained by reacting with the compound (3a) under the conditions.
  • Y, Z, q and R 6 have the meanings as described herein.
  • the compound intermediate (3c) of the present invention can be obtained by a synthetic method for synthesizing the intermediate scheme 3: the compound (3b) is reacted with the compound (1c) by heating to give the compound (3c).
  • X, Y, Z, q and R 6 have the meanings as described herein.
  • the compound intermediate (3d) of the present invention can be obtained by the synthesis method of the intermediate scheme 4: the compound (3c) and the compound (1d) are reacted under basic conditions to form the compound (2d); and the compound (2d) is under basic conditions.
  • the reaction with (2da) gives the compound (3d).
  • X, Y, Z, q, R 1 , R v and R 6 have the meanings as described herein.
  • the compound of the present invention can be obtained by a synthetic method of a synthetic scheme: a compound (3d) and a compound (1e) are subjected to a reduction reaction in a suitable solvent to obtain a target product.
  • X, Y, Z, q, R 1 , R 3 , R v and R 6 have the meanings as described herein.
  • Step 4) 4-((3'-(3-Bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro -2-hydroxybenzaldehyde
  • Step 5 7-(3-((3'-((2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'- Biphenyl]-3-yl)oxy)propyl)-7-azaspiro[3.5]decane-2-carbonitrile
  • Step 6 7-(3-((3'-((2-Cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)- 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]decane-2-carbonitrile
  • Step 7) (S)-1-(5-chloro-4-((3'-(3-(2-cyano-7-azaspiro[3.5] ⁇ -7-yl)propoxy)-2) , 2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid
  • Step 1) 4-((3'-(3-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)-methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2 5-((5-((3'-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2'-di Methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
  • the 2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester was dissolved in trifluoroacetic acid (4 mL) and DCM (25 mL). The liquid was concentrated to obtain 585.2 mg of a brown oily liquid, yield 51%;
  • Step 2) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 3 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridine-3-methoxy)benzaldehyde
  • Step 4) (S)-1-(4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2' -Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidin Pyridine-2-carboxylic acid
  • Step 2) 5-((4-chloro-5-((2,2'-dimethyl-3'-(3-(2-oxo-1,7-diazaspiro[4.4] ⁇ -7) -yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
  • Step 2) 5 - ((4-Chloro-2-formyl-5-((3'-(3-(6-hydroxy-2-azaspiro[3.4]oct-2-yl)propoxy)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
  • Step 2) 5-((4-Chloro-2-formyl-5-((3'-(3-(hexahydro-2H-pyrano[3,2-c]pyridine-6(7H)-yl) Propyloxy)-2,2-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
  • Step 2) 5-((4-Chloro-2-formyl-5-((3'-(3-(hexahydrofuro[3,4-c]pyridine-5(3H)-yl)propoxy) -2,2'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
  • Step 2) 5-(3-((3'-((2-Cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)- Tert-butyl carboxylate
  • Step 2) 5-((4-chloro-5-((2,2'-dimethyl-3'-(3-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H) )-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
  • Step 2) 5-((4-Chloro-2-formyl-((3'-(3-(5-hydroxyhexanedihydrocyclopenta[c]pyrrole-2(1H)-yl)propoxy) -2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
  • Step 1) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde
  • Example 12 8-(3-((3'-((2-Chloro-4-(morpholinomethyl)-5-(pyridin-3-ylmethoxy)phenoxy)methyl)-2) , 2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2-oxa-8-aza-spiro[4.5]decane (Compound 12)
  • Step 1) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde
  • Step 3) 8-(3-((3'-(2-Chloro-4-(morpholinomethyl)-5-(pyridin-3-ylmethoxy)phenoxy)methyl)-2) , 2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2-oxa-8-aza-spiro[4.5]decane
  • Step 1) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde
  • Step 2 5-((4-Chloro-2-formyl-5-((3'-(3-(2-hydroxy-7-azaspiro[3.5]indole-7-yl)propoxy)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
  • Step 1) 4-((3'-(3-(2-oxa-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2) 5-((5-((3)-(3-(2-oxa-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
  • Step 1) 4-((3'-(3-(2-oxa-6-azaspiro[3.5] ⁇ -6-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2) 5-((5-((3)-(3-(2-oxa-6-azaspiro[3.5]indole-6-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
  • Step 1) 4-((3'-(3-(2-oxa-7-azaspiro[4.5] ⁇ -7-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2) 5-((5-((3)-(3-(2-oxa-7-azaspiro[4.5]]-7-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
  • Step 1) 4-((3'-(3-(9-oxa-2-azaspiro[5.5]undec-2-yl)propoxy)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2 5-((5-((3-oxa-2-azaspiro[5.5]undec-2-yl)propoxy)-2,2'-di Methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
  • Step 1) 4-((3'-(3-(8-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2 5-((5-((3-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
  • Step 1) 4-((3'-(3-(7-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2 5-((5-((3-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
  • Step 1) 4-((3'-(3-(2-oxa-7-azaspiro[4.4] ⁇ -7-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2 5-((5-((3)-(3-(2-oxa-7-azaspiro[4.4]fluoren-7-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
  • Step 1) 4-((3'-(3-(2-oxa-6-azaspiro[3.4]oct-6-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2 5-((5-((3)-(3-(2-oxa-6-azaspiro[3.4]oct-6-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
  • Step 1) 4-((3'-(3-(7-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2 5-((5-((3-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
  • Step 1) 4-((3'-(3-(6-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2) 5-((5-((3'-(3-(6-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
  • Step 2) 5-((4-chloro-5-((2,2'-dimethyl-3'-(3-(2-oxo-1,9-diazaspiro[5.5]undeccarbon) -9-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
  • Step 1) tert-Butyl-7-(3-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2'-methyl-[1,1') -biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[4.4]decane-2-carboxylic acid methyl ester
  • Step 2 tert-Butyl-7-(3-((3'-((2-chloro-5-((5-cyanopyridin-3-yl))methoxy)-4-formylphenoxy) Methyl)-2'-methyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[4.4]decane-2-carboxylic acid ester
  • Step 2) 5-Chloro-4-((3'-(3-(2-hydroxy-7-azaspiro[3.5] ⁇ -7-yl)propoxy)-2,2'-dimethyl- [1,1'-biphenyl]-pyridin-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzaldehyde
  • Step 3) N-(2-((5-chloro-4-((3'-(3-(2-hydroxy-7-azaspiro[3.5]indole-7-yl)propoxy)-2, 2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl)acetamide
  • Step 1) 4-((3'-(3-(2-oxa-7-azaspiro[4.4] ⁇ -7-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2) 4-((3'-(3-(2-oxa-7-azaspiro[4.4] ⁇ -7-yl)propoxy)-2,2'-dimethyl-[1, 1'-Biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde
  • Step 3) N-(2-((4-((3)-(3-(2-oxa-7-azaspiro[4.4]]-7-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl)acetamide
  • Step 2 5-((4-Chloro-2-formyl-5-((3'-(3-(1-hydroxy-7-azaspiro[3.5]fluoren-7-yl)propoxy)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
  • Step 1) (7-(3-((3)-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1' -Biphenyl]-3-yl)oxy)propyl)-7-azaspiro[3.5]non-2-yl)aminocarboxylic acid tert-butyl ester
  • Step 2) (7-(3-((3'-((2-Cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl) -2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-7-azaspiro[3.5]non-2-yl)carbamic acid tert-butyl ester
  • Step 4) (S)-1-(4-((3'-(3-(2-Amino-7-azaspiro[3.5] ⁇ -7-yl)propoxy)-2,2'-di Methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine- 2-carboxylic acid trifluoroacetate
  • Step 1) 7-(3-((3'-((2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'- Biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]decane-2-carboxylic acid tert-butyl ester
  • Step 2) 7-(3-((3'-((2-Chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]decane-2-carboxylic acid tert-butyl ester
  • Step 4) (S)-1-(4-((3'-(3-(2,7-diazaspiro[3.5]fluoren-7-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2 -carboxylic acid trifluoroacetate
  • Step 1) 8-(3-((3'-(2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'- Biphenyl]-3-yl)oxy)propyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester
  • Step 2) 8-(3-((3'-((2-Chloro-5-(5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester
  • Step 4) (S)-1-(4-((3'-(3-(2,8-diazaspiro[4.5]decane-8-yl)propoxy)-2,2'-di Methyl-[1,1'-biphenyl]methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
  • the aqueous solution was adjusted to pH 7-8 with saturated sodium carbonate, and extracted with DCM (10mL ⁇ 3) and EA (10mL ⁇ 1), and the organic phase was washed with water (20mL).
  • the aqueous sodium sulfate was dried, suction filtered, washed, and then evaporated.
  • Step 1) 9-(3-((3'-((2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'- Biphenyl]-3-yl)oxy)propyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester
  • Step 2) 9-(3-((3'-((2-Chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid Butyl ester
  • Step 1) 9-(3-((3'-((2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'- Biphenyl]-3-yl)oxy)propyl)-2,9-diazaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester
  • Step 2) 9-(3-((3'-((2-Chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,9-diazaspiro[5.5]undecane-2-carboxylic acid Butyl ester
  • Step 4) 4-((3'-(3-Bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]-5-chloro -2-hydroxybenzaldehyde
  • Step 5 (7-(3-((3)-((2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2'-methyl-[1,1'-biphenyl) Tert-butyl ester of 3-yl)oxy)propyl)-7-azaspiro[3.5]non-2-yl)carbamate
  • Step 6) (7-(3-((3'-((2-Cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl) -2'-Methyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]non-2-yl)carbamic acid tert-butyl ester
  • Step 7) (S)-1-(4-((3'-(3-(2-((tert-butoxycarbonyl))amino)-7-azaspiro[3.5]indole-7-yl) Oxy)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy) Benzyl) piperidine-2-carboxylic acid
  • Step 8) (S)-1-(4-((3'-(3-(2-Amino-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2-methyl- [1,1'-biphenyl]-methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetic acid salt
  • Step 1) 7-(3-((2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2'-methyl-[1,1'-biphenyl]-3-yl) Oxy)propyl)-2,7-diazaspiro[3.5]indole-2-carboxylic acid tert-butyl ester
  • Step 2) 7-(3-((3'-((2-Chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-) 2'-Methyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]indole-2-carboxylic acid tert-butyl ester
  • Step 4) (S)-1-(4-((3'-(3-(2,7-diazaspiro[3.5]fluoren-7-yl)propoxy)-2-methyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoro Acetate
  • Step 1) 4-((3'-(3-(2-oxa-7-azaspiro[4.5] ⁇ -7-yl)propoxy)-2-methyl-[1,1'-linked Benzyl-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
  • Step 2) 5-((5-((3'-(3-(2-oxa-7-azaspiro[4.5]]-7-yl)propoxy)-2-methyl-[1, 1'-Biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
  • the PD-1 protein carries the HIS tag
  • the PD-1 ligand PD-L1 carries the hFc tag, which binds to the two tagged proteins with the Eu-labeled anti-hFc antibody and the XL665-labeled anti-HIS antibody, respectively.
  • energy can be transferred from the donor Eu to the acceptor XL665, causing the XL665 to illuminate.
  • the binding of PD-1 to the ligand PD-L1 was blocked, so that Eu and XL665 were far apart, energy could not be transferred, and XL665 did not emit light.
  • the PD1/PD-L1 binding assay was performed using the HTRF assay kit (catalog number 64 ICP01 PEG) of Cisbio Bioassays, and the specific method of operation was carried out with reference to the kit instructions. Briefly described below, the compound was dissolved in DMSO at a concentration of 10 mM using a 384-well white ELISA plate. The compound stock solution was first diluted 40-fold with a diluent and then diluted 5 times using a kit dilution buffer containing 2.5% DMSO. A 4 ul dilution or dilution of the target compound was added to each well to give a final DMSO concentration of 0.5%.
  • the PD1 and PD-L1 solutions were added at 3 ul per well, respectively. After pre-incubation of the compound with PD1 and PD-L1 for 10 minutes, 10 ul of the detection antibody prepared according to the manufacturer's instructions was added to each well. After incubating the plates overnight at room temperature, data were obtained by reading the plates in a PHERAstar FS plate reader (BMG, Germany). The HTRF signal is calculated to be 10000 x (665/620 ratio). The calculated signal is fitted to each of Compound S-shaped dose-response with variable slope - response curves and IC 50 values obtained by curve fitting (GraphPad Prism 7).
  • Example number IC 50 (nM) Example number IC 50 (nM) 2 1.81 twenty three 2.14 5 1.93 twenty four 2.14 7 2.35 25 1.83
  • the compound of the present invention can significantly inhibit the interaction of PD-1 with PD-L1 at the molecular level, and thus can be used for the treatment of diseases associated with the interaction of PD-1/PD-L1.

Abstract

A small molecule PD-1/PD-L1 inhibitor and the use thereof in drugs. Specifically, provided is a small molecule PD-1/PD-L1 inhibitor that is a chemical compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolic product, ester, pharmaceutically acceptable salt, or prodrug thereof. Further provided is a preparation method for the compound represented by formula (I), a pharmaceutical composition, and the use thereof in preparation of drugs for prevention or treatment of diseases relating to PD-1/PD-L1 signaling pathways.

Description

PD-1/PD-L1类小分子抑制剂及其在药物中的应用PD-1/PD-L1 small molecule inhibitors and their application in medicine
相关申请的交叉引用：Cross-reference to related applications:
本申请要求引用申请号为201810203812.4的中国专利的优先权，在先申请在中国国家知识产权局的申请日为2018.03.13，其全部内容通过引用并入本文。The present application claims priority to the Chinese Patent Application No. 201101203812.4, the filing date of the prior application in the Chinese National Intellectual Property Office is 2018.03.13, the entire contents of which is incorporated herein by reference.
发明领域Field of invention
本发明公开了一类用作PD-1/PD-L1蛋白相互作用的抑制剂的小分子化合物及其制备方法和药物组合物与用途，属于药物领域。The invention discloses a small molecule compound used as an inhibitor of PD-1/PD-L1 protein interaction, a preparation method thereof and a pharmaceutical composition and use thereof, and belongs to the field of medicine.
发明背景Background of the invention
随着社会经济的不断发展、人民生活水平逐渐提高、居民饮食结构改变加之人口老龄化、城市化、环境不断恶化等因素影响，我国的疾病谱和死亡谱发生明显的变化，恶性肿瘤的发病率呈现不断上升趋势。恶性肿瘤已成为危害人类生命健康、制约社会经济发展的头号杀手。随着医疗技术水平的提高，尽管人类对抗肿瘤的方法不断创新，目前临床运用的手术、化疗、放疗及新近出现的分子靶向药物治疗使大部分肿瘤患者得到缓解甚至治愈，但仍然有部分患者对上述治疗手段敏感性差，预后欠佳。相比其他类型的肿瘤疗法，免疫疗法能够提供持久的疗效，并已由最初的非特异性免疫治疗逐渐向特异性的免疫靶向治疗方向转化。近十多年，免疫检查点抑制剂与嵌合抗原受体T细胞疗法里程碑式的成功，推动肿瘤免疫成为继手术、放疗、化疗及靶向治疗后又一有效的癌症治疗手段。With the continuous development of social economy, the improvement of people's living standards, the changes in residents' diet structure and the aging of the population, urbanization, and deteriorating environment, the disease spectrum and death spectrum of China have changed significantly. The incidence of malignant tumors has changed. Showing an upward trend. Malignant tumors have become the number one killer of human health and social and economic development. With the improvement of medical technology, despite the continuous innovation of human anti-tumor methods, the current clinical use of surgery, chemotherapy, radiotherapy and the recent emergence of molecular targeted drug therapy have alleviated or even cured most patients with cancer, but there are still some patients The above treatments are less sensitive and have a poor prognosis. Compared to other types of cancer therapy, immunotherapy can provide long-lasting efficacy and has been gradually transformed from the initial non-specific immunotherapy to specific immunotargeting therapy. In the past ten years, the success of immunological checkpoint inhibitors and chimeric antigen receptor T cell therapy has promoted tumor immunity as another effective cancer treatment after surgery, radiotherapy, chemotherapy and targeted therapy.
而免疫治疗的机制是活化特异性T细胞，靶向攻击清除肿瘤细胞，激活患者体内抗肿瘤免疫***应答。T细胞活化主要是指“双信号”介入，即第一信号由抗原肽-主要组织相容性复合体与T细胞抗原受体复合体提供，CD 28与B7等协同刺激分子提供T细胞活化的第二信使。当缺乏协同刺激分子刺激时易引发T细胞应答失衡，使肿瘤逃逸机体免疫监控。作为T细胞活化的第二信号，程序性死亡受体1(programmed death receptor-1，PD-1)和其对应的配体(programmed death-ligand 1，PD-L1)信号通路的激活可抑制机体抗肿瘤免疫应答，从而通过药物阻断该通路能显著抑制肿瘤的生长。 The mechanism of immunotherapy is to activate specific T cells, target attacks to clear tumor cells, and activate anti-tumor immune system responses in patients. T cell activation mainly refers to "dual signal" intervention, that is, the first signal is provided by antigen peptide-major histocompatibility complex and T cell antigen receptor complex, and co-stimulatory molecules such as CD 28 and B7 provide T cell activation. Second messenger. In the absence of costimulatory molecules, it is easy to trigger an imbalance of T cell responses, allowing tumors to escape immune surveillance. As a second signal of T cell activation, the activation of programmed death receptor-1 (PD-1) and its corresponding ligand-ligand 1, PD-L1 signaling pathway can inhibit the body. Anti-tumor immune response, thereby blocking the pathway by drugs can significantly inhibit tumor growth.
PD-1又称CD279，是通过消减杂交技术在凋亡的T细胞杂交瘤中发现的一种免疫共抑制分子，它是由268个氨基酸组成的I型跨膜蛋白，属于CD 28家族成员。PD-1在结构上主要由胞外Ig V样结构域、疏水跨膜区以及胞质区3部分组成，胞质区保留有免疫受体酪氨酸抑制基序(ITIM)及免疫受体酪氨酸转化基序(ITSM)。PD-1不仅表达于活化的T淋巴细胞、B淋巴细胞、自然杀伤(NK)细胞以及单核细胞等免疫细胞中，还可表达于一些肿瘤细胞系或肿瘤细胞表面。PD-L1是PD-1的一个天然配体，生理状况下，PD-1与PD-L1相互作用产生的负向信号是一种“刹车”机制，主要防止过度免疫反应带来的附加损伤。例如，外周自体反应T细胞的PD-1与组织内非造血细胞表面的PD-L1相互作用，能够抑制该T细胞群的增殖及细胞因子分泌，从而达到免疫耐受效果。肿瘤免疫过程主要发生在外周，这时的T细胞已经在初级淋巴***接受过抗原呈递细胞的激动并成熟，表现PD-1高表达。而肿瘤细胞因受到胞外较高水平细胞因子的刺激或是某些通路的持续激活从而上调PD-L1的表达。一旦肿瘤被外周T细胞浸润，大量PD-1与PD-L1结合产生了过度的负向调节信号，使原本活跃的T细胞受体(T cell receptor，TCR)下游信号受到抑制，T细胞逐渐失能甚至凋亡，肿瘤从而实现了免疫逃逸。 PD-1, also known as CD279, is an immunosuppressive molecule found in apoptotic T cell hybridomas by subtractive hybridization. It is a type I transmembrane protein composed of 268 amino acids and belongs to the CD 28 family. PD-1 is structurally composed mainly of extracellular Ig V-like domain, hydrophobic transmembrane domain and cytoplasmic region. The cytoplasmic region retains immunoreceptor tyrosine inhibition motif (ITIM) and immunoreceptor cheese. Amino acid conversion motif (ITSM). PD-1 is expressed not only in activated T lymphocytes, B lymphocytes, natural killer (NK) cells, but also in immune cells such as monocytes, and can also be expressed on the surface of some tumor cell lines or tumor cells. PD-L1 is a natural ligand of PD-1. Under physiological conditions, the negative signal generated by the interaction between PD-1 and PD-L1 is a “brake” mechanism, mainly to prevent additional damage caused by excessive immune response. For example, PD-1 of peripheral autoreactive T cells interacts with PD-L1 on the surface of non-hematopoietic cells in tissues to inhibit proliferation and cytokine secretion of the T cell population, thereby achieving an immune tolerance effect. The tumor immune process mainly occurs in the periphery. At this time, the T cells have been stimulated and matured by the antigen presenting cells in the primary lymphatic system, showing high expression of PD-1. Tumor cells up-regulate the expression of PD-L1 by stimulation with higher levels of extracellular cytokines or by continuous activation of certain pathways. Once the tumor is infiltrated by peripheral T cells, a large number of PD-1 binds to PD-L1 to produce an excessive negative regulatory signal, which inhibits the downstream signal of the originally active T cell receptor (TCR), and the T cell gradually loses. Even with apoptosis, the tumor thus achieves immune escape.
靶向于PD-1的单抗药物于2014年问世，分别是默克(Merck)的派姆单抗(Pembrolizumab)和百时美施贵宝(Bristol-Myers Squibb，BMS)的纳武单抗(Nivolumab)，用于治疗转移性黑色素瘤。2016年3月，罗氏旗下基因泰克(Genentech)研发的PD-L1单抗阿特珠单抗(Atezolizumab)被美国FDA批准治疗膀胱癌，同年11月获批用于治疗肺癌。与抗体药物市场的如火如荼不同，小分子免疫检查点阻断剂的研发并没有呈现出井喷的模式。现有报道的小分子抑制剂包括哈佛Sharpe课题组的苯磺酰胺类化合物，百时美施贵宝 公开的2，6-二取代甲苯型免疫调节剂以及Curis/Aurigene合作开发的拟肽类分子，其中只有Curis/Aurigene合作开发的拟肽类小分子2016年6月获得美国FDA的IND申请，目前处于临床阶段。Monoclonal antibodies targeting PD-1 were introduced in 2014, Merck's Pembrolizumab and Bristol-Myers Squibb (BMS) Navumab (Nivolumab) ) for the treatment of metastatic melanoma. In March 2016, the PD-L1 monoclonal antibody Atezolizumab developed by Roche's Genentech was approved by the US FDA for bladder cancer, and was approved for the treatment of lung cancer in November of the same year. Unlike the antibody drug market, the development of small molecule immunoassay blockers has not shown a blowout pattern. The small molecule inhibitors reported in the past include the benzenesulfonamides of the Harvard Sharpe group, the 2,6-disubstituted toluene immunomodulators disclosed by Bristol-Myers Squibb, and the peptidomimetic molecules jointly developed by Curis/Aurigene. Only the peptide-like small molecule developed by Curis/Aurigene was approved by the US FDA in June 2016 and is currently in clinical stage.
相对于抗体药物，小分子抑制剂具有可控的药动学行为，且花费相对较低，很好地弥补了大分子药物的临床缺陷。因而，针对PD-1/PD-L1设计合成具有阻断作用的小分子抑制剂时具有实际意义。Compared with antibody drugs, small molecule inhibitors have controllable pharmacokinetic behavior and are relatively inexpensive, which makes up for the clinical defects of macromolecular drugs. Therefore, it is of practical significance to design and synthesize a small molecule inhibitor having a blocking effect against PD-1/PD-L1.
发明概述Summary of invention
本发明解决的技术问题是提供一种具有抑制PD-1/PD-L1相互作用的小分子抑制剂，其为如式(I)所示的化合物，或式(I)所示的化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，酯，药学上可接受的盐或前药，以及提供式(I)所示化合物的制备方法、药物组合物和其在制备预防或治疗与PD-1/PD-L1信号通路有关疾病药物中的用途。The technical problem to be solved by the present invention is to provide a small molecule inhibitor having an inhibitory effect on PD-1/PD-L1, which is a compound represented by formula (I) or a compound represented by formula (I). Isomers, geometric isomers, tautomers, oxynitrides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs, and compounds of formula (I) A preparation method, a pharmaceutical composition and use thereof for the preparation of a medicament for preventing or treating a disease associated with the PD-1/PD-L1 signaling pathway.
Figure PCTCN2019077582-appb-000001
Figure PCTCN2019077582-appb-000001
发明详述Detailed description of the invention
为解决本发明的技术问题，本发明提供如下技术方案：In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:
本发明技术方案的第一方面是提供一类PD-1/PD-L1类小分子抑制剂的化合物，其为如式(I)所示的结构或如式(I)所示结构的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，酯，药学上可接受的盐或前药，A first aspect of the technical solution of the present invention is to provide a compound of the PD-1/PD-L1 type small molecule inhibitor, which is a structure represented by the formula (I) or a stereoscopic structure of the structure represented by the formula (I) Constructs, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
Figure PCTCN2019077582-appb-000002
Figure PCTCN2019077582-appb-000002
式中，In the formula,
R 1为-(CH 2) nAr，其中，Ar为C 6-12芳基或C 5-12杂芳基；所述Ar任选地被1、2、3或4个取代基所取代，所述取代基各自独立地为H、D、氰基、卤素、氨基、甲磺酰基、乙酰氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或C 1-6烷氧基；n为1、2、3或4； R 1 is -(CH 2 ) n Ar, wherein Ar is a C 6-12 aryl group or a C 5-12 heteroaryl group; the Ar is optionally substituted with 1, 2, 3 or 4 substituents, The substituents are each independently H, D, cyano, halogen, amino, methylsulfonyl, acetylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1 -6 alkoxy; n is 1, 2, 3 or 4;
A为-CH 2O-、-OCH 2-、-CH 2-CH 2-、-C(O)NH-或-NHC(O)-； A is -CH 2 O-, -OCH 2 -, -CH 2 -CH 2 -, -C(O)NH- or -NHC(O)-;
R 2为
Figure PCTCN2019077582-appb-000003
R 2 is
Figure PCTCN2019077582-appb-000003
其中，R 5和R 6各自独立地为H、卤素、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；Z为CH或N； Wherein R 5 and R 6 are each independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; Z is CH or N;
R 7为
Figure PCTCN2019077582-appb-000004
q为1、2、3或4； R 7 is
Figure PCTCN2019077582-appb-000004
q is 1, 2, 3 or 4;
R v为
Figure PCTCN2019077582-appb-000005
其中，所述R v可任选地被0、1、2或3个取代基所取代，所述取代基为羟基、氰基、氨基、氧代(＝O)、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或氨基C 1- 6烷基，W 1、W 3和W 5各自独立地为CH 2、S、O、S(O) 2或NH，W 2和W 4各自独立地为CH或N；m1、m2、m3、m4、m5、m6、m7和m8各自独立地为0、1、2或3； R v is
Figure PCTCN2019077582-appb-000005
Wherein R v may be optionally substituted by 0, 1, 2 or 3 substituents which are hydroxy, cyano, amino, oxo (=O), C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or amino C 1- 6 alkyl, W 1 , W 3 and W 5 are each independently CH 2 , S, O, S(O) 2 or NH, W 2 and W 4 are each independently CH or N; m1, m2, m3, m4, m5, m6, m7 and m8 are each independently 0, 1, 2 or 3;
R 3为C 1-8烷氨基或C 3-9杂环基，其中，所述的C 3-9杂环基中至少含有一个N原子；所述的C 1-8烷氨基或C 3- 9杂环基任选地被0、1、2、3或4个取代基所取代，所述取代基为氢、羟基、卤素、羧基、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基、氨基、氨基C 1-6烷基、乙酰氨基、氰基、磺酰胺基或氧代(＝O)； R 3 is a C 1-8 alkylamino group or a C 3-9 heterocyclic group, wherein the C 3-9 heterocyclic group contains at least one N atom; the C 1-8 alkylamino group or C 3− The 9 heterocyclic group is optionally substituted by 0, 1, 2, 3 or 4 substituents which are hydrogen, hydroxy, halogen, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, amino, amino C 1-6 alkyl, acetylamino, cyano, sulfonamide or oxo (=O);
P为0、1、2或3；P is 0, 1, 2 or 3;
X和Y各自独立地为H、D、C 1-6烷基、C 1-6烷氧基、卤素或者氰基。 X and Y are each independently H, D, C 1-6 alkyl, C 1-6 alkoxy, halogen or cyano.
在一些实施方案中，本发明所述的Ar为苯基、吡啶基、嘧啶基、吲哚基或喹啉基；所述Ar任选地被1、2、3或4个取代基取代，所述取代基各自独立地为H、D、氰基、卤素、氨基、甲磺酰基、乙酰氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或C 1-6烷氧基。 In some embodiments, Ar according to the invention is phenyl, pyridyl, pyrimidinyl, indenyl or quinolinyl; said Ar is optionally substituted by 1, 2, 3 or 4 substituents, The substituents are each independently H, D, cyano, halogen, amino, methylsulfonyl, acetylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1- 6 alkoxy.
在一些实施方案中，本发明所述的R v为以下结构式形成的基团之一： In some embodiments, R v according to the invention is one of the groups formed by the following structural formula:
Figure PCTCN2019077582-appb-000006
Figure PCTCN2019077582-appb-000006
Figure PCTCN2019077582-appb-000007
Figure PCTCN2019077582-appb-000007
所述W 1、W 3和W 5各自独立地为CH2、S、O、S(O) 2或NH，W 2和W 4各自独立地为CH或N；R v任选地被0、1、2或3个取代基取代，所述取代基为羟基、氰基、氨基、氧代(＝O)、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或氨基C 1-6烷基。 The W 1 , W 3 and W 5 are each independently CH 2 , S, O, S(O) 2 or NH, and W 2 and W 4 are each independently CH or N; R v is optionally 0, 1 Substituted with 2 or 3 substituents which are hydroxy, cyano, amino, oxo (=O), C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or amino C 1-6 alkyl.
在另一些实施方案中，本发明所述的R v为以下结构式形成的基团之一： In other embodiments, R v according to the invention is one of the groups formed by the following structural formula:
Figure PCTCN2019077582-appb-000008
Figure PCTCN2019077582-appb-000008
Figure PCTCN2019077582-appb-000009
Figure PCTCN2019077582-appb-000009
其中，所述的R v任选地被0、1、2或3个取代基取代，所述取代基为羟基、氰基、氨基、氧代(＝O)、C 1- 6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或氨基C 1-6烷基。 Wherein R v is optionally substituted by 0, 1, 2 or 3 substituents which are hydroxy, cyano, amino, oxo (=O), C 1 - 6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or amino C 1-6 alkyl.
在一些实施方案中，本发明所述的R 5和R 6各自独立地为H、D、氟、氯、溴、甲基、乙基、正丙基、异丙基、叔丁基、异丁基、正丁基、三氟甲基、二氟甲基、一氟甲基、甲氧基或乙氧基。 In some embodiments, R 5 and R 6 of the invention are each independently H, D, fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl Base, n-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy or ethoxy.
在一些实施方案中，本发明所述的R 3为如下结构形成的基团之一： In some embodiments, R 3 of the invention is one of the groups formed by the structure:
Figure PCTCN2019077582-appb-000010
Figure PCTCN2019077582-appb-000010
一些实施方案中，本发明提供的一种具有抑制PD-1/PD-L1相互作用的小分子抑制剂，其为如式(II)所示的化合物，或其立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，酯，药学上可接受的盐或前药，In some embodiments, the invention provides a small molecule inhibitor having an inhibitory effect on PD-1/PD-L1, which is a compound of formula (II), or a stereoisomer thereof, geometrically isomerized , tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
Figure PCTCN2019077582-appb-000011
Figure PCTCN2019077582-appb-000011
式中，In the formula,
R 1为-(CH 2) nAr，其中，Ar为苯基、吡啶基、嘧啶基、吲哚基或喹啉基；所述Ar任选地被1、2、3或4个取代基取代，所述取代基各自独立地为H、氰基、卤素、氨基、甲磺酰基、乙酰氨基、C 1-6烷基或C 1-6烷氧基；n为1、2、3或4； R 1 is -(CH 2 ) n Ar, wherein Ar is phenyl, pyridyl, pyrimidinyl, indenyl or quinolyl; said Ar is optionally substituted by 1, 2, 3 or 4 substituents , the substituents are each independently H, cyano, halogen, amino, methylsulfonyl, acetylamino, C 1-6 alkyl or C 1-6 alkoxy; n is 1, 2, 3 or 4;
R 2、R 3、R 5、R 6、R v、X、Y、Z和p具有本发明所述的含义。 R 2 , R 3 , R 5 , R 6 , R v , X, Y, Z and p have the meanings indicated in the present invention.
一方面，本发明涉及药物组合物，该药物组合物，包含本发明式(I)或式(II)所述的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，及其药学上可接受的辅料或它们的组合。In one aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) or formula (II) of the invention, or a stereoisomer, geometric isomer, tautomer thereof, Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable excipients or combinations thereof.
一方面，本发明涉及式(I)或(II)所述的化合物或其药物组合物在制备用于防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病的药物的用途。In one aspect, the invention relates to a compound of formula (I) or (II) or a pharmaceutical composition thereof for use in the manufacture of a medicament for use in the protection, treatment, treatment or alleviation of a disease associated with a PD-1/PD-L1 signaling pathway in a patient use.
在一些实施方案中，本发明所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。In some embodiments, the disease associated with the PD-1/PD-L1 signaling pathway of the invention is a cancer, an infectious disease, or an autoimmune disease.
在一些实施方案中，本发明所述的癌症为器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述自身免疫性疾病为器官特异性自身免疫病或***性自身免疫病。In some embodiments, the cancer of the present invention is a disease in which an immortalized cell exists in an organ or a body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; the autoimmune Sexual diseases are organ-specific autoimmune diseases or systemic autoimmune diseases.
在一些实施方案中，本发明所述的器官或体组织中细胞无限增殖的疾病为骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、***区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、***、***癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌***癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、***癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经***(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤或环境诱发的癌症或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。In some embodiments, the diseases in which the cells in the organ or body tissue of the present invention are immortalized are bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer. , gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer , parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, solid tumor of children, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumor , primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmentally induced cancer Or a combination of the above; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, and chronic Pakistan leukemia.
在一些实施方案中，本发明所述的病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、***瘤病毒感染和流感。In some embodiments, the viral infectious diseases of the invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection, and influenza.
在一些实施方案中，本发明所述的器官特异性免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的***性自身免疫病为类风湿关节炎、***性红斑狼疮、***性血管炎、硬皮病、天疱疮、皮肌炎、混合性***病和自身免疫性溶血性贫血。另一方面，本发明提供一种调节受治疗者中由PD-1信号传导通路介导的免疫应答的方法，其包括向受治疗者使用治疗有效量本发明的化合物，从而调节受治疗者中的免疫应答。In some embodiments, the organ-specific immune disease of the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic Vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia. In another aspect, the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention, thereby modulating the subject Immune response.
在一些实施方案中，本发明描述了一种防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病的方法，所述方法包含给予患者有效治疗剂量的本发明所述的化合物或药物组合物。In some embodiments, the invention features a method of protecting, treating, treating or ameliorating a disease associated with a PD-1/PD-L1 signaling pathway in a patient, the method comprising administering to the patient a therapeutically effective amount of the invention described in the present invention A compound or pharmaceutical composition.
在一些实施方案中，本发明所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。In some embodiments, the disease associated with the PD-1/PD-L1 signaling pathway of the invention is a cancer, an infectious disease, or an autoimmune disease.
在一些实施方案中，本发明所述的癌症为器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述自身免疫性疾病为器官特异性自身免疫病或***性自身免疫病。In some embodiments, the cancer of the present invention is a disease in which an immortalized cell exists in an organ or a body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; the autoimmune Sexual diseases are organ-specific autoimmune diseases or systemic autoimmune diseases.
在一些实施方案中，本发明所述的器官或体组织中细胞无限增殖的疾病为骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、***区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、***、***癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌***癌症、甲 状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、***癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经***(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤或环境诱发的癌症或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。In some embodiments, the diseases in which the cells in the organ or body tissue of the present invention are immortalized are bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer. , gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer , parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, solid tumor of children, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumor , primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmentally induced cancer Or a combination of the above; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, and chronic Lymphocyte leukemia.
在一些实施方案中，本发明所述的病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、***瘤病毒感染和流感。In some embodiments, the viral infectious diseases of the invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection, and influenza.
在一些实施方案中，本发明所述的器官特异性免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的***性自身免疫病为类风湿关节炎、***性红斑狼疮、***性血管炎、硬皮病、天疱疮、皮肌炎、混合性***病和自身免疫性溶血性贫血。另一方面，本发明提供一种调节受治疗者中由PD-1信号传导通路介导的免疫应答的方法，其包括向受治疗者使用治疗有效量本发明的化合物，从而调节受治疗者中的免疫应答。In some embodiments, the organ-specific immune disease of the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic Vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia. In another aspect, the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention, thereby modulating the subject Immune response.
在一些实施方案中，将本发明所描述的化合物或药物组合物用于防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病。In some embodiments, the compounds or pharmaceutical compositions described herein are used to protect, treat, treat, or ameliorate a disease associated with a PD-1/PD-L1 signaling pathway in a patient.
在一些实施方案中，本发明所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。In some embodiments, the disease associated with the PD-1/PD-L1 signaling pathway of the invention is a cancer, an infectious disease, or an autoimmune disease.
在一些实施方案中，本发明所述的癌症为器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述自身免疫性疾病为器官特异性自身免疫病或***性自身免疫病。In some embodiments, the cancer of the present invention is a disease in which an immortalized cell exists in an organ or a body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; the autoimmune Sexual diseases are organ-specific autoimmune diseases or systemic autoimmune diseases.
在一些实施方案中，本发明所述的器官或体组织中细胞无限增殖的疾病为骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、***区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、***、***癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌***癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、***癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经***(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤或环境诱发的癌症或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。In some embodiments, the diseases in which the cells in the organ or body tissue of the present invention are immortalized are bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer. , gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer , parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, solid tumor of children, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumor , primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmentally induced cancer Or a combination of the above; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, and chronic Pakistan leukemia.
在一些实施方案中，本发明所述的病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、***瘤病毒感染和流感。In some embodiments, the viral infectious diseases of the invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection, and influenza.
在一些实施方案中，本发明所述的器官特异性免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的***性自身免疫病为类风湿关节炎、***性红斑狼疮、***性血管炎、硬皮病、天疱疮、皮肌炎、混合性***病和自身免疫性溶血性贫血。In some embodiments, the organ-specific immune disease of the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic Vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.
另一方面，本发明提供一种调节受治疗者中由PD-1信号传导通路介导的免疫应答的方法，其包括向受治疗者使用治疗有效量本发明的化合物，从而调节受治疗者中的免疫应答。In another aspect, the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention, thereby modulating the subject Immune response.
另一方面，本发明涉及式(I)或(II)所包含的化合物的制备、分离和纯化的方法。In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound comprised by formula (I) or (II).
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。其他的方面的内容将在下面作更加具体完整的描述。The foregoing description merely summarizes certain aspects of the invention, but is not limited thereto. Other aspects will be described in more detail below.
本发明详细说明书Detailed description of the invention
定义和一般术语Definitions and general terms
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Some embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and formulas. The invention is intended to cover all alternatives, modifications, and equivalents, which are within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the invention. The invention is in no way limited to the methods and materials described herein. Where one or more of the incorporated literature, patents, and similar materials are different or inconsistent with the present application (including but not limited to defined terms, terminology applications, described techniques, etc.), The application shall prevail.
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。It will be further appreciated that certain features of the invention are described in the various embodiments of the invention, and may be described in combination in a single embodiment. On the contrary, the various features of the invention are described in a single embodiment for the sake of brevity, but may be provided separately or in any suitable sub-combination.
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless otherwise stated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. All patents and publications related to the present invention are hereby incorporated by reference in their entirety.
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。The following definitions used herein should be applied unless otherwise stated. For the purposes of the present invention, chemical elements are consistent with the CAS version of the Periodic Table of the Elements, and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007. , the entire contents of which is incorporated herein by reference.
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。The articles "a", "an" and "the" Therefore, the articles used herein are used to refer to the articles of one or more than one (ie, at least one). For example, "a component" refers to one or more components, that is, there may be more than one component contemplated for use or use in embodiments of the embodiments.
本发明所使用的术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象，例如也指灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试对象是灵长类动物。在其他实施方案中，所述受试对象是人。The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (eg, humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。The term "patient" as used herein refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a human.
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open-ended expression that includes the subject matter of the invention, but does not exclude other aspects.
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。"Stereoisomer" refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。"Chirality" is a molecule that has properties that cannot overlap with its mirror image; "non-chiral" refers to a molecule that can overlap with its mirror image.
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。"Enantiomer" refers to two isomers of a compound that are not superimposable but are mirror images of each other.
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。"Diastereomer" refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。The stereochemical definitions and rules used in the present invention generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry Of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构 体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。Depending on the choice of starting materials and methods, the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。 The racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert) E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，即，该描述包括其中所述事件或情形出现的情况以及不出现的情况。例如，“任选地被1、2、3或4个…所取代”包括该基团被1个、或2个、或3个、或4个所述的取代基所取代的情况，以及该基团不被所述取代基取代的情况。进一步地，当该基团被1个以上所述取代基取代时，所述取代基之间是相互独立，即，所述的1个以上的取代基可以是互不相同的，也可以是相同的。The term "optional" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, that is, the description includes instances in which the event or circumstance occurs and instances where it does not. For example, "optionally substituted by 1, 2, 3 or 4" includes the case where the group is substituted by 1, 2, or 3, or 4 of the substituents described, and The case where the group is not substituted by the substituent. Further, when the group is substituted by one or more of the substituents, the substituents are independent of each other, that is, the one or more substituents may be different from each other or may be the same. of.
像本发明所描述的，本发明的化合物可以独立任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。术语“独立任选地”与术语“任选独立地”可以交换使用，一般而言，术语“独立任选地”不论是否位于术语“取代的”之前，表示所给结构中的一个或多个氢原子可以被具体取代基1所取代或未取代。除非其他方面表明，一个任选的取代基团可以有一个取代基1在基团的各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基1所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基1可以是，但并不限于：氢，氧代 (＝O)，氟，氯，溴，碘，羟基，氨基，羧基，烷基，烷基-S(＝O) t-，卤代烷基，羟基烷基，氨基烷基，醛基，氨基酰基，烷氧基，烷氨基，烷硫基，卤代烷氧基，氰基，芳基，杂芳基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基烷氧基，烷基-(C＝O)-，苄基，环丙基，苯基，烷氨基-C(＝O)-，CN-烷基-C(＝O)-，烷基-O-C(＝O)-烷基，酯基，羟基烷基酰基，或烷氧基烷基等。在合理的情况下，取代基1能进一步独立任选地被取代基2单取代或相同或不同的多取代。其中所述的取代基2可以是，但不限于：氢，氧代(＝O)，氟，氯，溴，碘，羟基，氨基，羧基，烷基，烷基-S(＝O) t-，卤代烷基，羟基烷基，氨基烷基，醛基，氨基酰基，烷氧基，烷氨基，烷硫基，卤代烷氧基，氰基，芳基，杂芳基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基烷氧基，烷基-(C＝O)-，苄基，环丙基，苯基，烷氨基-C(＝O)-，CN-烷基-C(＝O)-，烷基-O-C(＝O)-烷基，酯基，羟基烷基酰基，或烷氧基烷基等。其中，t为0，1，或2。 As described herein, the compounds of the invention may be independently and optionally substituted by one or more substituents, such as the compounds of the above formula, or as in the examples, subclasses, and the invention. a class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. The term "independently optional" is used interchangeably with the term "optionally independently". In general, the term "independently optional", whether or not preceded by the term "substituted", refers to one or more of the given structures. The hydrogen atom may be substituted or unsubstituted by the specific substituent 1. Unless otherwise indicated, an optional substituent group may have a substituent 1 substituted at each substitutable position of the group. When more than one position in the given formula can be substituted by one or more substituents 1 selected from a particular group, the substituents may be substituted at the various positions, either identically or differently. The substituent 1 described therein may be, but not limited to, hydrogen, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxy, amino, carboxyl, alkyl, alkyl-S(=O) t -, haloalkyl, hydroxyalkyl, aminoalkyl, aldehyde, aminoacyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, Heterocyclyl, fluorenyl, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, alkylamino-C(=O)-, CN- Alkyl-C(=O)-, alkyl-OC(=O)-alkyl, ester, hydroxyalkyl, or alkoxyalkyl, and the like. Where reasonable, the substituent 1 can be further independently, optionally, monosubstituted by the substituent 2 or substituted by the same or different. The substituent 2 described therein may be, but not limited to, hydrogen, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxy, amino, carboxyl, alkyl, alkyl-S(=O) t - ,haloalkyl,hydroxyalkyl,aminoalkyl,aldehyde,aminoacyl,alkoxy,alkylamino,alkylthio,haloalkoxy,cyano,aryl,heteroaryl,alkenyl,alkynyl,hybrid Cyclic, fluorenyl, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, alkylamino-C(=O)-, CN-alkane A group -C(=O)-, an alkyl-OC(=O)-alkyl group, an ester group, a hydroxyalkyl group, or an alkoxyalkyl group. Where t is 0, 1, or 2.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1- 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。 In each part of the specification, the substituents of the compounds disclosed herein are disclosed in terms of the type or range of groups. In particular, the invention includes each individual sub-combination of each member of the group and range of such groups. For example, the term "C 1 - 6-alkyl" refers particularly disclosed independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 and C 6 alkyl group.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable recited for that group is understood to be a linking group. For example, if the structure requires a linking group and the definition of the Markush group for the variable is "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represent the attached An alkylene group or an arylene group.
本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，烷基基团含有1-10个碳原子；另外一些实施例是，烷基基团含有1-8个碳原子；另外一些实施例是，烷基基团含有1-6个碳原子，另外一些实施例是，烷基基团含有1-4个碳原子；另外一些实施例是，烷基基团含有1-3个碳原子。烷基基团更进一步的实例包括，但并不限于，甲基(Me，-CH 3)，乙基(Et，-CH 2CH 3)，正丙基(n-Pr，-CH 2CH 2CH 3)，异丙基(i-Pr，-CH(CH 3) 2)，正丁基(n-Bu，-CH 2CH 2CH 2CH 3)，2-甲基丙基或异丁基(i-Bu，-CH 2CH(CH 3) 2)，1-甲基丙基或仲丁基(s-Bu，-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu，-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。烷基可以被本发明所述的取代基所取代。 The term "alkyl" as used herein, includes a straight or branched chain monovalent hydrocarbon radical of from 1 to 20 carbon atoms, wherein the alkyl radical can be independently and optionally substituted with one or more substituents as described herein. In some embodiments, the alkyl group contains 1-10 carbon atoms; in other embodiments, the alkyl group contains 1-8 carbon atoms; in other embodiments, the alkyl group contains 1-6 A further carbon atom, in other embodiments, the alkyl group contains from 1 to 4 carbon atoms; in other embodiments, the alkyl group contains from 1 to 3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu) , -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 ) CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 ) CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH (CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3 -pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3- Dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alk" are used herein to encompass both straight-chain and branched saturated carbon chains. The alkyl group may be substituted with a substituent as described herein.
术语“卤代烷基”表示烷基可以被一个或多个相同或不同卤素原子所取代的情况。其中烷基基团具有如本发明所述的含义，这样的实例包括，但并不限于三氟甲基，二氟甲基，一氟甲基，2,2-二氟乙基，3,3,3-三氟丙基等。卤代烷基可以被本发明所述的取代基所取代。The term "haloalkyl" denotes the case where the alkyl group may be substituted by one or more of the same or different halogen atoms. Wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 3,3 , 3-trifluoropropyl and the like. The haloalkyl group may be substituted with a substituent as described herein.
术语“氨基”是指具有式-NH 2的基团。 The term "amino" refers to a group having the formula -NH 2.
术语“羧基”，无论是单独使用还是和其他术语连用，表示-CO 2H；术语“羰基”，无论是单独使用还是和其他术语连用，表示-(C＝O)-。 The term "carboxy", whether used alone or in conjunction with other terms, denotes -CO 2 H; the term "carbonyl", used alone or in conjunction with other terms, denotes -(C=O)-.
术语“烷氨基”或者“烷基氨基”是指“N-烷基氨基”或“N,N-烷基氨基”，其中氨基基团的氢原子被一个或两个独立的烷基基团所取代，其中烷基基团具有如本发明所述的含义。其中一些实施例是，烷基氨基是一个C 1-8烷基连接到氮原子上的较低级的烷基氨基基团。另外一些实施例是，烷基氨基是C 1-3的较低级的烷基氨基基团。实例包括，但并不限于，N-甲氨基，N-乙氨基，N,N-二甲基氨基等等。“烷氨基”或者“烷基氨基”可以被本发明所述的取代基所取代。术语“C 1-8烷氨基”指烷氨基中每一个独立的烷基含碳原子数为1-8 个，烷氨基具有如上所述的定义。 The term "alkylamino" or "alkylamino" refers to "N-alkylamino" or "N,N-alkylamino" wherein the hydrogen atom of the amino group is held by one or two independent alkyl groups. Substituted wherein the alkyl group has the meaning as described herein. In some of these embodiments, the alkylamino group is a lower alkylamino group having a C1-8 alkyl group attached to the nitrogen atom. In other embodiments, the alkylamino group is a lower alkylamino group of C1-3 . Examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, and the like. "Alkylamino" or "alkylamino" may be substituted by the substituents described herein. The term "C 1-8 alkylamino" means that each of the individual alkyl groups in the alkylamino group has from 1 to 8 carbon atoms, and the alkylamino group has the definition as described above.
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中，烷基基团具有如本发明所述的含义。术语“C 1-6烷氧基”是指含碳原子数为1-6的烷基通过氧原子与分子其他部分相连。在一些实施方案中，烷氧基基团含有1-6个碳原子；在另一些实施方案中，烷氧基基团含有1-4个碳原子；在又一些实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明所描述的取代基所取代。烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH 3)，乙氧基(EtO、-OCH 2CH 3)，1-丙氧基(n-PrO、n-丙氧基、-OCH 2CH 2CH 3)，等等。 The term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. The term " C1-6 alkoxy" means that an alkyl group having from 1 to 6 carbon atoms is bonded to the other moiety of the molecule through an oxygen atom. In some embodiments, the alkoxy group contains from 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains from 1 to 4 carbon atoms; in still other embodiments, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group can be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propyloxy, -OCH 2 CH 2 CH 3 ), and the like.
术语“烷酰基”或“烷基酰基”表示烷基基团通过羰基(-C(＝O)-)与分子其余部分相连，其中，烷基基团具有如本发明所述的含义。所述烷酰基基团可以任选地被一个或多个本发明所描述的取代基所取代。烷酰基基团的实例包括，但并不限于，乙酰基(-C(＝O)CH 3)，丙酰基(-C(＝O)CH 2CH 3)，丁酰基(-C(＝O)CH 2CH 2CH 3)等等。 The term "alkanoyl" or "alkyl acyl" means that the alkyl group is attached to the remainder of the molecule via a carbonyl group (-C(=O)-), wherein the alkyl group has the meaning as described herein. The alkanoyl group can be optionally substituted with one or more substituents described herein. Examples of alkanoyl groups include, but are not limited to, acetyl (-C(=O)CH 3 ), propionyl (-C(=O)CH 2 CH 3 ), butyryl (-C(=O) CH 2 CH 2 CH 3 ) and so on.
术语“烷酰氨基”或“烷酰基氨基”表示烷酰基通过基团(-NH-)与分子的其他部分相连，其中烷酰基具有如本发明所述的含义。所述烷酰氨基基团可以任选地被一个或多个本发明所描述的取代基所取代。烷酰氨基基团的实例包括，但并不限于，乙酰氨基(CH 3-C(＝O)-NH-)，丙酰氨基(CH 3CH 2-C(＝O)-NH-)等等。 The term "alkanoylamino" or "alkanoylamino" denotes that the alkanoyl group is attached to the other part of the molecule via a group (-NH-), wherein the alkanoyl group has the meaning as described herein. The alkanoylamino group can be optionally substituted with one or more substituents described herein. Examples of alkanoylamino groups include, but are not limited to, acetylamino (CH 3 -C(=O)-NH-), propionylamino (CH 3 CH 2 -C(=O)-NH-), and the like .
术语“烷氧基酰基”、“烷氨基酰基”、“氨基酰基”表示烷氧基、烷氨基或氨基(-NH 2)基团通过羰基(-C(＝O)-)与分子其余部分相连，其中，烷氧基和烷氨基基团具有如本发明所述的含义。所述烷氧基酰基、烷氨基酰基、氨基酰基基团可以任选地被一个或多个本发明所描述的取代基所取代。烷氧基酰基、烷氨基酰基的实例包括，但并不限于，甲氧基酰基(-C(＝O)OCH 3)，乙氧基酰基(-C(＝O)OCH 2CH 3)，甲氨基酰基(-C(＝O)NHCH 3)，二甲氨基酰基(-C(＝O)N(CH 3) 2)等等。 The term "alkoxy group", "alkylamino group", "amino group" represents an alkoxy group, an alkylamino group or an amino group (-NH 2) group by a carbonyl group (-C (= O) -) is connected to the rest of the molecule Wherein the alkoxy and alkylamino groups have the meanings as described herein. The alkoxyacyl, alkanoyl, or aminoacyl group may be optionally substituted with one or more substituents described herein. Examples of alkoxyacyl and alkanoyl groups include, but are not limited to, methoxyacyl (-C(=O)OCH 3 ), ethoxyacyl (-C(=O)OCH 2 CH 3 ), A Aminoacyl (-C(=O)NHCH 3 ), dimethylaminoacyl (-C(=O)N(CH 3 ) 2 ), and the like.
术语“烷基磺酰基”、“烷氧基磺酰基”、“烷氨基磺酰基”、“氨基磺酰基”表示烷基、烷氧基、烷氨基或氨基(-NH 2)基团通过磺酰基(-SO 2-)与分子其余部分相连，其中，烷基、烷氧基、烷氨基基团具有如本发明所述的含义。所述烷基磺酰基、烷氧基磺酰基、烷氨基磺酰基、氨基磺酰基基团可以任选地被一个或多个本发明所描述的取代基所取代。烷基磺酰基基团的实例包括，但并不限于，甲磺酰基(-SO 2CH 3)，乙基磺酰基(-SO 2CH 2CH 3)，等等。 The term "alkyl sulfonyl", "alkoxy sulfonyl group,""alkylaminosulfonylgroup","aminosulfonyl" denotes an alkyl group, an alkoxy group, an alkylamino group or an amino group (-NH 2) group bonded through a sulfonyl group (-SO 2 -) is attached to the remainder of the molecule wherein the alkyl, alkoxy, alkylamino group has the meaning as described herein. The alkylsulfonyl, alkoxysulfonyl, alkylaminosulfonyl, aminosulfonyl group may be optionally substituted with one or more substituents described herein. Examples of alkylsulfonyl groups include, but are not limited to, methylsulfonyl (-SO 2 CH 3 ), ethylsulfonyl (-SO 2 CH 2 CH 3 ), and the like.
术语“芳基”可以是单环，双环，和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子，且只有一个连接点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用，如芳香环可以包括苯基，萘基和蒽。芳基可以被本发明所述的取代基所取代。术语“C 6-12芳基”指芳基中碳原子数为6-12个，芳基具有如上定义。 The term "aryl" may be a monocyclic, bicyclic, and tricyclic carbocyclic ring system in which at least one ring system is aromatic, wherein each ring system contains from 3 to 7 atoms and has only one point of attachment to the molecule The rest of the connection is connected. The term "aryl" may be used interchangeably with the term "aromatic ring", such as an aromatic ring which may include phenyl, naphthyl and anthracene. The aryl group may be substituted with a substituent as described herein. The term "C 6-12 aryl" means that the number of carbon atoms in the aryl group is from 6 to 12, and the aryl group has the above definition.
术语“杂芳基”，“杂芳环”在此处可交换使用，都是指单环，双环，三环或者四环体系，其中，双环杂芳环，三环杂芳环或者四环杂芳环体系以稠合的形式成环。其中，杂芳环体系整体是芳香性的，环上一个或多个原子独立独立任选地被杂原子所取代(杂原子选自N、O、P、S、在此S或P独立任选地被一个或多个氧原子所取代得到像SO、SO 2、PO、PO 2的基团)。杂芳体系可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。杂芳体系基团可以是3-7个原子组成的单环，或7-10个原子组成的双环，或10-15个原子组成的三环。具有7-10个原子的双环可以是二环[4,5]，[5,5]，[5,6]或[6,6]体系，具有10-15个原子的三环可以是三环[5,5,6]、[5,7,6]或[6,5,6]体系。术语“C 5-12杂芳基”指杂芳基中含碳原子数为5-12个，杂芳基具有如上定义。 The terms "heteroaryl" and "heteroaryl" are used interchangeably herein to refer to a monocyclic, bicyclic, tricyclic or tetracyclic ring system wherein a bicyclic heteroaryl ring, a tricyclic heteroaryl ring or a tetracyclic ring is used. The aromatic ring system is fused in a fused form. Wherein, the heteroaromatic ring system is aromatic in its entirety, and one or more atoms on the ring are independently and independently substituted by a hetero atom (the hetero atom is selected from N, O, P, S, and S or P is independently optional herein) The ground is replaced by one or more oxygen atoms to give groups like SO, SO 2 , PO, PO 2 ). The heteroaryl system can be attached to the main structure at any heteroatom or carbon atom to form a stable compound. The heteroaryl system group may be a single ring of 3-7 atoms, or a double ring of 7-10 atoms, or a tricyclic ring of 10-15 atoms. A bicyclic ring having 7 to 10 atoms may be a bicyclo[4,5], [5,5], [5,6] or [6,6] system, and a tricyclic ring having 10 to 15 atoms may be a tricyclic ring. [5,5,6], [5,7,6] or [6,5,6] system. The term "C 5-12 heteroaryl" means that the heteroaryl group has 5 to 12 carbon atoms, and the heteroaryl group has the above definition.
另外一些实施例是，杂芳体系(包含杂芳基，杂芳环)包括以下例子，但并不限于这些例子：呋喃-2-基，呋喃-3-基，N-咪唑基，咪唑-2-基，咪唑-4-基，咪唑-5-基，异噁唑-3-基，异噁唑-4-基，异噁唑-5-基，噁唑-2-基，噁唑-4-基，噁唑-5-基，4-甲基异噁唑-5-基，N-吡咯基，吡咯-2-基，吡咯-3-基，吡啶-2-基，吡啶-3-基，吡啶-4-基，嘧啶-2-基，嘧啶-4-基，嘧啶-5-基，哒嗪基(如哒嗪-3-基)，噻唑-2-基，噻唑-4-基，噻 唑-5-基，四唑基(如四唑-5-基)，***基(如***-2-基和***-5-基)，噻吩-2-基，噻吩-3-基，吡唑基(如吡唑-2-基)，异噻唑基，1,2,3-噁二唑基，1,2,5-噁二唑基，1,2,4-噁二唑基，1,2,3-***基，1,2,3-硫代二唑基，1,3,4-硫代二唑基，1,2,5-硫代二唑基，1,3,4-噻二唑-2-基，吡嗪基，吡嗪-2-基，1,3,5-三嗪基，苯并[d]噻唑-2-基，咪唑并[1,5-a]吡啶-6-基，苯并咪唑基，苯并恶唑基，喹喔啉基，1,8-二氮杂萘基，苯并噻吩基，苯并噻唑基，吲哚基(如吲哚-2-基)，嘌呤基，喹啉基(如喹啉-2-基，喹啉-3-基，喹啉-4-基)，异喹啉基(如异喹啉-1-基，异喹啉-3-基或异喹啉-4-基)，苯并吡唑基，吖啶基，苯并咪唑基，苯并吲哚基，苯并异噁嗪基，苯并[4,6]咪唑并[1,2-a]吡啶基，苯并[d]咪唑[2,1-b]噻唑基，苯并噻二唑基，苯并噻唑基，苯并硫代苯基，苯并***基，苯并硫代吡喃基，苯并噁嗪基，苯并噁唑基，苯并噻唑基，β-咔啉基，咔唑基，邻二氮杂萘基，二苯并呋喃基，咪唑并吡啶基，咪唑并噻唑基，吲唑基，吲哚嗪基，吲哚基，异苯并噻嗯基，异喹啉基，异噻唑烷基，异噻唑基，萘啶基，噁唑烷二酮基，噁唑烷基，噁唑并吡啶基，噁唑基，茶嵌二氮苯基，菲啶基，菲绕啉基，吩砒嗪基，吩嗪基，吩噻嗪基，吩噁嗪基，酞嗪基，蝶啶基，吡啶并吡啶基，喹唑啉基，喹噁啉基，硫代苯基，三嗪基，2H-吡咯并[3,4-c]吡啶基，吡唑并[2’,1’:2,3]恶唑并[4,5-c]吡啶基，咪唑并[2’,1’:2,3]噻唑并[4,5-c]吡啶基，咪唑并[2’,1’:2,3]噻唑并[4,5-b]吡啶基，咪唑并[2’,1’:2,3]噻唑并[5,4-b]吡啶基，吡唑并[2’,1’:2,3]噻唑并[4,5-b]吡嗪基，1H-苯并[4,5]噻吩并[2,3-d]咪唑基，苯并[4,5]噻吩并[2,3-d]咪唑基，咪唑并[2',1':2,3]噻唑并[4,5-b]吡嗪基，咪唑并[2',1':2,3]噻唑并[5,4-b]吡啶基，咪唑并[2',1':2,3]噻唑并[4,5-c]吡啶基，1H-苯并[f]咪唑并[4,5-b][1,4]硫氮杂卓基等。杂芳基可以被本发明所述的取代基所取代。In other embodiments, heteroaromatic systems (including heteroaryl, heteroaryl) include the following examples, but are not limited to these examples: furan-2-yl, furan-3-yl, N-imidazolyl, imidazole-2 -yl, imidazol-4-yl, imidazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, oxazol-2-yl, oxazole-4 -yl,oxazol-5-yl, 4-methylisoxazole-5-yl, N-pyrrolyl, pyrrol-2-yl, pyrrol-3-yl, pyridin-2-yl, pyridin-3-yl , pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazinyl (eg pyridazin-3-yl), thiazol-2-yl, thiazol-4-yl, Thiazol-5-yl, tetrazolyl (such as tetrazol-5-yl), triazolyl (such as triazol-2-yl and triazol-5-yl), thiophen-2-yl, thiophen-3-yl , pyrazolyl (such as pyrazol-2-yl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl , 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3 , 4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl, benzo[d]thiazol-2-yl, imidazo[1,5- a]pyridine-6-yl, benzimidazolyl, benzoxazolyl Quinoxalinyl, 1,8-naphthyridinyl, benzothienyl, benzothiazolyl, indenyl (eg indole-2-yl), fluorenyl, quinolinyl (eg quinoline-2) -yl, quinolin-3-yl, quinolin-4-yl), isoquinolinyl (eg isoquinolin-1-yl, isoquinolin-3-yl or isoquinolin-4-yl), benzene Pyrazolyl, acridinyl, benzimidazolyl, benzindenyl, benzisooxazinyl, benzo[4,6]imidazo[1,2-a]pyridyl, benzo[d Imidazole [2,1-b]thiazolyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl, benzoxazinyl , benzoxazolyl, benzothiazolyl, β-carbolinyl, oxazolyl, o-naphthyridinyl, dibenzofuranyl, imidazopyridyl, imidazothiazolyl, oxazolyl, anthracene Pyridazinyl, fluorenyl, isobenzothiophene, isoquinolyl, isothiazolidinyl, isothiazolyl, naphthyridinyl, oxazolidinedione, oxazolidinyl, oxazolopyridinyl , oxazolyl, tea, diazophenyl, phenanthryl, phenanthroline, phenoxazine, phenazine, phenothiazine, phenoxazinyl, pyridazinyl, pteridinyl, pyridine Pyridyl, quinazolinyl, quinoxalinyl, thiophenyl, triazinyl, 2H-pyrrolo[3,4-c]pyridyl, pyrazolo[2',1':2,3] Oxazo[4,5-c]pyridyl, imidazo[2',1':2,3]thiazolo[4,5-c]pyridyl, imidazo[2',1':2,3 Thiazolo[4,5-b]pyridyl, imidazo[2',1':2,3]thiazolo[5,4-b]pyridinyl,pyrazolo[2',1':2, 3]thiazolo[4,5-b]pyrazinyl, 1H-benzo[4,5]thieno[2,3-d]imidazolyl,benzo[4,5]thieno[2,3- d] imidazolyl, imidazo[2',1':2,3]thiazolo[4,5-b]pyrazinyl, imidazo[2',1':2,3]thiazolo[5,4 -b]pyridyl, imidazo[2',1':2,3]thiazolo[4,5-c]pyridyl, 1H-benzo[f]imidazo[4,5-b][1, 4] thiazepine and the like. The heteroaryl group can be substituted with a substituent as described herein.
术语“杂环基”，“杂环”，“杂脂环族”或“杂环基”在此处可交换使用，都是指单环，双环，三环或者四环体系，其中环上一个或多个原子独立任选地被杂原子所取代，环可以是完全饱和的或包含一个或多个不饱和度，但绝不是芳香族类，杂环体系整体不具有芳香性。例如一些实施例中，双环的杂环基，其中一个环具有芳香性，另一个环整体不具有芳香性。杂环体系可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。一个或多个环上的氢原子独立地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，“杂环基”，“杂环”，“杂脂环族”或“杂环的”基团是指4-12元单环或多环(3-9个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P独立任选地被一个或多个氧原子所取代得到像SO，SO 2，PO，PO 2的基团，同时，-CH 2-基团可以独立任选地被-C(＝O)-替代；当所述的环为三元环时，其中只有一个杂原子，当所述环为多环时，可任选地为桥环，螺环或稠环)。术语“C 3-9杂环基”指杂环基中含碳原子数为3-9个，其中杂环基具有如上定义。 The terms "heterocyclyl", "heterocycle", "heteroalicyclic" or "heterocyclyl" are used interchangeably herein and refer to a monocyclic, bicyclic, tricyclic or tetracyclic ring system wherein one ring Or the plurality of atoms are independently optionally substituted by a heteroatom, the ring may be fully saturated or contain one or more unsaturations, but are by no means aromatic, and the heterocyclic system as a whole has no aromaticity. For example, in some embodiments, a bicyclic heterocyclic group wherein one ring is aromatic and the other ring is not aromatic at all. The heterocyclic ring system can be attached to the main structure at any heteroatom or carbon atom to form a stable compound. Hydrogen atoms on one or more of the rings are independently substituted with one or more substituents described herein. In some embodiments, a "heterocyclyl", "heterocycle", "heteroalicyclic" or "heterocyclic" group refers to a 4-12 membered monocyclic or polycyclic ring (3-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is independently substituted with one or more oxygen atoms to give a group like SO, SO 2 , PO, PO 2 , Meanwhile, the -CH 2 - group may be independently and optionally replaced by -C(=O)-; when the ring is a three-membered ring, there is only one hetero atom, and when the ring is a polycyclic ring, Optionally a bridge ring, a spiro ring or a fused ring). The term "C 3-9 heterocyclic group" means that the heterocyclic group has 3 to 9 carbon atoms, wherein the heterocyclic group has the above definition.
“杂环基”可以是碳原子基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环并合所形成的基团。杂环的实例包括，但并不限于，吡咯烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，四氢吡喃基，二氢吡喃基，四氢噻喃基，哌啶基，噻噁烷基，氮杂环丁基，氧杂环丁基，硫杂环丁基，哌啶基，高哌啶基，环氧丙基，氮杂环庚基，氧杂环庚基，硫杂环庚基，N-吗啉基，2-吗啉基，3-吗啉基，硫代吗啉基，N-哌嗪基，2-哌嗪基，3-哌嗪基，高哌嗪基，1,2,3,6-四氢吡啶-1-基，氧氮杂卓基，二氮杂卓基，硫氮杂卓基，吡咯啉-1-基，2-吡咯啉基，3-吡咯啉基，二氢吲哚基，2-吲哚啉基，2H-吡喃基，4H-吡喃基，二氧杂环己基，1,3-二氧戊基，吡唑啉基，二噻烷基，二噻茂烷基，二氢噻吩基，咪唑烷基，1,2,3,4-四氢异喹啉基，1,2,6-噻二嗪烷1,1-二氧-2-基，六氢-2H-[1,4]二氧芑[2,3-c]吡咯基，喹嗪基，1,1-二氧化硫代吗啉基，2,3,3a,7a-四氢-1H-异吲哚基，异吲哚啉基，1,2,3,4-四氢喹啉基，二苯并呋喃基，二氢苯并异噻嗪基，二氢苯并异噁嗪基，二氧戊环基，二氢吡嗪基，二氢吡啶基，二氢吡唑基，二氢嘧啶基，二氢吡咯基，1,4-二噻烷基，呋喃酮基，呋喃基，咪唑烷基，咪唑啉基，咪唑基，咪唑并吡啶基，咪唑并噻唑基，吲唑基，二氢吲哚基，吲哚嗪基，异苯并四氢呋喃基，异苯并四氢噻嗯基，异苯并噻嗯基，异苯并二氢吡喃基，异香豆素基，异二氢吲哚基，异噻唑烷基，异噁唑烷基，吗啉基，十氢吲哚基，十氢异吲哚基，噁二唑基，噁唑烷二酮基，噁唑烷基，噁唑并吡啶基，环氧乙烷基，哌嗪基，哌啶基，4-哌啶酮基，吡咯基，喹宁环基， 四氢异喹啉基，四氢噻嗯基，硫吗啉基，噻唑烷基，1,3,5-三噻烷基，2-氧代吡咯烷基，氧代-1,3-噻唑烷基，2-哌啶酮基，3,5-二氧代哌啶基，1,2,3,4-四氢异喹啉基，1,3-苯并二噁茂基，2-氧杂-5-氮杂双环[2.2.1]庚-5-基，4-氧代吗啉基和嘧啶二酮基。The "heterocyclic group" may be a carbon atom group or a hetero atom group. "Heterocyclyl" also includes groups formed by the union of a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Thioxazyl, azetidinyl, oxetanyl, thioheterobutyl, piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxetan, sulfur Heterocyclic heptyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazine , 1,2,3,6-tetrahydropyridin-1-yl, oxazepine, diazepine, thiazepine, pyrrolin-1-yl, 2-pyrroline, 3 -pyrroline, indanyl, 2-carbolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxopentyl, pyrazolinyl, Dithiaalkyl, dithiamethane, dihydrothienyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinidine 1,1-di Oxy-2-yl, hexahydro-2H-[1,4]dioxan[2,3-c]pyrrolyl, quinazinyl, 1,1-dioxythiomorpholinyl, 2,3,3a,7a -tetrahydro-1H-isoindenyl, isoindolyl, 1,2,3,4-tetrahydro Polinyl, dibenzofuranyl, dihydrobenzoisothiazinyl, dihydrobenzoisooxazinyl, dioxolanyl, dihydropyrazinyl, dihydropyridyl, dihydropyrazolyl, Dihydropyrimidinyl, dihydropyrrolyl, 1,4-dithiazyl, furanone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazopyridyl, imidazothiazolyl, carbazolyl , indanyl, pyridazinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothiol, isobenzothiol, isochromanyl, isocoumarinyl, heterodi Hydroquinone, isothiazolidinyl, isoxazolidinyl, morpholinyl, decahydroindolyl, decahydroisodecyl, oxadiazolyl, oxazolidinedione, oxazolidinyl, Oxazolopyridyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidinone, pyrrolyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydrothiophene, sulfur Olinyl, thiazolidinyl, 1,3,5-trithiaalkyl, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone, 3,5-dioxo Piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxanyl, 2-oxa- 5-Azabicyclo[2.2.1]hept-5-yl, 4-oxomorpholinyl and pyrimidindione.
一些实施例中，杂环基为4-12个原子组成的杂环基，是指包含4-12个环原子的饱和或部分不饱和的单环或多环，其中至少一个环原子选自氮、硫和氧原子。4-12个原子组成的杂环基的实例包括，但不限于，氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2019077582-appb-000012
基，二氮杂
Figure PCTCN2019077582-appb-000013
基，硫氮杂
Figure PCTCN2019077582-appb-000014
基，等等。杂环基中-CH 2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基、嘧啶二酮基，等等。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、硫代吗啉基1,1-二氧化物，等等。所述的4-7个原子组成的杂环基基团任选地被一个或多个本发明所描述的取代基所取代。 In some embodiments, a heterocyclic group is a heterocyclic group of 4 to 12 atoms, and refers to a saturated or partially unsaturated monocyclic or polycyclic ring containing 4 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen. , sulfur and oxygen atoms. Examples of the heterocyclic group consisting of 4 to 12 atoms include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrroline, 3-pyrroline , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine Base, dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl, oxetanyl, thiaheptanyl, oxazepine
Figure PCTCN2019077582-appb-000012
Diaza
Figure PCTCN2019077582-appb-000013
Thioaza
Figure PCTCN2019077582-appb-000014
Base, and so on. Examples of the -CH 2 - group in the heterocyclic group substituted by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto group, 3,5-dioxopiperidinyl, pyrimidindione, and the like. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group, a thiomorpholino 1,1-dioxide, and the like. The heterocyclic group consisting of 4-7 atoms is optionally substituted by one or more substituents described herein.
术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。The term "heteroatom" refers to O, S, N, P, and Si, including any form of oxidation states of N, S, and P; forms of primary, secondary, tertiary, and quaternary ammonium salts; or nitrogen atoms in heterocycles. a form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。The term "halogen" means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
术语“螺环基”，“螺环”，“螺双环基”，“螺双环”表示一个环起源于另一个环上特殊的环状碳。例如，像下面所描述的，一个饱和的桥环体系(环D和B')被称为“稠合双环”，反之环A’和环D在两个饱和的环体系中共享一个碳原子，则被称为“螺环”。螺环里面的每一个环要么是碳环要么是杂环。这样的实例包括，但并不限于，4-氮杂螺[2.4]庚烷-5-基，4-氧杂螺[2.4]庚烷-5-基，5-氮杂螺[2.4]庚烷-5-基，螺[2.4]庚烷基，螺[4.4]壬烷基，7-羟基-5-氮杂螺[2.4]庚烷-5-基等。The terms "spirocyclyl", "spirocyclic", "spirobicyclo", and "spirobicyclic" mean that one ring originates from a particular cyclic carbon on the other ring. For example, as described below, a saturated bridged ring system (rings D and B') is referred to as a "fused bicyclic ring", whereas ring A' and ring D share a carbon atom in two saturated ring systems, It is called a "spiral ring." Each ring in the spiro ring is either a carbon ring or a heterocyclic ring. Such examples include, but are not limited to, 4-azaspiro[2.4]heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane -5-yl, spiro[2.4]heptanyl, spiro[4.4]decylalkyl, 7-hydroxy-5-azaspiro[2.4]heptane-5-yl and the like.
Figure PCTCN2019077582-appb-000015
Figure PCTCN2019077582-appb-000015
术语“螺杂双环基”表示一个环起源于另一个环上特殊的环状碳。例如，像上面所描述的，一个饱和的桥环体系(环D和B')被称为“稠合双环”，反之环A’和环D在两个饱和的环体系中共享一个碳原子，则被称为“螺环”。且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含3-7个原子，即包含1-6个碳原子和选自N，O，P，S的1-3个杂原子,在此N，S或P独立任选地被一个或多个氧原子所取代得到像NO，NO 2，SO，SO 2，PO，PO 2的基团，-CH 2-基团可以独立任选地被-C(＝O)-替代；这样的实例包括，但并不限于4-氮杂螺[2.4]庚烷基，4-氧杂螺[2.4]庚烷基，5-氮杂螺[2.4]庚烷基，2-氮杂螺[4.5]癸烷基，2-氮杂螺[3.3]庚烷基，2-氮杂螺[4.4]壬烷基，3-氮杂螺[5.4]癸烷基，2-氧-6-氮杂螺[3.3]庚烷基，2,6-二氮杂螺[3.3]庚烷基，2-硫-6-氮杂螺[3.3]庚烷基2-一氧化物，2-硫-6-氮杂螺[3.3]庚烷基2,2-二氧化物，2,8-二氮杂螺[4.5]癸烷基，2,7-二氮杂螺[4.4]辛烷基，2,7-二氮杂螺[4.5]癸烷基，2,6-二氮杂螺[4.5]癸烷基，2,8-二氮杂螺[4.5]癸烷-3-酮-基，1,8-二氮杂螺[4.5]癸烷基，1,7-二氮杂螺[4.4]壬烷基，1,7-二氮杂螺[4.4]壬烷-6-酮-基，2,9-二氮杂螺[5.5]十一烷-1-酮-基，1-氧-3,8-二氮杂螺[4.5]癸烷-2-酮-基，1-氧-3,7-二氮杂螺[4.5]癸烷-2-酮-基，2,6-二氮杂螺[3.4]辛烷基，2,5-二氮杂螺[3.5]壬烷基，2,6-二氮杂螺[3.3]庚烷基，2-氧-7-氮杂螺[3.5]壬烷基，2-氧-6-氮杂螺[3.4]辛烷基等。螺杂环基可以被本发明所述的取代基所取代。 The term "spirobicyclo" means that one ring originates from a particular cyclic carbon on the other ring. For example, as described above, a saturated bridged ring system (rings D and B') is referred to as a "fused bicyclic ring", whereas ring A' and ring D share a carbon atom in two saturated ring systems, It is called a "spiral ring." And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises from 3 to 7 atoms, ie from 1 to 6 carbon atoms and from 1 to 3 heteroatoms selected from N, O, P, S Wherein N, S or P is independently substituted by one or more oxygen atoms to give a group like NO, NO 2 , SO, SO 2 , PO, PO 2 , and the —CH 2 — group may be independently The ground is replaced by -C(=O)-; such examples include, but are not limited to, 4-azaspiro[2.4]heptyl, 4-oxaspiro[2.4]heptyl, 5-azaspiro [2.4] Heptyl, 2-azaspiro[4.5]decyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[4.4]decyl, 3-azaspiro[5.4癸alkyl, 2-oxo-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2-sulfo-6-azaspiro[3.3]heptane 2-Oxo, 2-sulfo-6-azaspiro[3.3]heptanyl 2,2-dioxide, 2,8-diazaspiro[4.5]decyl, 2,7-di Azaspiro[4.4]octyl, 2,7-diazaspiro[4.5]decyl, 2,6-diazaspiro[4.5]decyl,2,8-diazaspiro[4.5癸 -3--3-one-yl, 1,8-diazaspiro[4.5]decyl, 1,7-diazaspiro[4.4]decyl, 1,7-diazaspiro[4] .4]decane-6-keto-yl, 2,9-diazaspiro[5.5]undec-1-one-yl, 1-oxo-3,8-diazaspiro[4.5]decane -2-keto-yl, 1-oxo-3,7-diazaspiro[4.5]decane-2-one-yl, 2,6-diazaspiro[3.4]octyl, 2,5- Diazaspiro[3.5]decylalkyl, 2,6-diazaspiro[3.3]heptanyl, 2-oxo-7-azaspiro[3.5]decylalkyl, 2-oxo-6-aza Snail [3.4] octyl group and the like. The spiroheterocyclyl can be substituted with a substituent as described herein.
术语“稠合双环”，“稠环”，“稠合双环基”或“稠环基”表示饱和或不饱和的稠环体系，涉及到非芳香族的 双环体系，至少有一个环是非芳香性的。这样的体系可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。稠合双环中的每一个环要么是碳环要么是杂脂环族，这样的实例包括，但并不限于，六氢-呋喃[3,2-b]呋喃基，2,3,3a,4,7,7a-六氢-1H-茚基，7-氮杂双环[2.2.1]庚烷基，稠合双环[3.3.0]辛烷基，稠合双环[3.1.0]己烷基，1,2,3,4,4a,5,8,8a-八氢萘基，这些都包含在稠合双环的体系之内。The term "fused bicyclic", "fused ring", "fused bicyclic" or "fused ring" means a saturated or unsaturated fused ring system involving a non-aromatic bicyclic system, at least one of which is non-aromatic of. Such a system may contain an independent or conjugated unsaturated state, but its core structure does not contain an aromatic ring or an aromatic heterocyclic ring (but an aromatic may serve as a substituent thereon). Each of the fused bicyclic rings is either a carbocyclic ring or a heteroalicyclic group, and such examples include, but are not limited to, hexahydro-furan [3,2-b]furanyl, 2,3,3a,4 , 7,7a-hexahydro-1H-indenyl, 7-azabicyclo[2.2.1]heptyl, fused bicyclo[3.3.0]octyl, fused bicyclo[3.1.0]hexane 1,2,3,4,4a,5,8,8a-octahydronaphthyl, these are all contained within the fused bicyclic system.
术语“稠合杂双环基”表示饱和或不饱和的稠环体系，涉及到非芳香族的双环体系，至少有一个环是非芳香性的。这样的体系可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含3-7个原子组成的环，即包含1-6个碳原子和选自N，O，P，S的1-3个杂原子，在此N，S或P独立任选地被一个或多个氧原子所取代得到像NO，NO 2，SO，SO 2，PO，PO 2的基团，-CH 2-基团可以独立任选地被-C(＝O)-替代，这样的实例包括，但并不限于，六氢-2H-[1,4]二氧芑[2,3-c])吡咯基，3-氮杂双环[3.3.0]辛烷基，8-氮杂双环[4.3.0]壬烷基，8-氮杂双环[4.3.0]壬烷3-基，3-氮杂双环[4.3.0]壬烷-3-基，1,5-二氧-8-氮杂双环[4.3.0]壬烷基，(1R,6S)-2,5-二氧-8-氮杂双环[4.3.0]壬烷基，(1R,6R)-2,5-二氧-8-氮杂双环[4.3.0]壬烷基，异吲哚啉基，1,2,3,4-四氢喹啉基，(1S,5S)-1-羟基-3-氮杂双环[3.1.0]己烷基，(1R,5S)-1-羟基-3-氮杂双环[3.1.0]己烷基，3-氮-7-氧杂双环[3.3.0]辛烷基，3,7-二氮杂双环[3.3.0]辛烷基，2,6-二氮杂双环[3.3.0]辛烷基，2,7-二氮杂双环[3.3.0]辛烷基，2,7-二氮杂双环[3.3.0]辛烷基，2,8-二氮杂双环[4.3.0]壬烷基，3,8-二氮杂双环[4.3.0]壬烷基，3-氧-8-氮杂双环[4.3.0]壬烷基，2-氧-8-氮杂双环[4.3.0]壬烷基，2,8-二氮-5-氧杂双环[4.3.0]壬烷基，4,9-二氮杂双环[4.3.0]壬烷基，2,9-二氮杂双环[4.3.0]壬烷基，2-氧代-3-氧-8-氮杂双环[4.3.0]壬烷基，3-氧代-2,4,8-三氮杂双环[4.3.0]壬烷基，3-氧代-4-氧-2,8-二氮杂双环[4.3.0]壬烷基，3-氧代-2,8-二氮杂双环[4.3.0]壬烷基，3,8-二氮杂双环[4.3.0]壬烷基，3,7-二氮杂双环[4.3.0]壬烷基，3,9-二氮杂双环[4.3.0]壬烷基，3-氧-8-氮杂双环[4.3.0]壬烷基，3-硫-8-氮杂双环[4.3.0]壬烷基，5,6-二氢-4H-吡咯并[3,4-c]异恶唑基，[1,2,4]三氮唑[4,3-a]并哌啶基，异恶唑并[4,3-c]哌啶基，4,5,6,7-四氢异恶唑并[3,4-c]吡啶基，[1,2,4]三氮唑并[4,3-a]哌嗪基，2-氧代-3-氧-8-氮杂双环[4.3.0]壬烷基，2-氧-7-氮杂双环[4.4.0]癸烷基，1,5-二氧-9-氮杂双环[4.4.0]癸烷基，3-氮杂双环[4.4.0]癸烷基，2,7-二氮杂十氢萘基，2-氧-8-氮杂双环[4.4.0]癸烷基，六氢吡咯并[1,2-a]吡嗪-1(2H)-酮-基，十氢-1H-吡啶并[1,2-a]吡嗪-1-酮-基，3-氮杂双环[3,1,0]己烷-1-氨基-基等。稠合杂双环基可以被本发明所述的取代基所取代。 The term "fused heterobicyclic" means a saturated or unsaturated fused ring system involving a non-aromatic bicyclic system, at least one of which is non-aromatic. Such a system may contain an independent or conjugated unsaturated state, but its core structure does not contain an aromatic ring or an aromatic heterocyclic ring (but an aromatic may serve as a substituent thereon). And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a ring of 3-7 atoms, ie 1-3 atoms containing 1-6 carbon atoms and selected from N, O, P, S a hetero atom in which N, S or P is independently substituted by one or more oxygen atoms to give a group like NO, NO 2 , SO, SO 2 , PO, PO 2 , a -CH 2 - group It may be independently and optionally substituted by -C(=O)-, such examples include, but are not limited to, hexahydro-2H-[1,4]dioxo[2,3-c]pyrrolyl, 3 - azabicyclo[3.3.0]octyl, 8-azabicyclo[4.3.0]decyl, 8-azabicyclo[4.3.0]nonan-3-yl, 3-azabicyclo[4.3 .0]decane-3-yl, 1,5-dioxo-8-azabicyclo[4.3.0]nonanyl, (1R,6S)-2,5-dioxo-8-azabicyclo[ 4.3.0]decyl, (1R,6R)-2,5-dioxo-8-azabicyclo[4.3.0]nonanyl, isoindolyl, 1,2,3,4-tetra Hydroquinolinyl, (1S,5S)-1-hydroxy-3-azabicyclo[3.1.0]hexane, (1R,5S)-1-hydroxy-3-azabicyclo[3.1.0] Alkyl, 3-nitro-7-oxabicyclo[3.3.0]octyl, 3,7-diazabicyclo[3.3.0]octyl, 2,6-diazabicyclo[3.3.0 Octyl, 2,7-diaza Bicyclo[3.3.0]octyl, 2,7-diazabicyclo[3.3.0]octyl, 2,8-diazabicyclo[4.3.0]decyl, 3,8-diaza Heterobicyclo[4.3.0]nonyl, 3-oxo-8-azabicyclo[4.3.0]nonanyl, 2-oxo-8-azabicyclo[4.3.0]decyl, 2,8 -diaza-5-oxabicyclo[4.3.0]nonanyl, 4,9-diazabicyclo[4.3.0]nonanyl, 2,9-diazabicyclo[4.3.0]decane , 2-oxo-3-oxo-8-azabicyclo[4.3.0]nonanyl, 3-oxo-2,4,8-triazabicyclo[4.3.0]decyl, 3 -oxo-4-oxo-2,8-diazabicyclo[4.3.0]nonanyl, 3-oxo-2,8-diazabicyclo[4.3.0]decyl, 3,8 -diazabicyclo[4.3.0]nonanyl, 3,7-diazabicyclo[4.3.0]decyl, 3,9-diazabicyclo[4.3.0]decyl, 3- Oxy-8-azabicyclo[4.3.0]nonanyl, 3-thio-8-azabicyclo[4.3.0]nonanyl, 5,6-dihydro-4H-pyrrolo[3,4- c] isoxazolyl, [1,2,4]triazole [4,3-a]piperidinyl, isoxazolo[4,3-c]piperidinyl, 4,5,6, 7-tetrahydroisoxazo[3,4-c]pyridinyl, [1,2,4]triazolo[4,3-a]piperazinyl, 2-oxo-3-oxo-8 -azabicyclo[4.3.0]nonanyl, 2-oxo-7-azabicyclo[4.4.0] Alkyl, 1,5-dioxo-9-azabicyclo[4.4.0]nonanyl, 3-azabicyclo[4.4.0]nonanyl, 2,7-diazadecalinyl, 2-oxo-8-azabicyclo[4.4.0]nonanyl, hexahydropyrrolo[1,2-a]pyrazine-1(2H)-one-yl, decahydro-1H-pyrido[1] , 2-a] pyrazin-1-one-yl, 3-azabicyclo[3,1,0]hexane-1-amino-yl and the like. The fused heterobicyclic group may be substituted with a substituent as described herein.
像本发明所描述的，取代基画一个键连接到环上形成的环体系代表取代基在该环上任何可取代的位置都可以取代。例如，式(a)代表p个取代基R可以在吡啶环上任何可能被取代的位置上取代。As described herein, a substituent forming a ring to form a ring system formed on the ring means that the substituent can be substituted at any substitutable position on the ring. For example, formula (a) represents that p substituents R may be substituted at any position on the pyridine ring that may be substituted.
Figure PCTCN2019077582-appb-000016
Figure PCTCN2019077582-appb-000016
像本发明所描述的，一个连接键连接到环上形成的环体系(如式b所示)代表连接键可以在环体系上任何可连接的位置与分子其余部分相连。式b代表八氢环戊烯并吡咯环上任何可能连接的位置均可与分子其余部分相连。As described herein, a ring linkage to a ring system formed on the ring (as shown in Formula b) means that the linker can be attached to the remainder of the molecule at any linkable position on the ring system. Formula b represents the position of any possible linkage on the octahydrocyclopentenopyrrole ring to the remainder of the molecule.
Figure PCTCN2019077582-appb-000017
Figure PCTCN2019077582-appb-000017
像本发明所描述的，环C上有两个连接点可与分子其余部分相连，例如，如式c所示，除非以其他方式明确指出，否则表示式c中既可以是E端也可以是E’端与分子的其余部分相连，即两端的连接方式可以互换。As described in the present invention, there are two attachment points on ring C that can be attached to the rest of the molecule, for example, as shown in formula c, unless otherwise explicitly indicated, the expression c can be either E or E The E' end is connected to the rest of the molecule, ie the connections at both ends are interchangeable.
Figure PCTCN2019077582-appb-000018
Figure PCTCN2019077582-appb-000018
如本发明所描述，连接点可以在环上任何可连接的位置与分子其余部分连接，同时连接的两端可以互换。例如，式d代表环上任何可能被连接的位置均可作为连接的点，同时连接点的两端可以互换。As described herein, the attachment points can be joined to the remainder of the molecule at any connectable position on the ring, while the ends of the linkage can be interchanged. For example, the formula d represents that any position on the ring that may be connected can be used as a connection point, and both ends of the connection point can be interchanged.
另外，需要说明的是，除非以其他方式明确指出，在本文中通篇采用的描述方式“各…和…独立地为”、“…和…各自独立地为”和“…和…分别独立地为”可以互换，应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。例如，
Figure PCTCN2019077582-appb-000019
中N 1和N 2表示相同或不同的原子或基团，且相互之间不影响；“n1-n8”表示相同或不同的取值，且相互之间不影响。 In addition, it should be noted that, unless otherwise explicitly indicated, the descriptions used herein are "individually..." and "independently", "... and ... are independently" and "... and ... are independently "Alternatively, it should be understood in a broad sense. It can mean that in different groups, the specific options expressed between the same symbols do not affect each other, and can also be expressed in the same group, the same symbol. The specific options expressed between them do not affect each other. E.g,
Figure PCTCN2019077582-appb-000019
Wherein N 1 and N 2 represent the same or different atoms or groups and do not affect each other; "n1-n8" represents the same or different values and does not affect each other.
术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或相似不适当的反应，例如肠胃不适、眩晕等的分子实体和组合物。优选地，本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、更特别在人体中使用的。The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to a human and generally do not produce an allergic or similar inappropriate response, such as gastrointestinal upset, dizziness, and the like. Preferably, the term "pharmaceutically acceptable" as used herein refers to an animal, more particularly a human body, approved by a federal or national government or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia.
术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。这些药物载体可以是无菌液体，例如水和油类，包括石油、动物、植物或合成来源的，例如花生油、大豆油、矿物油、芝麻油等。水和水性溶液盐水溶液和水性葡萄糖与甘油溶液优选用作载体、特别是可注射溶液。适宜的药物载体描述于E.W.Martin的“Remington′s Pharmaceutical Sciences”中。The term "carrier" refers to a diluent, adjuvant, excipient or matrix with which the compound is administered. These pharmaceutical carriers may be sterile liquids such as water and oils including petroleum, animal, vegetable or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Aqueous solutions of water and aqueous solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, in particular injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.
本发明的“水合物”是指本发明所提供的化合物或其盐，其还包括化学量或非化学当量通过非共价分子间力结合的水，也可说是溶剂分子是水所形成的缔合物。The "hydrate" of the present invention refers to a compound provided by the present invention or a salt thereof, which further comprises a chemical amount or a non-chemical equivalent of water bound by a non-covalent intermolecular force, or a solvent molecule formed by water. Association.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，MeOH，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, MeOH, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.
本发明的“酯”是指含有羟基的式(I)-式(II)所示化合物可形成体内可水解的酯。这样的酯是例如在人或动物体内水解产生母体醇的药学上可接受的酯。含有羟基的式(I)-式(II)所示化合物体内可水解的酯的基团包括，但不限于，磷酸基，乙酰氧基甲氧基，2,2-二甲基丙酰氧基甲氧基，烷酰基，苯甲酰基，苯甲乙酰基，烷氧基羰基，二烷基氨基甲酰基和N-(二烷基氨基乙基)-N-烷基氨基甲酰基等。The "ester" of the present invention means that the compound of the formula (I)-formula (II) containing a hydroxyl group forms an in vivo hydrolysable ester. Such esters are, for example, pharmaceutically acceptable esters which are hydrolyzed in a human or animal body to yield the parent alcohol. The group of the in vivo hydrolysable ester of the compound of the formula (I)-formula (II) containing a hydroxyl group includes, but is not limited to, a phosphate group, an acetoxymethoxy group, and a 2,2-dimethylpropionyloxy group. Methoxy, alkanoyl, benzoyl, benzylacetyl, alkoxycarbonyl, dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl and the like.
本发明的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂例如DCM中，使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。The "nitrogen oxide" of the present invention means that when the compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form an N-oxide. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid such as peroxycarboxylic acid to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, the N-oxide can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514) wherein the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as DCM.
化合物可存在多种不同几何异构体和互变异构体，所述式(I)-式(II)化合物包括所有此类形式。为避免疑惑，当化合物以几种几何异构体或互变异构体之一存在并且只具体描述或显示一种时，显然所有其它形式包括在式(I)-式(II)中。Compounds may exist in a variety of different geometric isomers and tautomers, and the compounds of formula (I)-formula (II) include all such forms. For the avoidance of doubt, when a compound is present in one of several geometric isomers or tautomers and only one is specifically described or shown, it is apparent that all other forms are included in formula (I)-formula (II).
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)-式(II)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化 合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。 The term "prodrug" as used herein, denotes a compound which is converted in vivo to a compound of formula (I)-formula (II). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug-like compound of the present invention may be an ester. In the prior invention, the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C 1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters. For example, a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent. For a discussion of the completeness of prodrugs, refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008 , 51, 2328-2345.
除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention.
另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。本发明包括同位素标记的化合物，它们等同于式(I)-式(II)所述的化合物，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如 3H和 14C)的那些可用于药物和/或底物组织分布测定。同位素标记的本发明式(I)-式(II)所示化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。 Additionally, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms. The present invention includes isotopically-labeled compounds which are equivalent to the compounds of formula (I)-formula (II), but one or more of the atoms are different in atomic mass or mass from atoms of atomic mass or mass number which are common in nature. instead. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18, respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds of the invention, prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs containing such isotopes and/or other isotopes of other atoms are within the scope of the invention. Certain isotopically-labeled compounds of the invention, such as those incorporating radioisotopes (e.g., 3 H and 14 C), are useful in drug and/or substrate tissue distribution assays. Isotopically labeled compounds of the formula (I)-formula (II) of the present invention and prodrugs thereof can generally be prepared as described above, and are readily available when carrying out the processes disclosed in the following schemes and/or examples and preparations. Isotopically labeled reagents replace non-isotopically labeled reagents.
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolic product" refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
本发明化合物的各种药学上可接受的盐形式都是有用的。术语“药学上可接受的盐”是指那些盐形式对于制药化学家而言是显而易见的，即它们基本上无毒并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或***。其他因素，在性质上更加实用，对于选择也很重要，这些是：原材料的成本、结晶的容易、产率、稳定性、吸湿性和结果原料药的流动性。简单地讲，药物组合物可以通过有效成分与药学上可接受的载体制备得到。Various pharmaceutically acceptable salt forms of the compounds of the invention are useful. The term "pharmaceutically acceptable salts" means those salt forms are apparent to pharmaceutical chemists that they are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism Or excretion. Other factors, which are more practical in nature, are also important for selection: the cost of the raw materials, the ease of crystallization, the yield, stability, hygroscopicity, and the resulting fluidity of the drug substance. Briefly, the pharmaceutical composition can be prepared by the active ingredient together with a pharmaceutically acceptable carrier.
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，硝酸盐等，和有机酸盐如乙酸盐，丙酸盐，乙醇酸盐，草酸盐，马来酸盐，丙二酸盐，琥珀酸盐，富马酸盐，酒石酸盐，枸橼酸盐，苯甲酸盐，扁桃酸盐，甲磺酸盐，乙磺酸盐，甲苯磺酸盐，磺基水杨酸盐等，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。The "pharmaceutically acceptable salt" as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, Nitrate, etc., and organic acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, tannic acid Salt, benzoate, mandelate, methanesulfonate, ethanesulfonate, tosylate, sulfosalicylate, etc., or by other methods described in the literature, such as ion exchange These salts.
其他药学上可接受的盐包括己二酸盐、苹果酸盐、2-羟基丙酸、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐、等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。 Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionic acid, alginate, ascorbate, aspartate, besylate, benzoate, heavy sulfate, Borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumaric acid Salt, glucoheptonate, glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate , laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, Pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate , valerate, and so on. Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。胺盐，例如但不限于N,N’-二苄基乙二胺，氯普鲁卡因，胆碱，氨，二乙醇胺和其它羟烷基胺，乙二胺，N-甲基还原葡糖胺，普鲁卡因，N-苄基苯乙胺，1-对-氯苄基-2-吡咯烷-1’-基甲基-苯并咪唑，二乙胺和其它烷基胺，哌嗪和三(羟甲基)氨基甲烷；碱土金属盐，例如但不限于钡，钙和镁；过渡金属盐，例如但不限于锌。 The present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization. The alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate. Amine salts such as, but not limited to, N, N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methyl reduced glucose Amine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine And tris(hydroxymethyl)aminomethane; alkaline earth metal salts such as, but not limited to, barium, calcium and magnesium; transition metal salts such as, but not limited to, zinc.
术语“保护基团”或“Pg”是指一个取代基与别的官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC)，苄氧羰基(CBZ)和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH 2CH 2SO 2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005. The term "protecting group" or "Pg" refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups. For example, "protecting group of an amino group" refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl. (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent used to block or protect a hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "Carboxy protecting group" means a substituent of a carboxy group used to block or protect the functionality of a carboxy group. Typical carboxy protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenyl Phosphine) ethyl, nitroethyl, and the like. A general description of protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
本发明中“室温”指的是温度由10℃到40℃。在一些实施例中，“室温”指的是温度由20℃到30℃；在另一些实施例中，“室温”指的是25℃。"Room temperature" in the present invention means that the temperature is from 10 ° C to 40 ° C. In some embodiments, "room temperature" refers to a temperature of from 20 °C to 30 °C; in other embodiments, "room temperature" refers to 25 °C.
在本说明书中，如果在化学名称和化学结构间存在任何差异，结构是占优的。In this specification, if there is any difference between the chemical name and the chemical structure, the structure is dominant.
本发明所使用的任何保护基团、氨基酸和其它化合物的缩写，除非另有说明，都以它们通常使用的、公认的缩写为准，或参照IUPAC-IUB Commission on Biochemical Nomenclature(参见Biochem.1972，11：942-944)。Abbreviations for any protecting groups, amino acids, and other compounds used in the present invention, unless otherwise indicated, are based on their commonly accepted and accepted abbreviations, or with reference to the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11:942-944).
本发明化合物的描述Description of the compounds of the invention
本发明提供一种化合物或其药物组合物，其可作为PD-1/PD-L1的抑制剂。本发明进一步涉及所述化合物或其药物组合物用于制备药剂的用途，该药剂通过用所述化合物抑制PD-1活性来治疗疾病和/或病症。本发明又进一步描述了合成所述化合物的方法。本发明的化合物显示出改善的生物活性及药代动力学性质。The present invention provides a compound or a pharmaceutical composition thereof which is useful as an inhibitor of PD-1/PD-L1. The invention further relates to the use of said compound or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of a disease and/or condition by inhibiting PD-1 activity with said compound. The invention further describes a method of synthesizing the compound. The compounds of the invention exhibit improved biological activity and pharmacokinetic properties.
本发明一方面提供一种PD-1/PD-L1类小分子抑制剂的化合物，其为如式(I)所示的结构或如式(I)所示结构的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，酯，药学上可接受的盐或前药，In one aspect, the present invention provides a compound of the PD-1/PD-L1 type small molecule inhibitor, which is a structure represented by the formula (I) or a stereoisomer of the structure represented by the formula (I), geometrically different a construct, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug,
其中，A、X、R 1、R 2、R 3和p具有本发明所述的含义。 Among them, A, X, R 1 , R 2 , R 3 and p have the meanings described in the present invention.
在一些实施方案中，本发明所述的R 1为-(CH 2) nAr，其中，Ar为C 6-12芳基或C 5-12杂芳基；所述Ar任选地被1、2、3或4个取代基取代，所述取代基各自独立地为H、D、氰基、卤素、氨基、甲磺酰基、乙酰氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或C 1-6烷氧基；n为1、2、3或4。 In some embodiments, R 1 according to the invention is -(CH 2 ) n Ar, wherein Ar is C 6-12 aryl or C 5-12 heteroaryl; the Ar is optionally 1 2, 3 or 4 substituents, each of which is independently H, D, cyano, halogen, amino, methylsulfonyl, acetylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy; n is 1, 2, 3 or 4.
在一些实施方案中，本发明所述的R 1为-(CH 2) nAr，其中，所述Ar为苯基、吡啶基、嘧啶基、吲哚基或喹啉基；Ar任选地被1、2、3或4个取代基取代，所述取代基各自独立地为H、氰基、卤素、氨基、甲磺酰 基、乙酰氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或C 1-6烷氧基；n为1。 In some embodiments, R 1 according to the invention is -(CH 2 ) n Ar, wherein said Ar is phenyl, pyridyl, pyrimidinyl, indenyl or quinolyl; Ar is optionally Substituting 1, 2, 3 or 4 substituents, each independently being H, cyano, halogen, amino, methylsulfonyl, acetylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy; n is 1.
在一些实施方案中，本发明所述的A为-CH 2O-、-OCH 2-、-CH 2-CH 2-、-C(O)NH-或-NHC(O)-。 In some embodiments, the present invention is A is -CH 2 O -, - OCH 2 -, - CH 2 -CH 2 -, - C (O) NH- or -NHC (O) -.
在一些实施方案中，本发明所述的A为-CH 2O-。 In some embodiments, A is according to the present invention is -CH 2 O-.
在一些实施方案中，本发明所述的R 2为
Figure PCTCN2019077582-appb-000021
In some embodiments, the R 2 of the present invention is
Figure PCTCN2019077582-appb-000021
其中，R 5和R 6各自独立地为H、卤素、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；Z为CH或N； Wherein R 5 and R 6 are each independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; Z is CH or N;
R 7为
Figure PCTCN2019077582-appb-000022
q为1、2、3或4； R 7 is
Figure PCTCN2019077582-appb-000022
q is 1, 2, 3 or 4;
R v为
Figure PCTCN2019077582-appb-000023
其中，R v任选地被0、1、2或3个取代基取代，所述取代基为羟基、氰基、氨基、氧代(＝O)、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或氨基C 1-6烷基；W 1、W 3和W 5各自独立地为CH 2、S、O、S(O) 2或NH，W 2和W 4各自独立地为CH或N；m1、m2、m3、m4、m5、m6、m7和m8各自独立地为0、1、2或3； R v is
Figure PCTCN2019077582-appb-000023
Wherein R v is optionally substituted by 0, 1, 2 or 3 substituents which are hydroxy, cyano, amino, oxo (=O), C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or amino C 1-6 alkyl; W 1 , W 3 and W 5 are each independently CH 2 , S, O, S(O) 2 or NH, W 2 and W 4 are each independently CH or N; m1, m2, m3, m4, m5, m6, m7 and m8 are each independently 0, 1, 2 or 3;
X和Y为H、C 1-6烷基、C 1-6烷氧基、卤素或者氰基。 X and Y are H, C 1-6 alkyl, C 1-6 alkoxy, halogen or cyano.
在一些实施方案中，本发明所述的R 5或R 6各自独立的为H、D、氟、氯、溴、甲基、乙基、正丙基、异丙基、叔丁基、异丁基、正丁基、三氟甲基、二氟甲基、一氟甲基、甲氧基或乙氧基。 In some embodiments, R 5 or R 6 according to the invention are each independently H, D, fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl Base, n-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy or ethoxy.
在一些实施方案中，本发明所述的R 7为
Figure PCTCN2019077582-appb-000024
q为1。 In some embodiments, the R 7 of the present invention is
Figure PCTCN2019077582-appb-000024
q is 1.
在一些实施方案中，本发明所述的R v为
Figure PCTCN2019077582-appb-000025
其中，R v任选地被0、1、2或3个取代基取代，所述取代基为羟基、氰基、氨基、氧代(＝O)、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或氨基C 1-6烷基；W 1、W 3和W 5各自独立地为CH 2、S、O、S(O) 2或者NH，W 2和W 4各自独立地为CH或CH或N；m1、m2、m3、m4、m5、m6、m7和m8各自独立地为0、1、2或3。 In some embodiments, the R v of the present invention is
Figure PCTCN2019077582-appb-000025
Wherein R v is optionally substituted by 0, 1, 2 or 3 substituents which are hydroxy, cyano, amino, oxo (=O), C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or amino C 1-6 alkyl; W 1 , W 3 and W 5 are each independently CH 2 , S, O, S(O) 2 or NH, W 2 and W 4 are each independently CH or CH or N; m1, m2, m3, m4, m5, m6, m7 and m8 are each independently 0, 1, 2 or 3.
在一些实施方案中，本发明所述的R v为以下结构式形成的基团之一： In some embodiments, R v according to the invention is one of the groups formed by the following structural formula:
Figure PCTCN2019077582-appb-000026
Figure PCTCN2019077582-appb-000026
Figure PCTCN2019077582-appb-000027
Figure PCTCN2019077582-appb-000027
其中，所述W 1、W 3和W 5各自独立地为CH 2、S、O、S(O) 2或者NH，W 2和W 4各自独立地为CH或CH或N；m1、m2、m3、m4、m5、m6、m7和m8各自独立地为0、1、2或3； Wherein, W 1 , W 3 and W 5 are each independently CH 2 , S, O, S(O) 2 or NH, and W 2 and W 4 are each independently CH or CH or N; m1, m2 M3, m4, m5, m6, m7 and m8 are each independently 0, 1, 2 or 3;
所述R v任选地被0、1、2或3个取代基取代，所述取代基为羟基、氰基、氨基、氧代(＝O)、C 1-6烷基、C 1- 6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或氨基C 1-6烷基。 Said R v is optionally substituted by 0, 1, 2 or 3 substituents which are hydroxy, cyano, amino, oxo (=O), C 1-6 alkyl, C 1 - 6 Haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or amino C 1-6 alkyl.
在另一些实施方案中，本发明所述的R v为以下结构式形成的基团之一： In other embodiments, R v according to the invention is one of the groups formed by the following structural formula:
Figure PCTCN2019077582-appb-000028
Figure PCTCN2019077582-appb-000028
Figure PCTCN2019077582-appb-000029
Figure PCTCN2019077582-appb-000029
其中，所述R v任选地被0、1、2或3个取代基取代，所述取代基为羟基、氰基、氨基、氧代(＝O)、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或氨基C 1-6烷基。 Wherein R v is optionally substituted by 0, 1, 2 or 3 substituents which are hydroxy, cyano, amino, oxo (=O), C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or amino C 1-6 alkyl.
在一些实施方案中，本发明所述的Y为甲基、乙基、异丙基、正丙基、正丁基、叔丁基或异丁基；优选的，Y为甲基。In some embodiments, Y of the invention is methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl or isobutyl; preferably, Y is methyl.
在一些实施方案中，本发明所述的R 3为C 1-8烷氨基或C 3-9杂环基，其中，所述的C 3-9杂环基中至少含有一个N原子；所述的C 1-8烷氨基或C 3-9杂环基任选地被0、1、2、3或4个取代基所取代，所述取代基为氢、羟基、卤素、羧基、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基、氨基、氨基C 1-6烷基、乙酰氨基、氰基、磺酰胺基或氧代(＝O)。 In some embodiments, R 3 of the present invention is a C 1-8 alkylamino group or a C 3-9 heterocyclic group, wherein the C 3-9 heterocyclic group contains at least one N atom; The C 1-8 alkylamino group or the C 3-9 heterocyclic group is optionally substituted by 0, 1, 2, 3 or 4 substituents which are hydrogen, hydroxy, halogen, carboxyl, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, amino, amino C 1-6 alkyl, acetylamino, cyano, sulfonamide or oxo ( =O).
在一些实施方案中，本发明所述的R 3为如下结构形成的基团之一： In some embodiments, R 3 of the invention is one of the groups formed by the structure:
Figure PCTCN2019077582-appb-000030
Figure PCTCN2019077582-appb-000030
Figure PCTCN2019077582-appb-000031
Figure PCTCN2019077582-appb-000031
在一些实施方案中，本发明所述的p为0、1、2或3。In some embodiments, the p described herein is 0, 1, 2 or 3.
在一些实施方案中，本发明所述的X为H、C 1-6烷基、C 1-6烷氧基、卤素或者氰基；优选的，X为氟、氯、溴、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。 In some embodiments, the X of the present invention is H, C 1-6 alkyl, C 1-6 alkoxy, halogen or cyano; preferably, X is fluoro, chloro, bromo, methyl, B. Base, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
在一些试试方案中，本发明所述的化合物为如式(II)所示的结构或如式(II)所示结构的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，酯，药学上可接受的盐或前药，In some attempts, the compound of the present invention is a structure represented by formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen as shown in formula (II). An oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug,
Figure PCTCN2019077582-appb-000032
Figure PCTCN2019077582-appb-000032
其中，R 1、R 2、R 3、R 5、R 6、R v、X、Y、Z和p具有本发明所述的含义。 Wherein R 1 , R 2 , R 3 , R 5 , R 6 , R v , X, Y, Z and p have the meanings indicated in the present invention.
在一些实施方案中，本发明包含以下其中之一的化合物或以下其中之一的化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或前药：In some embodiments, the invention comprises a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolism of a compound of one of the following or a compound of one of the following Product, pharmaceutically acceptable salt or prodrug:
Figure PCTCN2019077582-appb-000033
Figure PCTCN2019077582-appb-000033
Figure PCTCN2019077582-appb-000034
Figure PCTCN2019077582-appb-000034
Figure PCTCN2019077582-appb-000035
Figure PCTCN2019077582-appb-000035
Figure PCTCN2019077582-appb-000036
Figure PCTCN2019077582-appb-000036
Figure PCTCN2019077582-appb-000037
Figure PCTCN2019077582-appb-000037
Figure PCTCN2019077582-appb-000038
Figure PCTCN2019077582-appb-000038
Figure PCTCN2019077582-appb-000039
Figure PCTCN2019077582-appb-000039
Figure PCTCN2019077582-appb-000040
Figure PCTCN2019077582-appb-000040
Figure PCTCN2019077582-appb-000041
Figure PCTCN2019077582-appb-000041
Figure PCTCN2019077582-appb-000042
Figure PCTCN2019077582-appb-000042
Figure PCTCN2019077582-appb-000043
Figure PCTCN2019077582-appb-000043
Figure PCTCN2019077582-appb-000044
Figure PCTCN2019077582-appb-000044
Figure PCTCN2019077582-appb-000045
Figure PCTCN2019077582-appb-000045
Figure PCTCN2019077582-appb-000046
Figure PCTCN2019077582-appb-000046
一方面，本发明涉及药物组合物，该药物组合物，包含本发明式(I)或式(II)所述的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，及其药学上可接受的辅料或它们的组合。In one aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) or formula (II) of the invention, or a stereoisomer, geometric isomer, tautomer thereof, Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable excipients or combinations thereof.
一方面，本发明涉及式(I)或(II)所述的化合物或其药物组合物在制备用于防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病的药物的用途。In one aspect, the invention relates to a compound of formula (I) or (II) or a pharmaceutical composition thereof for use in the manufacture of a medicament for use in the protection, treatment, treatment or alleviation of a disease associated with a PD-1/PD-L1 signaling pathway in a patient use.
在一些实施案中，本发明所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。In some embodiments, the disease associated with the PD-1/PD-L1 signaling pathway of the invention is a cancer, an infectious disease, or an autoimmune disease.
在另一些实施案中，本发明所述的癌症选自器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述自身免疫性疾病为器官特异性自身免疫病或***性自身免疫病。In other embodiments, the cancer of the present invention is selected from the group consisting of diseases in which an immortalized cell is present in an organ or body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; Autoimmune diseases are organ-specific autoimmune diseases or systemic autoimmune diseases.
在一些实施案中，本发明所述的器官或体组织中细胞无限增殖的疾病是为骨癌、头颈癌、胰腺癌、皮 肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、***区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、***、***癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌***癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、***癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经***(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤或环境诱发的癌症或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。In some embodiments, the diseases in which the cells in the organ or body tissue of the present invention are immortalized are bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area. Cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid Cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, solid tumor of children, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) Tumor, primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmentally induced a combination of cancer or a disease as described above; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, and chronic Lymphocyte leukemia.
在一些实施案中，本发明所述病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、***瘤病毒感染和流感。In some embodiments, the viral infectious diseases of the invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection, and influenza.
在一些实施案中，本发明所述的所述的器官特异性自身免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的***性自身免疫病为类风湿关节炎、***性红斑狼疮、***性血管炎、硬皮病、天疱疮、皮肌炎、混合性***病和自身免疫性溶血性贫血。In some embodiments, the organ-specific autoimmune disease of the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic Atrophic gastritis, pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic erythema Lupus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.
在一些实施方案中，本发明描述了一种防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病的方法，所述方法包含给予患者有效治疗剂量的本发明所述的化合物或药物组合物。In some embodiments, the invention features a method of protecting, treating, treating or ameliorating a disease associated with a PD-1/PD-L1 signaling pathway in a patient, the method comprising administering to the patient a therapeutically effective amount of the invention described in the present invention A compound or pharmaceutical composition.
在一些实施方案中，本发明所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。In some embodiments, the disease associated with the PD-1/PD-L1 signaling pathway of the invention is a cancer, an infectious disease, or an autoimmune disease.
在一些实施方案中，本发明所述的癌症为器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述自身免疫性疾病为器官特异性自身免疫病或***性自身免疫病。In some embodiments, the cancer of the present invention is a disease in which an immortalized cell exists in an organ or a body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; the autoimmune Sexual diseases are organ-specific autoimmune diseases or systemic autoimmune diseases.
在一些实施方案中，本发明所述的器官或体组织中细胞无限增殖的疾病为骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、***区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、***、***癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌***癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、***癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经***(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤或环境诱发的癌症或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。In some embodiments, the diseases in which the cells in the organ or body tissue of the present invention are immortalized are bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer. , gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer , parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, solid tumor of children, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumor , primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmentally induced cancer Or a combination of the above; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, and chronic Pakistan leukemia.
在一些实施方案中，本发明所述的病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、***瘤病毒感染和流感。In some embodiments, the viral infectious diseases of the invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection, and influenza.
在一些实施方案中，本发明所述的器官特异性免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的***性自身免疫病为类风湿关节炎、***性红斑狼疮、***性血管炎、硬皮病、天疱疮、皮肌炎、混合性***病和自身免疫性溶血性贫血。另一方面，本发明提供一种调节受治疗者中由PD-1信号传导通路介导的免疫应答的方法，其包括向受治疗者使用治疗有效量本发明的化合物，从而调节受治疗者中的免疫应答。In some embodiments, the organ-specific immune disease of the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic Vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia. In another aspect, the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention, thereby modulating the subject Immune response.
在一些实施方案中，将本发明所描述的化合物或药物组合物用于防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病。In some embodiments, the compounds or pharmaceutical compositions described herein are used to protect, treat, treat, or ameliorate a disease associated with a PD-1/PD-L1 signaling pathway in a patient.
在一些实施方案中，本发明所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性 疾病。In some embodiments, the disease associated with the PD-1/PD-L1 signaling pathway of the invention is a cancer, an infectious disease, or an autoimmune disease.
在一些实施方案中，本发明所述的癌症为器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述自身免疫性疾病为器官特异性自身免疫病或***性自身免疫病。In some embodiments, the cancer of the present invention is a disease in which an immortalized cell exists in an organ or a body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; the autoimmune Sexual diseases are organ-specific autoimmune diseases or systemic autoimmune diseases.
在一些实施方案中，本发明所述的器官或体组织中细胞无限增殖的疾病为骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、***区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、***、***癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌***癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、***癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经***(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤或环境诱发的癌症或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。In some embodiments, the diseases in which the cells in the organ or body tissue of the present invention are immortalized are bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer. , gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer , parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, solid tumor of children, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumor , primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmentally induced cancer Or a combination of the above; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, and chronic Pakistan leukemia.
在一些实施方案中，本发明所述的病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、***瘤病毒感染和流感。In some embodiments, the viral infectious diseases of the invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection, and influenza.
在一些实施方案中，本发明所述的器官特异性免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的***性自身免疫病为类风湿关节炎、***性红斑狼疮、***性血管炎、硬皮病、天疱疮、皮肌炎、混合性***病和自身免疫性溶血性贫血。In some embodiments, the organ-specific immune disease of the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic Vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.
另一方面，本发明提供一种调节受治疗者中由PD-1信号传导通路介导的免疫应答的方法，其包括向受治疗者使用治疗有效量本发明的化合物，从而调节受治疗者中的免疫应答。In another aspect, the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention, thereby modulating the subject Immune response.
另一方面，本发明涉及式(I)或(II)所包含的化合物的制备、分离和纯化的方法。In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound comprised by formula (I) or (II).
本发明的化合物的组合物Composition of a compound of the invention
像本发明所描述的，本发明药物组合物包含任何一种本发明的式(I)或(II)所示化合物，进一步包含药学上可接受的辅料，这些辅料，例如像本发明所应用的，包括任何溶剂、固体赋形剂、稀释剂、粘合剂、崩解剂、或其他液体赋形剂、分散剂、矫味剂或悬浮剂、表面活性剂、等渗剂、增稠剂、乳化剂、防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的辅料可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅料与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。As described in the present invention, the pharmaceutical composition of the present invention comprises any one of the compounds of the formula (I) or (II) of the present invention, further comprising a pharmaceutically acceptable adjuvant, such as, for example, as applied in the present invention. And includes any solvent, solid excipient, diluent, binder, disintegrating agent, or other liquid excipient, dispersing agent, flavoring or suspending agent, surfactant, isotonic agent, thickening agent, Emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the specific target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999 Marcel Dekker, New York, synthesizing the contents of the literature, indicates that different excipients are useful in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. In addition to any conventional excipients that are incompatible with the compounds of the present invention, such as any undesirable biological effects produced or interactions with any other component of a pharmaceutically acceptable composition in a detrimental manner, their Use is also within the scope of the invention.
可作为药学上可接受辅料的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适 的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。当本发明的化合物以药物的形式施用于哺乳动物例如人时，其可以以化合物本身的形式被给予或者可以以含有例如0.1至99.5％(更优选0.5至90％)活性成分以及药学可接受的载体的药物组合物的形式被给予。Substances which may be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins such as human serum proteins; buffer substances such as phosphate; glycine; sorbic acid; Potassium acid; a partial glyceride mixture of saturated vegetable fatty acids; water; salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt; colloidal silicon; magnesium trisilicate; Pyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-blocking polymer; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Cellulose sodium, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talcum powder; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid Pyrogen-free water; isotonic salt; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; Clothing; sweeteners; flavoring agents; flavors; preservatives and antioxidants. When the compound of the present invention is administered in a form of a medicament to a mammal such as a human, it may be administered as the compound itself or may contain, for example, 0.1 to 99.5%, more preferably 0.5 to 90%, of the active ingredient and pharmaceutically acceptable. The form of the pharmaceutical composition of the carrier is administered.
“治疗有效量”或“有效量”是指本发明的一种或多种化合物治疗或预防特定疾病、病症或综合征减轻、改善或消除特定疾病、病症或综合征的一个或多个症状或阻止或延迟本文所述的特定疾病、病症或综合征的一个或多个症状的开始的足够量。在癌症的情况下，治疗有效量的药物可以减少癌细胞的数量；降低癌尺寸；抑制(即，减慢到一定程度或备选地终止)癌细胞浸润入周围器官；压制(即，减慢到一定程度或备选地终止)肿瘤转移；一定程度上一直肿瘤生长；和/或一定程度上缓解与癌症相关的一个或多个症状。在感染性疾病状态的情况下，治疗有效量是足以降低或缓解感染性疾病(由细菌、病毒和真菌引起的感染症状)的量。本领域普通技术人员将能研究本文所包含的因素和在不进行过度实验的情况下确定本发明的化合物的有效量。"Therapeutically effective amount" or "effective amount" means that one or more compounds of the invention treat or prevent a particular disease, disorder or syndrome from alleviating, ameliorating or eliminating one or more symptoms of a particular disease, disorder or syndrome or A sufficient amount to prevent or delay the onset of one or more symptoms of a particular disease, disorder, or syndrome described herein. In the case of cancer, a therapeutically effective amount of the drug can reduce the number of cancer cells; reduce the size of the cancer; inhibit (ie, slow down to some extent or alternatively terminate) the infiltration of cancer cells into the surrounding organs; suppression (ie, slowing down) To some extent or alternatively termination) tumor metastasis; to some extent tumor growth; and/or to some extent alleviate one or more symptoms associated with cancer. In the case of an infectious disease state, the therapeutically effective amount is an amount sufficient to reduce or alleviate the infectious disease (symptoms of infection caused by bacteria, viruses and fungi). One of ordinary skill in the art will be able to study the factors contained herein and determine the effective amount of a compound of the invention without undue experimentation.
施用方案可影响有效量的构成。本发明的化合物可在与PD-1/PD-L1信号通路有关的病症发作之前或之后被施用于个体。此外，可以每天或相继施用多个分剂量以及错开的剂量，或者可以连续输注给药，或者可以推注给药。此外，本发明的化合物的剂量可以根据治疗或预防的情形的紧迫性按比例酌情增加或减少。The administration regimen can affect the composition of the effective amount. The compounds of the invention can be administered to an individual before or after the onset of a condition associated with the PD-1/PD-L1 signaling pathway. In addition, multiple divided doses and staggered doses may be administered daily or sequentially, or may be administered as a continuous infusion, or may be administered by bolus injection. Furthermore, the dose of the compound of the present invention may be increased or decreased as appropriate according to the urgency of the situation of treatment or prevention.
本发明的化合物可用于治疗本文所述的状态、病症或疾病，或用于制备治疗这些疾病的药物组合物。本发明的化合物在这些疾病治疗中的使用方法或用于治疗这些疾病的含有本发明的化合物的药物制剂。The compounds of the invention are useful in the treatment of the conditions, disorders or diseases described herein, or in the preparation of pharmaceutical compositions for the treatment of such diseases. A method of using a compound of the present invention in the treatment of these diseases or a pharmaceutical preparation containing the compound of the present invention for treating these diseases.
“药学可接受的载体”在本领域中是公认的，包括适于将本发明的化合物施用于哺乳动物的药学可接受的材料、组合物或载体。所述载体包括参与携带主题物质或将其从一个器官或机体的一部分转移到另一个器官或机体的另一部分的液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。各载体在与制剂中的其它成分相容和对患者无害的意义上必须是“可接受的”。可用作药学可接受的载体的材料的一些实例包括：糖类，如乳糖、葡萄糖和蔗糖；淀粉类，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，如羧甲基纤维素钠、乙基纤维素和醋酸纤维素；粉状西黄蓍胶；麦芽；明胶；滑石粉；赋形剂，如可可脂和栓剂蜡类；油类，如花生油、棉子油、红花油、芝麻油、橄榄油、玉米油和豆油；二醇类，如丙二醇；多元醇类，如甘油、山梨醇、甘露醇和聚乙二醇；酯类，如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等张盐水；林格氏溶液；乙醇；磷酸盐缓冲液；和药物制剂中所用的其它无毒的可相容的物质。"Pharmaceutically acceptable carrier" is recognized in the art and includes pharmaceutically acceptable materials, compositions or carriers suitable for administration of a compound of the invention to a mammal. The carrier includes a liquid or solid filler, diluent, excipient, solvent or encapsulating material that is involved in carrying the subject substance or transferring it from one part of the organ or body to another part of the body or body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, Ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil , olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffer Agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer; and other non-toxic compatible in pharmaceutical preparations substance.
在组合物中也可以存在润湿剂、乳化剂和润滑剂如十二烷基硫酸钠和硬脂酸镁，以及着色剂、释放剂、包衣剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧化剂。Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring agents and fragrances may also be present in the compositions. , preservatives and antioxidants.
药学可接受的抗氧化剂的实例包括：水溶性抗氧化剂，如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等；油溶性抗氧化剂，如棕榈酸抗坏血酸酯、丁基化羟基苯甲醚(BHA)、丁化羟基甲苯(BHT)、卵磷脂、棓酸丙酯、α-生育酚等；和金属螯合剂，如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium hydrogen sulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxybenzene Methyl ether (BHA), butylated hydroxytoluene (BHT), lecithin, propyl citrate, alpha-tocopherol, etc.; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid , phosphoric acid, etc.
本发明的制剂包括适于口服、鼻、局部、***、舌下、直肠、***和/或胃肠外施用的那些。制剂可以方便地以单位剂型形式存在并且可以通过药学领域公知的任何方法来制备。可以与载体物质组合来制备单剂量形式的活性成分的量一般是产生治疗作用的化合物的量。一般而言，以百分之一为单位，该量为约1％至约99％活性成分，优选约5％至约70％，最优选约10至约30％。Formulations of the invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods known in the art. The amount of active ingredient which may be combined with the carrier materials in the preparation of a single dosage form is generally the amount of the compound which produces a therapeutic effect. Generally, the amount is from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10 to about 30%, in units of one percent.
制备这些制剂或组合物的方法包括使本发明的化合物与载体、独立任选地和一种或多种辅助成分结合的步骤。一般而言，制剂是通过将本发明的化合物与液体载体或很细的固体载体或这二者均匀且紧密地结合在一起、然后如果需要的话，将该产物成型来制备的。Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with a carrier, optionally, optionally with one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately combining the compound of the present invention with a liquid carrier or a very fine solid carrier or both, and then shaping the product if desired.
适于口服施用的本发明的制剂可以是胶囊剂、扁囊剂、丸剂、片剂、锭剂(使用矫味的基质，通常为蔗糖和***胶或西黄蓍胶)、散剂、颗粒剂、或者在水性或非水性液体中的溶液剂或混悬剂、或者水包油或油包水型液体乳剂、或者酏剂或糖浆剂、或者软锭剂(使用惰性基质，如明胶和甘油、或蔗糖和***胶)和/或漱口剂等的形式，其各自含有既定量的本发明的化合物作为活性成分。本发明的化合物还可以以大丸剂、药糖剂或糊剂的形式施用。Formulations of the invention suitable for oral administration may be capsules, cachets, pills, tablets, lozenges (using a flavoring base, typically sucrose and acacia or tragacanth), powders, granules, Or a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion, or an elixir or syrup, or a soft lozenge (using an inert base such as gelatin and glycerin, or Forms of sucrose and gum arabic) and/or mouthwashes, each containing as an active ingredient a predetermined amount of a compound of the invention. The compounds of the invention may also be administered in the form of a bolus, electuary or paste.
在用于口服施用的本发明的固体剂型(胶囊剂、片剂、丸剂、糖衣丸、散剂、颗粒剂等)中，将活性成分与一种或多种药学可接受的载体如柠檬酸钠或磷酸二钙和/或任何下列物质混合：填充剂或增量剂，如淀粉类、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸；粘合剂，例如，羧甲基纤维素、藻酸盐类、明胶、聚乙烯吡咯烷酮、蔗糖和/或***胶；保湿剂，如甘油；崩解剂，如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、海藻酸、某些硅酸和碳酸钠；溶液阻滞剂(solution retarding agent)，如石蜡；吸收促进剂，如季铵化合物；润湿剂，例如，鲸蜡醇和甘油单硬脂酸酯；吸附剂，如高岭土和皂土；润滑剂，如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，以及其混合物；和着色剂。在胶囊剂、片剂和丸剂的情况下，药物组合物还可包含缓冲剂。类似类型的固体组合物还可在使用赋形剂如乳糖或奶糖以及高分子量聚乙二醇等的软和硬填充明胶胶囊中用作填充物。In a solid dosage form (capsule, tablet, pill, dragee, powder, granule, etc.) of the present invention for oral administration, the active ingredient is combined with one or more pharmaceutically acceptable carriers such as sodium citrate or Dicalcium phosphate and/or any of the following: fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; binders, for example, carboxymethylcellulose, alginate Class, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; humectants such as glycerin; disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicic acid and sodium carbonate; Solution retarding agent such as paraffin; absorption enhancer such as quaternary ammonium compound; wetting agent such as cetyl alcohol and glyceryl monostearate; adsorbent such as kaolin and bentonite; lubricant such as talc Powder, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
片剂可以通过压制或模制来制备，可任选地使用一种或多种辅助成分。压制片可以用粘合剂(例如，明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如，羟乙酸淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂来制备。模制片可以通过将用惰性液体稀释剂润湿的粉状化合物的混合物在合适的机器中进行模制来制备。Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. The compressed tablet may be coated with a binder (for example, gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (for example, sodium starch glycolate or croscarmellose sodium). ), a surfactant or a dispersant to prepare. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.
片剂和本发明的药物组合物的其它固体剂型如糖衣丸、胶囊剂、丸剂和颗粒剂可任选地被刻痕或用包衣和壳如肠溶衣和制药领域公知的其它包衣来制备。也可以将它们用例如提供所需释放性质的各种比例的羟丙基甲基纤维素、其它聚合物基质、脂质体和/或微球进行配制以便提供其中的活性成分的缓慢释放或控制释放。可将它们例如通过用截留细菌的滤器过滤或通过在使用前即刻掺入可溶解于无菌水或一些其它可注射无菌溶媒中的无菌固体组合物形式的灭菌剂来进行灭菌。这些组合物还可任选地含有遮光剂并且可以是仅在或优先在胃肠道的某个部分中释放活性成分、任选以延迟方式释放活性成分的组合物。可使用的包埋组合物的实例包括聚合物物质和蜡类。活性成分也可以是微囊化的形式，如果适宜的话，使用一种或多种上述赋形剂。Tablets and other solid dosage forms of the pharmaceutical compositions of the invention, such as dragees, capsules, pills and granules, may optionally be scored or coated with a shell and shell such as enteric coatings and other coatings known in the pharmaceutical arts. preparation. They may also be formulated with various ratios of hydroxypropyl methylcellulose, other polymer matrices, liposomes and/or microspheres to provide the desired release properties to provide slow release or control of the active ingredients therein. freed. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation into a sterilizing agent in the form of a sterile solid composition which is soluble in sterile water or some other injectable sterile vehicle immediately prior to use. These compositions may also optionally contain opacifying agents and may be compositions which release the active ingredient(s) only, or preferentially, in a portion of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric materials and waxes. The active ingredient may also be in microencapsulated form, if appropriate, using one or more of the above-mentioned excipients.
用于口服施用的本发明的化合物的液体剂型包括药学可接受的乳剂、微乳、溶液、混悬液、糖浆剂和酏剂。除活性成分以外，液体剂型还可含有本领域中常用的惰性稀释剂例如水或其它溶剂、增溶剂和乳化剂如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油类(特别是棉子油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇醇、聚乙二醇和失水山梨醇的脂肪酸酯以及其混合物。Liquid dosage forms of the compounds of the invention for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. The liquid dosage form may contain, in addition to the active ingredient, inert diluents such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, which are commonly used in the art. Ester, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and Fatty acid esters of sorbitol and mixtures thereof.
除惰性稀释剂以外，口服组合物还可包含辅剂(adjuvant)如润湿剂、乳化剂和助悬剂、甜味剂、矫味剂、着色剂、芳香剂和防腐剂。Besides the inert diluent, the oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservatives.
除活性化合物以外，混悬剂还可包含助混剂，例如乙氧基化异硬脂醇、聚氧乙烯山梨醇和失水山梨醇酯、微晶纤维素、偏氢氧化铝(aluminummetahydroxide)、皂土、琼脂和西黄蓍胶以及其混合物。In addition to the active compound, the suspension may contain admixtures such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydrate, soap Soil, agar and tragacanth and mixtures thereof.
用于直肠或***施用的本发明的药物组合物的制剂可以以栓剂的形式存在，其可以通过将一种或多种本发明的化合物与一种或多种合适的无刺激的赋形剂或载体(包括例如可可脂、聚乙二醇、栓剂蜡或水杨酸酯)混合来制备，并且其在室温下是固体，但是在体温下是液体，因此将在直肠或***腔中熔化并释放出活性化合物。Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository by combining one or more compounds of the invention with one or more suitable non-irritating excipients or The carrier (including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate) is prepared by mixing, and it is solid at room temperature, but liquid at body temperature, and thus will melt and release in the rectum or vaginal cavity The active compound is obtained.
适于***施用的本发明的制剂还包括含有本领域中已知适宜的载体的***栓、卫生栓、乳膏剂、凝胶 剂、糊剂、泡沫剂或喷雾制剂。Formulations of the invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art.
本发明的化合物的用于局部或透皮施用的剂型包括散剂、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液剂、贴剂和吸入剂。可以将活性成分在无菌条件下与药学可接受的载体和可能需要的任何防腐剂、缓冲剂或抛射剂混合。Dosage forms for topical or transdermal administration of the compounds of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with apharmaceutically acceptable carrier and any preservatives, buffers or propellants which may be required.
除本发明的活性化合物以外，软膏剂、糊剂、乳膏剂和凝胶剂还可包含赋形剂，如动物和植物脂肪、油类、蜡类、石蜡类、淀粉、西黄蓍胶、纤维素衍生物、聚乙二醇类、硅氧烷类、皂土类、硅酸、滑石粉和氧化锌、或其混合物。Ointments, pastes, creams and gels may contain excipients, such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, fiber, in addition to the active compounds of the present invention. A derivative, a polyethylene glycol, a siloxane, a bentonite, silicic acid, talc, and zinc oxide, or a mixture thereof.
除本发明的化合物以外，散剂和喷雾剂还可包含赋形剂如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末或这些物质的混合物。喷雾剂还可包含常规抛射剂如氯氟烃类和挥发性的未被取代的烃类，如丁烷和丙烷。Powders and sprays can contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these materials. Sprays can also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.
透皮贴剂具有为机体提供本发明的化合物的控制传递的另外的优点。该类剂型可以通过将化合物溶解或分散于合适的溶媒中来制备。还可以使用吸收促进剂来增加通过皮肤的化合物通量。可以通过提供控速膜或将活性化合物分散于聚合物基质或凝胶中来控制该类流动的速度。Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the invention to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable vehicle. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate of such flow can be controlled by providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
在本发明的范围内还包括眼用制剂、眼用软膏剂、散剂、溶液剂等。Ophthalmic formulations, ophthalmic ointments, powders, solutions, and the like, are also included within the scope of the invention.
适于胃肠外施用的本发明的药物组合物包含一种或多种本发明的化合物以及一种或多种药学可接受的无菌的等张的水性或非水性溶液、分散物、混悬剂或乳剂、或者可在使用前即刻被重组到无菌的可注射溶液或分散物中的无菌粉末，其可包含抗氧化剂、缓冲剂、抑菌剂、使得制剂与接受者的血液等张的溶质或助悬剂或增稠剂。Pharmaceutical compositions of the invention suitable for parenteral administration comprise one or more compounds of the invention together with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions An agent or emulsion, or a sterile powder which can be reconstituted into a sterile injectable solution or dispersion immediately prior to use, which may contain an antioxidant, a buffer, a bacteriostatic agent, such that the formulation and the recipient's blood are invigorating Solute or suspending agent or thickener.
可用于本发明的药物组合物中的合适的水性和非水性载体的实例包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)以及其合适的混合物、植物油类如橄榄油和可注射的有机酯类如油酸乙酯。可以例如通过使用包衣材料如卵磷脂、在分散物的情况下通过维持所需的粒度、和通过使用表面活性剂来维持合适的流动性。Examples of suitable aqueous and nonaqueous vehicles which may be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like) as well as suitable mixtures thereof, vegetable oils such as olive oil, and Injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
这些组合物还可包含辅剂如防腐剂、润湿剂、乳化剂和分散剂。可以通过包含各种抗细菌剂和抗真菌剂例如尼泊金酯、三氯叔丁醇、苯酚、山梨酸等来确保预防微生物的作用。还可能需要在组合物中包含等张剂如糖类、氯化钠等。此外，可以通过包含延迟吸收的物质如单硬脂酸铝和明胶来造成可注射药物形式的延长吸收。These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of materials which delay absorption, such as aluminum monostearate and gelatin.
在一些情况中，为了延长药物的作用，需要减慢得自皮下或肌内注射的药物吸收。这可以通过使用水溶性差的结晶性或无定形物质的液体混悬液来实现。这样，药物的吸收速率将取决于其溶出速率，溶出速率又可能取决于晶体大小和晶形。或者，通过将药物溶解或混悬于油性基质中来实现胃肠外施用的药物形式的延长吸收。In some cases, in order to prolong the action of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. Thus, the rate of absorption of the drug will depend on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, prolonged absorption of the parenterally administered drug form is accomplished by dissolving or suspending the drug in an oily base.
可注射的储库形式是通过在可生物降解的聚合物如聚丙交酯-聚乙交酯中形成主题化合物的微囊基质来制备的。根据药物与聚合物的比例以及所用的具体化合物的性质，可以控制药物释放速率。其它可生物降解的聚合物的实例包括聚(原酸酯)和聚(酸酐)。可注射的储库制剂也可以通过将药物包在与机体组织相容的脂质体或微乳中来制备。Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular compound employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by encapsulating the drug in liposomes or microemulsions which are compatible with body tissues.
本发明的制剂可以被口服、胃肠外、局部或直肠施用。它们当然是以适合于各施用途径的形式被给予。例如，它们以片剂或胶囊剂的形式被施用，通过注射剂、吸入剂、眼用洗剂、软膏剂、栓剂等被施用，通过注射、输注或吸入被施用；通过洗剂或软膏剂被局部施用；通过栓剂被直肠施用。优选的是口服和/或静脉内施用。The formulations of the invention may be administered orally, parenterally, topically or rectally. They are of course given in a form suitable for each route of administration. For example, they are administered in the form of tablets or capsules, administered by injection, inhalation, ophthalmic lotion, ointment, suppository, etc., by injection, infusion or inhalation; by lotion or ointment Topical application; administered rectally by suppository. Preferred is oral and/or intravenous administration.
本文所用的措辞“胃肠外施用”意指除肠内和局部施用以外的施用方式，通常是通过注射施用，非限制性地包括静脉内、肌内、动脉内、鞘内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、 关节内、囊下、蛛网膜下、脊柱内和胸骨内注射和输注。As used herein, the phrase "parenteral administration" means a mode of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, sputum. Intra, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injections and infusions.
本文所用的措辞“全身施用”和“外周施用”意指化合物、药物或其它材料的除直接施用于中枢神经***以外的施用，从而使得其进入患者的***中并因此进行代谢和其它相似过程，例如皮下施用。As used herein, the terms "systemic administration" and "peripheral administration" mean the administration of a compound, drug or other material other than direct administration to the central nervous system, such that it enters the patient's system and thus undergoes metabolism and other similar processes, For example, subcutaneous administration.
这些化合物可通过任何合适的施用途径被施用于人和其它动物来进行治疗，包括口服、鼻(例如以喷雾剂形式)、直肠、***内、胃肠外、脑池内和局部(以散剂、软膏剂或滴剂形式)施用，所述局部施用包括***和舌下施用。These compounds can be administered to humans and other animals by any suitable route of administration, including oral, nasal (eg, in the form of a spray), rectal, intravaginal, parenteral, intracisternal, and topical (as a powder, ointment). Administration in the form of a dose or drop, including topical and sublingual administration.
不管所选择的施用途径如何，用本领域技术人员已知的常规方法将可以以合适的水合形式使用的本发明的化合物和/或本发明的药物组合物配制成药学可接受的剂型。Regardless of the route of administration selected, the compounds of the invention and/or pharmaceutical compositions of the invention, which may be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.
可以改变本发明的药物组合物中活性成分的实际剂量水平以获得对特定患者、组合物和施用方式而言可有效实现所需治疗响应、对患者无毒的活性成分的量。The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to achieve an amount of active ingredient that is effective to achieve the desired therapeutic response, non-toxic to the patient for a particular patient, composition, and mode of administration.
所选择的剂量水平将取决于多种因素，包括所用的具体的本发明的化合物或其酯、盐或酰胺的活性、施用途径、施用时间、所用的具体化合物的***速率、治疗的持续时间、与所用的具体化合物组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、情况、一般健康状况和既往医学史以及医学领域中公知的类似因素。The selected dosage level will depend on a variety of factors, including the particular compound of the invention or its ester, salt or amide activity employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of treatment, Other drugs, compounds and/or materials used in combination with the particular compound employed, age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical arts.
具有本领域普通技能的医师或兽医可容易地确定和开具出所需的药物组合物的有效量。例如，医师或兽医可以以低于获得所需治疗作用所需要的剂量的水平开始药物组合物中所用的本发明的化合物的剂量并逐渐增加其剂量直至实现所需的作用。A physician or veterinarian having ordinary skill in the art can readily determine and formulate an effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can begin doses of the compounds of the invention used in the pharmaceutical compositions at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
一般而言，本发明的化合物的合适的日剂量将是有效产生治疗作用的最低剂量的化合物量。该类有效剂量一般将取决于上述因素。一般而言，当用于所示的镇痛作用时，本发明的化合物用于患者的静脉内和皮下剂量为约0.0001至约100mg/kg体重/天，更优选约0.01至约50mg/kg/天，还更优选为约1.0至约100mg/kg/天。有效量是治疗与蛋白激酶有关的病症的量。In general, a suitable daily dose of a compound of the invention will be the lowest amount of the compound effective to produce a therapeutic effect. Such effective doses will generally depend on the above factors. In general, when used for the analgesic effect shown, the intravenous and subcutaneous doses of the compounds of the invention for use in a subject are from about 0.0001 to about 100 mg/kg body weight per day, more preferably from about 0.01 to about 50 mg/kg/ Still more preferably, it is from about 1.0 to about 100 mg/kg/day. An effective amount is an amount that treats a condition associated with a protein kinase.
如果需要的话，活性化合物的有效日剂量可以在一天中以分开施用的二、三、四、五、六或更多个亚剂量以适宜的时间间隔施用，任选地，所述亚剂量是单位剂型。If desired, an effective daily dose of the active compound can be administered in divided doses of two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, the sub-dose is a unit Dosage form.
对于约50-70kg的个体，本发明的药物组合物或组合可以为约1-1000mg活性成分的单位剂量，或者约1-500mg或者约1-250mg或者约1-150mg或者约0.5-100mg或者约1-50mg的活性成分。化合物、其药物组合物或组合的治疗有效剂量取决于个体的种类、体重、年龄和个体条件、治疗的障碍或疾病或其严重程度。具有普通技术的医师、临床医师或兽医能够容易地确定预防、治疗或抑制障碍或疾病的进程所需的每种活性成分的有效量。For an individual of about 50-70 kg, the pharmaceutical composition or combination of the invention may be a unit dose of from about 1 to 1000 mg of the active ingredient, or from about 1 to 500 mg or from about 1 to 250 mg or from about 1 to 150 mg or from about 0.5 to 100 mg or about 1-50 mg of active ingredient. The therapeutically effective dose of a compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and individual condition of the individual, the disorder or disease being treated, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a disorder or disease.
上述剂量性质在体外和体内试验中应用有利的哺乳动物，例如小鼠、大鼠、狗、猴或其相关器官、组织或制备物可进行说明。本发明化合物可以在体外以溶液剂例如水溶液剂的形式应用，并且可以在体内以肠内、非肠道、有利地以静脉内例如作为混悬剂或水溶液剂应用。体外剂量范围可以是约10-3摩尔至10-9摩尔浓度之间。体内治疗有效量范围可以取决于施用途径，为约0.1-500mg/kg或约1-100mg/kg之间。The above dosage properties can be illustrated by the use of advantageous mammals in in vitro and in vivo assays, such as mice, rats, dogs, monkeys or related organs, tissues or preparations. The compounds of the present invention can be used in the form of a solution such as an aqueous solution in vitro, and can be administered enterally, parenterally, advantageously intravenously, for example, as a suspension or aqueous solution in vivo. The in vitro dosage range can be between about 10-3 moles and 10-9 molar concentrations. The therapeutically effective amount in vivo may range from about 0.1 to 500 mg/kg or from about 1 to 100 mg/kg, depending on the route of administration.
本文所用的术语“个体”意指动物。通常，动物是哺乳动物。个体还意指例如灵长类(例如人，男性或女性)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施例中，个体是灵长类。在其它实施例中，个体是人。The term "individual" as used herein means an animal. Usually, the animal is a mammal. An individual also means, for example, a primate (eg, human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the individual is a primate. In other embodiments, the individual is a human.
虽然本发明的化合物可以单独施用，但是优选以药物组合物的形式施用所述化合物。While the compounds of the invention may be administered alone, it is preferred to administer the compounds in the form of a pharmaceutical composition.
药物联合Drug combination
使用本发明所提供的一种或多种化合物或组合物，或其药学上可接受的衍生物与其它的药物活化剂联合来组合治疗，用于治疗本文所述的疾病和病症。One or more compounds or compositions provided herein, or a pharmaceutically acceptable derivative thereof, in combination with other pharmaceutically active agents, are used in combination therapy for the treatment of the diseases and conditions described herein.
将配制用于口服、全身性传递包括肠道外或静脉内传递或用于局部或表面施用的有效量的化合物或包 含治疗有效浓度的化合物的组合物给予表现出疾病或病症症状而需要治疗的个体。所述量有效地治疗、控制或缓解了该疾病或病症的一种或多种症状。An effective amount of a compound or a composition comprising a therapeutically effective concentration of a compound for oral, systemic delivery, including parenteral or intravenous delivery, or for topical or topical administration, is administered to an individual in need of treatment for a disease or condition . The amount is effective to treat, control or ameliorate one or more symptoms of the disease or condition.
本领域普通技术人员能够理解本发明所提供的化合物、异构体、前体药物和药学上可接受的衍生物，包括药物组合物和包含这些化合物的制剂，可广泛应用于联合治疗以治疗本发明所述的不适和疾病。因此，本发明预期将本发明所提供的化合物、异构体、前体药物和药学上可接受的衍生物与其它活性药物联合使用，以用于治疗本发明所述的疾病/不适。Those of ordinary skill in the art will appreciate that the compounds, isomers, prodrugs, and pharmaceutically acceptable derivatives provided by the present invention, including pharmaceutical compositions and formulations comprising these compounds, are widely used in combination therapy to treat the present invention. The discomfort and disease described in the invention. Accordingly, the present invention contemplates the use of the compounds, isomers, prodrugs, and pharmaceutically acceptable derivatives provided herein in combination with other active agents for the treatment of the diseases/discomforts described herein.
一般合成方法General synthetic method
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)-(II)所示化合物。下面的反应方案和实施例用于进一步举例说明本发明的内容。In general, the compounds of the invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for the compounds of formula (I)-(II). The following reaction schemes and examples are provided to further illustrate the contents of the present invention.
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare a number of other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modifications by those skilled in the art, such as appropriate protection of the interfering group, by the use of other known reagents in addition to those described herein, or The reaction conditions are subject to some conventional modifications. Additionally, the reactions or known reaction conditions disclosed herein are also recognized to be suitable for the preparation of other compounds of the invention.
下面所描述的实施例，除非其他方面表明所有的温度定为℃。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。The examples described below, unless otherwise indicated, all temperatures are set to °C. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. The general reagents were purchased from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.
无水四氢呋喃，二氧六环，甲苯，***是经过金属钠回流干燥得到。无水DCM和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N，N-二甲基乙酰胺和N，N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal. Anhydrous DCM and chloroform were obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。The following reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe. The glassware is dry.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。核磁共振光谱以CDC1 3,d 6-DMSO,CD 3OD或d 6-丙酮为溶剂(报导以ppm为单位)，用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰),d(doublet，双峰),t(triplet，三重峰),m(multiplet，多重峰),br(broadened，宽峰),dd(doublet of doublets，四重峰),dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。 The column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The nuclear magnetic resonance spectrum was measured by CDC1 3 , d 6 -DMSO, CD 3 OD or d 6 -acetone (reported in ppm) using TMS (0 ppm) or chloroform (7.25 ppm) as a reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide) Peak), dd (doublet of doublets), dt (doublet of triplets). Coupling constant, expressed in Hertz (Hz).
低分辨率质谱(MS)数据通过配备G1312A二元泵和a G1316A TCC(柱温保持在30℃)的Agilent 6320系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315B DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (MS) data was measured with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C) Agilent 6320 Series LC-MS spectrometer, G1329A autosampler and G1315B DAD detector applied For analysis, the ESI source was applied to an LC-MS spectrometer.
低分辨率质谱(MS)数据通过配备G1311A四元泵和G1316A TCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315D DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (MS) data was measured with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30 °C) Agilent 6120 Series LC-MS spectrometer, G1329A autosampler and G1315D DAD detector for analysis The ESI source was applied to an LC-MS spectrometer.
以上两种光谱仪都配备了Agilent Zorbax SB-C18柱，规格为2.1×30mm，5μm。注射体积是通过样品浓度来确定；流速为0.6mL/min；HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。流动相为0.1％的甲酸乙腈溶液(相A)和0.1％的甲酸超纯水溶液(相B)。梯度洗脱条件如表1所示：Both spectrometers are equipped with an Agilent Zorbax SB-C18 column measuring 2.1 x 30 mm, 5 μm. The injection volume was determined by sample concentration; the flow rate was 0.6 mL/min; the peak of HPLC was recorded by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase was a 0.1% formic acid acetonitrile solution (Phase A) and a 0.1% formic acid ultrapure aqueous solution (Phase B). The gradient elution conditions are shown in Table 1:
表1Table 1
Figure PCTCN2019077582-appb-000047
Figure PCTCN2019077582-appb-000047
化合物纯化是通过Agilent 1100系列高效液相色谱(HPLC)来评价的，其中UV检测在210nm和254nm处，Zorbax SB-C18柱，规格为2.1×30mm，4μm，10分钟，流速为0.6mL/min，5-95％的(0.1％甲酸乙腈溶液)的(0.1％甲酸水溶液)，柱温保持在40℃。Compound purification was evaluated by Agilent 1100 Series High Performance Liquid Chromatography (HPLC) with UV detection at 210 nm and 254 nm, Zorbax SB-C18 column, size 2.1 x 30 mm, 4 μm, 10 min, flow rate 0.6 mL/min 5-95% (0.1% formic acid in acetonitrile) (0.1% aqueous formic acid), the column temperature was kept at 40 °C.
下面简写词的使用贯穿本发明：The following abbreviations are used throughout the invention:
BOC,Boc   叔丁氧基羰基BOC, Boc tert-butoxycarbonyl
(pin) 2B 2  联硼酸频那醇酯 (pin) 2 B 2 boronic acid pinacol ester
CHCl 3     氯仿 CHCl 3 chloroform
CDC1 3     氘代氯仿 CDC1 3 deuterated chloroform
DCM       二氯甲烷DCM dichloromethane
DMF       N,N-二甲基甲酰胺DMF N,N-dimethylformamide
DMSO      二甲基亚砜DMSO dimethyl sulfoxide
d 6-DMSO   氘代二甲基亚砜 d 6 -DMSO deuterated dimethyl sulfoxide
DIAD      偶氮二甲酸二异丙酯DIAD diisopropyl azodicarboxylate
EDC,EDCI  1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐EDC, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HATU      2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
H 2        氢气 H 2 hydrogen
MeOH,CH 3OH  甲醇 MeOH, CH 3 OH methanol
mL,ml     毫升mL, ml ml
N 2        氮气 N 2 nitrogen
Pd/C      钯/碳Pd/C palladium/carbon
Pd(OAc) 2  醋酸钯 Pd(OAc) 2 palladium acetate
Pd 2(dba) 3  三(二亚苄基丙酮)二钯 Pd 2 (dba) 3 tris(dibenzylideneacetone) dipalladium
PdCl 2(dppf)   1,1'-双二苯基膦二茂铁二氯化钯 PdCl 2 (dppf) 1,1'-bisdiphenylphosphinoferrocene palladium dichloride
AcOK      乙酸钾AcOK potassium acetate
EA        乙酸乙酯EA ethyl acetate
XPhos-Pd-G2  氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)XPhos-Pd-G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1 '-Biphenyl)]Palladium(II)
PPh 3      三苯基膦 PPh 3 triphenylphosphine
PE        石油醚PE petroleum ether
HEX       正己烷HEX n-hexane
RT rt     室温RT rt room temperature
Rt        保留时间Rt retention time
TFA       三氟乙酸TFA trifluoroacetic acid
NBS       N-溴丁二酰亚胺NBS N-bromosuccinimide
Cs 2CO 3     碳酸铯 Cs 2 CO 3 strontium carbonate
Xantphos    9,9-二甲基-4,5-双二苯基膦氧杂蒽Xantphos 9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene
合成方案Synthetic scheme
下面的实施例可以对本发明做进一步的描述，然而，这些实施例不应作为对本发明的范围的限制。The invention is further described in the following examples, which should not be construed as limiting the scope of the invention.
合成中间体方案1Synthetic intermediates 1
Figure PCTCN2019077582-appb-000048
Figure PCTCN2019077582-appb-000048
本发明化合物中间体(3a)可以通过合成中间体方案1的合成方法得到：化合物(1a)与化合物(2a)在碱性条件下，加热反应生成化合物(3a)。其中Z、q和R 6具有如本发明所述的含义。 The compound intermediate (3a) of the present invention can be obtained by the synthesis method of the synthesis intermediate scheme 1: the compound (1a) and the compound (2a) are heated under basic conditions to form the compound (3a). Wherein Z, q and R 6 have the meanings as described herein.
合成中间体方案2Synthetic intermediates 2
Figure PCTCN2019077582-appb-000049
Figure PCTCN2019077582-appb-000049
本发明化合物中间体(3b)可以通过中间体方案2的合成方法得到：化合物(1b)与(pin) 2B 2在碱的条件下，反应生成化合物(2b)；化合物(2b)在碱性条件下与化合物(3a)反应得到化合物(3b)。其中Y、Z、q和R 6具有如本发明所述的含义。 The intermediate compound (3b) of the present invention can be obtained by the synthesis method of the intermediate scheme 2: the compound (1b) and (pin) 2 B 2 are reacted under a base to form a compound (2b); the compound (2b) is alkaline. The compound (3b) is obtained by reacting with the compound (3a) under the conditions. Wherein Y, Z, q and R 6 have the meanings as described herein.
合成中间体方案3Synthetic intermediate scheme 3
Figure PCTCN2019077582-appb-000050
Figure PCTCN2019077582-appb-000050
本发明化合物中间体(3c)可以通过合成中间体方案3的合成方法得到：化合物(3b)与化合物(1c)加热反应生成化合物(3c)。其中X、Y、Z、q和R 6具有如本发明所述的含义。 The compound intermediate (3c) of the present invention can be obtained by a synthetic method for synthesizing the intermediate scheme 3: the compound (3b) is reacted with the compound (1c) by heating to give the compound (3c). Wherein X, Y, Z, q and R 6 have the meanings as described herein.
合成中间体方案4Synthetic intermediates 4
Figure PCTCN2019077582-appb-000051
Figure PCTCN2019077582-appb-000051
本发明化合物中间体(3d)可以通过中间体方案4的合成方法得到：化合物(3c)与化合物(1d)在碱性条件下，反应生成化合物(2d)；化合物(2d)在碱性条件下与(2da)反应得到化合物(3d)。其中X、Y、Z、q、R 1、R v和R 6具有如本发明所述的含义。 The compound intermediate (3d) of the present invention can be obtained by the synthesis method of the intermediate scheme 4: the compound (3c) and the compound (1d) are reacted under basic conditions to form the compound (2d); and the compound (2d) is under basic conditions. The reaction with (2da) gives the compound (3d). Wherein X, Y, Z, q, R 1 , R v and R 6 have the meanings as described herein.
合成方案Synthetic scheme
Figure PCTCN2019077582-appb-000052
Figure PCTCN2019077582-appb-000052
本发明化合物可以通过合成方案的合成方法得到：化合物(3d)与化合物(1e)在合适的溶剂中发生还原反应，得到目标产物。其中X、Y、Z、q、R 1、R 3、R v和R 6具有如本发明所述的含义。 The compound of the present invention can be obtained by a synthetic method of a synthetic scheme: a compound (3d) and a compound (1e) are subjected to a reduction reaction in a suitable solvent to obtain a target product. Wherein X, Y, Z, q, R 1 , R 3 , R v and R 6 have the meanings as described herein.
下面的实施例可以对本发明做进一步的描述，然而，这些实施例不应作为对本发明的范围的限制。The invention is further described in the following examples, which should not be construed as limiting the scope of the invention.
实施例Example
实施例1(S)-1-(5-氯-4-((3'-(3-(2-氰基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物1)Example 1 (S)-1-(5-chloro-4-((3'-(3-(2-cyano-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2) , 2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid (Compound 1)
Figure PCTCN2019077582-appb-000053
Figure PCTCN2019077582-appb-000053
步骤1)[2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基]甲醇Step 1) [2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol
将PdCl 2(dppf)(7.28g,9.95mmol)、AcOK(29.3g,299mmol)和联硼酸频那醇酯(37.9g,149mmol)溶于1,4-二氧六环(200.1mL)中，再加入(3-溴-2-甲基-苯基)甲醇(20.1g,100mmol)。反应混合物升温至90℃反应10h。反应混合物停止搅拌，并冷却至室温，然后减压浓缩。所得残留物经硅胶柱层析分离纯化(HEX/EA＝10/1,v/v)得标题化合物为淡绿色固体23.9g，产率为96％； PdCl 2 (dppf) (7.28 g, 9.95 mmol), AcOK (29.3 g, 299 mmol) and benzoic acid pinacol ester (37.9 g, 149 mmol) were dissolved in 1,4-dioxane (200.1 mL). Further, (3-bromo-2-methyl-phenyl)methanol (20.1 g, 100 mmol) was added. The reaction mixture was warmed to 90 ° C for 10 h. The reaction mixture was stopped and cooled to room temperature and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (HHHHHHHHHHHHHHHHHHHHHH
LC-MS:(pos.ion)m/z：231.1[M-18+1] +； LC-MS: (pos.ion) m/z: 231.1 [M-18+1] + ;
1H NMR(400MHz,d 6-DMSO)δ7.50(d,J＝7.3Hz,1H),7.45(d,J＝7.4Hz,1H),7.14(t,J＝7.5Hz,1H),5.05(t,J＝5.4Hz,1H),4.48(d,J＝5.3Hz,2H),2.39(s,3H),1.29(s,12H). 1 H NMR (400 MHz, d 6 -DMSO) δ 7.50 (d, J = 7.3 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 5.05 (t, J = 5.4 Hz, 1H), 4.48 (d, J = 5.3 Hz, 2H), 2.39 (s, 3H), 1.29 (s, 12H).
步骤2)1-溴-3-(3-溴丙氧基)-2-甲基苯Step 2) 1-Bromo-3-(3-bromopropoxy)-2-methylbenzene
将3-溴-2-甲基苯酚(15.1g,80.7mmol)溶于丙酮(180.1mL)，加入碳酸钾(33.3g,241mmol)，然后加入1,3-二溴丙烷(20.4mL,201mmol)，氮气保护，反应混合物升温回流反应12h。停止搅拌，冷却至室温，抽滤，并用DCM冲洗滤饼，然后减压滤液浓缩。所得浓缩残留物经硅胶柱层析(正己烷)分离纯化,得标题化合物为无色油状物24.1g，产率为97％；3-Bromo-2-methylphenol (15.1 g, 80.7 mmol) was dissolved in acetone (180.1 mL), potassium carbonate (33.3 g, 241 mmol) was added, then 1,3-dibromopropane (20.4 mL, 201 mmol) The reaction mixture was heated under reflux for 12 h. Stirring was stopped, cooled to room temperature, suction filtered, and the filter cake was rinsed with DCM and then filtered. The obtained residue was purified by silica gel column chromatography eluting
1H NMR(400MHz,CDCl 3)δ7.20(d,J＝8.0Hz,1H),7.03(t,J＝8.1Hz,1H),6.82(d,J＝8.2Hz,1H),4.12(t,J＝5.7Hz,2H),3.65(t,J＝6.4Hz,2H),2.40–2.36(m,2H),2.35(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.20 (d, J = 8.0Hz, 1H), 7.03 (t, J = 8.1Hz, 1H), 6.82 (d, J = 8.2Hz, 1H), 4.12 (t , J = 5.7 Hz, 2H), 3.65 (t, J = 6.4 Hz, 2H), 2.40 - 2.36 (m, 2H), 2.35 (s, 3H).
步骤3)(3'–(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲醇Step 3) (3'-(3-Bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methanol
将[2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基]甲醇(20.0g,80.6mmol)和1-溴-3-(3-溴丙氧基)-2-甲基苯(26.1g,84.7mmol)溶于THF(400.1mL)，再加入磷酸钾溶液(400.1mL,200mmol)。反应混合物于氮气保护及室温下搅拌20min，然后加入XPhos-Pd-G2(1.27g,1.62mmol)，并于氮气保护下，继续室温搅拌10h。反应结束后，加水稀释(300mL)，再用乙酸乙酯萃取(150mL×3)，合并有机相。合并的有机相用无水硫酸钠干燥，然后减压浓缩，所得残留物经硅胶柱层析分离纯化(PE/EA＝3/1,v/v)分离纯化，得标题化合物为橙红色粘稠油15.9g，产率为57％；[2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (20.0 g, 80.6 mmol) And 1-bromo-3-(3-bromopropoxy)-2-methylbenzene (26.1 g, 84.7 mmol) was dissolved in THF (400.1 mL), and then potassium phosphate solution (400.1 mL, 200 mmol). The reaction mixture was stirred with EtOAc EtOAc EtOAc (EtOAc). After completion of the reaction, it was diluted with water (300 mL), and then extracted with ethyl acetate (150 mL × 3), and the organic phase was combined. The combined organic phase was dried over anhydrous sodium sulfate and evaporated, evaporated, evaporated, evaporated 15.9 g of oil, the yield was 57%;
LC-MS:(pos.ion)m/z：332.0[M-18+1] +； LC-MS: (pos.ion) m/z: 332.0 [M - 18 + 1] + ;
1H NMR(400MHz,CDCl 3)δ7.41(d,J＝7.5Hz,1H),7.27(t,J＝7.3Hz,1H),7.21(t,J＝7.9Hz,1H),7.11(d,J＝7.4Hz,1H),6.90(d,J＝8.1Hz,1H),6.78(d,J＝7.5Hz,1H),4.78(s,2H),4.27–4.09(m,2H),3.68(t,J＝6.5Hz,2H),2.45–2.36(m,2H),2.08(s,3H),1.95(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.41 (d, J = 7.5Hz, 1H), 7.27 (t, J = 7.3Hz, 1H), 7.21 (t, J = 7.9Hz, 1H), 7.11 (d , J = 7.4 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 4.78 (s, 2H), 4.27 - 4.09 (m, 2H), 3.68 (t, J = 6.5 Hz, 2H), 2.45 - 2.36 (m, 2H), 2.08 (s, 3H), 1.95 (s, 3H).
步骤4)4-((3'-(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 4) 4-((3'-(3-Bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro -2-hydroxybenzaldehyde
0℃下将(3'-(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲醇(15.9g,45.5mmol)，5-氯-2,4-二羟基-苯甲醛(8.64g,50.1mmol)溶于THF(242.1mL)，加入PPh 3(17.9g,68.2mmol)，氮气保护，缓慢注入DIAD(13.4mL,68.1mmol)，室温条件下搅拌5h。反应结束后停止搅拌，加水(100mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(PE/EA＝8/1,v/v)分离得黄色固体5.3g，产率为23％； (3'-(3-Bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methanol (15.9 g, 45.5 mmol) at 0 ° C, 5 - chloro -2,4 - dihydroxy-benzaldehyde (8.64g, 50.1mmol) was dissolved in THF (242.1mL), was added PPh 3 (17.9g, 68.2mmol), nitrogen, was slowly injected DIAD (13.4mL, 68.1mmol ), stirring at room temperature for 5 h. After the completion of the reaction, the mixture was stirred, and water (100 mL) was evaporated. Separation and purification by silica gel column chromatography (PE/EA=8/1, v/v) 5.3 g of a yellow solid, yield 23%;
LC-MS:(pos.ion)m/z：504.2[M+1] +； LC-MS: (pos.ion) m/z: 504.2 [M + 1] + ;
1H NMR(400MHz,d 6-DMSO)δ11.16(s,1H),10.03(s,1H),7.71(s,1H),7.50(d,J＝7.4Hz,1H),7.29(t,J＝7.6Hz,1H),7.22(t,J＝7.9Hz,1H),7.09(d,J＝7.4Hz,1H),6.98(d,J＝8.2Hz,1H),6.87(s,1H),6.70(d,J＝7.5Hz,1H),5.31(s,2H),4.18–4.04(m,2H),3.71(t,J＝6.5Hz,2H),2.29(dd,J＝12.3,6.1Hz,2H),2.01(s,3H),1.84(s,3H). 1 H NMR (400 MHz, d 6 -DMSO) δ 11.16 (s, 1H), 10.3 (s, 1H), 7.71 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 7.09 (d, J=7.4 Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.87 (s, 1H) , 6.70 (d, J = 7.5 Hz, 1H), 5.31 (s, 2H), 4.18 - 4.04 (m, 2H), 3.71 (t, J = 6.5 Hz, 2H), 2.29 (dd, J = 12.3, 6.1 Hz, 2H), 2.01 (s, 3H), 1.84 (s, 3H).
步骤5)7-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-7-氮杂螺[3.5]壬烷-2-腈Step 5) 7-(3-((3'-((2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'- Biphenyl]-3-yl)oxy)propyl)-7-azaspiro[3.5]decane-2-carbonitrile
将4-((3'-(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(1g,1.98mmol)和7-氮杂螺[3.5]壬烷-2-腈(0.357g,2.37mmol)溶于DMF(15mL)，加入碳酸钾(0.685g,4.96mmol)，加入NaI(0.357g,2.38mmol)，氮气保护，升温至75℃搅拌13h。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到淡黄色固体0.71g，产率为62.4％；4-((3'-(3-Bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2 -Hydroxybenzaldehyde (1 g, 1.98 mmol) and 7-azaspiro[3.5]decane-2-carbonitrile (0.357 g, 2.37 mmol) were dissolved in DMF (15 mL). NaI (0.357 g, 2.38 mmol) was added, and the mixture was evaporated. Stirring was continued, and the mixture was cooled to room temperature, diluted with water (50 mL), ethyl acetate (100 mL×3). Separation and purification by silica gel column chromatography (DCM /MeOH = 10/1, v / v)
LC-MS:(pos.ion)m/z：573.2[M+1] +。 LC-MS: (pos.ion) m / z: 573.2 [M + 1] +.
步骤6)7-(3–((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-7-氮杂-螺[3.5]壬烷-2-腈Step 6) 7-(3-((3'-((2-Cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)- 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]decane-2-carbonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.295g,1.48mmol)溶于DMF(12mL)，加入碳酸铯(1g,3.1mmol)，室温搅拌10min。加入7-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-7-氮杂螺[3.5]壬烷-2-腈(0.71g,1.24mmol)和NaI(18mg,0.124mmol)，氮气保护，升温至75℃搅拌4h。随后停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)得黄色固体160mg，产率为18.74％；5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.295 g, 1.48 mmol) was dissolved in DMF (12 mL). Add 7-(3-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl) ]-3-yl)oxy)propyl)-7-azaspiro[3.5]decane-2-carbonitrile (0.71 g, 1.24 mmol) and NaI (18 mg, 0.124 mmol), mp. Stir for 4 h. After the stirring was stopped, the mixture was cooled to room temperature, diluted with water (30 mL), ethyl acetate (100 mL×3). Separation and purification by silica gel column chromatography (DCM /MeOH = 10/1, v / v)
LC-MS:(pos.ion)m/z：689.2[M+1] +。 LC-MS: (pos.ion) m / z: 689.2 [M + 1] +.
步骤7)(S)-1-(5-氯-4-((3'-(3-(2-氰基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 7) (S)-1-(5-chloro-4-((3'-(3-(2-cyano-7-azaspiro[3.5]壬-7-yl)propoxy)-2) , 2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid
将7-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-7-氮杂-螺[3.5]壬烷-2-腈(160mg,0.23mmol)和D-哌啶酸(0.044g,0.34mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，随后冷却至室温，缓慢加入氰基硼氢化钠(0.072g,1.15mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)，分离得黄色固体47mg，产率为25.23％；7-(3-((3'-((2-Chloropyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2, 2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]decane-2-carbonitrile (160 mg, 0.23 mmol) and D-piperidine acid (0.044 g, 0.34 mmol) was dissolved in DMF (15.0 mL), pH was adjusted to about 5 by adding acetic acid, heated to 60 ° C for 1 h, then cooled to room temperature, and sodium cyanoborohydride (0.072 g) was slowly added. , 1.15 mmol), nitrogen-protected, stirred at room temperature for 12 h. Stirring was continued, and the mixture was cooled to room temperature. EtOAc (3 mL)EtOAc. Separation and purification by silica gel column chromatography (DCM / MeOH=8/1, v/v),
LC-MS:(pos.ion)m/z：802.3[M+1] +； LC-MS: (pos.ion) m/z: 802.3 [M+1] + ;
1H NMR(600MHz,d 6-DMSO)δ9.00(d,J＝10.7Hz,2H),8.46(s,1H),7.48(d,J＝7.4Hz,1H),7.41(s,1H),7.26(t,J＝7.5Hz,1H),7.20(t,J＝7.8Hz,1H),7.11(s,1H),7.06(d,J＝7.5Hz,1H),6.94(d,J＝8.2Hz,1H),6.67(d,J＝7.4Hz,1H),5.36–5.29(m,2H),5.29–5.23(m,2H),4.02(dt,J＝22.1,7.6Hz,2H),3.77(d,J＝13.8Hz,1H),3.60(d,J＝13.6Hz,1H),3.51(s,1H),3.31(dt,J＝17.1,8.6Hz,2H),3.13(s,1H),2.88(d,J＝6.7Hz,1H),2.38(s,2H),2.28(d,J＝5.7Hz,2H),2.16(t,J＝10.2Hz,2H),2.02(s,3H),2.00(d,J＝11.7Hz,2H),1.92(d,J＝6.2Hz,2H),1.91(s,1H),1.81(s,3H),1.79–1.76(m,1H),1.72(d,J＝8.9Hz,1H),1.62(s,2H),1.58(s,2H),1.48(s,3H),1.37(s,1H). 1 H NMR (600 MHz, d 6 -DMSO) δ 9.00 (d, J = 10.7 Hz, 2H), 8.46 (s, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.41 (s, 1H) , 7.26 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.11 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 5.36 - 5.29 (m, 2H), 5.29 - 5.23 (m, 2H), 4.02 (dt, J = 22.1, 7.6 Hz, 2H), 3.77 (d, J = 13.8 Hz, 1H), 3.60 (d, J = 13.6 Hz, 1H), 3.51 (s, 1H), 3.31 (dt, J = 17.1, 8.6 Hz, 2H), 3.13 (s, 1H) ), 2.88 (d, J = 6.7 Hz, 1H), 2.38 (s, 2H), 2.28 (d, J = 5.7 Hz, 2H), 2.16 (t, J = 10.2 Hz, 2H), 2.02 (s, 3H) ), 2.00 (d, J = 11.7 Hz, 2H), 1.92 (d, J = 6.2 Hz, 2H), 1.91 (s, 1H), 1.81 (s, 3H), 1.79 - 1.76 (m, 1H), 1.72 (d, J = 8.9 Hz, 1H), 1.62 (s, 2H), 1.58 (s, 2H), 1.48 (s, 3H), 1.37 (s, 1H).
实施例2(S)-1-(4–((3'–(3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2–((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物2)Example 2(S)-1-(4-((3'-(3-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2 '-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl) Piperidine-2-carboxylic acid (Compound 2)
Figure PCTCN2019077582-appb-000054
Figure PCTCN2019077582-appb-000054
步骤1)4-((3'-(3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)-甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)-methoxy)-5-chloro-2-hydroxybenzaldehyde
将4-((3'-(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯基]-3-基)-甲氧基)-5-氯-2-羟基-苯甲醛(0.65g,1.29mmol)和9-氧杂-3-氮杂螺[5.5]十一烷(0.24g,1.54mmol)溶于DMF(15mL)，加入碳酸钾(0.445g,3.22mmol)，加入NaI(0.23g,1.55mmol)，氮气保护，升温至75℃搅拌13h。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)得到淡黄色固体0.51g，产率为68.3％；4-((3'-(3-Bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-methoxy)-5-chloro 2-Hydroxy-benzaldehyde (0.65 g, 1.29 mmol) and 9-oxa-3-azaspiro[5.5]undecane (0.24 g, 1.54 mmol) were dissolved in DMF (15 mL). g, 3.22 mmol), NaI (0.23 g, 1.55 mmol). Stirring was continued, and the mixture was cooled to room temperature, diluted with water (50 mL), ethyl acetate (100 mL×3). Separation and purification by silica gel column chromatography (DCM / MeOH=8/1, v/v)
LC-MS:(pos.ion)m/z：578.2[M+1] +。 LC-MS: (pos.) m/z: 578.2 [M+1] + .
步骤2)5-((5-((3'-(3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3'-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2'-di Methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.161g,1.05mmol)溶于DMF(12mL)，加入碳酸铯(0.574g,1.76mmol)，室温搅拌10min。加入4-((3'-(3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(0.51g,0.88mmol)和NaI(13mg,0.088mmol)，氮气保护，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)得黄色固体175mg，产率为 28.5％；5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.161 g, 1.05 mmol) was dissolved in DMF (12 mL). 4-((3'-(3-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2'-dimethyl-[1, 1'-Biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (0.51 g, 0.88 mmol) and NaI (13 mg, 0.088 mmol), mp. . Stirring was continued, and the mixture was cooled to room temperature, diluted with water (30 mL), ethyl acetate (100 mL, 3). Separation and purification by silica gel column chromatography (DCM /MeOH = 10/1, v / v)
LC-MS:(pos.ion)m/z：694.3[M+1] +。 LC-MS: (pos.ion) m / z: 694.3 [M + 1] +.
步骤3)(S)-1-(4–((3'–(3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2–((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4–((3'–(3-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2 '-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl) Piperidine-2-carboxylic acid
将5-((5-((3'-(3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(0.17g,0.244mmol)和D-哌啶酸(0.063g,0.487mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.076g,1.21mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)，分离得棕黄色固体38mg，产率为19.2％；5-((5-((3'-(3-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (0.17 g, 0.244 mmol) and D-pipecolic acid (0.063g, 0.487mmol) was dissolved in DMF (15.0mL), added with acetic acid to adjust the pH to about 5, heated to 60 ° C for 1 h, cooled to room temperature, slowly added sodium cyanoborohydride (0.076 g, 1.21 mmol), nitrogen Protected and stirred at room temperature for 12 h. Stirring was continued, and the mixture was cooled to room temperature. EtOAc (3 mL)EtOAc. Separation and purification by silica gel column chromatography (DCM / MeOH=8/1, v/v),
LC-MS:(pos.ion)m/z：807.4[M+1] +； LC-MS: (pos.ion) m/z: 807.4 [M+1] + ;
1H NMR(600MHz,d 6-DMSO)δ9.00(d,J＝9.3Hz,2H),8.46(s,1H),7.49(d,J＝7.3Hz,1H),7.41(s,1H),7.26(t,J＝7.4Hz,1H),7.20(t,J＝7.7Hz,1H),7.11(s,1H),7.06(d,J＝7.4Hz,1H),6.95(d,J＝8.1Hz,1H),6.68(d,J＝7.4Hz,1H),5.34(d,J＝13.5Hz,2H),5.27(d,J＝12.7Hz,2H),4.08–3.99(m,2H),3.77(d,J＝13.7Hz,1H),3.61(d,J＝13.7Hz,1H),3.52(d,J＝7.6Hz,6H),3.14(s,1H),2.89(s,1H),2.67(s,2H),2.58(s,3H),2.28(s,1H),2.02(s,3H),1.99(s,2H),1.81(s,3H),1.80–1.76(m,1H),1.72(s,1H),1.55(s,3H),1.48(s,3H),1.40(s,5H). 1 H NMR (600 MHz, d 6 -DMSO) δ 9.00 (d, J = 9.3 Hz, 2H), 8.46 (s, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.41 (s, 1H) , 7.26 (t, J = 7.4 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.11 (s, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 7.4 Hz, 1H), 5.34 (d, J = 13.5 Hz, 2H), 5.27 (d, J = 12.7 Hz, 2H), 4.08 - 3.99 (m, 2H) , 3.77 (d, J = 13.7 Hz, 1H), 3.61 (d, J = 13.7 Hz, 1H), 3.52 (d, J = 7.6 Hz, 6H), 3.14 (s, 1H), 2.89 (s, 1H) , 2.67 (s, 2H), 2.58 (s, 3H), 2.28 (s, 1H), 2.02 (s, 3H), 1.99 (s, 2H), 1.81 (s, 3H), 1.80 - 1.76 (m, 1H) ), 1.72 (s, 1H), 1.55 (s, 3H), 1.48 (s, 3H), 1.40 (s, 5H).
实施例3(S)-1-(4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2–((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物3)Example 3(S)-1-(4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2' -Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)per Pyridine-2-carboxylic acid (compound 3)
Figure PCTCN2019077582-appb-000055
Figure PCTCN2019077582-appb-000055
步骤1)2-氧杂-8-氮杂螺[4.5]癸烷Step 1) 2-oxa-8-azaspiro[4.5]decane
在氮气保护下，将2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯溶于三氟乙酸(4mL)和DCM(25mL)中，室温反应23h，将反应液浓缩，得到棕褐色油状液体585.2mg,产率51％；The 2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester was dissolved in trifluoroacetic acid (4 mL) and DCM (25 mL). The liquid was concentrated to obtain 585.2 mg of a brown oily liquid, yield 51%;
LC-MS:(pos.ion)m/z：142.1[M+1] +。 LC-MS: (pos.ion) m / z: 142.1 [M + 1] +.
步骤2)4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 2) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
将2-氧杂-8-氮杂螺[4.5]癸烷(300mg,2.1245mmol)和4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1.04g,2.06mmol)溶于DMF(15mL)中，依次加入K 2CO 3(600mg,4.34mmol)和NaI(300mg,2.00mmol)，加热至75℃，反应17h。用乙酸乙酯萃取(30mL×3)，水洗(50mL)，用无水硫酸钠干燥，过滤，浓缩。用硅胶柱层析(DCM/MeOH＝10/1,v/v)分离纯化，得到橙红色固体350mg，产率30％； 2-oxa-8-azaspiro[4.5]decane (300 mg, 2.1245 mmol) and 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]- methyl - phenyl] methoxy] -5-chloro-2-hydroxy - benzaldehyde (1.04g, 2.06mmol) was dissolved in DMF (15mL) added sequentially K 2 CO 3 (600mg, 4.34mmol ) And NaI (300 mg, 2.00 mmol), heated to 75 ° C, and reacted for 17 h. It was extracted with EtOAc (3 mL, EtOAc)EtOAc. Separation and purification by silica gel column chromatography (DCM / MeOH = 10/1, v / v) to give an orange-red solid 350 mg, yield 30%;
LC-MS:(pos.ion)m/z：564.1[M+1] +。 LC-MS: (pos.) m/z: 564.1 [M+1] + .
步骤3)4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2- (吡啶-3-甲氧基)苯甲醛Step 3) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridine-3-methoxy)benzaldehyde
4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯(350mg,0.62mmol)和5-(氯甲基)吡啶-3-甲腈盐酸盐(123mg,0.80mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入碳酸铯(404mg,1.23mmol)和碘化钠(9.3mg,0.06mmol)，加热至75℃，反应3h。将反应冷却到室温，用乙酸乙酯萃取(30mL×3)，加水洗(50mL)，用无水硫酸钠干燥，过滤。浓缩后的粗产物，用硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v),得到黄色固体342mg，产率81％；4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1,1' -biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzene (350 mg, 0.62 mmol) and 5-(chloromethyl)pyridine-3-carbonitrile hydrochloride (123 mg, 0.80 mmol) Dissolved in N,N-dimethylformamide (20 mL), cesium carbonate (404 mg, 1.23 mmol) and sodium iodide (9.3 mg, 0.06 mmol), heated to 75 ° C, and reacted for 3 h. The reaction was cooled to room temperature, extracted with EtOAc EtOAc. The concentrated crude product was purified by silica gel column chromatography eluting elut elut elut elut
LC-MS:(pos.ion)m/z：681.4[M+1] +。 LC-MS: (pos.ion) m / z: 681.4 [M + 1] +.
步骤4)(S)-1-(4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 4) (S)-1-(4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2' -Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidin Pyridine-2-carboxylic acid
将4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-甲氧基)苯甲醛(342mg,0.50mmol)和(2S)-哌啶-2-甲酸(130mg,1.00mmol)溶于N，N-二甲基甲酰胺(10mL)中，加入乙酸(0.1mL,2.0mmol)，加热至60℃，反应1.5小时。冷却至室温，缓慢加入氰基硼氢化钠(158mg,2.51mmol)，室温反应16小时。随后加热至80℃，反应5小时。将反应冷却至室温，加入饱和碳酸钾溶液(30mL)，室温搅拌30min。停止反应，用乙酸乙酯萃取(30mL×3)，加水洗(50mL)，用无水硫酸钠干燥，过滤。浓缩后的粗产物，用硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到淡黄色固体60mg，产率15％；4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1,1 '-Biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridine-3-methoxy)benzaldehyde (342 mg, 0.50 mmol) and (2S)-piperidine-2-carboxylic acid ( 130 mg, 1.00 mmol) was dissolved in N,N-dimethylformamide (10 mL), acetic acid (0.1 mL, 2.0 mmol) After cooling to room temperature, sodium cyanoborohydride (158 mg, 2.51 mmol) was slowly added and allowed to react at room temperature for 16 hours. It was then heated to 80 ° C and reacted for 5 hours. The reaction was cooled to room temperature and aq. EtOAc (30 mL) The reaction was quenched, extracted with EtOAc EtOAc (EtOAc)EtOAc. The concentrated crude product was purified by silica gel column chromatography (DCM / MeOH = 10/1, v / v)
LC-MS:(pos.ion)m/z：794.2[M+1] +； LC-MS: (pos.ion) m/z: 794.2 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.00(d,J＝5.2Hz,2H),8.46(s,1H),7.49(d,J＝7.3Hz,1H),7.41(s,1H),7.27(t,J＝7.6Hz,1H),7.21(d,J＝7.7Hz,1H),7.12(s,1H),7.06(d,J＝7.5Hz,1H),6.97(d,J＝8.3Hz,1H),6.70(d,J＝7.4Hz,1H),5.33(s,2H),5.27(s,2H),4.08(d,J＝7.0Hz,2H),3.74(t,J＝7.1Hz,3H),3.62(d,J＝13.5Hz,2H),3.51(s,2H),3.15(s,2H),2.95(s,3H),2.89(s,3H),2.29(s,1H),2.13(s,2H),2.03(s,3H),1.83(s,3H),1.78(s,1H),1.71(d,J＝7.2Hz,6H),1.48(s,3H),1.38(s,1H). 1 H NMR (400MHz, d 6 -DMSO) δ9.00 (d, J = 5.2Hz, 2H), 8.46 (s, 1H), 7.49 (d, J = 7.3Hz, 1H), 7.41 (s, 1H) , 7.27 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.12 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 5.33 (s, 2H), 5.27 (s, 2H), 4.08 (d, J = 7.0 Hz, 2H), 3.74 (t, J = 7.1 Hz, 3H), 3.62 (d, J = 13.5 Hz, 2H), 3.51 (s, 2H), 3.15 (s, 2H), 2.95 (s, 3H), 2.89 (s, 3H), 2.29 (s, 1H), 2.13 (s, 2H), 2.03 (s, 3H), 1.83 (s, 3H), 1.78 (s, 1H), 1.71 (d, J = 7.2 Hz, 6H), 1.48 (s, 3H), 1.38(s,1H).
实施例4(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2,2'-二甲基-3'-(3-(2-氧代-1,7-二氮杂螺[4.4]壬-7-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物4)Example 4(2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-3'-( 3-(2-Oxo-1,7-diazaspiro[4.4]dec-7-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)benzyl Piperidine-2-carboxylic acid (Compound 4)
Figure PCTCN2019077582-appb-000056
Figure PCTCN2019077582-appb-000056
步骤1)5-氯-4-((2,2'-二甲基-3'-(3-(2-氧代-1,7-二氮杂螺[4.4]壬-7-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)-2-羟基苯甲醛Step 1) 5-Chloro-4-((2,2'-dimethyl-3'-(3-(2-oxo-1,7-diazaspiro[4.4]fluoren-7-yl)propane) Oxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1.5g,3.0mmol)和4,8-二氮杂螺[4.4]壬-3-酮(500mg,3.56mmol)溶于N,N-二甲基甲酰胺(25mL)中，依次加入K 2CO 3(1g,7.23mmol)和NaI(540mg,3.60mmol)，加热至75℃，反应23h。将反应冷却到室温，用乙酸乙酯萃取(30mL×3)，水洗，饱和食盐洗，用无水硫酸钠干燥，过滤。浓缩后的粗产物，用硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)。得到橙红色固体粉末365mg,产率22％； 4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzene Formaldehyde (1.5 g, 3.0 mmol) and 4,8-diazaspiro[4.4]indol-3-one (500 mg, 3.56 mmol) were dissolved in N,N-dimethylformamide (25 mL). 2 CO 3 (1 g, 7.23 mmol) and NaI (540 mg, 3.60 mmol), heated to 75 ° C, and reacted for 23 h. The reaction was cooled to room temperature, extracted with ethyl acetate (30 mL×3). The concentrated crude product was purified by silica gel column chromatography (DCM/MeOH = 10/1, v/v). Obtaining an orange-red solid powder of 365 mg in a yield of 22%;
LC-MS:(pos.ion)m/z：564.4[M+1] +。 LC-MS: (pos.) m/z: 564.4 [M + 1] + .
步骤2)5-((4-氯-5-((2,2'-二甲基-3'-(3-(2-氧代-1,7-二氮杂螺[4.4]壬-7-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((4-chloro-5-((2,2'-dimethyl-3'-(3-(2-oxo-1,7-diazaspiro[4.4]壬-7) -yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
将5-氯-4-((2,2'-二甲基-3'-(3-(2-氧代-1,7-二氮杂螺[4.4]壬-7-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)-2-羟基苯甲醛(365mg,0.64mmol)和5-(氯甲基)吡啶-3-甲腈盐酸盐(160mg,0.84mmol)溶于N，N-二甲基甲酰胺(25mL)中，加入碳酸铯(634mg,1.94mmol)和碘化钠(9.7mg,0.065mmol)，加热至75℃，反应3小时。待反应冷却到室温，用乙酸乙酯萃取(30mL×3)，水洗(50mL)，用无水硫酸钠干燥，过滤。浓缩后的粗产物，用硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到黄色固体100mg,产率81％；5-Chloro-4-((2,2'-dimethyl-3'-(3-(2-oxo-1,7-diazaspiro[4.4]fluoren-7-yl)propoxy) )-[1,1'-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde (365 mg, 0.64 mmol) and 5-(chloromethyl)pyridine-3-carbonitrile hydrochloride ( 160 mg, 0.84 mmol) was dissolved in N,N-dimethylformamide (25 mL), cesium carbonate (634 mg, 1.94 mmol) and sodium iodide (9.7 mg, 0.065 mmol) were added and heated to 75 ° C for 3 hours. . The reaction was cooled to room temperature, extracted with EtOAc EtOAc EtOAc. The concentrated crude product was purified by silica gel column chromatography (DCM / MeOH = 10/1, v / v)
LC-MS:(pos.ion)m/z：601.1[M+1] +。 LC-MS: (pos.) m/z: 601.1 [M + 1] + .
步骤3)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2,2'-二甲基-3'-(3-(2-氧代-1,7-二氮杂螺[4.4]壬-7-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-Chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-3'-( 3-(2-Oxo-1,7-diazaspiro[4.4]dec-7-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)benzyl Piperidine-2-carboxylic acid
将5-((4-氯-5-((2,2'-二甲基-3'-(3-(2-氧代-1,7-二氮杂螺[4.4]壬-7-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)-2-甲酰基苯氧基)甲基)烟腈(100mg,0.15mmol)和(2S)-哌啶-2-甲酸(38mg,0.29mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入乙酸(0.1mL)，加热至60℃，搅拌1.5h。停止加热，冷却至室温，加入氰基硼氢化钠(46.3mg,0.74mmol)，室温反应14h。将反应加热至80℃，反应5h。将反应冷却至室温，加入饱和碳酸钾溶液(30mL)，搅拌30分钟。停止反应，用乙酸乙酯萃取(30mL×3)，加水洗(50mL)，用无水硫酸钠干燥，过滤。浓缩后的粗产物，用硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到淡红色固体28mg，产率24％；5-((4-chloro-5-((2,2'-dimethyl-3'-(3-(2-oxo-1,7-diazaspiro[4.4]壬-7-yl) )propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (100 mg, 0.15 mmol) and (2S)-piperidin The pyridine-2-carboxylic acid (38 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (10 mL). The heating was stopped, cooled to room temperature, sodium cyanoborohydride (46.3 mg, 0.74 mmol). The reaction was heated to 80 ° C and allowed to react for 5 h. The reaction was cooled to room temperature, a saturated aqueous solution of potassium carbonate (30 mL) was then added and stirred for 30 min. The reaction was quenched, extracted with EtOAc EtOAc (EtOAc)EtOAc. The concentrated crude product was purified by silica gel column chromatography (DCM / MeOH = 10/1, v / v)
LC-MS:(pos.ion)m/z：793.5[M+1] +； LC-MS: (pos.ion) m/z: 793.5 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.01(s,2H),8.47(s,1H),7.93(s,1H),7.49(d,J＝7.4Hz,1H),7.43(s,1H),7.27(t,J＝7.7Hz,1H),7.21(t,J＝7.9Hz,1H),7.14(s,1H),7.07(d,J＝7.3Hz,1H),6.96(d,J＝8.2Hz,1H),6.68(d,J＝7.4Hz,1H),5.31(d,J＝30.5Hz,4H),4.07(d,J＝5.9Hz,2H),3.80(d,J＝14.0Hz,1H),3.64(d,J＝13.6Hz,2H),3.48(d,J＝5.2Hz,1H),3.42(d,J＝4.6Hz,1H),3.17(s,2H),2.88(s,1H),2.67(s,4H),2.31(s,1H),2.17(dd,J＝15.5,7.3Hz,2H),2.03(s,3H),1.96(s,2H),1.91(s,2H),1.82(s,3H),1.81–1.76(m,1H),1.73(s,1H),1.49(s,3H),1.37(s,1H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.01 (s, 2H), 8.47 (s, 1H), 7.93 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.43 (s, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.14 (s, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 7.4 Hz, 1H), 5.31 (d, J = 30.5 Hz, 4H), 4.07 (d, J = 5.9 Hz, 2H), 3.80 (d, J = 14.0 Hz, 1H), 3.64 (d, J = 13.6 Hz, 2H), 3.48 (d, J = 5.2 Hz, 1H), 3.42 (d, J = 4.6 Hz, 1H), 3.17 (s, 2H), 2.88 (s, 1H), 2.67 (s, 4H), 2.31 (s, 1H), 2.17 (dd, J = 15.5, 7.3 Hz, 2H), 2.03 (s, 3H), 1.96 (s, 2H), 1.91 ( s, 2H), 1.82 (s, 3H), 1.81 - 1.76 (m, 1H), 1.73 (s, 1H), 1.49 (s, 3H), 1.37 (s, 1H).
实施例5(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3'-(3-(6-羟基-2-氮杂螺[3.4]辛-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物5)Example 5(2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(6-hydroxy-2-) Azaspiro[3.4]oct-2-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine- 2-carboxylic acid (compound 5)
Figure PCTCN2019077582-appb-000057
Figure PCTCN2019077582-appb-000057
步骤1)5-氯-2-羟基-4-((3'-(3-(6-羟基-2-氮杂螺[3.4]辛-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛Step 1) 5-Chloro-2-hydroxy-4-((3'-(3-(6-hydroxy-2-azaspiro[3.4]oct-2-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(0.8g,1.58mmol)和2-氮杂-螺[3.4]辛-7-醇(0.242g,1.58mmol)溶于DMF(15mL)，加入碳酸钾(0.658g,4.76mmol)，加入NaI(0.285g,1.90mmol)，氮气保护，升温至75℃条件下搅拌13h。停止搅拌，冷却至室温，加水(50mL)稀 释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到淡黄色粘稠物0.37g，产率为42.3％；4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzene Formaldehyde (0.8 g, 1.58 mmol) and 2-aza-spiro[3.4]oct-7-ol (0.242 g, 1.58 mmol) were dissolved in DMF (15 mL), EtOAc (EtOAc) (0.285 g, 1.90 mmol), nitrogen-protected, stirred at 75 ° C for 13 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (50 mL),EtOAc. Separation and purification by silica gel column chromatography (DCM / MeOH = 10/1, v / v) afforded 0.37 g of pale yellow viscous, yield 42.3%;
LC-MS:(pos.ion)m/z：550.2[M+1] +。 LC-MS: (pos.ion) m / z: 550.2 [M + 1] +.
步骤2)5–((4-氯-2-甲酰基-5-((3'-(3-(6-羟基-2-氮杂螺[3.4]辛-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈Step 2) 5 - ((4-Chloro-2-formyl-5-((3'-(3-(6-hydroxy-2-azaspiro[3.4]oct-2-yl)propoxy)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.17g,0.85mmol)溶于DMF(12mL)，加入碳酸铯(0.533g,1.64mmol)，室温搅拌10min。加入5-氯-2-羟基-4-((3'-(3-(6-羟基-2-氮杂螺[3.4]辛-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛(360mg,0.65mmol)和NaI(9mg,0.065mmol)，氮气保护，体系于75℃条件下搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)得黄色固体0.135g，产率为30.96％；5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.17 g, 0.85 mmol) was dissolved in DMF (12 mL). Add 5-chloro-2-hydroxy-4-((3'-(3-(6-hydroxy-2-azaspiro[3.4]oct-2-yl)propoxy)-2,2'-dimethyl Base-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde (360 mg, 0.65 mmol) and Na.sub.1 (9 mg, 0.065 mmol). Stirring was continued, and the mixture was cooled to room temperature, diluted with water (30 mL), ethyl acetate (100 mL, 3). Separation and purification by silica gel column chromatography (DCM / MeOH = 10/1, v / v).
LC-MS:(pos.ion)m/z：666.2[M+1] +。 LC-MS: (pos.ion) m / z: 666.2 [M + 1] +.
步骤3)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3'-(3-(6-羟基-2-氮杂螺[3.4]辛-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-Chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(6-hydroxy-2-) Azaspiro[3.4]oct-2-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine- 2-formic acid
将5-((4-氯-2-甲酰基-5-((3'-(3-(6-羟基-2-氮杂-螺[3.4]辛-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈(134mg,0.2011mmol)和D-哌啶酸(0.038g,0.29mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.063g,1.00mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)，分离得黄色固体0.025g，产率为15.9％；5-((4-Chloro-2-formyl-5-((3'-(3-(6-hydroxy-2-aza-spiro[3.4]oct-2-yl)propoxy)-2) , 2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (134 mg, 0.2011 mmol) and D-pipecolic acid (0.038 g) , 0.29mmol) dissolved in DMF (15.0mL), added acetic acid to adjust the pH to about 5, heated to 60 ° C for 1h, cooled to room temperature, slowly added sodium cyanoborohydride (0.063g, 1.00mmol), nitrogen protection, room temperature Stir for 12 h. Stirring was continued, and the mixture was cooled to room temperature. EtOAc (3 mL)EtOAc. Separation and purification by silica gel column chromatography (DCM / MeOH=8/1, v/v),
LC-MS:(pos.ion)m/z：779.3[M+1] +； LC-MS: (pos.ion) m / z: 779.3 [M + 1] +;
1H NMR(400MHz,d 6-DMSO)δ9.00(d,J＝2.8Hz,2H),8.46(s,1H),7.49(d,J＝7.5Hz,1H),7.42(s,1H),7.27(t,J＝7.5Hz,1H),7.21(t,J＝7.8Hz,1H),7.13(s,1H),7.06(d,J＝7.5Hz,1H),6.96(d,J＝8.2Hz,1H),6.70(d,J＝7.5Hz,1H),5.34(s,2H),5.27(s,2H),4.08(s,2H),3.79(d,J＝13.4Hz,2H),3.63(d,J＝14.0Hz,2H),3.51(s,2H),3.16(s,2H),2.89(s,2H),2.30(s,2H),2.03(s,4H),1.96(s,2H),1.89(d,J＝4.4Hz,1H),1.83(d,J＝1.8Hz,3H),1.79(s,1H),1.76–1.66(m,3H),1.48(s,5H),1.37(s,2H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.00 (d, J = 2.8 Hz, 2H), 8.46 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.42 (s, 1H) , 7.27 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.13 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H), 5.34 (s, 2H), 5.27 (s, 2H), 4.08 (s, 2H), 3.79 (d, J = 13.4 Hz, 2H) , 3.63 (d, J = 14.0 Hz, 2H), 3.51 (s, 2H), 3.16 (s, 2H), 2.89 (s, 2H), 2.30 (s, 2H), 2.03 (s, 4H), 1.96 ( s, 2H), 1.89 (d, J = 4.4 Hz, 1H), 1.83 (d, J = 1.8 Hz, 3H), 1.79 (s, 1H), 1.76 - 1.66 (m, 3H), 1.48 (s, 5H) ), 1.37 (s, 2H).
实施例159(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3'-(3-(六氢-2H-吡喃并[3,2-c]吡啶-6(7H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物159)Example 159(2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(hexahydro-2H-py)) Succinyl [3,2-c]pyridine-6(7H)-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy) Benzyl) piperidine-2-carboxylic acid (compound 159)
Figure PCTCN2019077582-appb-000058
Figure PCTCN2019077582-appb-000058
步骤1)5-氯-4–((3'-(3-(六氢-2H-吡喃并[3,2-c]吡啶-6(7H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-2-羟基苯甲醛Step 1) 5-Chloro-4-((3'-(3-(hexahydro-2H-pyrano[3,2-c]pyridine-6(7H)-yl)propoxy)-2,2 '-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基苯甲醛(0.6g,1.19mmol)和反-3,4,4a,5,6,7,8,8a-八氢-2H-吡喃并[3,2-c]吡啶(0.2g,1.42mmol)溶于DMF(15mL)，加入碳酸钾(0.197g,1.42mmol)，加入NaI(0.214g,1.42mmol)，氮气保护，体系于75℃条件下搅拌13h。停止搅拌，冷却 至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到淡黄色粘稠物0.38g，产率为56.65％；4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxybenzaldehyde (0.6 g, 1.19 mmol) and trans-3,4,4a,5,6,7,8,8a-octahydro-2H-pyrano[3,2-c]pyridine (0.2 g, 1.42 mmol) Potassium carbonate (0.197 g, 1.42 mmol) was added to DMF (15 mL). Stirring was continued, the mixture was cooled to room temperature, diluted with water (50 mL), ethyl acetate (100 mL×3). Separation and purification by silica gel column chromatography (DCM / MeOH = 10/1, v / v) to give a pale yellow viscous material 0.38 g, yield 56.65%;
LC-MS:(pos.ion)m/z：564.2[M+1] +。 LC-MS: (pos.) m/z: 564.2 [M+1] + .
步骤2)5-((4-氯-2-甲酰基-5-((3'-(3-(六氢-2H-吡喃并[3,2-c]吡啶-6(7H)-基)丙氧基)-2,2-二甲基-[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈Step 2) 5-((4-Chloro-2-formyl-5-((3'-(3-(hexahydro-2H-pyrano[3,2-c]pyridine-6(7H)-yl) Propyloxy)-2,2-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.175g,0.879mmol)溶于DMF(12mL)，加入碳酸铯(0.548g,1.68mmol)，室温搅拌10min。加入5-氯-4-((3'-(3-(六氢-2H-吡喃并[3,2-c]吡啶-6(7H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯基]-3-基)甲氧基)-2-羟基苯甲醛(0.38mg,0.67mmol)和NaI(10mg,0.067mmol)，氮气保护，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)得黄色固体0.128g，产率为27.9％；5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.175 g, 0.879 mmol) was dissolved in DMF (12 mL). Add 5-chloro-4-((3'-(3-(hexahydro-2H-pyrano[3,2-c]pyridine-6(7H)-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde (0.38 mg, 0.67 mmol) and NaI (10 mg, 0.067 mmol). Stir at 75 ° C for 4 h. Stirring was continued, and the mixture was cooled to room temperature, diluted with water (30 mL), ethyl acetate (100 mL, 3). Separation and purification by silica gel column chromatography (DCM /MeOH = 10/1, v / v)
LC-MS:(pos.ion)m/z：680.3[M+1] +。 LC-MS: (pos.) m/z: 680.3 [M + 1] + .
步骤3)(2S)-1-(5-氯-2–((5-氰基吡啶-3-基)甲氧基)-4-((3'-(3-(六氢-2H-吡喃并[3,2-c]吡啶-6(7H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-Chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(hexahydro-2H-py) Succinyl [3,2-c]pyridine-6(7H)-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy) Benzyl) piperidine-2-carboxylic acid
将5-((4-氯-2-甲酰基-5-((3'-(3-(六氢-2H-吡喃并[3,2-c]吡啶-6(7H)-基)丙氧基)-2,2-二甲基-[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈(0.123g,0.180mmol)和D-哌啶酸(0.035g,0.27mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.056g,0.89mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)，室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)，分离得淡黄色固体0.02g，产率为13.9％。5-((4-chloro-2-formyl-5-((3'-(3-(hexahydro-2H-pyrano[3,2-c]pyridine-6(7H)-yl)-propyl) Oxy)-2,2-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (0.123 g, 0.180 mmol) and D-piper The pyridine acid (0.035g, 0.27mmol) was dissolved in DMF (15.0mL), added with acetic acid to adjust the pH to about 5, heated to 60 ° C for 1 h, cooled to room temperature, slowly added sodium cyanoborohydride (0.056 g, 0.89 mmol) , nitrogen protection, stirring at room temperature for 12 h. Stirring was continued, and the mixture was cooled to room temperature. EtOAc (3 mL)EtOAc. The oil was separated and purified by silica gel column chromatography (DCM / MeOH=8/1, v/v).
LC-MS:(pos.ion)m/z：793.3[M+1] +； LC-MS: (pos.ion) m/z: 793.3 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.01(d,J＝2.0Hz,2H),8.47(s,1H),7.49(d,J＝7.5Hz,1H),7.42(s,1H),7.27(t,J＝7.5Hz,1H),7.22(t,J＝7.9Hz,1H),7.13(s,1H),7.07(d,J＝7.5Hz,1H),6.97(d,J＝8.2Hz,1H),6.70(d,J＝7.5Hz,1H),5.38–5.30(m,2H),5.29(d,J＝13.7Hz,2H),4.09(d,J＝6.2Hz,2H),3.90(d,J＝10.2Hz,1H),3.82–3.75(m,2H),3.66(s,1H),3.62(s,1H),3.58(s,2H),3.41(s,2H),3.16(s,2H),2.89(s,1H),2.31(d,J＝13.1Hz,1H),2.24(s,2H),2.16(s,1H),2.03(s,4H),1.84(s,4H),1.79(s,1H),1.74(d,J＝4.8Hz,2H),1.60(d,J＝12.1Hz,2H),1.49(s,3H),1.38(s,1H),1.29(d,J＝8.7Hz,2H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.01 (d, J = 2.0 Hz, 2H), 8.47 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.42 (s, 1H) , 7.27 (t, J = 7.5 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.13 (s, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H), 5.38 - 5.30 (m, 2H), 5.29 (d, J = 13.7 Hz, 2H), 4.09 (d, J = 6.2 Hz, 2H) , 3.90 (d, J = 10.2 Hz, 1H), 3.82 - 3.75 (m, 2H), 3.66 (s, 1H), 3.62 (s, 1H), 3.58 (s, 2H), 3.41 (s, 2H), 3.16(s,2H), 2.89(s,1H), 2.31(d,J=13.1Hz,1H), 2.24(s,2H), 2.16(s,1H),2.03(s,4H),1.84(s , 4H), 1.79 (s, 1H), 1.74 (d, J = 4.8 Hz, 2H), 1.60 (d, J = 12.1 Hz, 2H), 1.49 (s, 3H), 1.38 (s, 1H), 1.29 (d, J = 8.7 Hz, 2H).
实施例7(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4–((3'-(3-(六氢呋喃并[3,4-c]吡啶-5(3H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物7)Example 7(2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(hexahydrofuran)[3 ,4-c]pyridine-5(3H)-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)per Pyridine-2-carboxylic acid (compound 7)
Figure PCTCN2019077582-appb-000059
Figure PCTCN2019077582-appb-000059
步骤1)5-氯-4-((3'-(3-(六氢呋喃并[3,4-c]吡啶-5(3H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-2-羟基苯甲醛Step 1) 5-Chloro-4-((3'-(3-(hexahydrofuro[3,4-c]pyridine-5(3H)-yl)propoxy)-2,2'-dimethyl Base-[1,1'-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(0.6g,1.19mmol)和 1,3,3a,4,5,6,7,7a-八氢呋喃并[3,4-c]吡啶盐酸盐(0.233mg,1.42mmol)溶于DMF(15mL)，加入碳酸钾(0.411g,2.97mmol)，加入NaI(0.214g,1.43mmol)，氮气保护，升温至75℃搅拌13h。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到淡黄色固体0.4g，产率为61.06％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzene Formaldehyde (0.6 g, 1.19 mmol) and 1,3,3a,4,5,6,7,7a-octahydrofuro[3,4-c]pyridine hydrochloride (0.233 mg, 1.42 mmol) were dissolved in DMF (15 mL), potassium carbonate (0.411 g, 2.97 mmol) was added, and NaI (0.214 g, 1.43 mmol) was added. Stirring was continued, and the mixture was cooled to room temperature, diluted with water (50 mL), ethyl acetate (100 mL×3). Purification by silica gel column chromatography (DCM / MeOH = 10/1, v/v) afforded 0.4 g of pale yellow solid.
LC-MS:(pos.ion)m/z：550.2[M+1] +； LC-MS: (pos.ion) m/z: 550.2 [M+1] + ;
步骤2)5-((4-氯-2-甲酰基-5-((3'-(3-(六氢呋喃并[3,4-c]吡啶-5(3H)-基)丙氧基)-2,2'-二甲基[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈Step 2) 5-((4-Chloro-2-formyl-5-((3'-(3-(hexahydrofuro[3,4-c]pyridine-5(3H)-yl)propoxy) -2,2'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.188g,0.94mmol)溶于DMF(12mL)，加入碳酸铯(0.592g,1.82mmol)，室温搅拌10min。加入5-氯-4-((3'-(3-(六氢呋喃并[3,4-c]吡啶-5(3H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-2-羟基苯甲醛(400mg,0.73mmol)和NaI(10mg,0.073mmol)，氮气保护，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)得黄色固体400mg，产率为82.57％。5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.188 g, 0.94 mmol) was dissolved in DMF (12 mL). Add 5-chloro-4-((3'-(3-(hexahydrofuro[3,4-c]pyridine-5(3H)-yl)propoxy)-2,2'-dimethyl- [1,1'-Biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde (400 mg, 0.73 mmol) and NaI (10 mg, 0.073 mmol). Stirring was continued, and the mixture was cooled to room temperature, diluted with water (30 mL), ethyl acetate (100 mL, 3). Separation and purification by silica gel column chromatography (DCM / MeOH = / / / / / / / / / / /
LC-MS:(pos.ion)m/z：666.2[M+1] +； LC-MS: (pos.ion) m/z: 666.2 [M+1] + ;
步骤3)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3'-(3-(六氢呋喃并[3,4-c]吡啶-5(3H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-Chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(hexahydrofuran)[3 ,4-c]pyridine-5(3H)-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)per Pyridine-2-carboxylic acid
将5-((4-氯-2-甲酰基-5-((3'-(3-(六氢呋喃并[3,4-c]吡啶-5(3H)-基)丙氧基)-2,2'-二甲基[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈(0.4mg,0.60mmol)和D-哌啶酸(0.118g,0.91mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.192g,3.05mmol)，氮气保护，室温搅拌12小时。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)，分离得淡黄色固体70mg，产率为14.96％。5-((4-Chloro-2-formyl-5-((3'-(3-(hexahydrofuro[3,4-c]pyridine-5(3H)-yl)propoxy)-) 2,2'-Dimethyl[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (0.4 mg, 0.60 mmol) and D-pipecolic acid (0.118) g, 0.91 mmol) dissolved in DMF (15.0 mL), added with acetic acid to adjust the pH to about 5, heated to 60 ° C for 1 h, cooled to room temperature, slowly added sodium cyanoborohydride (0.192 g, 3.05 mmol), nitrogen, Stir at room temperature for 12 hours. Stirring was continued, and the mixture was cooled to room temperature. EtOAc (3 mL)EtOAc. It was separated and purified by silica gel column chromatography (DCM / MeOH=8/1, v/v).
LC-MS:(pos.ion)m/z：779.5[M+1] +； LC-MS: (pos.ion) m/z: 779.5 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.01(s,2H),8.46(s,1H),7.49(d,J＝7.4Hz,1H),7.42(s,1H),7.26(t,J＝7.5Hz,1H),7.21(t,J＝7.9Hz,1H),7.13(s,1H),7.06(d,J＝7.5Hz,1H),6.96(d,J＝8.2Hz,1H),6.69(d,J＝7.5Hz,1H),5.38–5.30(m,2H),5.27(s,2H),4.07(d,J＝6.4Hz,2H),3.82(d,J＝5.7Hz,1H),3.77(s,1H),3.72(dd,J＝16.6,7.9Hz,3H),3.65(s,1H),3.60(d,J＝16.9Hz,3H),3.16–3.13(m,1H),2.88(s,2H),2.30(s,2H),2.11(s,2H),2.03(s,4H),1.83(s,5H),1.72(d,J＝9.7Hz,3H),1.49(s,3H),1.37(s,2H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.01 (s, 2H), 8.46 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.42 (s, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.13 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H) , 6.69 (d, J = 7.5 Hz, 1H), 5.38 - 5.30 (m, 2H), 5.27 (s, 2H), 4.07 (d, J = 6.4 Hz, 2H), 3.82 (d, J = 5.7 Hz, 1H), 3.77 (s, 1H), 3.72 (dd, J = 16.6, 7.9 Hz, 3H), 3.65 (s, 1H), 3.60 (d, J = 16.9 Hz, 3H), 3.16 - 3.13 (m, 1H) ), 2.88 (s, 2H), 2.30 (s, 2H), 2.11 (s, 2H), 2.03 (s, 4H), 1.83 (s, 5H), 1.72 (d, J = 9.7 Hz, 3H), 1.49 (s, 3H), 1.37 (s, 2H).
实施例8(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3'-(3-(六氢-1H-吡咯并[3,4-c]吡啶-5(6H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物8)Example 8(2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(hexahydro-1H-pyrrole) And [3,4-c]pyridine-5(6H)-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl Pipiridin-2-carboxylic acid (compound 8)
Figure PCTCN2019077582-appb-000060
Figure PCTCN2019077582-appb-000060
步骤1)5-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)六氢-1H-吡咯 并[3,4-c]吡啶-2(3H)-羧酸叔丁酯Step 1) 5-(3-((3)-((2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'- Biphenyl]-3-yl)oxy)propyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylic acid tert-butyl ester
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1g,1.98mmol)和1,3,3a,4,5,6,7,7a-八氢吡咯并[3,4-c]吡啶-2-甲酸叔丁酯盐酸盐(0.625g,2.37mmol)溶于DMF(15mL)，加入碳酸钾(0.685g,4.96mmol)，加入NaI(0.357g,2.38mmol)，氮气保护，升温至75℃搅拌13h。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到淡黄色粘稠物1.03g，产率为79.9％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzene Formaldehyde (1 g, 1.98 mmol) and 1,3,3a,4,5,6,7,7a-octahydropyrrolo[3,4-c]pyridine-2-carboxylic acid tert-butyl ester hydrochloride (0.625 g, 2.37 mmol) was dissolved in DMF (15 mL), EtOAc (EtOAc:EtOAc. Stirring was continued, and the mixture was cooled to room temperature, diluted with water (50 mL), ethyl acetate (100 mL×3). Purification by silica gel column chromatography (DCM /MeOH = 10/1, v/v) afforded
LC-MS:(pos.ion)m/z：649.3[M+1] +； LC-MS: (pos.ion) m/z: 649.3 [M + 1] + ;
步骤2)5-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)六氢-1H-吡咯并[3,4-c]吡啶-2(3H)-羧酸叔丁酯Step 2) 5-(3-((3'-((2-Cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)- Tert-butyl carboxylate
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.44g,2.21mmol)溶于DMF(12mL)，加入碳酸铯(1.4g,4.2mmol)，室温搅拌10min。加入5-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)六氢-1H-吡咯并[3,4-c]吡啶-2(3H)-羧酸叔丁酯(1.1g,1.7mmol)和NaI(0.025g,0.17mmol)，氮气保护，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)得黄色固体0.482g，产率为37％。5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.44 g, 2.21 mmol) was dissolved in DMF (12 mL). Add 5-(3-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl) ]-3-yl)oxy)propyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylic acid tert-butyl ester (1.1 g, 1.7 mmol) and NaI (0.025 g) , 0.17 mmol), nitrogen-protected, warmed to 75 ° C and stirred for 4 h. Stirring was continued, and the mixture was cooled to room temperature, diluted with water (30 mL), ethyl acetate (100 mL, 3). The oil was separated and purified by silica gel column chromatography (DCM / MeOH = 10/1, v/v).
LC-MS:(pos.ion)m/z：765.3[M+1] +； LC-MS: (pos.ion) m/z: 765.3 [M + 1] + ;
步骤3)(2S)-1-(4-((3'-(3-(2-(叔丁氧基羰基)六氢-1H-吡咯并[3,4-c]吡啶-5(6H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(4-((3'-(3-(2-(tert-Butoxycarbonyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)) -yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridine- 3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将5-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)六氢-1H-吡咯并[3,4-c]吡啶-2(3H)-羧酸叔丁酯(0.482g,0.63mmol)和D-哌啶酸(0.122g,0.94mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.197g,3.13mmol)，氮气保护，室温搅拌12小时。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)，分离得黄色固体0.183g，产率为33.07％。5-(3-((3'-((2-Chloropyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2, 2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylic acid tert-Butyl ester (0.482 g, 0.63 mmol) and D-pipecolic acid (0.122 g, 0.94 mmol) were dissolved in DMF (15.0 mL), pH was adjusted to about 5 by adding acetic acid, heated to 60 ° C for 1 h, cooled to room temperature. Sodium cyanoborohydride (0.197 g, 3.13 mmol) was slowly added, and the mixture was evaporated and evaporated. Stirring was continued, and the mixture was cooled to room temperature. EtOAc (3 mL)EtOAc. The oil was separated and purified by silica gel column chromatography (DCM/MeOH=8/1, v/v).
LC-MS:(pos.ion)m/z：878.4[M+1] +； LC-MS: (pos.ion) m/z: 878.4 [M+1] + ;
步骤4)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3'-(3-(六氢-1H-吡咯并[3,4-c]吡啶-5(6H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 4) (2S)-1-(5-Chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(hexahydro-1H-pyrrole) And [3,4-c]pyridine-5(6H)-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl Piperidine-2-carboxylic acid
将(2S)-1-(4-(3'-(3-(2-(叔丁氧基羰基)六氢-1H-吡咯并[3,4-c]吡啶-5(6H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2–((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.183g,0.20mmol)溶于DCM(20mL)，加入TFA(2mL)，室温搅拌反应5小时。停止搅拌，浓缩溶剂,加入饱和碳酸钾溶液(40mL)，室温搅拌反应15min,乙酸乙酯萃取(30mL×3),合并有机相，无水硫酸钠干燥，过滤，浓缩。薄层析分离纯化(DCM/MeOH＝6/1)，得到白色固体0.043g，产率26.5％。(2S)-1-(4-(3'-(3-(2-(tert-Butoxycarbonyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-yl)) Propyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl) The methoxy)benzyl)piperidine-2-carboxylic acid (0.183 g, 0.20 mmol) was dissolved in DCM (20 mL). Stirring was continued, the solvent was concentrated, EtOAc (EtOAc)EtOAc. Purification by thin chromatography (DCM / MeOH = 6 / 1)
LC-MS:(pos.ion)m/z：778.3[M+1] +； LC-MS: (pos.ion) m/z: 778.3 [M+1] + ;
1H NMR(600MHz,d 6-DMSO)δ9.62(s,1H),9.04–8.99(m,2H),8.48(s,1H),7.50(d,J＝7.5Hz,1H),7.43(s,1H),7.27(t,J＝7.5Hz,1H),7.21(t,J＝7.9Hz,1H),7.15(s,1H),7.07(d,J＝7.3Hz,1H),6.96(d,J＝8.3Hz,1H),6.68(d,J＝7.5Hz,1H),5.40–5.32(m,2H),5.31–5.24(m,2H),4.04(dd,J＝11.9,6.2Hz,2H),3.81(d,J＝13.6Hz,1H),3.66(d,J＝13.6Hz,1H),3.51(s,1H),3.21–3.12(m,5H),2.98(d,J＝8.7Hz,1H),2.91(s,1H),2.62(s,2H),2.33(s,3H),2.22(s,1H),2.10(s,1H),2.03(s,3H),1.92(s,2H),1.82(d,J＝2.1Hz,4H),1.72(d,J＝9.6Hz,1H),1.63(s,1H),1.57(s,1H),1.50(s,3H),1.42–1.32(m,2H). 1 H NMR (600 MHz, d 6 -DMSO) δ 9.62 (s, 1H), 9.04 - 8.9 (m, 2H), 8.48 (s, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.43 ( s, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.15 (s, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.96 ( d, J = 8.3 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 5.40 - 5.32 (m, 2H), 5.31 - 5.24 (m, 2H), 4.04 (dd, J = 11.9, 6.2 Hz , 2H), 3.81 (d, J = 13.6 Hz, 1H), 3.66 (d, J = 13.6 Hz, 1H), 3.51 (s, 1H), 3.21 - 3.12 (m, 5H), 2.98 (d, J = 8.7 Hz, 1H), 2.91 (s, 1H), 2.62 (s, 2H), 2.33 (s, 3H), 2.22 (s, 1H), 2.10 (s, 1H), 2.03 (s, 3H), 1.92 ( s, 2H), 1.82 (d, J = 2.1 Hz, 4H), 1.72 (d, J = 9.6 Hz, 1H), 1.63 (s, 1H), 1.57 (s, 1H), 1.50 (s, 3H), 1.42–1.32 (m, 2H).
实施例9(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2,2'-二甲基-3'-(3-(四氢-1H-呋喃并[3,4-c]吡咯- 5(3H)-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物9)Example 9(2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-3'-( 3-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)benzyl Pipiridin-2-carboxylic acid (compound 9)
Figure PCTCN2019077582-appb-000061
Figure PCTCN2019077582-appb-000061
步骤1)5-氯-4-((2,2'-二甲基-3'-(3-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)丙氧基)-[1,1'-联苯基]-3-基)甲氧基)-2-羟基苯甲醛Step 1) 5-Chloro-4-((2,2'-dimethyl-3'-(3-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)) Propyl)-[1,1'-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(0.9g,1.78mmol)，3,3a,4,5,6,6a-六氢-1H-呋喃并[3,4-c]吡咯盐酸盐(0.32g,2.14mmol)溶于DMF(15mL)，加入碳酸钾(0.62g,4.46mmol)，加入NaI(0.32g,2.14mmol)，氮气保护，升温至75℃搅拌13小时。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)得到淡黄色固体0.62g，产率为64.7％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzene Formaldehyde (0.9 g, 1.78 mmol), 3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (0.32 g, 2.14 mmol) was dissolved in DMF ( 15 mL), potassium carbonate (0.62 g, 4.46 mmol) was added, and NaI (0.32 g, 2.14 mmol) was added, and the mixture was evaporated. Stirring was continued, and the mixture was cooled to room temperature, diluted with water (50 mL), ethyl acetate (100 mL×3). Purification by silica gel column chromatography (DCM /MeOH =EtOAc /EtOAc
LC-MS:(pos.ion)m/z：536.2[M+1] +； LC-MS: (pos.ion) m/z: 536.2 [M + 1] + ;
步骤2)5-((4-氯-5-((2,2'-二甲基-3'-(3-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((4-chloro-5-((2,2'-dimethyl-3'-(3-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H) )-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.273g,1.38mmol)溶于DMF(12mL)，加入碳酸铯(0.753g,2.31mmol)，室温搅拌10min。加入5-氯-4-((2,2'-二甲基-3'-(3-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)丙氧基)-[1,1'-联苯基]-3-基)甲氧基)-2-羟基苯甲醛(0.62g,1.15mmol)和NaI(17mg,0.115mmol)，氮气保护，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)得黄色固体112mg，产率为14.85％。5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.273 g, 1.38 mmol) was dissolved in DMF (12 mL). Add 5-chloro-4-((2,2'-dimethyl-3'-(3-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)propoxy) -[1,1'-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde (0.62 g, 1.15 mmol) and NaI (17 mg, 0.115 mmol). Stir at °C for 4 h. Stirring was continued, and the mixture was cooled to room temperature, diluted with water (30 mL), ethyl acetate (100 mL, 3). Purification by silica gel column chromatography (DCM /MeOH = 10/1, v/v)
LC-MS:(pos.ion)m/z：652.2[M+1] +； LC-MS: (pos.ion) m/z: 652.2 [M + 1] + ;
步骤3)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2,2'-二甲基-3'-(3-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-Chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-3'-( 3-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)benzyl Piperidine-2-carboxylic acid
将5-((4-氯-5-((2,2'-二甲基-3'-(3-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)-2-甲酰基苯氧基)甲基)烟腈(0.112g,0.17mmol)和D-哌啶酸(0.033g,0.255mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.053g,0.84mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)，分离得黄色固体22mg，产率为16.7％。5-((4-chloro-5-((2,2'-dimethyl-3'-(3-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-) Propyl)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (0.112 g, 0.17 mmol) and D-piper The pyridine acid (0.033g, 0.255mmol) was dissolved in DMF (15.0mL), added to acetic acid to adjust the pH to about 5, heated to 60 ° C for 1 h, cooled to room temperature, slowly added sodium cyanoborohydride (0.053 g, 0.84 mmol) , nitrogen protection, stirring at room temperature for 12 h. Stirring was continued, and the mixture was cooled to room temperature. EtOAc (3 mL)EtOAc. It was separated and purified by silica gel column chromatography (DCM / MeOH=8/1, v/v).
LC-MS:(pos.ion)m/z：765.3[M+1] +； LC-MS: (pos.ion) m/z: 765.3 [M + 1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.01(s,2H),8.46(s,1H),7.49(d,J＝7.5Hz,1H),7.42(s,1H),7.26(t,J＝7.5Hz,1H),7.21(t,J＝7.9Hz,1H),7.12(s,1H),7.07(d,J＝7.3Hz,1H),6.95(d,J＝8.3Hz,1H),6.68(d,J＝7.5Hz,1H),5.33(s,2H),5.26(s,2H),4.06(d,J＝6.2Hz,2H),3.79(d,J＝13.6Hz,1H),3.65(s,3H),3.15(s,2H),2.89(s,3H),2.80(s,4H),2.31(d,J＝6.8Hz,2H),2.03(s,6H),1.82(s,4H),1.73(s,1H),1.49(s,3H),1.35(d,J＝15.1Hz,2H). 1 H NMR (400MHz, d 6 -DMSO) δ9.01 (s, 2H), 8.46 (s, 1H), 7.49 (d, J = 7.5Hz, 1H), 7.42 (s, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.12 (s, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H) , 6.68 (d, J = 7.5 Hz, 1H), 5.33 (s, 2H), 5.26 (s, 2H), 4.06 (d, J = 6.2 Hz, 2H), 3.79 (d, J = 13.6 Hz, 1H) , 3.65 (s, 3H), 3.15 (s, 2H), 2.89 (s, 3H), 2.80 (s, 4H), 2.31 (d, J = 6.8 Hz, 2H), 2.03 (s, 6H), 1.82 ( s, 4H), 1.73 (s, 1H), 1.49 (s, 3H), 1.35 (d, J = 15.1 Hz, 2H).
实施例10(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3'-(3-(5-羟基己二氢环戊二烯并[c]吡咯-2(1H)-丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物10)Example 10(2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(5-hydroxyhexanedihydro) Cyclopenta[c]pyrrole-2(1H)-propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl) Piperidine-2-carboxylic acid (Compound 10)
Figure PCTCN2019077582-appb-000062
Figure PCTCN2019077582-appb-000062
步骤1)5-氯-2-羟基-4-((3'-(3-(5-羟基己二氢环戊二烯并[c]吡咯-2(1H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯甲醛Step 1) 5-Chloro-2-hydroxy-4-((3'-(3-(5-hydroxyhexanedihydrocyclopenta[c]pyrrole-2(1H)-yl)propoxy)- 2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(0.8g,1.59mmol)和1,2,3,4,5,6,6a-八氢环戊[c]吡咯-5-醇(0.242g,1.90mmol)溶于DMF(15mL)，加入碳酸钾(0.658g,4.76mmol)，加入NaI(0.285g,1.90mmol)，氮气保护，升温至75℃搅拌13h。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到淡黄色粘稠物0.7g，产率为80.14％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzene Formaldehyde (0.8 g, 1.59 mmol) and 1,2,3,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-ol (0.242 g, 1.90 mmol) were dissolved in DMF (15 mL). Potassium carbonate (0.658 g, 4.76 mmol) was added NaI (0.285 g, 1.90 mmol). Stirring was continued, and the mixture was cooled to room temperature, diluted with water (50 mL), ethyl acetate (100 mL×3). Separation and purification by silica gel column chromatography (DCM / MeOH = 10/1, v/v) afforded 0.7 g of pale yellow viscous.
LC-MS:(pos.ion)m/z：550.2[M+1] +； LC-MS: (pos.ion) m/z: 550.2 [M+1] + ;
步骤2)5-((4-氯-2-甲酰基-((3'-(3-(5-羟基己二氢环戊二烯并[c]吡咯-2(1H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈Step 2) 5-((4-Chloro-2-formyl-((3'-(3-(5-hydroxyhexanedihydrocyclopenta[c]pyrrole-2(1H)-yl)propoxy) -2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.33g,1.65mmol)溶于DMF(12mL)，加入碳酸铯(1.03g,3.18mmol)，室温搅拌10min。加入5-氯-2-羟基-4-((3'-(3-(5-羟基己二氢环戊二烯并[c]吡咯-2(1H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯基]-3-基)甲氧基)苯甲醛(0.71g,1.24mmol)和NaI(19mg,0.13mmol)，氮气保护，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)得黄色固体460mg，产率为54.26％。5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.33 g, 1.65 mmol) was dissolved in DMF (12 mL). Add 5-chloro-2-hydroxy-4-((3'-(3-(5-hydroxyhexanedihydrocyclopenta[c]pyrrole-2(1H)-yl)propoxy)-2, 2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde (0.71 g, 1.24 mmol) and NaI (19 mg, 0.13 mmol). Stir at °C for 4 h. Stirring was continued, and the mixture was cooled to room temperature, diluted with water (30 mL), ethyl acetate (100 mL, 3). Separation and purification by silica gel column chromatography (DCM /MeOH-10/1, v/v)
LC-MS:(pos.ion)m/z：666.2[M+1] +； LC-MS: (pos.ion) m/z: 666.2 [M+1] + ;
步骤3)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3'-(3-(5-羟基己二氢环戊二烯并[c]吡咯-2(1H)-丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-Chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(5-hydroxyhexanedihydro)) Cyclopenta[c]pyrrole-2(1H)-propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl) Piperidine-2-carboxylic acid
将((4-氯-2-甲酰基-5-((3'-(3-(5-羟基己二氢环戊二烯并[c]吡咯-2(1H)-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈(460mg,0.69mmol)和D-哌啶酸(0.033g,1.03mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.216g,3.44mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)，分离得黄色固体80mg，产率为14.87％。((4-Chloro-2-formyl-5-((3'-(3-(5-hydroxyhexanedihydrocyclopenta[c]pyrrole-2(1H)-yl)propoxy)) -2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (460 mg, 0.69 mmol) and D-piperidine acid ( 0.033g, 1.03mmol) dissolved in DMF (15.0mL), added acetic acid to adjust the pH to about 5, heated to 60 ° C for 1 h, cooled to room temperature, slowly added sodium cyanoborohydride (0.216 g, 3.44 mmol), nitrogen protection Stir at room temperature for 12 h. Stirring was continued, and the mixture was cooled to room temperature. EtOAc (3 mL)EtOAc. It was separated and purified by silica gel column chromatography (DCM / MeOH=8/1, v/v).
LC-MS:(pos.ion)m/z：779.3[M+1] +； LC-MS: (pos.ion) m / z: 779.3 [M + 1] +;
1H NMR(400MHz,d 6-DMSO)δ9.01(s,2H),8.46(s,1H),7.49(d,J＝7.3Hz,1H),7.42(s,1H),7.24(dt,J＝15.8,7.7Hz,2H),7.13(s,1H),7.06(d,J＝7.5Hz,1H),6.95(d,J＝8.1Hz,1H),6.69(d,J＝7.4Hz,1H),5.30(d,J＝28.4Hz,4H),4.07(d,J＝6.3Hz,3H),3.79(d,J＝13.6Hz,2H),3.63(d,J＝13.6Hz,2H),3.51(s,1H),3.16–3.12(m,1H),3.02(s,4H),2.89(s,1H),2.73(s,2H),2.30(s,1H),2.09(s,2H),2.03(s,3H),1.83(s,6H), 1.73(s,1H),1.58–1.44(m,5H),1.37(s,1H). 1 H NMR (400MHz, d 6 -DMSO) δ9.01 (s, 2H), 8.46 (s, 1H), 7.49 (d, J = 7.3Hz, 1H), 7.42 (s, 1H), 7.24 (dt, J = 15.8, 7.7 Hz, 2H), 7.13 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 5.30 (d, J = 28.4 Hz, 4H), 4.07 (d, J = 6.3 Hz, 3H), 3.79 (d, J = 13.6 Hz, 2H), 3.63 (d, J = 13.6 Hz, 2H) , 3.51 (s, 1H), 3.16 - 3.12 (m, 1H), 3.02 (s, 4H), 2.89 (s, 1H), 2.73 (s, 2H), 2.30 (s, 1H), 2.09 (s, 2H) ), 2.03 (s, 3H), 1.83 (s, 6H), 1.73 (s, 1H), 1.58 - 1.44 (m, 5H), 1.37 (s, 1H).
实施例11(S)-1-(4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苄基)哌啶-2-甲酸(化合物11)Example 11(S)-1-(4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2' -Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzyl)piperidine-2-carboxylic acid ( Compound 11)
Figure PCTCN2019077582-appb-000063
Figure PCTCN2019077582-appb-000063
步骤1)4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(2.8g,5.6mmol)和3-氧杂-8-氮杂螺[4.5]癸烷(940mg,6.65mmol)溶于DMF(12mL)，依次加入K 2CO 3(1.9g,14mmol)和NaI(1g,6.67mmol)加热至75℃，反应12.5h。停止加热，冷却至室温，加水稀释(80mL)，乙酸乙酯萃取(50mL×3)，收集有机相，无水硫酸钠干燥，过滤，浓缩。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v),得到棕褐色粘稠物600mg，产率19％。 4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzene formaldehyde (2.8g, 5.6mmol) and 3-oxa-8-aza-spiro [4.5] decane (940mg, 6.65mmol) was dissolved in DMF (12mL), were successively added K 2 CO 3 (1.9g, 14mmol ) and NaI (1 g, 6.67 mmol) was heated to 75 ° C for 12.5 h. The reaction was quenched, cooled to rt EtOAc (EtOAc)EtOAc. It was separated and purified by silica gel column chromatography (DCM / MeOH = / / / / / / / / / / / / /
LC-MS:(pos.ion)m/z：564.1[M+1] +； LC-MS: (pos.ion) m/z: 564.1 [M+1] + ;
步骤2)4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛Step 2) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde
将4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(550mg,0.97mmol)和3-(溴甲基)吡啶氢溴酸盐(320mg,1.26mmol)溶于DMF(15mL)，加入Cs 2CO 3(794mg,2.43mmol)，和NaI(14mg,0.10mmol)，加热至75℃反应3.5h。停止反应，冷却至室温，加水稀释(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到黄色固体380mg，产率59.48％。 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1,1 '-Biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (550 mg, 0.97 mmol) and 3-(bromomethyl)pyridine hydrobromide (320 mg, 1.26 mmol) To DMF (15 mL), Cs 2 CO 3 (794 mg, 2.43 mmol), and NaCI (14 mg, 0.10 mmol). The reaction was quenched, cooled to EtOAc EtOAc (EtOAc)EtOAc. The oil was separated and purified by silica gel column chromatography (DCM/MeOH = 10/1, v/v)
LC-MS:(pos.ion)m/z：655.1[M+1] +； LC-MS: (pos.ion) m/z: 655.1 [M+1] + ;
步骤3)(S)-1-(4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2' -Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzyl)piperidine-2-carboxylic acid
将4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛(120mg,0.18mmol)和D-哌啶酸(35mg,0.27mmol)溶于DMF(8mL)，加入乙酸调节溶液pH至5左右，加热至60℃搅拌反应1h，冷却至室温，缓慢加入氰基硼氢化钠(57mg,0.90mmol)，室温搅拌反应15h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)，分离得白色固体30mg，产率为21.32％。4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1,1 '-Biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde (120 mg, 0.18 mmol) and D-piperidine (35 mg, 0.27 mmol) Dissolved in DMF (8 mL), added acetic acid to adjust the pH of the solution to about 5, heated to 60 ° C, stirred for 1 h, cooled to room temperature, slowly added sodium cyanoborohydride (57 mg, 0.90 mmol), and stirred at room temperature for 15 h. Stirring was continued, and the mixture was cooled to room temperature. The mixture was stirred with EtOAc EtOAc (EtOAc) /1, v/v), 30 mg of white solid isolated, yield 21.32%.
LC-MS:(pos.ion)m/z：768.2[M+1] +； LC-MS: (pos.ion) m / z: 768.2 [M + 1] +;
1H NMR(400MHz,d 6-DMSO)δ8.70(s,1H),8.56(d,J＝4.3Hz,1H),7.90(d,J＝7.7Hz,1H),7.49(d,J＝7.5Hz,1H),7.43(s,2H),7.27(t,J＝7.4Hz,1H),7.21(t,J＝7.9Hz,1H),7.14(s,1H),7.07(d,J＝7.4Hz,1H),6.96(d,J＝8.1Hz,1H),6.69(d,J＝7.4Hz,1H),5.26(d,J＝6.6Hz,4H),4.06(d,J＝6.3Hz,2H),3.75–3.69(m,3H),3.62(d,J＝13.9Hz,2H),3.51(s,1H),3.44(s,2H),3.15(s,1H),2.89(s,2H),2.73(s,4H),2.29(s,1H),2.03 (s,5H),1.83(s,3H),1.80–1.76(m,1H),1.69(s,3H),1.64(s,3H),1.47(s,3H),1.36(s,1H). 1 H NMR (400 MHz, d 6 - DMSO) δ 8.70 (s, 1H), 8.56 (d, J = 4.3 Hz, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.43 (s, 2H), 7.27 (t, J = 7.4 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.14 (s, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 5.26 (d, J = 6.6 Hz, 4H), 4.06 (d, J = 6.3 Hz) , 2H), 3.75–3.69 (m, 3H), 3.62 (d, J = 13.9 Hz, 2H), 3.51 (s, 1H), 3.44 (s, 2H), 3.15 (s, 1H), 2.89 (s, 2H), 2.73 (s, 4H), 2.29 (s, 1H), 2.03 (s, 5H), 1.83 (s, 3H), 1.80 - 1.76 (m, 1H), 1.69 (s, 3H), 1.64 (s) , 3H), 1.47 (s, 3H), 1.36 (s, 1H).
实施例12 8-(3-((3'-((2-氯-4-(吗啉代甲基)-5-(吡啶-3-基甲氧基)苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-2-氧杂-8-氮杂-螺[4.5]癸烷(化合物12)Example 12 8-(3-((3'-((2-Chloro-4-(morpholinomethyl)-5-(pyridin-3-ylmethoxy)phenoxy)methyl)-2) , 2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2-oxa-8-aza-spiro[4.5]decane (Compound 12)
Figure PCTCN2019077582-appb-000064
Figure PCTCN2019077582-appb-000064
步骤1)4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(2.8g,5.6mmol)和3-氧杂-8-氮杂螺[4.5]癸烷(940mg,6.65mmol)溶于DMF(12mL)，依次加入K 2CO 3(1.9g,14mmol)和NaI(1g,6.67mmol)。随后加热至75℃，反应12.5h。停止加热，冷却至室温，加水稀释(80mL)，乙酸乙酯萃取(50mL×3)，收集有机相，无水硫酸钠干燥，过滤，浓缩。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)，得到棕褐色粘稠物600mg，产率19％。 4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzene formaldehyde (2.8g, 5.6mmol) and 3-oxa-8-aza-spiro [4.5] decane (940mg, 6.65mmol) was dissolved in DMF (12mL), were successively added K 2 CO 3 (1.9g, 14mmol ) and NaI (1 g, 6.67 mmol). It was then heated to 75 ° C and reacted for 12.5 h. The reaction was quenched, cooled to rt EtOAc (EtOAc)EtOAc. It was separated and purified by silica gel column chromatography (DCM / MeOH = / / / / / / / / / / / / /
LC-MS:(pos.ion)m/z：564.1[M+1] +； LC-MS: (pos.ion) m/z: 564.1 [M+1] + ;
步骤2)4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛Step 2) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde
将4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(550mg,0.97mmol)和3-(溴甲基)吡啶氢溴酸盐(320mg,1.26mmol)溶于DMF(15mL)，加入Cs 2CO 3(794mg,2.43mmol)，和NaI(14mg,0.10mmol)，加热至75℃反应3.5h。停止反应，冷却至室温，加水稀释(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到黄色固体380mg，产率59.48％。 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1,1 '-Biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (550 mg, 0.97 mmol) and 3-(bromomethyl)pyridine hydrobromide (320 mg, 1.26 mmol) To DMF (15 mL), Cs 2 CO 3 (794 mg, 2.43 mmol), and NaCI (14 mg, 0.10 mmol). The reaction was quenched, cooled to EtOAc EtOAc (EtOAc)EtOAc. The oil was separated and purified by silica gel column chromatography (DCM/MeOH = 10/1, v/v)
LC-MS:(pos.ion)m/z：655.1[M+1] +； LC-MS: (pos.ion) m/z: 655.1 [M+1] + ;
步骤3)8-(3-((3'-((2-氯-4-(吗啉代甲基)-5-(吡啶-3-基甲氧基)苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-2-氧杂-8-氮杂-螺[4.5]癸烷Step 3) 8-(3-((3'-(2-Chloro-4-(morpholinomethyl)-5-(pyridin-3-ylmethoxy)phenoxy)methyl)-2) , 2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2-oxa-8-aza-spiro[4.5]decane
将4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛(130mg,0.20mmol)和吗啉(24mg,0.27mmol)溶于DMF(8mL)，加入乙酸调节溶液pH至5左右，加热至60℃搅拌反应1h，冷却至室温，缓慢加入氰基硼氢化钠(62mg,0.98mmol)，室温搅拌反应15h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)，分离得白色固体40mg，产率为27.76％。4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1,1 '-Biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde (130 mg, 0.20 mmol) and morpholine (24 mg, 0.27 mmol) DMF (8 mL), acetic acid was added to adjust the pH of the solution to about 5, and the mixture was heated to 60 ° C. The reaction was stirred for 1 hour, cooled to room temperature, sodium cyanoborohydride (62 mg, 0.98 mmol) was slowly added, and the mixture was stirred at room temperature for 15 h. Stirring was continued, and the mixture was cooled to room temperature. The mixture was stirred with EtOAc EtOAc (EtOAc) /1, v/v), 40 mg of white solid isolated, yield 27.76%.
LC-MS:(pos.ion)m/z：726.2[M+1] +； LC-MS: (pos.ion) m/z: 726.2 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ8.72(s,1H),8.55(d,J＝3.4Hz,1H),7.90(d,J＝7.4Hz,1H),7.49(d,J＝7.4Hz,1H),7.47–7.40(m,1H),7.31(s,1H),7.26(d,J＝7.4Hz,1H),7.21(t,J＝7.7Hz,1H),7.14(s,1H),7.07(d,J＝7.3Hz,1H),6.96(d,J＝8.1Hz,1H),6.69(d,J＝7.3Hz,1H),5.25(s,4H),4.06(d,J＝5.7Hz,2H),3.72(t,J＝6.5Hz,2H),3.55(s,3H),3.42(d,J＝13.5Hz,4H),3.34(s,6H),2.73(s,3H),2.33(s,4H),2.03(s,4H),1.83 (s,3H),1.67(d,J＝22.4Hz,5H). 1 H NMR (400 MHz, d 6 -DMSO) δ 8.72 (s, 1H), 8.85 (d, J = 3.4 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.47 - 7.40 (m, 1H), 7.31 (s, 1H), 7.26 (d, J = 7.4 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.14 (s, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 7.3 Hz, 1H), 5.25 (s, 4H), 4.06 (d, J = 5.7 Hz, 2H), 3.72 (t, J = 6.5 Hz, 2H), 3.55 (s, 3H), 3.42 (d, J = 13.5 Hz, 4H), 3.34 (s, 6H), 2.73 (s, 3H), 2.33 (s, 4H), 2.03 (s, 4H), 1.83 (s, 3H), 1.67 (d, J = 22.4 Hz, 5H).
实施例13(R)-2-((4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苄基)氨基)丙酸(化合物13)Example 13(R)-2-((4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2 '-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzyl)amino)propanoic acid (compound) 13)
Figure PCTCN2019077582-appb-000065
Figure PCTCN2019077582-appb-000065
步骤1)4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(2.8g,5.6mmol)和3-氧杂-8-氮杂螺[4.5]癸烷(940mg,6.65mmol)溶于DMF(12mL)，依次加入K 2CO 3(1.9g,14mmol)和NaI(1g,6.67mmol)。随后加热至75℃，反应12.5h。停止加热，冷却至室温，加水稀释(80mL)，乙酸乙酯萃取(50mL×3)，收集有机相，无水硫酸钠干燥，过滤，浓缩。硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)，得到棕褐色粘稠物600mg，产率19％。 4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzene formaldehyde (2.8g, 5.6mmol) and 3-oxa-8-aza-spiro [4.5] decane (940mg, 6.65mmol) was dissolved in DMF (12mL), were successively added K 2 CO 3 (1.9g, 14mmol ) and NaI (1 g, 6.67 mmol). It was then heated to 75 ° C and reacted for 12.5 h. The reaction was quenched, cooled to rt EtOAc (EtOAc)EtOAc. It was separated and purified by silica gel column chromatography (DCM / MeOH = / / / / / / / / / / / / /
LC-MS:(pos.ion)m/z：564.1[M+1] +； LC-MS: (pos.ion) m/z: 564.1 [M+1] + ;
步骤2)4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛Step 2) 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde
将4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(550mg,0.97mmol)和3-(溴甲基)吡啶氢溴酸盐(320mg,1.26mmol)溶于DMF(15mL)，加入Cs 2CO 3(794mg,2.43mmol)和NaI(14mg,0.097mmol)，随后加热至75℃反应3.5h。停止反应，冷却至室温，加水稀释(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩。硅胶柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到黄色固体380mg，产率59.48％。 4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1,1 '-Biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (550 mg, 0.97 mmol) and 3-(bromomethyl)pyridine hydrobromide (320 mg, 1.26 mmol) To DMF (15 mL), Cs 2 CO 3 (794 mg, 2.43 mmol) and NaI (14 mg, 0.097 mmol) were added and then heated to 75 ° C for 3.5 h. The reaction was quenched, cooled to EtOAc EtOAc (EtOAc)EtOAc. The oil was separated and purified by silica gel column chromatography (DCM/MeOH = 10/1, v/v)
LC-MS:(pos.ion)m/z：655.1[M+1] +； LC-MS: (pos.ion) m/z: 655.1 [M+1] + ;
步骤3)(R)-2-((4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苄基)氨基)丙酸Step 3) (R)-2-((4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2 '-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzyl)amino)propanoic acid
将4-((3'-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛(120mg,0.183mmol)和(2R)-2-氨基丙酸(24mg,0.26mmol)溶于DMF(8mL)，加入乙酸调节溶液pH至5左右，加热至60℃搅拌反应1h，冷却至室温，缓慢加入氰基硼氢化钠(57mg,0.90mmol)，室温搅拌反应15h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，硅胶柱层析分离纯化(DCM/MeOH＝8/1,v/v)，分离得白色固体15mg，产率为11.25％。4-((3'-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2'-dimethyl-[1,1 '-Biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde (120 mg, 0.183 mmol) and (2R)-2-aminopropionic acid ( 24 mg, 0.26 mmol) dissolved in DMF (8 mL), added acetic acid to adjust the pH of the solution to about 5, heated to 60 ° C, stirred for 1 h, cooled to room temperature, slowly added sodium cyanoborohydride (57 mg, 0.90 mmol), stirred at room temperature 15h. Stirring was continued, and the mixture was cooled to room temperature. The mixture was stirred with EtOAc EtOAc (EtOAc) /1, v/v), 15 mg of white solid isolated, yield 11.25%.
LC-MS:(pos.ion)m/z：728.2[M+1] +； LC-MS: (pos.ion) m/z: 728.2 [M + 1] + ;
1H NMR(400MHz,d 6-DMSO)δ8.74(s,1H),8.57(d,J＝4.1Hz,1H),7.97(s,1H),7.54(s,1H),7.49(d,J＝7.0Hz,1H),7.44(dd,J＝7.8,4.9Hz,1H),7.27(t,J＝7.5Hz,1H),7.21(t,J＝7.9Hz,1H),7.20–7.13(m,1H),7.07(d,J＝7.5Hz,1H),6.96(d,J＝8.4Hz,1H),6.69(d,J＝7.6Hz,1H),5.39–5.19(m,4H),4.07(d,J＝6.9Hz,2H),3.94–3.85(m,2H),3.73(t,J＝7.0Hz,2H),3.51(s,2H),3.45(s,3H),3.19–3.14(m,2H),2.89(s,6H),2.10 (s,2H),2.03(s,3H),1.82(d,J＝8.0Hz,3H),1.70(d,J＝7.0Hz,6H). 1 H NMR (400 MHz, d 6 -DMSO) δ 8.74 (s, 1H), 8.57 (d, J = 4.1 Hz, 1H), 7.97 (s, 1H), 7.54 (s, 1H), 7.49 (d, J=7.0 Hz, 1H), 7.44 (dd, J=7.8, 4.9 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H), 7.21 (t, J=7.9 Hz, 1H), 7.20–7.13 ( m, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 5.39 - 5.19 (m, 4H), 4.07 (d, J = 6.9 Hz, 2H), 3.94 - 3.85 (m, 2H), 3.73 (t, J = 7.0 Hz, 2H), 3.51 (s, 2H), 3.45 (s, 3H), 3.19 - 3.14 (m, 2H), 2.89 (s, 6H), 2.10 (s, 2H), 2.03 (s, 3H), 1.82 (d, J = 8.0 Hz, 3H), 1.70 (d, J = 7.0 Hz, 6H) .
实施例14(S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3'-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物14)Example 14(S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(2-hydroxy-7-) Azaspiro[3.5]dec-7-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine- 2-carboxylic acid (compound 14)
Figure PCTCN2019077582-appb-000066
Figure PCTCN2019077582-appb-000066
步骤1)5-氯-2-羟基-4-((3'-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛Step 1) 5-Chloro-2-hydroxy-4-((3'-(3-(2-hydroxy-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(700mg,1.39mmol)和2-羟基-2,7-二氮杂螺环[3.5]壬烷盐酸盐(370.3mg,2.08mmol)的DMF(20mL)溶液中，依次加入碳酸钾(576.1mg,4.17mmol)和碘化钠(312.4mg,2.08mmol)，随后加热至70℃，反应16h。停止搅拌，冷却至室温，原料反应完全。加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到黄色固体685mg，产率87.4％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen -Hydroxy-benzaldehyde (700 mg, 1.39 mmol) and 2-hydroxy-2,7-diazaspiro[3.5]decane hydrochloride (370.3 mg, 2.08 mmol) in DMF (20 mL) Potassium carbonate (576.1 mg, 4.17 mmol) and sodium iodide (312.4 mg, 2.08 mmol) were then heated to 70 ° C for 16 h. Stirring was stopped, cooling to room temperature, and the starting material was completely reacted. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 10/1, v/v) afforded </RTI> s.
LC-MS:(pos.ion)m/z：564.0[M+1] +； LC-MS: (pos.ion) m/z: 564.0 [M+1] + ;
步骤2)5-((4-氯-2-甲酰基-5-((3'-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈Step 2) 5-((4-Chloro-2-formyl-5-((3'-(3-(2-hydroxy-7-azaspiro[3.5]indole-7-yl)propoxy)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
向5-氯-2-羟基-4-((3'-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛(680mg,1.21mmol)和5-氯甲基-3-氰基吡啶盐酸盐(273.5mg,1.45mmol)的DMF溶液(20mL)中，依次加入碳酸铯(981.9mg,3.01mmol)和碘化钠(36.14mg,0.24mmol)，N 2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到黄色固体476mg，产率58.05％。 To 5-chloro-2-hydroxy-4-((3'-(3-(2-hydroxy-7-azaspiro[3.5]壬-7-yl)propoxy)-2,2'-dimethyl Benzyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde (680 mg, 1.21 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (273.5 mg, 1.45 mmol) In a solution of DMF (20 mL), cesium carbonate (981.9 mg, 3.01 mmol) and sodium iodide (36.14 mg, 0.24 mmol) were sequentially added, and the mixture was protected with N 2 and reacted at 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc (EtOAc) Separation and purification (DCM / MeOH = 10/1, v/v) afforded 476 g of a yellow solid.
LC-MS:(pos.ion)m/z：680.2[M+1] +； LC-MS: (pos.ion) m/z: 680.2 [M + 1] + ;
步骤3)(S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3'-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(5-Chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(2-hydroxy-7-) Azaspiro[3.5]dec-7-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine- 2-formic acid
向5-((4-氯-2-甲酰基-5-((3'-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈(250mg,0.37mmol)和D-哌啶酸(94.94mg,0.74mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，60℃反应1h，冷却至室温，再向反应体系中加入硼***(115.5mg,1.84mmol)，室温反应3h后，80℃反应16h。停止搅拌，随后加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1,v/v)，得到淡黄色固体70mg，产率24.01％。To 5-((4-chloro-2-formyl-5-((3'-(3-(2-hydroxy-7-azaspiro[3.5]壬-7-yl)propoxy)-2, 2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (250 mg, 0.37 mmol) and D-pipecolic acid (94.94 mg, Add acetic acid to a solution of 0.74 mmol) in DMF (10 mL), adjust the pH to about 5, react at 60 ° C for 1 h, cool to room temperature, then add sodium borohydride (115.5 mg, 1.84 mmol) to the reaction system, and react at room temperature for 3 h. , reaction at 80 ° C for 16 h. Stirring was stopped, followed by the addition of saturated potassium carbonate solution and stirring for 30 min. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 4/1, v/v) afforded 70 mg of pale yellow solid.
LC-MS:(pos.ion)m/z：793.2[M+1] +； LC-MS: (pos.ion) m/z: 793.2 [M + 1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.01(s,1H),8.99(s,1H),8.45(s,1H),7.49(d,J＝7.4Hz,1H),7.41(s,1H),7.26(t,J＝7.5Hz,1H),7.20(t,J＝7.9Hz,1H),7.11(s,1H),7.06(d,J＝7.4Hz,1H),6.94(d,J＝8.1Hz, 1H),6.67(d,J＝7.4Hz,1H),5.32(s,2H),5.26(s,2H),4.05(dd,J＝16.0,7.0Hz,4H),3.76(d,J＝13.9Hz,2H),3.60(d,J＝13.9Hz,3H),3.51(s,2H),3.14(d,J＝6.9Hz,2H),2.11–2.04(m,2H),2.02(s,3H),1.92(s,2H),1.81(s,4H),1.51(dd,J＝14.6,7.9Hz,9H),1.36(s,1H),1.23(s,3H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.01 (s, 1H), 8.99 (s, 1H), 8.45 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.41 (s, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.11 (s, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 5.32 (s, 2H), 5.26 (s, 2H), 4.05 (dd, J = 16.0, 7.0 Hz, 4H), 3.76 ( d, J = 13.9 Hz, 2H), 3.60 (d, J = 13.9 Hz, 3H), 3.51 (s, 2H), 3.14 (d, J = 6.9 Hz, 2H), 2.11 - 2.04 (m, 2H), 2.02 (s, 3H), 1.92 (s, 2H), 1.81 (s, 4H), 1.51 (dd, J = 14.6, 7.9 Hz, 9H), 1.36 (s, 1H), 1.23 (s, 3H).
实施例15(S)-1-(4-((3'-(3-(2-氧杂-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物15)Example 15(S)-1-(4-((3'-(3-(2-oxa-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid (compound 15)
Figure PCTCN2019077582-appb-000067
Figure PCTCN2019077582-appb-000067
步骤1)4-((3'-(3-(2-氧杂-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(2-oxa-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(500mg,0.99mmol)和2-氧-7-氮杂螺环[3.5]壬烷草酸盐(323.4mg,1.49mmol)的DMF(20mL)溶液中，依次加入碳酸钾(617.3mg,4.47mmol)和NaI(223.1mg,1.49mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，原料反应完全。加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到黄色固体307mg，产率56.23％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen -Hydroxy-benzaldehyde (500 mg, 0.99 mmol) and 2-oxo-7-azaspiro[3.5]decane oxalate (323.4 mg, 1.49 mmol) in DMF (20 mL) 617.3 mg, 4.47 mmol) and NaI (223.1 mg, 1.49 mmol) were heated to 70 ° C for 16 h. Stirring was stopped, cooling to room temperature, and the starting material was completely reacted. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 10/1, v/v) afforded 307 mg as a yellow solid.
LC-MS:(pos.ion)m/z：550.1[M+1] +； LC-MS: (pos.ion) m/z: 550.1 [M+1] + ;
步骤2)5-((5-((3'-(3-(2-氧杂-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-吡啶-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3)-(3-(2-oxa-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3'-(3-(2-氧杂-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(300mg,0.55mmol)和5-氯甲基-3-氰基吡啶盐酸盐(154.6mg,0.82mmol)的DMF溶液(20mL)中，依次加入碳酸铯(309.9mg,1.2mmol)和碘化钠(16.35mg,0.11mmol)，N 2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1)得到黄色油状液体73mg，产率20.09％。 To 4-((3'-(3-(2-oxa-7-azaspiro[3.5]壬-7-yl)propoxy)-2,2'-dimethyl-[1,1' -biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (300 mg, 0.55 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (154.6 mg, 0.82 mmol) In a solution of DMF (20 mL), cesium carbonate (309.9 mg, 1.2 mmol) and sodium iodide (16.35 mg, 0.11 mmol) were sequentially added, and the mixture was protected with N 2 and reacted at 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc (EtOAc) Separation and purification (DCM / MeOH = 10/1) afforded (yel.
LC-MS:(pos.ion)m/z：666.4[M+1] +； LC-MS: (pos.ion) m/z: 666.4 [M+1] + ;
步骤3)(S)-1-(4-((3'-(3-(2-氧杂-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(2-oxa-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid
向5-((5-((3'-(3-(2-氧杂-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-吡啶-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(70mg,0.11mmol)和D-哌啶酸(27.14mg,0.21mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，60℃反应1h，冷却至室温，再向反应体系中加入硼***(33.01mg,0.53mmol)，室温反应3h后，升温至80℃反应16h。随后停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1,v/v)，得到淡黄色固体15mg，产率18.32％。To 5-((5-((3'-(3-(2-oxa-7-azaspiro[3.5]壬-7-yl)propoxy)-2,2'-dimethyl-[ 1,1'-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (70 mg, 0.11 mmol) and D-piperidine acid ( Add acetic acid to a solution of 27.14 mg, 0.21 mmol) in DMF (10 mL), adjust the pH to about 5, react at 60 ° C for 1 h, cool to room temperature, then add sodium borohydride (33.01 mg, 0.53 mmol) to the reaction system, room temperature After reacting for 3 h, the temperature was raised to 80 ° C for 16 h. Stirring was then stopped, saturated potassium carbonate solution was added and stirred for 30 min. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 4/1, v/v) gave 15 mg of pale yellow solid.
LC-MS:(pos.ion)m/z：779.5[M+1] +； LC-MS: (pos.ion) m/z: 779.5 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.01(d,J＝7.7Hz,2H),8.46(s,1H),7.49(d,J＝7.5Hz,1H),7.42(s,1H),7.32–7.16(m,2H),7.12(s,1H),7.07(d,J＝7.4Hz,1H),6.96(d,J＝8.2Hz,1H),6.69(d,J＝7.5Hz,1H),5.32(d,J＝14.0Hz,2H),5.27(s,2H),4.29(s,3H),4.05(d,J＝6.4Hz,2H),3.77(d,J＝13.5Hz,2H),3.61(d,J＝13.6Hz,1H),3.52(s,6H),2.03(s,3H),1.82(s,4H),1.49(s,3H),1.24(s,9H),0.85(d,J＝7.0Hz,2H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.01 (d, J = 7.7 Hz, 2H), 8.46 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.42 (s, 1H) , 7.32–7.16(m,2H), 7.12(s,1H),7.07(d,J=7.4Hz,1H),6.96(d,J=8.2Hz,1H),6.69(d,J=7.5Hz, 1H), 5.32 (d, J = 14.0 Hz, 2H), 5.27 (s, 2H), 4.29 (s, 3H), 4.05 (d, J = 6.4 Hz, 2H), 3.77 (d, J = 13.5 Hz, 2H), 3.61 (d, J = 13.6 Hz, 1H), 3.52 (s, 6H), 2.03 (s, 3H), 1.82 (s, 4H), 1.49 (s, 3H), 1.24 (s, 9H), 0.85 (d, J = 7.0 Hz, 2H).
实施例16(S)-1-(4-((3'-(3-(2-氧杂-6-氮杂螺[3.5]壬-6-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物16)Example 16(S)-1-(4-((3'-(3-(2-oxa-6-azaspiro[3.5]fluoren-6-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid (compound 16)
Figure PCTCN2019077582-appb-000068
Figure PCTCN2019077582-appb-000068
步骤1)4-((3'-(3-(2-氧杂-6-氮杂螺[3.5]壬-6-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(2-oxa-6-azaspiro[3.5]壬-6-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(600mg,1.19mmol)和2-氧-6-氮杂螺环[3.5]壬烷草酸盐(388mg,1.79mmol)的DMF(20mL)溶液中，依次加入碳酸钾(740.7mg,5.36mmol)和NaI(267.8mg,1.79mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到红色油状液体427mg，产率65.18％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen -Hydroxy-benzaldehyde (600 mg, 1.19 mmol) and 2-oxo-6-azabicyclo[3.5]decane oxalate (388 mg, 1.79 mmol) in DMF (20 mL). Mg, 5.36 mmol) and NaI (267.8 mg, 1.79 mmol), heated to 70 ° C for 16 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc)EtOAc. Purification by chromatography (DCM / MeOH = 10/1, v / v) afforded 427mg
LC-MS:(pos.ion)m/z：550.1[M+1] +； LC-MS: (pos.ion) m/z: 550.1 [M+1] + ;
步骤2)5-((5-((3'-(3-(2-氧杂-6-氮杂螺[3.5]壬-6-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-吡啶-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3)-(3-(2-oxa-6-azaspiro[3.5]indole-6-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3'-(3-(2-氧杂-6-氮杂螺[3.5]壬-6-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(420mg,0.76mmol)和5-氯甲基-3-氰基吡啶盐酸盐(173.2mg,0.92mmol)的DMF溶液(20mL)中，依次加入碳酸铯(621.9mg,1.91mmol)和碘化钠(22.89mg,0.15mmol)，N 2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到红色油状液体342mg，产率67.24％。 To 4-((3'-(3-(2-oxa-6-azaspiro[3.5]壬-6-yl)propoxy)-2,2'-dimethyl-[1,1' -biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (420 mg, 0.76 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (173.2 mg, 0.92 mmol) In a solution of DMF (20 mL), cesium carbonate (621.9 mg, 1.91 mmol) and sodium iodide (22.89 mg, 0.15 mmol) were sequentially added, and the mixture was protected with N 2 and reacted at 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc (EtOAc) Separation and purification (DCM / MeOH = 10/1, v/v) afforded 342 mg ofyel.
LC-MS:(pos.ion)m/z：666.5[M+1] +； LC-MS: (pos.ion) m/z: 666.5 [M+1] + ;
步骤3)(S)-1-(4-((3'-(3-(2-氧杂-6-氮杂螺[3.5]壬-6-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(2-oxa-6-azaspiro[3.5]fluoren-6-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid
向5-((5-((3'-(3-(2-氧杂-6-氮杂螺[3.5]壬-6-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-吡啶-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(340mg,0.51mmol)和D-哌啶酸(131.8mg,1.02mmol)的DMF(20mL)溶液中加入乙酸调节pH至5左右，随后升温至60℃反应1h，再冷却至室温，向反应体系中加入硼***(160.4mg,2.55mmol)，室温搅拌反应3h后，再升温至80℃反应16h。停止搅拌，加入饱和碳酸钾溶 液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝6/1,v/v)，得到淡红色固体52mg，产率13.07％。To 5-((5-((3'-(3-(2-oxa-6-azaspiro[3.5]壬-6-yl)propoxy)-2,2'-dimethyl-[ 1,1'-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (340 mg, 0.51 mmol) and D-piperidine acid ( 131.8 mg, 1.02 mmol) of DMF (20 mL) was added to acetic acid to adjust the pH to about 5, then the temperature was raised to 60 ° C for 1 h, and then cooled to room temperature, sodium borohydride (160.4 mg, 2.55 mmol) was added to the reaction system. After stirring at room temperature for 3 h, the mixture was further heated to 80 ° C for 16 h. Stirring was stopped and a saturated solution of potassium carbonate was added and stirred for 30 min. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 6/1, v/v) afforded 52 mg of pale red solid.
LC-MS:(pos.ion)m/z：779.6[M+1] +； LC-MS: (pos.ion) m/z: 779.6 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.01(s,2H),8.48(s,1H),7.46(d,J＝18.6Hz,2H),7.23(d,J＝23.1Hz,2H),7.15(s,1H),7.07(s,1H),6.97(s,1H),6.69(s,1H),5.31(d,J＝31.0Hz,4H),4.26(d,J＝31.9Hz,5H),4.05(s,4H),3.81(s,6H),2.00(d,J＝18.4Hz,6H),1.83(s,4H),1.75(s,3H),1.50(s,5H),1.37(s,1H),1.17(s,1H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.01 (s, 2H), 8.48 (s, 1H), 7.46 (d, J = 18.6 Hz, 2H), 7.23 (d, J = 23.1 Hz, 2H) , 7.15 (s, 1H), 7.07 (s, 1H), 6.97 (s, 1H), 6.69 (s, 1H), 5.31 (d, J = 31.0 Hz, 4H), 4.26 (d, J = 31.9 Hz, 5H), 4.05 (s, 4H), 3.81 (s, 6H), 2.00 (d, J = 18.4 Hz, 6H), 1.83 (s, 4H), 1.75 (s, 3H), 1.50 (s, 5H), 1.37(s,1H), 1.17(s,1H).
实施例17(2S)-1-(4-((3'-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物17)Example 17(2S)-1-(4-((3'-(3-(2-oxa-7-azaspiro[4.5]fluoren-7-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid (compound 17)
Figure PCTCN2019077582-appb-000069
Figure PCTCN2019077582-appb-000069
步骤1)4-((3'-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(2-oxa-7-azaspiro[4.5]癸-7-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(600mg,1.191mmol)和2-氧-7-氮杂螺环[4.5]癸烷盐酸盐(317.4mg,1.79mmol)的DMF(20mL)溶液中，依次加入碳酸钾(411.5mg,2.98mmol)和NaI(267.8mg,1.79mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温。随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到棕红色油状液体200mg，产率29.77％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen -Hydroxy-benzaldehyde (600 mg, 1.191 mmol) and 2-oxo-7-azaspiro[4.5]decane hydrochloride (317.4 mg, 1.79 mmol) in DMF (20 mL) 411.5 mg, 2.98 mmol) and NaI (267.8 mg, 1.79 mmol) were heated to 70 ° C for 16 h. Stirring was stopped and cooled to room temperature. Then, it was diluted with water (20 mL), and extracted with ethyl acetate (50 mL×3). The organic phase was combined, and the organic phase was washed with brine (50 mL) and dried over anhydrous sodium sulfate. /MeOH = 10/1, v/v) gave a brown-brown oily liquid 200mg, yield 29.97%.
LC-MS:(pos.ion)m/z：564.4[M+1] +； LC-MS: (pos.ion) m/z: 564.4 [M + 1] + ;
步骤2)5-((5-((3'-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-吡啶-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3)-(3-(2-oxa-7-azaspiro[4.5]]-7-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3'-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(450mg,0.80mmol)和5-氯甲基-3-氰基吡啶盐酸盐(181mg,0.96mmol)的DMF溶液(20mL)中，依次加入碳酸铯(649.8mg,1.99mmol)和碘化钠(23.92mg,0.16mmol)，N 2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到红色油状液体520mg，产率95.83％。 To 4-((3'-(3-(2-oxa-7-azaspiro[4.5]癸-7-yl)propoxy)-2,2'-dimethyl-[1,1' -biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (450 mg, 0.80 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (181 mg, 0.96 mmol) In a solution of DMF (20 mL), cesium carbonate (649.8 mg, 1.99 mmol) and sodium iodide (23.92 mg, 0.16 mmol) were sequentially added, and the mixture was protected with N 2 and reacted at 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc (EtOAc) Separation and purification (DCM / MeOH = 10/1, v / v) afforded 520mg as a red oily.
LC-MS:(pos.ion)m/z：680.5[M+1] +； LC-MS: (pos.ion) m/z: 680.5 [M+1] + ;
步骤3)(2S)-1-(4-((3'-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(4-((3'-(3-(2-oxa-7-azaspiro[4.5]癸-7-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid
向5-((5-((3'-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-吡啶-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(520mg,0.76mmol)和D-哌啶酸(197.5mg,1.53mmol)的DMF(20mL)溶液 中加入乙酸，调节pH至5左右，60℃反应1h，冷却至室温，再向反应体系中加入硼***(240.2mg,3.82mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1,v/v)，得到淡红色固体112mg，产率18.47％。To 5-((5-((3'-(3-(2-oxa-7-azaspiro[4.5]癸-7-yl)propoxy)-2,2'-dimethyl-[ 1,1'-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (520 mg, 0.76 mmol) and D-pipecolic acid ( Add acetic acid to a solution of 197.5 mg, 1.53 mmol) in DMF (20 mL), adjust the pH to about 5, react at 60 ° C for 1 h, cool to room temperature, then add sodium borohydride (240.2 mg, 3.82 mmol) to the reaction system, room temperature After reacting for 3 h, the reaction was carried out at 80 ° C for 16 h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 4/1, v/v) afforded 112 mg of pale red solid.
LC-MS:(pos.ion)m/z：793.3[M+1] +； LC-MS: (pos.ion) m/z: 793.3 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.01(d,J＝1.3Hz,2H),8.47(s,1H),7.49(d,J＝7.5Hz,1H),7.43(s,1H),7.26(t,J＝7.6Hz,1H),7.20(t,J＝7.9Hz,1H),7.15(s,1H),7.06(d,J＝7.5Hz,1H),6.96(d,J＝8.2Hz,1H),6.68(d,J＝7.5Hz,1H),5.35(s,2H),5.27(s,2H),4.06(d,J＝6.2Hz,3H),3.84(s,3H),3.66(d,J＝13.9Hz,9H),2.03(s,4H),1.82(s,5H),1.71(d,J＝9.7Hz,2H),1.50(t,J＝48.5Hz,9H),1.23(s,2H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.01 (d, J = 1.3 Hz, 2H), 8.47 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.43 (s, 1H) , 7.26 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 5.35 (s, 2H), 5.27 (s, 2H), 4.06 (d, J = 6.2 Hz, 3H), 3.84 (s, 3H) , 3.66 (d, J = 13.9 Hz, 9H), 2.03 (s, 4H), 1.82 (s, 5H), 1.71 (d, J = 9.7 Hz, 2H), 1.50 (t, J = 48.5 Hz, 9H) , 1.23 (s, 2H).
实施例18(S)-1-(4-((3'-(3-(9-氧杂-2-氮杂螺[5.5]十一烷-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物18)Example 18(S)-1-(4-((3'-(3-(9-oxa-2-azaspiro[5.5]undec-2-yl)propoxy)-2,2 '-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl) Piperidine-2-carboxylic acid (Compound 18)
Figure PCTCN2019077582-appb-000070
Figure PCTCN2019077582-appb-000070
步骤1)4-((3'-(3-(9-氧杂-2-氮杂螺[5.5]十一烷-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(9-oxa-2-azaspiro[5.5]undec-2-yl)propoxy)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(800mg,1.59mmol)和9-氧-2-氮杂螺环[5.5]十一烷(369.8mg,2.38mmol)的DMF(20mL)溶液中，依次加入碳酸钾(329.2mg,2.38mmol)和NaI(357mg,2.38mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到棕红色油状液体566mg，产率61.66％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen -Hydroxy-benzaldehyde (800 mg, 1.59 mmol) and 9-oxo-2-azaspiro[5.5]undecane (369.8 mg, 2.38 mmol) in DMF (20 mL). , 2.38 mmol) and NaI (357 mg, 2.38 mmol), heated to 70 ° C, and reacted for 16 h. The mixture was stirred and cooled to room temperature, then diluted with EtOAc EtOAc EtOAc. Separation and purification by column chromatography (DCM /MeOH = 10/1, v/v) afforded
LC-MS:(pos.ion)m/z：578.4[M+1] +； LC-MS: (pos.ion) m/z: 578.4 [M+1] + ;
步骤2)5-((5-((3'-(3-(9-氧杂-2-氮杂螺[5.5]十一烷-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3-oxa-2-azaspiro[5.5]undec-2-yl)propoxy)-2,2'-di Methyl-[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3'-(3-(9-氧杂-2-氮杂螺[5.5]十一烷-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(560mg,0.97mmol)和5-氯甲基-3-氰基吡啶盐酸盐(219.7mg,1.16mmol)的DMF溶液(20mL)中，依次加入碳酸铯(789mg,2.42mmol)和碘化钠(29.04mg,0.19mmol)，N 2保护，75℃反应4h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝20/1,v/v)得到红色油状液体408mg，产率60.66％。 To 4-((3'-(3-(9-oxa-2-azaspiro[5.5]undec-2-yl)propoxy)-2,2'-dimethyl-[1, 1'-Biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (560 mg, 0.97 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (219.7 mg, 1.16 mmol) in DMF (20mL) were sequentially added cesium carbonate (789mg, 2.42mmol) and sodium iodide (29.04mg, 0.19mmol), N 2 protection, 75 deg.] C reaction 4h. Stirring was continued, the mixture was cooled to room temperature, then diluted with water (20 mL), EtOAc (EtOAc)EtOAc. Purification by chromatography (DCM / MeOH = 20/1, v/v)
LC-MS:(pos.ion)m/z：694.5[M+1] +； LC-MS: (pos.ion) m/z: 694.5 [M + 1] + ;
步骤3)(S)-1-(4-((3'-(3-(9-氧杂-2-氮杂螺[5.5]十一烷-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(9-oxa-2-azaspiro[5.5]undec-2-yl)propoxy)-2,2 '-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl) Piperidine-2-carboxylic acid
向5-((5-((3'-(3-(9-氧杂-2-氮杂螺[5.5]十一烷-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(300mg,0.43mmol)和D-哌啶酸(111.6mg,0.86mmol)的DMF(20mL)溶液中加入乙酸，调节pH至5左右，60℃反应1h，冷却至室温，再向反应体系中加入硼***(135.8mg,2.16mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到淡红色固体18mg，产率5.16％。5-((5-((3'-(3-(9-oxa-2-azaspiro[5.5]undec-2-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (300 mg, 0.43 mmol) and D-piperidine ( 111.6 mg, 0.86 mmol) of DMF (20 mL) was added with acetic acid, the pH was adjusted to about 5, and reacted at 60 ° C for 1 h, cooled to room temperature, and sodium borohydride (135.8 mg, 2.16 mmol) was added to the reaction system at room temperature. After reacting for 3 h, the reaction was carried out at 80 ° C for 16 h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 10/1, v/v) gave a pale red solid (yield: &lt
LC-MS:(pos.ion)m/z：807.6[M+1] +； LC-MS: (pos.ion) m/z: 807.6 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.00(d,J＝6.1Hz,2H),8.46(s,1H),7.49(d,J＝7.3Hz,1H),7.42(s,1H),7.25(dt,J＝15.9,7.7Hz,2H),7.12(d,J＝2.7Hz,1H),7.06(d,J＝7.4Hz,1H),6.97(d,J＝8.3Hz,1H),6.70(d,J＝7.5Hz,1H),5.33(s,2H),5.27(s,2H),4.13–4.03(m,2H),3.81(d,J＝13.6Hz,2H),3.65(d,J＝14.0Hz,3H),3.52(d,J＝12.6Hz,6H),2.06–1.95(m,5H),1.84(d,J＝3.7Hz,4H),1.71(s,4H),1.48(d,J＝9.4Hz,4H),1.39(s,2H),1.23(s,6H),0.85(s,1H). 1 H NMR (400MHz, d 6 -DMSO) δ9.00 (d, J = 6.1Hz, 2H), 8.46 (s, 1H), 7.49 (d, J = 7.3Hz, 1H), 7.42 (s, 1H) , 7.25 (dt, J = 15.9, 7.7 Hz, 2H), 7.12 (d, J = 2.7 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H) , 6.70 (d, J = 7.5 Hz, 1H), 5.33 (s, 2H), 5.27 (s, 2H), 4.13 - 4.03 (m, 2H), 3.81 (d, J = 13.6 Hz, 2H), 3.65 ( d, J = 14.0 Hz, 3H), 3.52 (d, J = 12.6 Hz, 6H), 2.06 - 1.95 (m, 5H), 1.84 (d, J = 3.7 Hz, 4H), 1.71 (s, 4H), 1.48 (d, J = 9.4 Hz, 4H), 1.39 (s, 2H), 1.23 (s, 6H), 0.85 (s, 1H).
实施例19(S)-1-(4-((3'-(3-(8-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物19)Example 19(S)-1-(4-((3'-(3-(8-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid (compound 19)
Figure PCTCN2019077582-appb-000071
Figure PCTCN2019077582-appb-000071
步骤1)4-((3'-(3-(8-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(8-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(800mg,1.59mmol)和8-氧杂-2-氮杂螺[4.5]癸烷(336.3mg,2.38mmol)的DMF(20mL)溶液中，依次加入碳酸钾(329.2mg,2.38mmol)和NaI(357mg,2.38mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到棕红色油状液体640mg，产率71.45％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen - a solution of hydroxy-benzaldehyde (800 mg, 1.59 mmol) and 8-oxa-2-azaspiro[4.5]decane (336.3 mg, 2.38 mmol) in DMF (20 mL). 2.38 mmol) and NaI (357 mg, 2.38 mmol), heated to 70 ° C, and reacted for 16 h. The mixture was stirred and cooled to room temperature, then diluted with EtOAc EtOAc EtOAc. Purification by column chromatography (DCM / MeOH = 10/1, v/v) afforded
LC-MS:(pos.ion)m/z：564.2[M+1] + LC-MS: (pos.ion) m/z: 564.2 [M+1] +
步骤2)5-((5-((3'-(3-(8-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3'-(3-(8-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(640mg,1.14mmol)和5-氯甲基-3-氰基吡啶盐酸盐(257.4mg,1.36mmol)的DMF溶液(20mL)中，依次加入碳酸铯(924.1mg,2.83mmol)和碘化钠(34.01mg,0.23mmol)，N 2保护，75℃反应4h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到红色油状液体190mg，产率24.62％。 To 4-((3'-(3-(8-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'-dimethyl-[1,1' -biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (640 mg, 1.14 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (257.4 mg, 1.36 mmol) In a solution of DMF (20 mL), cesium carbonate (924.1 mg, 2.83 mmol) and sodium iodide (34.01 mg, 0.23 mmol) were sequentially added, and the mixture was protected with N 2 and reacted at 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, then diluted with water (20 mL), EtOAc (EtOAc)EtOAc. Purification by chromatography (DCM / MeOH = 10/1, v/v)
LC-MS:(pos.ion)m/z：680.1[M+1] +； LC-MS: (pos.ion) m/z: 680.1 [M+1] + ;
步骤3)(S)-1-(4-((3'-(3-(8-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(8-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid
向5-((5-((3'-(3-(8-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(190mg,0.28mmol)和D-哌啶酸(72.16mg,0.56mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，随后升温至60℃反应1h，再冷却至室温，向反应体系中加入硼***(87.77mg,1.40mmol)，室温搅拌3h后，升温至80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1,v/v)，得到淡黄色固体35mg，产率15.79％。To 5-((5-((3'-(3-(8-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (190 mg, 0.28 mmol) and D-pipecolic acid (72.16 mg) Add acetic acid to a solution of 0.56 mmol) in DMF (10 mL), adjust the pH to about 5, then warm to 60 ° C for 1 h, then cool to room temperature, and add sodium borohydride (87.77 mg, 1.40 mmol) to the reaction system. After stirring at room temperature for 3 h, the mixture was heated to 80 ° C for 16 h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 4/1, v/v) gave 35 mg as pale yellow solid.
LC-MS:(pos.ion)m/z：793.3[M+1] +； LC-MS: (pos.ion) m/z: 793.3 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.04–8.96(m,2H),8.46(s,1H),7.49(d,J＝7.4Hz,1H),7.42(s,1H),7.26(t,J＝7.5Hz,1H),7.18(d,J＝7.8Hz,1H),7.12(s,1H),7.06(d,J＝7.5Hz,1H),6.95(d,J＝8.2Hz,1H),6.68(d,J＝7.5Hz,1H),5.32(d,J＝11.3Hz,2H),5.25(d,J＝12.6Hz,2H),3.83–3.75(m,3H),3.64(s,1H),3.60(s,1H),3.50(t,J＝10.8Hz,6H),3.15(dd,J＝11.3,4.3Hz,1H),2.89(s,3H),2.62(s,2H),2.02(s,3H),1.82(s,5H),1.68(t,J＝6.7Hz,3H),1.49(t,J＝13.0Hz,7H),1.36(s,1H),1.22(s,1H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.04 - 8.96 (m, 2H), 8.46 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.42 (s, 1H), 7.26 ( t, J = 7.5 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 5.32 (d, J = 11.3 Hz, 2H), 5.25 (d, J = 12.6 Hz, 2H), 3.83 - 3.75 (m, 3H), 3.64 ( s, 1H), 3.60 (s, 1H), 3.50 (t, J = 10.8 Hz, 6H), 3.15 (dd, J = 11.3, 4.3 Hz, 1H), 2.89 (s, 3H), 2.62 (s, 2H) ), 2.02 (s, 3H), 1.82 (s, 5H), 1.68 (t, J = 6.7 Hz, 3H), 1.49 (t, J = 13.0 Hz, 7H), 1.36 (s, 1H), 1.22 (s) , 1H).
实施例20(2S)-1-(4-((3'-(3-(7-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物20)Example 20(2S)-1-(4-((3'-(3-(7-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid (compound 20)
Figure PCTCN2019077582-appb-000072
Figure PCTCN2019077582-appb-000072
步骤1)4-((3'-(3-(7-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(7-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基苯甲醛(800mg,1.59mmol)和7-氧杂-2-氮杂螺[4.5]癸烷半草酸盐(414.1mg,1.11mmol)的DMF(20mL)溶液中，依次加入碳酸钾(548.7mg,3.97mmol)和NaI(357mg,2.38mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1)，得到棕红色油状液体548mg，产率61.18％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen -Hydroxybenzaldehyde (800 mg, 1.59 mmol) and 7-oxa-2-azaspiro[4.5]decane hemioxalate (414.1 mg, 1.11 mmol) in DMF (20 mL) 548.7 mg, 3.97 mmol) and NaI (357 mg, 2.38 mmol) were heated to 70 ° C for 16 h. The mixture was stirred and cooled to room temperature, then diluted with EtOAc EtOAc EtOAc. Separation and purification by column chromatography (DCM / MeOH = 10/1) afforded 548mg of yd
LC-MS:(pos.ion)m/z：564.4[M+1] + LC-MS: (pos.ion) m/z: 564.4 [M+1] +
步骤2)5-((5-((3'-(3-(7-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3'-(3-(7-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(540mg,0.96mmol)和5-氯甲基-3-氰基吡啶盐酸盐(221.2mg,1.17mmol)的DMF溶液(20mL) 中，依次加入碳酸铯(794.2mg,2.44mmol)和碘化钠(29.23mg,0.19mmol)，N 2保护，75℃反应4h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝20/1,v/v)得到黄色油状液体616mg，产率94.6％。 To 4-((3'-(3-(7-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'-dimethyl-[1,1' -biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (540 mg, 0.96 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (221.2 mg, 1.17 mmol) In a solution of DMF (20 mL), cesium carbonate (794.2 mg, 2.44 mmol) and sodium iodide (29.23 mg, 0.19 mmol) were sequentially added, and the mixture was protected with N 2 and reacted at 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, then diluted with water (20 mL), EtOAc (EtOAc)EtOAc. Purification by chromatography (DCM / MeOH = 20/1, v/v)
LC-MS:(pos.ion)m/z：680.2[M+1] +； LC-MS: (pos.ion) m/z: 680.2 [M + 1] + ;
步骤3)(2S)-1-(4-((3'-(3-(7-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(4-((3'-(3-(7-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid
向5-((5-((3'-(3-(7-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(300mg,0.44mmol)和D-哌啶酸(113.9mg,0.88mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，60℃反应1h,冷却至室温，再向反应体系中加入硼***(138.6mg,2.21mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。随后加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到淡红色固体48mg，产率13.72％。To 5-((5-((3'-(3-(7-oxa-2-azaspiro[4.5]indol-2-yl)propoxy)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (300 mg, 0.44 mmol) and D-pipecolic acid (113.9 mg) Add acetic acid to a solution of 0.88 mmol) in DMF (10 mL), adjust the pH to about 5, react at 60 ° C for 1 h, cool to room temperature, then add sodium borohydride (138.6 mg, 2.21 mmol) to the reaction system, and react at room temperature for 3 h. After that, the reaction was carried out at 80 ° C for 16 h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. The mixture was diluted with water (20 mL), EtOAc (EtOAc) /MeOH = 10/1, v/v) afforded a pale red solid (yield: </RTI>
LC-MS:(pos.ion)m/z：793.3[M+1] +； LC-MS: (pos.ion) m/z: 793.3 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.03–8.97(m,2H),8.46(s,1H),7.49(d,J＝7.4Hz,1H),7.42(s,1H),7.27(t,J＝7.5Hz,1H),7.21(t,J＝7.9Hz,1H),7.12(s,1H),7.07(d,J＝7.3Hz,1H),6.96(d,J＝8.1Hz,1H),6.69(d,J＝7.5Hz,1H),5.33(s,2H),5.27(s,2H),4.07(d,J＝6.5Hz,3H),3.78(d,J＝13.9Hz,2H),3.64(s,4H),3.51(s,4H),2.03(s,5H),1.83(s,4H),1.64(s,2H),1.52(d,J＝25.4Hz,9H),1.38(d,J＝7.0Hz,1H),1.24(s,3H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.03 - 8.97 (m, 2H), 8.46 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.42 (s, 1H), 7.27 ( t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.12 (s, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 5.33 (s, 2H), 5.27 (s, 2H), 4.07 (d, J = 6.5 Hz, 3H), 3.78 (d, J = 13.9 Hz, 2H), 3.64 (s, 4H), 3.51 (s, 4H), 2.03 (s, 5H), 1.83 (s, 4H), 1.64 (s, 2H), 1.52 (d, J = 25.4 Hz, 9H), 1.38 (d, J = 7.0 Hz, 1H), 1.24 (s, 3H).
实施例160(2S)-1-(4-((3'-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物160)Example 160(2S)-1-(4-((3'-(3-(2-oxa-7-azaspiro[4.4]fluoren-7-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid (compound 160)
Figure PCTCN2019077582-appb-000073
Figure PCTCN2019077582-appb-000073
步骤1)4-((3'-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(2-oxa-7-azaspiro[4.4]壬-7-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(600mg,1.91mmol)和2-氧杂-7-氮杂螺[4.4]壬烷(227.2mg,1.79mmol)的DMF(20mL)溶液中，依次加入碳酸钾(246.9mg,1.79mmol)和NaI(267.8mg,1.79mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到棕红色油状液体200mg，产率30.53％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen - a solution of hydroxy-benzaldehyde (600 mg, 1.91 mmol) and 2-oxa-7-azaspiro[4.4]nonane (227.2 mg, 1.79 mmol) in DMF (20 mL). 1.79 mmol) and NaI (267.8 mg, 1.79 mmol), heated to 70 ° C, and reacted for 16 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc)EtOAc. Purification by chromatography (DCM / MeOH = 10/1, v/v) afforded:
LC-MS:(pos.ion)m/z：550.4[M+1] + LC-MS: (pos.ion) m/z: 550.4 [M+1] +
步骤2)5-((5-((3'-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰 基苯氧基)甲基)烟腈Step 2) 5-((5-((3)-(3-(2-oxa-7-azaspiro[4.4]fluoren-7-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3'-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(550mg,0.99mmol)和5-氯甲基-3-氰基吡啶盐酸盐(226.8mg,1.2mmol)的DMF溶液(20mL)中，依次加入碳酸铯(814.4mg,2.5mmol)和碘化钠(29.97mg,0.2mmol)，N 2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到黄色固体274mg，产率41.14％。 To 4-((3'-(3-(2-oxa-7-azaspiro[4.4]壬-7-yl)propoxy)-2,2'-dimethyl-[1,1' -biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (550 mg, 0.99 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (226.8 mg, 1.2 mmol) In a solution of DMF (20 mL), cesium carbonate (814.4 mg, 2.5 mmol) and sodium iodide (29.97 mg, 0.2 mmol) were sequentially added, and the mixture was protected with N 2 and reacted at 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc (EtOAc) Separation and purification (DCM / MeOH = 10/1, v / v) afforded
LC-MS:(pos.ion)m/z：666.2[M+1] +； LC-MS: (pos.ion) m/z: 666.2 [M+1] + ;
步骤3)(2S)-1-(4-((3'-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(4-((3'-(3-(2-oxa-7-azaspiro[4.4]壬-7-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid
向5-((5-((3'-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(270mg,0.40mmol)和D-哌啶酸(104.7mg,0.81mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，随后升温至60℃反应1h，再冷却至室温，向反应体系中加入硼***(127.3mg,2.02mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1,v/v)，得到淡黄色固体53mg，产率16.78％。To 5-((5-((3'-(3-(2-oxa-7-azaspiro[4.4]壬-7-yl)propoxy)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (270 mg, 0.40 mmol) and D-pipecolic acid (104.7 mg) Add acetic acid to a solution of 0.81 mmol) in DMF (10 mL), adjust the pH to about 5, then heat to 60 ° C for 1 h, then cool to room temperature, and add sodium borohydride (127.3 mg, 2.02 mmol) to the reaction system. After reacting at room temperature for 3 h, the reaction was carried out at 80 ° C for 16 h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 4/1, v/v) afforded a pale yellow solid, mp.
LC-MS:(pos.ion)m/z：779.3[M+1] +； LC-MS: (pos.ion) m / z: 779.3 [M + 1] +;
1H NMR(400MHz,d 6-DMSO)δ9.00(d,J＝2.8Hz,2H),8.45(s,1H),7.49(d,J＝7.4Hz,1H),7.42(s,1H),7.26(t,J＝7.6Hz,1H),7.20(t,J＝7.9Hz,1H),7.11(s,1H),7.06(d,J＝7.4Hz,1H),6.95(d,J＝8.2Hz,1H),6.68(d,J＝7.4Hz,1H),5.33(s,2H),5.26(s,2H),4.05(dt,J＝12.9,6.5Hz,3H),3.79(d,J＝13.7Hz,2H),3.73–3.68(m,3H),3.62(d,J＝13.7Hz,1H),3.55(s,1H),3.51(s,1H),3.44(d,J＝8.1Hz,1H),3.17(s,1H),2.03(s,3H),1.99–1.93(m,3H),1.89(d,J＝7.1Hz,1H),1.87–1.75(m,9H),1.73(s,1H),1.48(s,3H),1.36(s,1H),1.23(s,1H). 1 H NMR (400MHz, d 6 -DMSO) δ9.00 (d, J = 2.8Hz, 2H), 8.45 (s, 1H), 7.49 (d, J = 7.4Hz, 1H), 7.42 (s, 1H) , 7.26 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.11 (s, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 7.4 Hz, 1H), 5.33 (s, 2H), 5.26 (s, 2H), 4.05 (dt, J = 12.9, 6.5 Hz, 3H), 3.79 (d, J=13.7 Hz, 2H), 3.73–3.68 (m, 3H), 3.62 (d, J=13.7 Hz, 1H), 3.55 (s, 1H), 3.51 (s, 1H), 3.44 (d, J=8.1) Hz, 1H), 3.17 (s, 1H), 2.03 (s, 3H), 1.99 - 1.93 (m, 3H), 1.89 (d, J = 7.1 Hz, 1H), 1.87 - 1.75 (m, 9H), 1.73 (s, 1H), 1.48 (s, 3H), 1.36 (s, 1H), 1.23 (s, 1H).
实施例22(S)-1-(4-((3'-(3-(2-氧杂-6-氮杂螺[3.4]辛-6-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物22)Example 22(S)-1-(4-((3'-(3-(2-oxa-6-azaspiro[3.4]oct-6-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid (compound 22)
Figure PCTCN2019077582-appb-000074
Figure PCTCN2019077582-appb-000074
步骤1)4-((3'-(3-(2-氧杂-6-氮杂螺[3.4]辛-6-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(2-oxa-6-azaspiro[3.4]oct-6-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(600mg,1.19mmol)和2-氧杂-6-氮杂螺[3.4]辛烷(263.8mg,0.83mmol)的DMF(20mL)溶液中，依次加入碳酸钾(411.5mg,2.97mmol)和NaI(267.8mg,1.78mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到红色油状液体260mg， 产率40.72％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen - a solution of hydroxy-benzaldehyde (600 mg, 1.19 mmol) and 2-oxa-6-azaspiro[3.4]octane (263.8 mg, 0.83 mmol) in DMF (20 mL). 2.97 mmol) and NaI (267.8 mg, 1.78 mmol) were heated to 70 ° C for 16 h. The mixture was stirred and cooled to room temperature, then diluted with EtOAc EtOAc EtOAc. Purification by column chromatography (DCM /MeOH = 10/1, v/v)
LC-MS:(pos.ion)m/z：536.2[M+1] +； LC-MS: (pos.ion) m/z: 536.2 [M + 1] + ;
步骤2)5-((5-((3'-(3-(2-氧杂-6-氮杂螺[3.4]辛-6-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3)-(3-(2-oxa-6-azaspiro[3.4]oct-6-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3'-(3-(2-氧杂-6-氮杂螺[3.4]辛-6-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(260mg,0.48mmol)和5-氯甲基-3-氰基吡啶盐酸盐(110mg,0.58mmol)的DMF溶液(20mL)中，依次加入碳酸铯(395mg,1.21mmol)和碘化钠(14.54mg,0.10mmol)，N 2保护，升温至75℃反应4h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到红色油状液体240mg，产率75.88％。 To 4-((3'-(3-(2-oxa-6-azaspiro[3.4]oct-6-yl)propoxy)-2,2'-dimethyl-[1,1' -biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (260 mg, 0.48 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (110 mg, 0.58 mmol) In a solution of DMF (20 mL), cesium carbonate (395 mg, 1.21 mmol) and sodium iodide (14.54 mg, 0.10 mmol) were successively added, and the mixture was protected with N 2 and warmed to 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, then diluted with water (20 mL), EtOAc (EtOAc)EtOAc. Purification by chromatography (DCM / MeOH = 10/1, v/v)
LC-MS:(pos.ion)m/z：652.5[M+1] +； LC-MS: (pos.ion) m/z: 652.5 [M + 1] + ;
步骤3)(S)-1-(4-((3'-(3-(2-氧杂-6-氮杂螺[3.4]辛-6-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(2-oxa-6-azaspiro[3.4]oct-6-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid
向5-((5-((3'-(3-(2-氧杂-6-氮杂螺[3.4]辛-6-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(240mg,0.37mmol)和D-哌啶酸(95.06mg,0.74mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，随后升温至60℃反应1h，再冷却至室温，向反应体系中加入硼***(115.6mg,1.84mmol)，室温搅拌3h后，再升温至80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1,v/v)，得到白色固体31mg，产率11.01％。To 5-((5-((3'-(3-(2-oxa-6-azaspiro[3.4]oct-6-yl)propoxy)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (240 mg, 0.37 mmol) and D-pipecolic acid (95.06 mg) Add acetic acid to a solution of 0.74 mmol) in DMF (10 mL), adjust the pH to about 5, then warm to 60 ° C for 1 h, then cool to room temperature, and add sodium borohydride (115.6 mg, 1.84 mmol) to the reaction system. After stirring at room temperature for 3 h, the mixture was further heated to 80 ° C for 16 h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 4/1, v/v) afforded 31 mg of white solid.
LC-MS:(pos.ion)m/z：765.5[M+1] +； LC-MS: (pos.ion) m/z: 765.5 [M + 1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.01(s,2H),8.48(s,1H),7.49(d,J＝7.6Hz,1H),7.44(s,1H),7.30–7.14(m,3H),7.06(d,J＝7.3Hz,1H),6.95(d,J＝8.1Hz,1H),6.67(d,J＝7.4Hz,1H),5.36(s,2H),5.28(s,2H),4.49(dd,J＝19.7,5.6Hz,4H),4.04(dd,J＝14.1,6.8Hz,3H),3.83(d,J＝13.7Hz,2H),3.67(d,J＝13.6Hz,4H),2.72(s,2H),2.13(s,2H),2.00(d,J＝17.2Hz,6H),1.81(s,4H),1.72(s,1H),1.50(s,3H),1.36(s,1H),1.22(s,1H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.01 (s, 2H), 8.48 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.30 - 7.14 ( m, 3H), 7.06 (d, J = 7.3 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 5.36 (s, 2H), 5.28 ( s, 2H), 4.49 (dd, J = 19.7, 5.6 Hz, 4H), 4.04 (dd, J = 14.1, 6.8 Hz, 3H), 3.83 (d, J = 13.7 Hz, 2H), 3.67 (d, J) =13.6 Hz, 4H), 2.72 (s, 2H), 2.13 (s, 2H), 2.00 (d, J = 17.2 Hz, 6H), 1.81 (s, 4H), 1.72 (s, 1H), 1.50 (s) , 3H), 1.36 (s, 1H), 1.22 (s, 1H).
实施例23(S)-1-(4-((3'-(3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物23)Example 23(S)-1-(4-((3'-(3-(7-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid (compound 23)
Figure PCTCN2019077582-appb-000075
Figure PCTCN2019077582-appb-000075
步骤1)4-((3'-(3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(7-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1000mg,1.98mmol)和7-氧-2-氮杂螺环[3.5]壬烷半草酸盐(478.5mg,1.39mmol)的DMF(20mL)溶液中，依次加入碳酸钾(685.8mg,4.96mmol)和NaI(446.3mg,2.98mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50 mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到棕红色油状液体553mg，产率50.65％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen -Hydroxy-benzaldehyde (1000 mg, 1.98 mmol) and 7-oxo-2-azaspiro[3.5]decane hemioxalate (478.5 mg, 1.39 mmol) in DMF (20 mL) (685.8 mg, 4.96 mmol) and NaI (446.3 mg, 2.98 mmol), heated to 70 ° C, and reacted for 16 h. Stirring was continued, and the mixture was cooled to room temperature, then diluted with water (20 mL), EtOAc (EtOAc) Separation and purification by column chromatography (DCM / MeOH = 10/1, v/v) afforded 553 mg of brown-brown oily.
LC-MS:(pos.ion)m/z：550.4[M+1] +； LC-MS: (pos.ion) m/z: 550.4 [M+1] + ;
步骤2)5-((5-((3'-(3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3'-(3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(550mg,0.10mmol)和5-氯甲基-3-氰基吡啶盐酸盐(226.8mg,1.2mmol)的DMF溶液(20mL)中，依次加入碳酸铯(814.4mg,2.5mmol)和碘化钠(29.97mg,0.20mmol)，N 2保护，升温至75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到红色油状液体220mg，产率33.03％。 To 4-((3'-(3-(7-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'-dimethyl-[1,1' -biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (550 mg, 0.10 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (226.8 mg, 1.2 mmol) ) in DMF (20mL) were sequentially added cesium carbonate (814.4mg, 2.5mmol) and sodium iodide (29.97mg, 0.20mmol), N 2 protection, the reaction temperature was raised to 75 deg.] C 4h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc (EtOAc) Separation and purification (DCM / MeOH = 10/1, v / v) afforded 220 mg as a red oily liquid.
LC-MS:(pos.ion)m/z：666.2[M+1] +； LC-MS: (pos.ion) m/z: 666.2 [M+1] + ;
步骤3)(S)-1-(4-((3'-(3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(7-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid
向5-((5-((3'-(3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(220mg,0.33mmol)和D-哌啶酸(85.31mg,0.66mmol)的DMF(20mL)溶液中加入乙酸，调节pH至5左右，随后升温至60℃反1h，再冷却至室温，向反应体系中加入硼***(103.8mg,1.652mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1,v/v)，得到淡黄色固体20mg，产率7.77％。To 5-((5-((3'-(3-(7-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (220 mg, 0.33 mmol) and D-piperidine (85.31 mg) Add acetic acid to a solution of 0.66 mmol) in DMF (20 mL), adjust the pH to about 5, then warm to 60 ° C for 1 h, then cool to room temperature, and add sodium borohydride (103.8 mg, 1.652 mmol) to the reaction system. After reacting at room temperature for 3 h, the reaction was carried out at 80 ° C for 16 h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 4/1, v/v) gave 20 mg as pale yellow solid.
LC-MS:(pos.ion)m/z：779.3[M+1] +； LC-MS: (pos.ion) m / z: 779.3 [M + 1] +;
1H NMR(400MHz,d 6-DMSO)δ9.01(s,2H),8.47(s,1H),7.49(d,J＝7.2Hz,1H),7.42(s,1H),7.26(t,J＝7.5Hz,1H),7.21(t,J＝7.9Hz,1H),7.14(s,1H),7.06(d,J＝7.5Hz,1H),6.96(d,J＝8.2Hz,1H),6.69(d,J＝7.5Hz,1H),5.35(s,2H),5.27(s,2H),4.07(d,J＝6.0Hz,3H),3.81(s,1H),3.77(d,J＝5.0Hz,1H),3.68–3.58(m,5H),2.02(d,J＝6.3Hz,3H),1.99–1.88(m,3H),1.82(s,4H),1.75(s,6H),1.49(s,4H),1.36(s,1H),1.23(s,4H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.01 (s, 2H), 8.47 (s, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.42 (s, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.14 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H) , 6.69 (d, J = 7.5 Hz, 1H), 5.35 (s, 2H), 5.27 (s, 2H), 4.07 (d, J = 6.0 Hz, 3H), 3.81 (s, 1H), 3.77 (d, J=5.0 Hz, 1H), 3.68–3.58 (m, 5H), 2.02 (d, J=6.3 Hz, 3H), 1.99–1.88 (m, 3H), 1.82 (s, 4H), 1.75 (s, 6H) ), 1.49 (s, 4H), 1.36 (s, 1H), 1.23 (s, 4H).
实施例24(S)-1-(4-((3'-(3-(6-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物24)Example 24(S)-1-(4-((3'-(3-(6-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'-) Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid (compound 24)
Figure PCTCN2019077582-appb-000076
Figure PCTCN2019077582-appb-000076
步骤1)4-((3'-(3-(6-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(6-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1000mg,1.98mmol)和6-氧-2-氮杂螺环[3.5]壬烷半草酸盐(478.5mg,1.39mmol)的DMF(20mL)溶液中，依次加入碳酸钾(685.8mg,4.96mmol)和NaI(446.3mg,2.97mmol)，加热至70℃，反应16h。停止搅 拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到红色油状液体356mg，产率32.60％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen -Hydroxy-benzaldehyde (1000 mg, 1.98 mmol) and 6-oxo-2-azaspiro[3.5]decane hemioxalate (478.5 mg, 1.39 mmol) in DMF (20 mL) (685.8 mg, 4.96 mmol) and NaI (446.3 mg, 2.97 mmol), heated to 70 ° C, and reacted for 16 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc)EtOAc. Purification by chromatography (DCM / MeOH = 10/1, v/v)
LC-MS:(pos.ion)m/z：550.4[M+1] +； LC-MS: (pos.ion) m/z: 550.4 [M+1] + ;
步骤2)5-((5-((3'-(3-(6-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3'-(3-(6-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3'-(3-(6-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(350mg,0.64mmol)和5-氯甲基-3-氰基吡啶盐酸盐(144.3mg,0.76mmol)的DMF溶液(20mL)中，依次加入碳酸铯(518.3mg,1.59mmol)和碘化钠(19.07mg,0.13mmol)，N 2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到红色油状液体168mg，产率39.63％。 To 4-((3'-(3-(6-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'-dimethyl-[1,1' -biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (350 mg, 0.64 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (144.3 mg, 0.76 mmol) In a solution of DMF (20 mL), cesium carbonate (518.3 mg, 1.59 mmol) and sodium iodide (19.07 mg, 0.13 mmol) were sequentially added, and the mixture was protected with N 2 and reacted at 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc (EtOAc) Separation and purification (DCM / MeOH = 10/1, v / v) afforded 168 mg of the crude oil.
LC-MS:(pos.ion)m/z：666.2[M+1] +； LC-MS: (pos.ion) m/z: 666.2 [M+1] + ;
步骤3)(S)-1-(4-((3'-(3-(6-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(6-oxa-2-azaspiro[3.5]indol-2-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid
向5-((5-((3'-(3-(6-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(160mg,0.24mmol)和D-哌啶酸(62.04mg,0.66mmol)的DMF(20mL)溶液中加入乙酸，调节pH至5左右，随后升温至60℃反应1h，再冷却至室温，向反应体系中加入硼***(62.04mg,0.98mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝7/1,v/v)，得到白色固体33mg，产率17.63％。To 5-((5-((3'-(3-(6-oxa-2-azinospiro[3.5]indol-2-yl)propoxy)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (160 mg, 0.24 mmol) and D-pipecolic acid (62.04 mg , 0.66 mmol) of DMF (20 mL) was added with acetic acid to adjust the pH to about 5, then the temperature was raised to 60 ° C for 1 h, and then cooled to room temperature, sodium borohydride (62.04 mg, 0.98 mmol) was added to the reaction system. After reacting at room temperature for 3 h, the reaction was carried out at 80 ° C for 16 h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 7/1, v/v) gave a white solid (yield: 33.
LC-MS:(pos.ion)m/z：779.4[M+1] +； LC-MS: (pos.ion) m/z: 779.4 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.00(d,J＝5.9Hz,2H),8.45(s,1H),7.48(d,J＝7.3Hz,1H),7.41(s,1H),7.26(t,J＝7.5Hz,1H),7.19(t,J＝7.9Hz,1H),7.10(s,1H),7.06(d,J＝7.6Hz,1H),6.93(d,J＝8.2Hz,1H),6.67(d,J＝7.5Hz,1H),5.29(d,J＝24.5Hz,4H),4.04–3.96(m,3H),3.77(d,J＝13.8Hz,2H),3.61(s,3H),3.03(d,J＝6.9Hz,2H),2.59(t,J＝6.8Hz,2H),2.26(s,1H),2.00(d,J＝13.8Hz,5H),1.80(s,4H),1.74(d,J＝6.7Hz,3H),1.69–1.63(m,2H),1.48(s,3H),1.43(d,J＝5.5Hz,3H),1.23(s,2H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.00 (d, J = 5.9 Hz, 2H), 8.45 (s, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.41 (s, 1H) , 7.26 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 7.10 (s, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 5.29 (d, J = 24.5 Hz, 4H), 4.04 - 3.96 (m, 3H), 3.77 (d, J = 13.8 Hz, 2H) , 3.61 (s, 3H), 3.03 (d, J = 6.9 Hz, 2H), 2.59 (t, J = 6.8 Hz, 2H), 2.26 (s, 1H), 2.00 (d, J = 13.8 Hz, 5H) , 1.80 (s, 4H), 1.74 (d, J = 6.7 Hz, 3H), 1.69 - 1.63 (m, 2H), 1.48 (s, 3H), 1.43 (d, J = 5.5 Hz, 3H), 1.23 ( s, 2H).
实施例25(S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2,2'-二甲基-3'-(3-(2-氧代-1,9-二氮杂螺[5.5]十一烷-9-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物25)Example 25(S)-1-(5-Chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-3'-( 3-(2-oxo-1,9-diazaspiro[5.5]undec-9-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy) Benzyl) piperidine-2-carboxylic acid (compound 25)
Figure PCTCN2019077582-appb-000077
Figure PCTCN2019077582-appb-000077
步骤1)5-氯-4-((2,2'-二甲基-3'-(3-(2-氧代-1,9-二氮杂螺[5.5]十一碳-9-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)-2-羟基苯甲醛Step 1) 5-Chloro-4-((2,2'-dimethyl-3'-(3-(2-oxo-1,9-diazaspiro[5.5]undec-9-yl) )propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1000mg, 1.09mmol)和5,9-二氮杂螺环[5.5]十一烷盐酸盐(609.5mg,2.978mmol)的DMF(20mL)溶液中，依次加入碳酸钾(435.2mg,5.95mmol)和NaI(446.3mg,2.98mmol)，随后加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到黄色固体422mg，产率54.29％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen -Hydroxy-benzaldehyde (1000 mg, 1.09 mmol) and 5,9-diazaspiro[5.5]undecane hydrochloride (609.5 mg, 2.978 mmol) in DMF (20 mL) 435.2 mg, 5.95 mmol) and NaI (446.3 mg, 2.98 mmol), then heated to 70 ° C for 16 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc)EtOAc. Purification by chromatography (DCM /MeOH = 10/1, v/v)
LC-MS:(pos.ion)m/z：591.4[M+1] + LC-MS: (pos.ion) m/z: 591.4 [M+1] +
步骤2)5-((4-氯-5-((2,2'-二甲基-3'-(3-(2-氧代-1,9-二氮杂螺[5.5]十一碳-9-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((4-chloro-5-((2,2'-dimethyl-3'-(3-(2-oxo-1,9-diazaspiro[5.5]undeccarbon) -9-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
向5-氯-4-((2,2'-二甲基-3'-(3-(2-氧代-1,9-二氮杂螺[5.5]十一碳-9-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)-2-羟基苯甲醛(630mg,1.07mmol)和5-氯甲基-3-氰基吡啶盐酸盐(241.8mg,1.28mmol)的DMF溶液(20mL)中，依次加入碳酸铯(868.2mg,2.66mmol)和碘化钠(31.95mg,0.21mmol)，N 2保护，升温至75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到红色固体422mg，产率55.98％。 To 5-chloro-4-((2,2'-dimethyl-3'-(3-(2-oxo-1,9-diazaspiro[5.5]undec-9-yl)-propyl) Oxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde (630 mg, 1.07 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride ( 241.8mg, 1.28mmol) in DMF (20mL) were sequentially added cesium carbonate (868.2mg, 2.66mmol) and sodium iodide (31.95mg, 0.21mmol), N 2 protection, the reaction temperature was raised to 75 deg.] C 4h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc (EtOAc) Separation and purification (DCM / MeOH = 10/1, v / v) afforded 422 g of s.
LC-MS:(pos.ion)m/z：707.2[M+1] +； LC-MS: (pos.ion) m/z: 707.2 [M + 1] + ;
步骤3)(S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2,2'-二甲基-3'-(3-(2-氧代-1,9-二氮杂螺[5.5]十一烷-9-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(5-Chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2'-dimethyl-3'-( 3-(2-oxo-1,9-diazaspiro[5.5]undec-9-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy) Benzyl) piperidine-2-carboxylic acid
向5-((4-氯-5-((2,2'-二甲基-3'-(3-(2-氧代-1,9-二氮杂螺[5.5]十一碳-9-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)-2-甲酰基苯氧基)甲基)烟腈(200mg,0.28mmol)和D-哌啶酸(73.04mg,0.56mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，随后升温至60℃反应1h，冷却至室温，再向反应体系中加入硼***(88.84mg,0.14mmol)，室温搅拌3h后，升温至80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1,v/v)，得到白色固体22mg，产率9.48％。To 5-((4-chloro-5-((2,2'-dimethyl-3'-(3-(2-oxo-1,9-diazaspiro[5.5]undec-9) -yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (200 mg, 0.28 mmol) and D-piper Acetic acid was added to a solution of pyridine acid (73.04 mg, 0.56 mmol) in DMF (10 mL), and the pH was adjusted to about 5, then the temperature was raised to 60 ° C for 1 h, cooled to room temperature, and sodium borohydride (88.84 mg) was added to the reaction system. After stirring at room temperature for 3 h, the mixture was heated to 80 ° C for 16 h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 4/1, v/v) gave 22 mg as a white solid.
LC-MS:(pos.ion)m/z：820.6[M+1] +； LC-MS: (pos.ion) m/z: 820.6 [M + 1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.00(dd,J＝7.1,1.7Hz,2H),8.46(s,1H),7.49(d,J＝7.5Hz,1H),7.41(s,1H),7.27(t,J＝7.7Hz,1H),7.21(t,J＝7.9Hz,1H),7.11(s,1H),7.07(d,J＝7.2Hz,1H),6.95(d,J＝8.2Hz,1H),6.68(d,J＝7.5Hz,1H),5.33(s,2H),5.26(s,2H),4.05(d,J＝7.2Hz,2H),3.77(d,J＝13.8Hz,2H),3.61(d,J＝13.7Hz,3H),3.51(s,5H),3.43–3.39(m,3H),2.09(s,2H),2.03(s,3H),1.82(s,4H),1.63(s,6H),1.48(s,3H),1.37(s,1H),1.23(s,3H). 1 H NMR (400 MHz, d 6 - DMSO) δ 9.00 (dd, J = 7.1, 1.7 Hz, 2H), 8.46 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.41 (s, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.11 (s, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 5.33 (s, 2H), 5.26 (s, 2H), 4.05 (d, J = 7.2 Hz, 2H), 3.77 (d, J = 13.8 Hz, 2H), 3.61 (d, J = 13.7 Hz, 3H), 3.51 (s, 5H), 3.43 - 3.39 (m, 3H), 2.09 (s, 2H), 2.03 (s, 3H), 1.82(s,4H), 1.63(s,6H), 1.48(s,3H), 1.37(s,1H), 1.23(s,3H).
实施例26(2S)-1-(4-((3'-(3-(2,7-二氮杂螺[4.4]壬-2-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物26)Example 26(2S)-1-(4-((3'-(3-(2,7-diazaspiro[4.4]indol-2-yl)propoxy)-2-methyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (compound) 26)
Figure PCTCN2019077582-appb-000078
Figure PCTCN2019077582-appb-000078
步骤1)叔丁基-7-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2'-甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,7-二氮杂螺[4.4]壬烷-2-羧酸甲酯Step 1) tert-Butyl-7-(3-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2'-methyl-[1,1') -biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[4.4]decane-2-carboxylic acid methyl ester
氮气保护下，向4-((3'-(3-溴丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(1000mg,2.04mmol)和2,7-二氮杂螺[4.4]壬烷-2-甲酸叔丁酯(693.1mg,3.06mmol)的DMF(20mL)溶液中，依次加入碳酸钾(425mg,3.07mmol)，碘化钠(460mg,3.06mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到红色油状液体920mg，产率70.94％。To 4-((3'-(3-bromopropoxy)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2 under nitrogen -Hydroxybenzaldehyde (1000 mg, 2.04 mmol) and 2,7-diazaspiro[4.4]decane-2-carboxylic acid tert-butyl ester (693.1 mg, 3.06 mmol) in DMF (20 mL) (425 mg, 3.07 mmol), sodium iodide (460 mg, 3.06 mmol), heated to 70 ° C, and reacted for 16 h. The mixture was stirred and cooled to room temperature, then diluted with EtOAc EtOAc EtOAc. Purification by column chromatography (DCM /MeOH = 10/1, v/v)
LC-MS:(pos.ion)m/z：635.3[M-1] +； LC-MS: (pos.ion) m/z: 635.3 [M-1] + ;
步骤2)叔丁基-7-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2'-甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,7-二氮杂螺[4.4]壬烷-2-羧酸甲酯Step 2) tert-Butyl-7-(3-((3'-((2-chloro-5-((5-cyanopyridin-3-yl))methoxy)-4-formylphenoxy) Methyl)-2'-methyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[4.4]decane-2-carboxylic acid ester
向叔丁基-7-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2'-甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,7-二氮杂螺[4.4]壬烷-2-羧酸甲酯(920mg,1.44mmol)和5-氯甲基-3-氰基吡啶盐酸盐(328.6mg,1.73mmol)的DMF溶液(20mL)中，依次加入碳酸铯(1.18g,3.62mmol)和碘化钠(43.42mg,0.28mmol)，N 2保护，升温至75℃反应4h。停止搅拌，冷却至室温。加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到红色油状液体840mg，产率77.19％。 To tert-butyl-7-(3-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2'-methyl-[1,1'-linked Methyl benzyl-3-yl)oxy)propyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (920 mg, 1.44 mmol) and 5-chloromethyl-3-cyanide pyridine hydrochloride (328.6mg, 1.73mmol) in DMF (20mL) were sequentially added cesium carbonate (1.18g, 3.62mmol) and sodium iodide (43.42mg, 0.28mmol), N 2 protection, was warmed to 75 °C reaction for 4h. Stirring was stopped and cooled to room temperature. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. =10/1, v/v) 840 mg of a red oily liquid was obtained, yield 77.19%.
LC-MS:(pos.ion)m/z：751.3[M+1] +； LC-MS: (pos.ion) m/z: 751.3 [M + 1] + ;
步骤3)(2S)-1-(4-((3'-(3-(7-(叔丁氧基羰基)-2,7-二氮杂螺[4.4]壬-2-基)丙氧基)-2-甲基-[1,1'联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(4-((3'-(3-(7-(tert-Butoxycarbonyl)-2,7-diazaspiro[4.4]indol-2-yl)propoxy) 2-methyl-[1,1'biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl Piperidine-2-carboxylic acid
向叔丁基-7-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2'-甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,7-二氮杂螺[4.4]壬烷-2-羧酸甲酯(840mg,1.11mmol)和D-哌啶酸(288.8mg,2.23mmol)的DMF(20mL)溶液中加入乙酸，调节pH至5左右，60℃反应1h，冷却至室温，再向反应体系中加入硼***(351.3mg,5.59mmol)，室温反应3h后，随后升温至80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。随后加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1,v/v)，得到淡红色固体240mg，产率24.83％。tert-Butyl-7-(3-((3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl) -2'-Methyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid methyl ester ( 840mg, 1.11mmol) and D-pipecolic acid (288.8mg, 2.23mmol) in DMF (20mL) solution was added acetic acid, adjust the pH to about 5, 60 ° C reaction for 1h, cooled to room temperature, and then added boron to the reaction system Sodium cyanide (351.3 mg, 5.59 mmol) was reacted at room temperature for 3 h, then was warmed to 80 ° C for 16 h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. The mixture was diluted with water (20 mL), EtOAc (EtOAc) /MeOH = 4/1, v/v) afforded 240 mg of pale red solid.
LC-MS:(pos.ion)m/z：864.4[M+1] +； LC-MS: (pos.ion) m/z: 864.4 [M + 1] + ;
步骤4)(2S)-1-(4-((3'-(3-(2,7-二氮杂螺[4.4]壬-2-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 4) (2S)-1-(4-((3'-(3-(2,7-diazaspiro[4.4]indol-2-yl)propoxy)-2-methyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向(2S)-1-(4-((3'-(3-(7-(叔丁氧基羰基)-2,7-二氮杂螺[4.4]壬-2-基)丙氧基)-2-甲基-[1,1'联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(240mg,0.31mmol)的DCM(25mL)溶液中，加入三氟乙酸(1mL)，室温反应3h。停止搅拌，TLC检测。浓缩溶剂，制备分离纯化得到淡黄色固体产物45mg，产率18.85％。To (2S)-1-(4-((3'-(3-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]indol-2-yl)propoxy) -2-methyl-[1,1'biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)per A solution of pyridine-2-carboxylic acid (240 mg, 0.31 mmol) in EtOAc (EtOAc) Stirring was stopped and TLC was detected. The solvent was concentrated, and the residue was purified to give a pale yellow solid product (yield:
LC-MS:(pos.ion)m/z：764.5[M+1] +； LC-MS: (pos.ion) m/z: 764.5 [M + 1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.00(s,1H),8.97(s,1H),8.43(s,1H),7.46(d,J＝10.0Hz,2H),7.34(t,J＝7.9Hz,1H),7.25(t,J＝7.4Hz,1H),7.20(d,J＝7.3Hz,1H),7.08(s,1H),6.91(d,J＝8.2Hz,1H),6.85(d,J＝7.5Hz,1H),6.78(s,1H),5.30(s,2H),5.27(s,2H),4.03(t,J＝6.2Hz,2H),3.72(d,J＝13.8Hz,2H),3.50(d,J＝13.3Hz,2H),3.07(s,2H),2.96(s,1H),2.23(s,3H),2.14(s,1H),1.99(s,1H),1.88–1.79(m,3H),1.73(dd,J＝13.5,7.0Hz,6H),1.44(s,3H),1.24(s,7H). 1 H NMR (400MHz, d 6 -DMSO) δ9.00 (s, 1H), 8.97 (s, 1H), 8.43 (s, 1H), 7.46 (d, J = 10.0Hz, 2H), 7.34 (t, J = 7.9 Hz, 1H), 7.25 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.3 Hz, 1H), 7.08 (s, 1H), 6.91 (d, J = 8.2 Hz, 1H) , 6.85 (d, J = 7.5 Hz, 1H), 6.78 (s, 1H), 5.30 (s, 2H), 5.27 (s, 2H), 4.03 (t, J = 6.2 Hz, 2H), 3.72 (d, J = 13.8 Hz, 2H), 3.50 (d, J = 13.3 Hz, 2H), 3.07 (s, 2H), 2.96 (s, 1H), 2.23 (s, 3H), 2.14 (s, 1H), 1.99 ( s, 1H), 1.88 - 1.79 (m, 3H), 1.73 (dd, J = 13.5, 7.0 Hz, 6H), 1.44 (s, 3H), 1.24 (s, 7H).
实施例27 N-(2-((5-氯-4-((3'-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苄基)氨基)乙基)乙酰胺(化合物27)Example 27 N-(2-((5-chloro-4-((3'-(3-(2-hydroxy-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2, 2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl)acetamide (compound) 27)
Figure PCTCN2019077582-appb-000079
Figure PCTCN2019077582-appb-000079
步骤1)5-氯-2-羟基-4-((3'-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛Step 1) 5-Chloro-2-hydroxy-4-((3'-(3-(2-hydroxy-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(800mg,1.588mmol)和2-羟基-2,7-二氮杂螺环[3.5]壬烷盐酸盐(423.2mg,2.38mmol)的DMF(20mL)溶液中，依次加入碳酸钾(658.4mg,4.76mmol)，碘化钠(357mg,2.38mmol)，随后加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到黄色固体437mg，产率48.79％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen -Hydroxy-benzaldehyde (800 mg, 1.588 mmol) and 2-hydroxy-2,7-diazaspiro[3.5]decane hydrochloride (423.2 mg, 2.38 mmol) in DMF (20 mL) Potassium carbonate (658.4 mg, 4.76 mmol), sodium iodide (357 mg, 2.38 mmol), then heated to 70 ° C for 16 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (50 mL), EtOAc (EtOAc)EtOAc. Purification by chromatography (DCM /MeOH = 10/1, v/v)
LC-MS:(pos.ion)m/z：564.2[M+1] +； LC-MS: (pos.ion) m/z: 564.2 [M + 1] + ;
步骤2)5-氯-4-((3'-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-吡啶-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苯甲醛Step 2) 5-Chloro-4-((3'-(3-(2-hydroxy-7-azaspiro[3.5]壬-7-yl)propoxy)-2,2'-dimethyl- [1,1'-biphenyl]-pyridin-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzaldehyde
向5-氯-2-羟基-4-((3'-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛(330mg,0.58mmol)和3-溴甲基吡啶溴酸盐(221.9mg,0.87mmol)的DMF溶液(20mL)中，依次加入碳酸铯(571.8mg,1.75mmol)和碘化钠(17.54mg,0.11mmol)，N 2保护，升温至75℃反应4h。停止搅拌，冷却至室温，加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到红色油状液体240mg，产率62.62％。 To 5-chloro-2-hydroxy-4-((3'-(3-(2-hydroxy-7-azaspiro[3.5]壬-7-yl)propoxy)-2,2'-dimethyl A solution of benzyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde (330 mg, 0.58 mmol) and 3-bromomethylpyridine bromide (221.9 mg, 0.87 mmol) in DMF (20 mL) Among them, cesium carbonate (571.8 mg, 1.75 mmol) and sodium iodide (17.54 mg, 0.11 mmol) were added in this order, protected with N 2 and heated to 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (50 mL), EtOAc (EtOAc)EtOAc. Separation and purification (DCM / MeOH = 10/1, v / v) afforded 240 mg as a red oily liquid, yield 62.62%.
LC-MS:(pos.ion)m/z：655.1[M+1] +； LC-MS: (pos.ion) m/z: 655.1 [M+1] + ;
步骤3)N-(2-((5-氯-4-((3'-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苄基)氨基)乙基)乙酰胺Step 3) N-(2-((5-chloro-4-((3'-(3-(2-hydroxy-7-azaspiro[3.5]indole-7-yl)propoxy)-2, 2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl)acetamide
向5-氯-4-((3'-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-吡啶-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苯甲醛(150mg,0.22mmol)和N-(2-氨基乙基)乙酰胺(35.08mg,0.34mmol)的CH 3OH(10mL)溶液中加入乙酸，调节pH至5左右，室温反应15min，再向反应体系中加入硼***(71.93mg,1.14mmol)，室温反应2h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到白色固体50mg，产率29.46％。 To 5-chloro-4-((3'-(3-(2-hydroxy-7-azaspiro[3.5]壬-7-yl)propoxy)-2,2'-dimethyl-[1] ,1'-biphenyl]-pyridin-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzaldehyde (150 mg, 0.22 mmol) and N-(2-aminoethyl) Add acetic acid to a solution of amide (35.08 mg, 0.34 mmol) in CH 3 OH (10 mL), adjust the pH to about 5, react at room temperature for 15 min, then add sodium borohydride (71.93 mg, 1.14 mmol) to the reaction system and react at room temperature. 2h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. Diluted with water (50 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 10/1, v/v) afforded 50 mg as a white solid.
LC-MS:(pos.ion)m/z：741.4[M+1] +； LC-MS: (pos.ion) m/z: 741.4 [M + 1] + ;
1H NMR(400MHz,d 6-DMSO)δ8.70(s,1H),8.55(s,1H),7.89(d,J＝7.6Hz,1H),7.80(s,1H),7.45(dd,J＝17.6,6.3Hz,2H),7.37(s,1H),7.26(t,J＝7.3Hz,1H),7.19(t,J＝7.6Hz,1H),7.12(s,1H),7.06(d,J＝7.3Hz,1H),6.94(d,J＝8.0Hz,1H),6.67(d,J＝7.5Hz,1H),5.24(s,4H),4.04(dd,J＝16.7,6.9Hz,3H),3.63(s,2H), 3.11(d,J＝5.9Hz,2H),2.42(s,2H),2.27(d,J＝14.2Hz,4H),2.09–1.96(m,6H),1.87(d,J＝15.6Hz,3H),1.82(s,3H),1.77(s,3H),1.53–1.42(m,6H). 1 H NMR (400 MHz, d 6 -DMSO) δ 8.70 (s, 1H), 8.55 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.45 (dd, J = 17.6, 6.3 Hz, 2H), 7.37 (s, 1H), 7.26 (t, J = 7.3 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.12 (s, 1H), 7.06 ( d, J = 7.3 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 5.24 (s, 4H), 4.04 (dd, J = 16.7, 6.9 Hz, 3H), 3.63 (s, 2H), 3.11 (d, J = 5.9 Hz, 2H), 2.42 (s, 2H), 2.27 (d, J = 14.2 Hz, 4H), 2.09 - 1.96 (m, 6H) ), 1.87 (d, J = 15.6 Hz, 3H), 1.82 (s, 3H), 1.77 (s, 3H), 1.53 - 1.42 (m, 6H).
实施例121 N-(2-((4-((3'-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苄基)氨基)乙基)乙酰胺(化合物121)Example 121 N-(2-((4-(3-Oxo-7-azaspiro[4.4]壬-7-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl)acetamide Compound 121)
Figure PCTCN2019077582-appb-000080
Figure PCTCN2019077582-appb-000080
步骤1)4-((3'-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(2-oxa-7-azaspiro[4.4]壬-7-yl)propoxy)-2,2'-dimethyl-[1, 1'-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1000mg,1.95mmol)和2-氧杂-7-氮杂螺[4.4]壬烷(378.7mg,2.97mmol)的DMF(20mL)溶液中，依次加入碳酸钾(411.5mg,2.97mmol)，碘化钠(446.3mg,2.97mmol)，随后加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(50mL)，再用乙酸乙酯萃取(100mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到棕红色固体680mg，产率62.28％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen - a solution of hydroxy-benzaldehyde (1000 mg, 1.95 mmol) and 2-oxa-7-azaspiro[4.4]nonane (378.7 mg, 2.97 mmol) in DMF (20 mL). 2.97 mmol), sodium iodide (446.3 mg, 2.97 mmol), then heated to 70 ° C for 16 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (50 mL), EtOAc (EtOAc (EtOAc) Separation and purification by column chromatography (DCM / MeOH = 10/1, v/v) afforded 280 mg of brown red solid.
LC-MS:(pos.ion)m/z：550.1[M+1] -； LC-MS: (pos.ion) m/z: 550.1 [M+1] - ;
步骤2)4-((3'-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛Step 2) 4-((3'-(3-(2-oxa-7-azaspiro[4.4]壬-7-yl)propoxy)-2,2'-dimethyl-[1, 1'-Biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde
向4-((3'-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(420mg,0.76mmol)和3-溴甲基吡啶溴酸盐(231.7mg,0.91mmol)的DMF溶液(20mL)中，依次加入碳酸铯(621.9mg,1.9mmol)和碘化钠(22.89mg,0.15mmol)，N 2保护，升温至75℃反应4h。停止搅拌，冷却至室温，加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到黄色固体250mg，产率51.07％。 To 4-((3'-(3-(2-oxa-7-azaspiro[4.4]壬-7-yl)propoxy)-2,2'-dimethyl-[1,1' a solution of -biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (420 mg, 0.76 mmol) and 3-bromomethylpyridine bromide (231.7 mg, 0.91 mmol) in DMF ( In 20 mL), cesium carbonate (621.9 mg, 1.9 mmol) and sodium iodide (22.89 mg, 0.15 mmol) were added in that order, and protected with N 2 and warmed to 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (50 mL), EtOAc (EtOAc)EtOAc. Separation and purification (DCM / MeOH = 10/1, v/v) afforded 250 mg as a yellow solid.
LC-MS:(pos.ion)m/z：641.1[M+1] +； LC-MS: (pos.ion) m/z: 641.1 [M + 1] + ;
步骤3)N-(2-((4-((3'-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苄基)氨基)乙基)乙酰胺Step 3) N-(2-((4-((3)-(3-(2-oxa-7-azaspiro[4.4]]-7-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl)acetamide
向4-((3'-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛(150mg,0.22mmol)和N-(2-氨基乙基)乙酰胺(35.08mg,0.34mmol)的CH 3OH(10mL)溶液中加入乙酸，调节pH至5，室温反应15min，再向反应体系中加入硼***(71.93mg,1.14mmol)，室温反应2h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。随后加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到白色固体50mg，产率29.46％。 To 4-((3'-(3-(2-oxa-7-azaspiro[4.4]壬-7-yl)propoxy)-2,2'-dimethyl-[1,1' -biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde (150 mg, 0.22 mmol) and N-(2-aminoethyl)acetamide (35.08 mg, 0.34 mmol) in CH 3 OH (10 mL) was added acetic acid, the pH was adjusted to 5, and the mixture was reacted at room temperature for 15 min, and sodium borohydride (71.93 mg, 1.14 mmol) was added to the reaction system, and reacted at room temperature for 2 h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. Then, it was diluted with water (50 mL), and extracted with ethyl acetate (80 mL×3). The organic phase was combined, and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. /MeOH = 10/1, v/v) afforded 50 mg as a white solid.
LC-MS:(pos.ion)m/z：727.2[M+1] +； LC-MS: (pos.ion) m/z: 727.2 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ8.70(s,1H),8.55(s,1H),7.89(d,J＝7.1Hz,1H),7.80(s,1H),7.51–7.41(m,2H),7.37(s,1H),7.26(t,J＝7.3Hz,1H),7.19(t,J＝7.6Hz,1H),7.12(s,1H),7.06(d,J＝7.1Hz,1H),6.95(d,J＝7.9Hz,1H),6.67(d,J＝7.3Hz,1H),5.24(s,4H),4.04(d,J＝5.5Hz,2H),3.69(s,2H),3.63(s,2H),3.55–3.49(m,2H),3.41(d,J＝7.8Hz,2H),3.11(d,J＝5.7Hz,2H),2.56(s,2H),2.37(d,J＝8.4Hz,1H),2.04(s,3H),1.90(s,3H),1.82(s,5H),1.77(s,4H),1.74(d,J＝7.2Hz,3H). 1 H NMR (400 MHz, d 6 -DMSO) δ 8.70 (s, 1H), 8.55 (s, 1H), 7.89 (d, J = 7.1 Hz, 1H), 7.80 (s, 1H), 7.51 - 7.41 ( m, 2H), 7.37 (s, 1H), 7.26 (t, J = 7.3 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.12 (s, 1H), 7.06 (d, J = 7.1) Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 6.67 (d, J = 7.3 Hz, 1H), 5.24 (s, 4H), 4.04 (d, J = 5.5 Hz, 2H), 3.69 ( s, 2H), 3.63 (s, 2H), 3.55–3.49 (m, 2H), 3.41 (d, J = 7.8 Hz, 2H), 3.11 (d, J = 5.7 Hz, 2H), 2.56 (s, 2H) ), 2.37 (d, J = 8.4 Hz, 1H), 2.04 (s, 3H), 1.90 (s, 3H), 1.82 (s, 5H), 1.77 (s, 4H), 1.74 (d, J = 7.2 Hz) , 3H).
实施例29 N-(2-((5-氯-4-((2,2'-二甲基-3'-(3-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苄基)氨基)乙基)乙酰胺(化合物29)Example 29 N-(2-((5-chloro-4-((2,2'-dimethyl-3'-(3-(tetrahydro-1H-furo[3,4-c]pyrrole- 5(3H)-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl )acetamide (compound 29)
Figure PCTCN2019077582-appb-000081
Figure PCTCN2019077582-appb-000081
步骤1)5-氯-4-((2,2'-二甲基-3'-(3-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)丙氧基)-[1,1'-联苯基]-3-基)甲氧基)-2-羟基苯甲醛Step 1) 5-Chloro-4-((2,2'-dimethyl-3'-(3-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)) Propyl)-[1,1'-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(800mg,1.58mmol)和六氢-1H-呋喃并[3,4-C]吡咯盐酸盐(356.4mg,2.38mmol)的DMF(20mL)溶液中，依次加入碳酸钾(658.4mg,4.76mmol)，碘化钠(357mg,2.38mmol)，随后加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(50mL)，乙酸乙酯萃取(100mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到黄色油状液体400mg，产率62.28％。4-[[3-[3-(3-Bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2 under nitrogen -Hydroxy-benzaldehyde (800 mg, 1.58 mmol) and hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (356.4 mg, 2.38 mmol) in DMF (20 mL) 658.4 mg, 4.76 mmol), sodium iodide (357 mg, 2.38 mmol), then heated to 70 ° C for 16 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (50 mL), EtOAc (EtOAc (EtOAc) Purification by chromatography (DCM / MeOH = 10/1, v/v) afforded
LC-MS:(pos.ion)m/z：536.3[M+1] -； LC-MS: (pos.ion) m/z: 536.3 [M+1] - ;
步骤2)5-氯-4-((2,2'-二甲基-3'-(3-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)丙氧基)-[1,1'-联苯基]-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苯甲醛Step 2) 5-Chloro-4-((2,2'-dimethyl-3'-(3-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)) Propyl)-[1,1'-biphenyl]-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzaldehyde
向5-氯-4-((2,2'-二甲基-3'-(3-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)丙氧基)-[1,1'-联苯基]-3-基)甲氧基)-2-羟基苯甲醛(400mg,0.74mmol)和3-溴甲基吡啶溴酸盐(226.5mg,0.89mmol)的DMF溶液(20mL)中，依次加入碳酸铯(607.8mg,1.86mmol)和碘化钠(22.37mg,0.14mmol)，N 2保护，升温至75℃反应4h。停止搅拌，冷却至室温，随后加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到红色油状液体300mg，产率51.07％。 To 5-chloro-4-((2,2'-dimethyl-3'-(3-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)propoxy) -[1,1'-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde (400 mg, 0.74 mmol) and 3-bromomethylpyridine bromide (226.5 mg, 0.89 mmol In a solution of DMF (20 mL), cesium carbonate (607.8 mg, 1.86 mmol) and sodium iodide (22.37 mg, 0.14 mmol) were sequentially added, protected with N 2 and warmed to 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, then diluted with water (50 mL), EtOAc (EtOAc (EtOAc) Purification by chromatography (DCM / MeOH = 10/1, v/v) afforded
LC-MS:(pos.ion)m/z：627.1[M+1] +； LC-MS: (pos.ion) m/z: 627.1 [M + 1] + ;
步骤3)N-(2-((5-氯-4-((2,2'-二甲基-3'-(3-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)丙氧基)-[1,1'-联苯]-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苄基)氨基)乙基)乙酰胺Step 3) N-(2-((5-chloro-4-((2,2'-dimethyl-3'-(3-(tetrahydro-1H-furo[3,4-c]pyrrole- 5(3H)-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl Acetamide
向5-氯-4-((2,2'-二甲基-3'-(3-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)丙氧基)-[1,1'-联苯基]-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苯甲醛(300mg,0.4783mmol)和N-(2-氨基乙基)乙酰胺(73.28mg,0.71mmol)的CH 3OH(10mL)溶液中加入乙酸，调节pH至5左右，室温反应15min，再向反应体系中加入硼***(150.3mg,2.39mmol)，室温继续反应2h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥， 过滤，浓缩，柱层析分离纯化(DCM/MeOH＝15/1,v/v)，得到淡黄色色固体110mg，产率32.24％。 To 5-chloro-4-((2,2'-dimethyl-3'-(3-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)propoxy) -[1,1'-biphenyl]-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzaldehyde (300 mg, 0.4783 mmol) and N-(2-amino Add acetic acid to a solution of ethyl acetamide (73.28 mg, 0.71 mmol) in CH 3 OH (10 mL), adjust the pH to about 5, react at room temperature for 15 min, and add sodium borohydride (150.3 mg, 2.39 mmol) to the reaction system. ), the reaction was continued at room temperature for 2 h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. Diluted with water (50 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 15/1, v/v) gave a pale yellow solid, 110 mg, yield 32.24%.
LC-MS:(pos.ion)m/z：713.3[M+1] +； LC-MS: (pos.ion) m/z: 713.3 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ8.71(s,1H),8.56(s,1H),7.94–7.83(m,2H),7.52–7.36(m,3H),7.25(d,J＝6.9Hz,1H),7.18(d,J＝7.3Hz,1H),7.14(s,1H),7.06(d,J＝6.8Hz,1H),6.94(d,J＝7.8Hz,1H),6.67(d,J＝7.0Hz,1H),5.26(s,4H),4.04(d,J＝5.1Hz,2H),3.71(s,6H),3.50(s,1H),3.37(d,J＝5.8Hz,2H),3.14(d,J＝5.0Hz,2H),2.68(s,2H),2.59(s,2H),2.34(d,J＝7.5Hz,2H),2.03(s,3H),1.89(s,3H),1.82(s,3H),1.78(s,3H). 1 H NMR (400 MHz, d 6 -DMSO) δ 8.71 (s, 1H), 8.56 (s, 1H), 7.94 - 7.83 (m, 2H), 7.52 - 7.36 (m, 3H), 7.25 (d, J) = 6.9 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.14 (s, 1H), 7.06 (d, J = 6.8 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.67 (d, J = 7.0 Hz, 1H), 5.26 (s, 4H), 4.04 (d, J = 5.1 Hz, 2H), 3.71 (s, 6H), 3.50 (s, 1H), 3.37 (d, J) = 5.8 Hz, 2H), 3.14 (d, J = 5.0 Hz, 2H), 2.68 (s, 2H), 2.59 (s, 2H), 2.34 (d, J = 7.5 Hz, 2H), 2.03 (s, 3H) ), 1.89 (s, 3H), 1.82 (s, 3H), 1.78 (s, 3H).
实施例30(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3'-(3-(1-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物30)Example 30(2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(1-hydroxy-7-) Azaspiro[3.5]dec-7-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine- 2-carboxylic acid (compound 30)
Figure PCTCN2019077582-appb-000082
Figure PCTCN2019077582-appb-000082
步骤1)5-氯-2-羟基-4-((3'-(3-(1-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛Step 1) 5-Chloro-2-hydroxy-4-((3'-(3-(1-hydroxy-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde
将7-氮杂螺[3.5]壬-1-醇盐酸盐(0.4g,2mmol)溶于DMF(10.1mL)，加入碳酸钾(1.0g,7.2mmol)，室温搅拌10min。加入4-((3'-(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(0.5g,1mmol)，NaI(0.2g,1mmol)，升温至75℃条件下搅拌12h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝10/1,v/v)得黄色固体0.42g，产率为80％。7-Azaspiro[3.5]indol-1-ol hydrochloride (0.4 g, 2 mmol) was dissolved in DMF (10.1 mL). Add 4-((3'-(3-bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2 -Hydroxybenzaldehyde (0.5 g, 1 mmol), NaI (0.2 g, 1 mmol), and the mixture was warmed to 75 ° C and stirred for 12 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (30 mL), EtOAc (EtOAc (EtOAc)EtOAc. /1, v/v) gave a yellow solid, 0.42 g, yield 80%.
LC-MS:(pos.ion)m/z：565.2[M+1] +； LC-MS: (pos.ion) m/z: 565.2 [M + 1] + ;
步骤2)5-((4-氯-2-甲酰基-5-((3'-(3-(1-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈Step 2) 5-((4-Chloro-2-formyl-5-((3'-(3-(1-hydroxy-7-azaspiro[3.5]fluoren-7-yl)propoxy)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
将5-(氯甲基)烟腈盐酸盐(0.17g,0.90mmol)溶于DMF(15.0mL)，加入碳酸铯(1.5g,4.6mmol)，室温搅拌10min。加入5-氯-2-羟基-4-((3'-(3-(1-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛(0.42g,0.74mmol)和NaI(22.0mg,0.147mmol)，升温至75℃条件下搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝5/1,v/v)得黄色固体0.37g，产率为73％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.17 g, 0.90 mmol) was dissolved in DMF (15.0 mL). Add 5-chloro-2-hydroxy-4-((3'-(3-(1-hydroxy-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2,2'-dimethyl Base-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde (0.42 g, 0.74 mmol) and NaI (22.0 mg, 0.147 mmol) were stirred and warmed to 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (15 mL), EtOAc (EtOAc) (EtOAc) Separation (DCM / MeOH = 5/1, v/v) afforded 0.37 g of a yellow solid.
LC-MS:(pos.ion)m/z：681.1[M+1] +； LC-MS: (pos.ion) m/z: 681.1 [M+1] + ;
步骤3)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3'-(3-(1-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-Chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(1-hydroxy-7-) Azaspiro[3.5]dec-7-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine- 2-formic acid
将5-((4-氯-2-甲酰基-5-((3'-(3-(1-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈(0.37g,0.54mmol)和D-哌啶酸(0.14g,1.1mmol)溶于DMF(15.1mL)，加入乙酸(0.2mL,3mmol)，随后加热至60℃搅拌1.5h，冷却至室温，缓慢加入氰基硼氢化钠(0.17g,2.7mmol)， 氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸氢钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝3/1,v/v)分离得淡黄色固体22.5mg，产率为5％。5-((4-Chloro-2-formyl-5-((3'-(3-(1-hydroxy-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2, 2'-Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (0.37 g, 0.54 mmol) and D-pipecolic acid (0.14 g) , 1.1 mmol), dissolved in DMF (15.1 mL), EtOAc (2 mL, EtOAc, EtOAc, EtOAc, EtOAc. Protected and stirred at room temperature for 12 h. Stirring was continued, the mixture was cooled to room temperature, and then added with aq. EtOAc (EtOAc) (EtOAc) The mixture was concentrated under reduced pressure and purified (jjjjjjjjjjj
LC-MS:(pos.ion)m/z：794.2[M+1] +； LC-MS: (pos.ion) m/z: 794.2 [M+1] + ;
1H NMR(400MHz,d 6-DMSO)δ9.01(d,J＝6.9Hz,2H),8.46(s,1H),7.49(d,J＝7.4Hz,1H),7.43(s,1H),7.29-7.21(m,2H),7.12(d,J＝3.5Hz,1H),7.07(d,J＝7.4Hz,1H),6.98(d,J＝8.2Hz,1H),6.71(d,J＝7.7Hz,1H),5.34(s,2H),5.27(s,2H),4.14–4.04(m,2H),3.81(d,J＝14.2Hz,2H),3.65(d,J＝13.3Hz,2H),3.51(s,1H),3.19–3.13(m,4H),2.95–2.87(m,2H),2.38–2.27(m,2H),2.22–2.16(m,3H),2.12–2.07(m,1H),2.03(s,3H),1.84–1.71(m,9H),1.55–1.43(m,4H),1.43–1.33(m,2H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.01 (d, J = 6.9 Hz, 2H), 8.46 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.43 (s, 1H) , 7.29-7.21 (m, 2H), 7.12 (d, J = 3.5 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 7.7 Hz, 1H), 5.34 (s, 2H), 5.27 (s, 2H), 4.14 - 4.04 (m, 2H), 3.81 (d, J = 14.2 Hz, 2H), 3.65 (d, J = 13.3) Hz, 2H), 3.51 (s, 1H), 3.19–3.13 (m, 4H), 2.95–2.87 (m, 2H), 2.38–2.27 (m, 2H), 2.22–2.16 (m, 3H), 2.12– 2.07 (m, 1H), 2.03 (s, 3H), 1.84 - 1.71 (m, 9H), 1.55 - 1.43 (m, 4H), 1.43 - 1.33 (m, 2H).
实施例31(S)-1-(4-((3'-(3-(2-氨基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐(化合物31)Example 31(S)-1-(4-((3'-(3-(2-Amino-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2,2'-di Methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine- 2-carboxylic acid trifluoroacetate (compound 31)
Figure PCTCN2019077582-appb-000083
Figure PCTCN2019077582-appb-000083
步骤1)(7-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-7-氮杂螺[3.5]壬-2-基)胺基甲酸叔丁酯Step 1) (7-(3-((3)-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1' -Biphenyl]-3-yl)oxy)propyl)-7-azaspiro[3.5]non-2-yl)aminocarboxylic acid tert-butyl ester
将4-((3'-(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯代-2-羟基苯甲醛(0.5g,1mmol)，7-氮杂螺[3.5]壬-2-基胺基甲酸叔丁酯(0.3g,1mmol)溶于DMF(10.1mL)，加入碳酸钾(0.8g,6mmol)，加入NaI(0.2g,1mmol)，升温至75℃反应12h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝10/1,v/v)得红色油0.6g，产率为90％。4-((3'-(3-Bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro- 2-Hydroxybenzaldehyde (0.5 g, 1 mmol), tert-butyl 7-azaspiro[3.5]indol-2-ylcarbamate (0.3 g, 1 mmol) dissolved in DMF (10.1 mL). g, 6 mmol), NaI (0.2 g, 1 mmol) was added, and the mixture was warmed to 75 ° C for 12 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (30 mL), EtOAc (EtOAc (EtOAc)EtOAc. /1, v/v) gave a red oil of 0.6 g and a yield of 90%.
LC-MS:(pos.ion)m/z：664.2[M+1] +； LC-MS: (pos.ion) m/z: 664.2 [M+1] + ;
步骤2)(7-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-7-氮杂螺[3.5]壬-2-基)胺基甲酸叔丁酯Step 2) (7-(3-((3'-((2-Cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl) -2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-7-azaspiro[3.5]non-2-yl)carbamic acid tert-butyl ester
将5-(氯甲基)烟腈盐酸盐(0.2g,1mmol)溶于DMF(20.1mL)，加入碳酸铯(2.0g,6.1mmol)，室温搅拌10min。加入(7-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3基)氧基)丙基)-7-氮杂-螺[3.5]壬-2-基)胺基甲酸叔丁酯(0.6g,0.9mmol)和NaI(30.0mg,0.200mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝10/1,v/v)得红色固体0.6g，产率为90％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.2 g, 1 mmol) was dissolved in DMF (20.1 mL). Add (7-(3-((3)-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-linked Benzene-3-yl)oxy)propyl)-7-aza-spiro[3.5]non-2-yl)carbamic acid tert-butyl ester (0.6 g, 0.9 mmol) and NaI (30.0 mg, 0.200 mmol) The temperature was raised to 75 ° C and stirred for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (15 mL), EtOAc (EtOAc) (EtOAc) Separation (DCM / MeOH = 10/1, v / v) afforded s.
LC-MS:(pos.ion)m/z：780.1[M+1] +； LC-MS: (pos.ion) m/z: 780.1 [M+1] + ;
步骤3)(S)-1-(4-((3'-(3-(2-((叔丁氧基羰基)胺基)-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(2-((tert-butoxycarbonyl))amino)-7-azaspiro[3.5]indole-7-yl) Oxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl) Methoxy)benzyl)piperidine-2-carboxylic acid
将(7-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-7-氮杂-螺[3.5]壬-2-基)胺基甲酸叔丁酯(0.6g,0.8mmol)和D-哌啶酸(0.2g,2mmol)溶于DMF(15.0mL)，加入乙酸(0.2mL,3mmol)，加热至60℃搅拌1.0h，冷却至室温，缓慢加入氰基硼氢化钠(0.2g,3.0mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸氢钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝3/1,v/v)分离得黄色固体0.13g，产率为20％。(7-(3-((3'-((2-Chloropyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2 , 2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]non-2-yl)carbamic acid tert-butyl ester (0.6 g, 0.8 mmol) and D-pipecolic acid (0.2 g, 2 mmol) were dissolved in DMF (15.0 mL), EtOAc (0.2 mL, 3 mmol), and then warmed to 60 ° C for 1.0 h, cooled to room temperature, slowly added Sodium cyanoborohydride (0.2 g, 3.0 mmol). Stirring was continued, the mixture was cooled to room temperature, and then added with aq. EtOAc (EtOAc) (EtOAc) The residue was concentrated under reduced pressure. EtOAcjjjjjjj
LC-MS:(pos.ion)m/z：446.70[0.5(M+1)] +； LC-MS: (pos.ion) m/z: 446.70 [0.5 (M+1)] + ;
步骤4)(S)-1-(4-((3'-(3-(2-氨基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐Step 4) (S)-1-(4-((3'-(3-(2-Amino-7-azaspiro[3.5]壬-7-yl)propoxy)-2,2'-di Methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine- 2-carboxylic acid trifluoroacetate
将(S)-1-(4-((3'-(3-(2-((叔丁氧基羰基)胺基)-7-氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.13g,0.15mmol)溶于DCM(25.1mL)，加入TFA(2.0mL)，室温搅拌4h。减压浓缩体系，送制备分离得淡黄色固体32.7mg，产率为25％。(S)-1-(4-((3'-(3-(2-((tert-Butoxycarbonyl))amino)-7-azaspiro[3.5]indole-7-yl)propoxy -2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy The benzyl)piperidine-2-carboxylic acid (0.13 g, 0.15 mmol) was dissolved in EtOAc (EtOAc)EtOAc. The system was concentrated under reduced pressure, and was taken to give a pale yellow solid (32.7 g).
LC-MS:(pos.ion)m/z：396.7[0.5(M+1)] +； LC-MS: (pos.ion) m/z: 396.7 [0.5 (M+1)] + ;
1H NMR(600MHz,d 6-DMSO)δ9.66(s,1H),9.04(d,J＝14.6Hz,2H),8.48(s,1H),8.10(s,2H),7.53(s,1H),7.52–7.48(m,1H),7.30-7.28(m,1H),7.26–7.22(m,2H),7.08(d,J＝7.5Hz,1H),6.98(d,J＝8.3Hz,1H),6.71(d,J＝7.5Hz,1H),5.45–5.36(m,2H),5.36–5.30(m,2H),4.31-4.26(m,2H),4.15–4.05(m,2H),3.75–3.67(m,2H),3.25(s,4H),3.03–2.92(m,2H),2.89–2.82(m,2H),2.37–2.28(m,1H),2.24–2.16(m,2H),2.12–2.08(m,2H),2.04(s,3H),2.01–1.93(m,2H),1.92–1.82(m,4H),1.82–1.59(m,6H),1.49(s,2H). 1 H NMR (600 MHz, d 6 -DMSO) δ 9.66 (s, 1H), 9.04 (d, J = 14.6 Hz, 2H), 8.48 (s, 1H), 8.10 (s, 2H), 7. 1H), 7.52–7.48 (m, 1H), 7.30-7.28 (m, 1H), 7.26–7.22 (m, 2H), 7.08 (d, J=7.5 Hz, 1H), 6.98 (d, J=8.3 Hz) , 1H), 6.71 (d, J = 7.5 Hz, 1H), 5.45 - 5.36 (m, 2H), 5.36 - 5.30 (m, 2H), 4.31-4.26 (m, 2H), 4.15 - 4.05 (m, 2H) ), 3.75–3.67 (m, 2H), 3.25 (s, 4H), 3.03–2.92 (m, 2H), 2.89–2.82 (m, 2H), 2.37–2.28 (m, 1H), 2.24–2.16 (m) , 2H), 2.12–2.08 (m, 2H), 2.04 (s, 3H), 2.01–1.93 (m, 2H), 1.92–1.82 (m, 4H), 1.82–1.59 (m, 6H), 1.49 (s) , 2H).
实施例32(S)-1-(4–((3'-(3-(2,7-二氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐(化合物32)Example 32(S)-1-(4-((3'-(3-(2,7-diazaspiro[3.5]fluoren-7-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2 -carboxylic acid trifluoroacetate (compound 32)
Figure PCTCN2019077582-appb-000084
Figure PCTCN2019077582-appb-000084
步骤1)7-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯Step 1) 7-(3-((3'-((2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'- Biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]decane-2-carboxylic acid tert-butyl ester
将4-((3'-(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯]3-基)甲氧基)-5-氯代-2-羟基苯甲醛(0.5g,1mmol)，2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.3g,1mmol)溶于DMF(10.1mL)，加入碳酸钾(0.8g,6mmol)，加入NaI(0.2g,1mmol)，升温至75℃搅拌12h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝100/1,v/v)得红色固体0.533g，产率为80％。4-((3'-(3-Bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]3-yl)methoxy)-5-chloro-2 -hydroxybenzaldehyde (0.5 g, 1 mmol), 2,7-diazaspiro[3.5]decane-2-carboxylic acid tert-butyl ester (0.3 g, 1 mmol) dissolved in DMF (10.1 mL). 0.8 g, 6 mmol), NaI (0.2 g, 1 mmol) was added, and the mixture was warmed to 75 ° C and stirred for 12 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (30 mL), EtOAc (EtOAc (EtOAc) Separation (DCM / MeOH = 100/1, v / v) gave a red solid, 0.533 g, yield 80%.
LC-MS:(pos.ion)m/z：650.2[M+1] +； LC-MS: (pos.ion) m/z: 650.2 [M+1] + ;
步骤2)7-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯Step 2) 7-(3-((3'-((2-Chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]decane-2-carboxylic acid tert-butyl ester
将5-(氯甲基)烟腈盐酸盐(0.186g,0.984mmol)溶于DMF(10.1mL)，加入碳酸铯(1.61g,4.94mmol)，室温搅拌10min。加入7-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙 基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.533g,0.821mmol)和NaI(24.6mg,0.164mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝10/1,v/v)得黄色固体0.6g，产率为95％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.186 g, 0.984 mmol) was dissolved in DMF (10.1 mL). Add 7-(3-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl) ]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]decane-2-carboxylic acid tert-butyl ester (0.533 g, 0.821 mmol) and NaI (24.6 mg, 0.164 mmol) The temperature was raised to 75 ° C and stirred for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (15 mL), EtOAc (EtOAc) (EtOAc) Separation (DCM / MeOH = 10/1, v / v) afforded s.
LC-MS:(pos.ion)m/z：766.3[M+1] +； LC-MS: (pos.ion) m/z: 766.3 [M+1] + ;
步骤3)(S)-1-(4-((3'-(3-(2-(叔丁氧基羰基)-2,7-二氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(2-(tert-Butoxycarbonyl)-2,7-diazaspiro[3.5]壬-7-yl)propoxy) -2,2'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy Benzyl)piperidine-2-carboxylic acid
将7-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.6g,0.8mmol)和D-哌啶酸(0.2g,2mmol)溶于DMF(15.0mL)，加入乙酸(0.2mL,3mmol)，加热至60℃搅拌1.5h，随后冷却至室温，缓慢加入氰基硼氢化钠(0.25g,4.0mmol)，氮气保护，室温搅拌12h。停止搅拌，加入饱和碳酸氢钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝3/1,v/v)分离得黄色固体0.44g，产率为60％。7-(3-((3'-((2-Chloropyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2, 2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]decane-2-carboxylic acid tert-butyl ester ( 0.6 g, 0.8 mmol) and D-pipecolic acid (0.2 g, 2 mmol) were dissolved in DMF (15.0 mL), EtOAc (0.2 mL, 3 mmol), and then warmed to 60 ° C for 1.5 h, then cooled to room temperature and slowly added Sodium cyanoborohydride (0.25 g, 4.0 mmol), mp. The mixture was stirred, and the mixture was stirred with EtOAc EtOAc EtOAc. Column chromatography (DCM / MeOH = 3/1, v/v) afforded 0.44 g of a yellow solid.
LC-MS:(pos.ion)m/z：879.3[M+1] +； LC-MS: (pos.ion) m / z: 879.3 [M + 1] +;
步骤4)(S)-1-(4-((3'-(3-(2,7-二氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐Step 4) (S)-1-(4-((3'-(3-(2,7-diazaspiro[3.5]fluoren-7-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2 -carboxylic acid trifluoroacetate
将(S)-1-(4-((3'-(3-(2-(叔丁氧基羰基)-2,7-二氮杂螺[3.5]壬-7-基)丙氧基)-2,2'-二甲基[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.44g,0.50mmol)溶于DCM(25.1mL)，加入TFA(2.5mL)，室温搅拌4h。浓缩溶剂，送制备分离得黄色固体66.0mg，产率为15％。(S)-1-(4-((3'-(3-(2-(tert-Butoxycarbonyl)-2,7-diazaspiro[3.5]fluoren-7-yl)propoxy) -2,2'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy) Benzyl)piperidine-2-carboxylic acid (0.44 g, 0.50 mmol) was dissolved in EtOAc (EtOAc) The solvent was concentrated to give 66.0 mg ofyel.
LC-MS:(pos.ion)m/z：779.2[M+1] +； LC-MS: (pos.ion) m / z: 779.2 [M + 1] +;
1H NMR(600MHz,d 6-DMSO)δ10.14(s,1H),9.19(s,2H),9.04(s,2H),8.49(s,1H),7.52(d,J＝29.4Hz,2H),7.32–7.26(m,1H),7.26–7.17(m,2H),7.08(d,J＝6.4Hz,1H),6.97(d,J＝7.4Hz,1H),6.71(d,J＝6.8Hz,1H),5.44–5.38(m,2H),5.37–5.28(m,2H),4.40–4.32(m,2H),4.31–4.23(m,2H),3.91-3.82(m,4H),3.79–3.72(m,2H),3.55–3.50(m,2H),3.29–3.19(m,2H),3.11–2.81(m,4H),2.80–2.67(m,1H),2.23–2.14(m,4H),2.04(s,3H),1.96–1.88(m,2H),1.85(s,3H),1.78–1.58(m,4H). 1 H NMR (600MHz, d 6 -DMSO) δ10.14 (s, 1H), 9.19 (s, 2H), 9.04 (s, 2H), 8.49 (s, 1H), 7.52 (d, J = 29.4Hz, 2H), 7.32–7.26 (m, 1H), 7.26–7.17 (m, 2H), 7.08 (d, J=6.4 Hz, 1H), 6.97 (d, J=7.4 Hz, 1H), 6.71 (d, J) = 6.8 Hz, 1H), 5.44 - 5.38 (m, 2H), 5.37 - 5.28 (m, 2H), 4.40 - 4.32 (m, 2H), 4.31 - 4.23 (m, 2H), 3.91-3.82 (m, 4H) ), 3.79–3.72 (m, 2H), 3.55–3.50 (m, 2H), 3.29–3.19 (m, 2H), 3.11–2.81 (m, 4H), 2.80–2.67 (m, 1H), 2.23–2.14 (m, 4H), 2.04 (s, 3H), 1.96–1.88 (m, 2H), 1.85 (s, 3H), 1.78–1.58 (m, 4H).
实施例33(S)-1-(4-((3'-(3-(2,8-二氮杂螺[4.5]癸-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物33)Example 33(S)-1-(4-((3'-(3-(2,8-diazaspiro[4.5]dec-8-yl)propoxy)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2 -formic acid (compound 33)
Figure PCTCN2019077582-appb-000085
Figure PCTCN2019077582-appb-000085
步骤1)8-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,8-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯Step 1) 8-(3-((3'-(2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'- Biphenyl]-3-yl)oxy)propyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester
将2,7-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯盐酸盐(0.3g,1mmol)溶于DMF(10.1mL)，加入碳酸钾(0.8g,6mmol)，室温搅拌10min，加入4-((3'-(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基]-5-氯-2-羟基苯甲醛(0.5g,1mmol)，NaI(0.2g,1mmol)，升温至75℃搅拌12h。停止搅拌，冷却至室温，加水(30mL) 稀释，EA(20mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，硅胶柱层析分离(DCM/MeOH＝8/1,v/v)得粉红色固体0.43g，产率为70％。2,7-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester hydrochloride (0.3 g, 1 mmol) was dissolved in DMF (10.1 mL) and potassium carbonate (0.8 g, 6 mmol) After stirring for 10 min, 4-((3'-(3-bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]-5- was added. Chloro-2-hydroxybenzaldehyde (0.5 g, 1 mmol), NaI (0.2 g, 1 mmol), warmed to 75 ° C and stirred for 12 h. Stirring was stopped, cooled to room temperature, diluted with water (30 mL), EA (20 mL×3) The organic phase was combined and washed with brine (30 mL), dried over anhydrous sodium sulfatessssssssssssssssssssssssssssssss g, the yield was 70%.
LC-MS:(pos.ion)m/z：664.5[M+1] +； LC-MS: (pos.ion) m/z: 664.5 [M + 1] + ;
步骤2)8-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,8-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯Step 2) 8-(3-((3'-((2-Chloro-5-(5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester
将5-(氯甲基)烟腈盐酸盐(0.15g,0.79mmol)溶于DMF(10.1mL)，加入碳酸铯(1.3g,4.0mmol)，室温搅拌10min。加入8-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,8-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯(0.43g,0.65mmol)和NaI(19.0mg,0.127mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，硅胶柱层析分离(DCM/MeOH＝5/1,v/v)得棕色固体0.47g，产率为93％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.15 g, 0.79 mmol) was dissolved in DMF (10.1 mL). Add 8-(3-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl) ]-3-yl)oxy)propyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (0.43 g, 0.65 mmol) and NaI (19.0 mg, 0.127 mmol) The temperature was raised to 75 ° C and stirred for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (15 mL), EtOAc (15 mL··············· Chromatography (DCM/MeOH = 5/1, v/v)
LC-MS:(pos.ion)m/z：780.3[M+1] +； LC-MS: (pos.ion) m/z: 780.3 [M + 1] + ;
步骤3)(S)-1-(4-((3'-(3-(2-(叔丁氧基羰基)-2,8-二氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(2-(tert-Butoxycarbonyl)-2,8-diazaspiro[4.5]decane-8-yl)propane Oxy)-2,2'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)- Oxy)benzyl)piperidine-2-carboxylic acid
将8-(3-((3-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,8-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯(0.47g,0.60mmol)和D-哌啶酸(0.16g,1.2mmol)溶于DMF(15.1mL)，加入AcOH(0.2mL,3mmol)，加热至60℃搅拌1.5h，冷却至室温，缓慢加入NaBH 3CN(0.2g,3.0mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸氢钠溶液室温搅拌30min，EA(25mL×3)萃取，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝5/1,v/v)分离得红色固体0.16g，产率为30％。 8-(3-((3-(2-Chloropyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2 '-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (0.47 g, 0.60 mmol) and D-pipecolic acid (0.16 g, 1.2 mmol) were dissolved in DMF (15.1 mL), AcOH (0.2 mL, 3 mmol), then warmed to 60 ° C for 1.5 h, cooled to room temperature, slowly added NaBH 3 CN (0.2 g, 3.0 mmol), nitrogen-protected, stirred at room temperature for 12 h. Stirring was continued, the mixture was cooled to room temperature, and the mixture was stirred with EtOAc EtOAc EtOAc EtOAc. The red solid was isolated (DCM/MeOH = 5/1, v/v).
LC-MS:(pos.ion)m/z：446.8[0.5(M+1)] +； LC-MS: (pos.ion) m/z: 446.8 [0.5 (M+1)] + ;
步骤4)(S)-1-(4-((3'-(3-(2,8-二氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 4) (S)-1-(4-((3'-(3-(2,8-diazaspiro[4.5]decane-8-yl)propoxy)-2,2'-di Methyl-[1,1'-biphenyl]methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将(S)-1-(4-((3'-(3-(2-(叔丁氧基羰基)-2,8-二氮杂螺[4.5]癸烷-8-基)丙氧基)-2,2'-二甲基[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.16g,0.18mmol)溶于DCM(25.0mL)，加入TFA(2.0mL)，室温搅拌4h。浓缩溶剂，送制备分离后浓缩有机溶剂，水溶液用饱和碳酸钠将pH调至7-8，依次用DCM(10mL×3)和EA(10mL×1)萃取，有机相用水(20mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，浓缩有机相得黄色固体22.8mg，产率为16％。(S)-1-(4-((3'-(3-(2-(tert-Butoxycarbonyl)-2,8-diazaspiro[4.5]decane-8-yl)propoxy) -2,2'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy Benzyl)piperidine-2-carboxylic acid (0.16 g, 0.18 mmol) was dissolved in EtOAc (EtOAc)EtOAc. The solvent was concentrated, and the organic solvent was concentrated and concentrated. The aqueous solution was adjusted to pH 7-8 with saturated sodium carbonate, and extracted with DCM (10mL×3) and EA (10mL×1), and the organic phase was washed with water (20mL). The aqueous sodium sulfate was dried, suction filtered, washed, and then evaporated.
LC-MS:(pos.ion)m/z：397.3[0.5(M+1)] +； LC-MS: (pos.ion) m/z: 397.3 [0.5 (M+1)] + ;
1H NMR(400MHz,d 6-DMSO)δ8.98(d,J＝10.8Hz,2H),8.43(s,1H),7.53–7.41(m,2H),7.26–7.21(m,1H),7.19–7.15(m,1H),7.07–7.03(m,2H),6.98–6.87(m,1H),6.67(d,J＝7.3Hz,1H),5.35–5.19(m,4H),4.81–4.74(m,1H),4.03–3.98(m,2H),3.51(s,1H),3.08–3.03(m,2H),2.86–2.79(m,4H),2.43–2.36(m,2H),2.34–2.29(m,2H),2.25–2.21(m,2H),2.11–1.92(m,5H),1.86–1.73(m,5H),1.70–1.65(m,2H),1.63–1.55(m,2H),1.55–1.34(m,8H). 1 H NMR (400 MHz, d 6 -DMSO) δ 8.98 (d, J = 10.8 Hz, 2H), 8.43 (s, 1H), 7.53 - 7.41 (m, 2H), 7.26 - 7.21 (m, 1H), 7.19–7.15(m,1H), 7.07–7.03(m,2H), 6.98–6.87(m,1H), 6.67(d,J=7.3Hz,1H),5.35–5.19(m,4H),4.81– 4.74 (m, 1H), 4.03–3.98 (m, 2H), 3.51 (s, 1H), 3.08–3.03 (m, 2H), 2.86–2.79 (m, 4H), 2.43–2.36 (m, 2H), 2.34–2.29 (m, 2H), 2.25–2.21 (m, 2H), 2.11–1.92 (m, 5H), 1.86–1.73 (m, 5H), 1.70–1.65 (m, 2H), 1.63–1.55 (m) , 2H), 1.55–1.34 (m, 8H).
实施例34(S)-1-(4-((3'-(3-(3,9-二氮杂螺[5.5]十一烷-3-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐(化合物34)Example 34(S)-1-(4-((3'-(3-(3,9-diazaspiro[5.5]undec-3-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid trifluoroacetate (compound 34)
Figure PCTCN2019077582-appb-000086
Figure PCTCN2019077582-appb-000086
步骤1)9-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯Step 1) 9-(3-((3'-((2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'- Biphenyl]-3-yl)oxy)propyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester
将3,9-二氮杂螺[5.5]十一烷-9-甲酸叔丁酯盐酸盐(0.3g,1mmol)溶于DMF(10.1mL)，加入碳酸钾(0.8g,6mmol)，室温搅拌10min。加入4-((3'-(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基]-5-氯-2-羟基苯甲醛(0.5g,1mmol)，NaI(0.2g,1mmol)，升温至75℃条件下搅拌12h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝8/1,v/v)得黄色粘稠油0.63g，产率为90％。3,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester hydrochloride (0.3 g, 1 mmol) was dissolved in DMF (10.1 mL) and potassium carbonate (0.8 g, 6 mmol) Stir for 10 min. Add 4-((3'-(3-bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]-5-chloro-2 -Hydroxybenzaldehyde (0.5 g, 1 mmol), NaI (0.2 g, 1 mmol), EtOAc (EtOAc, EtOAc) The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated.
LC-MS:(pos.ion)m/z：678.0[M+1] +； LC-MS: (pos.ion) m/z: 678.0 [M+1] + ;
步骤2)9-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯Step 2) 9-(3-((3'-((2-Chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid Butyl ester
将5-(氯甲基)烟腈盐酸盐(0.21g,1.1mmol)溶于DMF(15.1mL)，加入碳酸铯(1.8g,5.5mmol)，室温搅拌10min。加入9-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯(0.63g,0.93mmol)和NaI(28.0mg,0.19mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝5/1,v/v)得红色固体0.63g，产率为85％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.21 g, 1.1 mmol) was dissolved in DMF (15.1 mL). Add 9-(3-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl) ]-3-yl)oxy)propyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (0.63 g, 0.93 mmol) and NaI (28.0 mg, 0.19 mmol) ), the temperature was raised to 75 ° C and stirred for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (15 mL), EtOAc (EtOAc) (EtOAc) Separation (DCM / MeOH = 5 / 1 , v / v) gave a red solid.
LC-MS:(pos.ion)m/z：397.2[0.5(M+1)] +； LC-MS: (pos.ion) m/z: 397.2 [0.5 (M+1)] + ;
步骤3)(S)-1-(4-((3'-(3-(9-(叔丁氧基羰基)-3,9-二氮杂螺[5.5]十一烷-3-基)丙氧基)-2,2'-二甲基[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(9-(tert-Butoxycarbonyl)-3,9-diazaspiro[5.5]undec-3-yl) Propyl)-2,2'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl) Methoxy)benzyl)piperidine-2-carboxylic acid
将9-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯(0.63g,0.79mmol)和D-哌啶酸(0.21g,1.6mmol)溶于DMF(15.1mL)，加入乙酸(0.2mL,3mmol)，加热至60℃搅拌1.0h，冷却至室温，缓慢加入氰基硼氢化钠(0.25g,4.0mmol)，氮气保护，室温搅拌12h。升温至80℃，搅拌3.0h。停止搅拌，冷却至室温，加入饱和碳酸氢钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝5/1,v/v)分离得黄色固体0.13g，产率为18％。9-(3-((3'-((2-Chloro-5-(5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2, 2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (0.63 g, 0.79 mmol) and D-piperidine acid (0.21 g, 1.6 mmol) were dissolved in DMF (15.1 mL), EtOAc (0.2 mL, 3 mmol), EtOAc. Sodium cyanoborohydride (0.25 g, 4.0 mmol) was added <RTI ID=0.0> The temperature was raised to 80 ° C and stirred for 3.0 h. Stirring was continued, the mixture was cooled to room temperature, and then added with aq. EtOAc (EtOAc) (EtOAc) It was concentrated under reduced pressure and purified (jjjjjjjjj
LC-MS:(pos.ion)m/z：454.0[0.5(M+1)] +； LC-MS: (pos.ion) m/z: 454.0 [0.5 (M+1)] + ;
步骤4)(S)-1-(4-((3'-(3-(3,9-二氮杂螺[5.5]十一烷-3-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐Step 4) (S)-1-(4-((3'-(3-(3,9-diazaspiro[5.5]undec-3-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid trifluoroacetate
将(S)-1-(4-((3'-(3-(9-(叔丁氧基羰基)-3,9-二氮杂螺[5.5]十一烷-3-基)丙氧基)-2,2'-二甲基[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.13g,0.14mmol)溶于DCM(25.0mL)， 加入TFA(2.0mL)，室温搅拌4h。减压浓缩体系，送制备分离得淡黄色固体32.9mg，产率为25％。(S)-1-(4-((3'-(3-(9-(tert-Butoxycarbonyl)-3,9-diazaspiro[5.5]undec-3-yl)propoxy) -2,2'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy The benzyl)piperidine-2-carboxylic acid (0.13 g, 0.14 mmol) was dissolved in EtOAc (EtOAc) The system was concentrated under reduced pressure, and was taken to yield 32.9 mg of pale yellow solid.
LC-MS:(pos.ion)m/z：404.4[0.5(M+1)] +； LC-MS: (pos.ion) m/z: 404.4 [0.5 (M+1)] + ;
1H NMR(600MHz,d 6-DMSO)δ9.44(s,1H),9.03(d,J＝15.5Hz,2H),8.53(s,2H),8.47(s,1H),7.54–7.43(m,2H),7.32–7.26(m,1H),7.25–7.21(m,1H),7.16(d,J＝4.4Hz,1H),7.08–7.06(m,1H),6.98(d,J＝8.4Hz,1H),6.72(d,J＝7.5Hz,1H),5.39–5.34(m,2H),5.33–5.27(m,2H),4.13–4.07(m,2H),3.63–3.50(m,6H),3.22–3.16(m,4H),3.13–3.00(m,6H),2.21–2.16(m,2H),2.04(s,3H),1.90–1.84(m,4H),1.79–1.76(m,2H),1.74–1.64(m,2H),1.60–1.50(m,6H),1.45–1.34(m,2H). 1 H NMR (600 MHz, d 6 -DMSO) δ 9.44 (s, 1H), 9.03 (d, J = 15.5 Hz, 2H), 8.53 (s, 2H), 8.47 (s, 1H), 7.54 - 7.43 ( m, 2H), 7.32 - 7.26 (m, 1H), 7.25 - 7.21 (m, 1H), 7.16 (d, J = 4.4 Hz, 1H), 7.08 - 7.06 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 5.39 - 5.34 (m, 2H), 5.33 - 5.27 (m, 2H), 4.13 - 4.07 (m, 2H), 3.63 - 3.50 (m , 6H), 3.22–3.16 (m, 4H), 3.13–3.00 (m, 6H), 2.21–2.16 (m, 2H), 2.04 (s, 3H), 1.90–1.84 (m, 4H), 1.79–1.76 (m, 2H), 1.74–1.64 (m, 2H), 1.60–1.50 (m, 6H), 1.45–1.34 (m, 2H).
实施例35(S)-1-(4–((3'-(3-(2,9-二氮杂螺[5.5]十一烷-9-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐(化合物35)Example 35(S)-1-(4-((3'-(3-(2,9-diazaspiro[5.5]undec-9-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine -2-carboxylic acid trifluoroacetate (compound 35)
Figure PCTCN2019077582-appb-000087
Figure PCTCN2019077582-appb-000087
步骤1)9-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,9-二氮杂螺[5.5]十一烷-2-羧酸叔丁酯Step 1) 9-(3-((3'-((2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'- Biphenyl]-3-yl)oxy)propyl)-2,9-diazaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester
将4-((3'-(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基]-5-氯-2-羟基苯甲醛(0.75g,1.5mmol)，2,9-二氮杂螺[5.5]十一烷-4-羧酸叔丁酯(0.45g,1.8mmol)溶于DMF(10.1mL)，加入碳酸钾(1.2g,8.7mmol)，加入NaI(0.27g,1.8mmol)，升温至75℃搅拌12h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM)得红色油0.8g，产率为80％。4-((3'-(3-Bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]-5-chloro-2 -hydroxybenzaldehyde (0.75 g, 1.5 mmol), 2,9-diazaspiro[5.5]undecane-4-carboxylic acid tert-butyl ester (0.45 g, 1.8 mmol) dissolved in DMF (10.1 mL) Potassium carbonate (1.2 g, 8.7 mmol), added NaI (0.27 g, 1.8 mmol), warmed to 75 ° C and stirred for 12 h. Stirring was stopped, cooled to room temperature, diluted with water (30 mL), EA (20 mL×3) The mixture was dried over anhydrous sodium sulfate, filtered, filtered, evaporated, evaporated, evaporated.
LC-MS:(pos.ion)m/z：678.2[M+1] +； LC-MS: (pos.ion) m/z: 678.2 [M+1] + ;
步骤2)9-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,9-二氮杂螺[5.5]十一烷-2-羧酸叔丁酯Step 2) 9-(3-((3'-((2-Chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-) 2,2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,9-diazaspiro[5.5]undecane-2-carboxylic acid Butyl ester
将5-(氯甲基)烟腈盐酸盐(0.3g,2mmol)溶于DMF(20.1mL)，加入碳酸铯(2.0g,6.1mmol)，室温搅拌10min。加入9-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,9-二氮杂螺[5.5]十一烷-2-羧酸叔丁酯(0.8g,1mmol)和NaI(40.0mg,0.267mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝10/1,v/v)得淡红色固体0.6g，产率为60％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.3 g, 2 mmol) was dissolved in DMF (20.1 mL). Add 9-(3-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl) ]-3-yl)oxy)propyl)-2,9-diazaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester (0.8 g, 1 mmol) and NaI (40.0 mg, 0.267 mmol) The temperature was raised to 75 ° C and stirred for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (15 mL), EtOAc (EtOAc) (EtOAc) Separation (DCM / MeOH = 10/1, v / v) gave a pale red solid (0.6 g).
LC-MS:(pos.ion)m/z：794.2[M+1] +； LC-MS: (pos.ion) m/z: 794.2 [M+1] + ;
步骤3)(S)-1-(4-((3'-(3-(2-(叔丁氧基羰基)-2,9-二氮杂螺[5.5]十一烷-9-基)丙氧基)-2,2'-二甲基[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(2-(tert-Butoxycarbonyl)-2,9-diazaspiro[5.5]undec-9-yl)) Propyl)-2,2'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl) Methoxy)benzyl)piperidine-2-carboxylic acid
将9-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2,2'-二甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,9-二氮杂螺[5.5]十一烷-2-羧酸叔丁酯(0.6g,0.8mmol)和D-哌啶酸(0.2g,2mmol)溶于DMF(15.0mL)，加入乙酸(0.2mL,3mmol)，加热至60℃搅拌1.5h，冷却至室温，缓慢加入氰基硼氢化钠(0.2g,3mmol)，氮气保护，室温搅拌12h，升温至80℃搅拌5h。停止搅拌，冷却至室温，加入饱和碳酸氢 钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝4/1,v/v)分离黄色固体0.38g，产率为60％。9-(3-((3'-((2-Chloro-5-(5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2, 2'-Dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,9-diazaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester (0.6 g, 0.8 mmol) and D-piperidine acid (0.2 g, 2 mmol) were dissolved in DMF (15.0 mL), EtOAc (0.2 mL, 3 mmol), EtOAc. Sodium cyanoborohydride (0.2 g, 3 mmol), mp. Stirring was continued, the mixture was cooled to room temperature, and then added with aq. EtOAc (EtOAc) (EtOAc) The organic layer was concentrated under reduced pressure. EtOAc (EtOAc m.
LC-MS:(pos.ion)m/z：907.3[M+1] +； LC-MS: (pos.ion) m/z: 907.3 [M + 1] + ;
步骤4)(S)-1-(4-((3'-(3-(2,9-二氮杂螺[5.5]十一碳-9-基)丙氧基)-2,2'-二甲基-[1,1'-联苯]甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐Step 4) (S)-1-(4-((3'-(3-(2,9-diazaspiro[5.5]undec-9-yl)propoxy)-2,2'- Dimethyl-[1,1'-biphenyl]methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid Fluoroacetate
将(S)-1-(4-((3'-(3-(2-(叔丁氧基羰基)-2,9-二氮杂螺[5.5]十一烷-9-基)丙氧基)-2,2'-二甲基[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.38g,0.42mmol)溶于DCM(25.1mL)，加入TFA(2.5mL)，室温搅拌4h。减压浓缩体系，送制备分离得黄色固体47.6mg，产率为12％。(S)-1-(4-((3'-(3-(2-(tert-Butoxycarbonyl)-2,9-diazaspiro[5.5]undec-9-yl)propoxy -2,2'-dimethyl[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy The benzyl)piperidine-2-carboxylic acid (0.38 g, 0.42 mmol) was dissolved in EtOAc (EtOAc) The system was concentrated under reduced pressure, and then was taken to yield 47.6 mg of a yellow solid.
LC-MS:(pos.ion)m/z：807.3[M+1] +； LC-MS: (pos.ion) m/z: 807.3 [M + 1] + ;
1H NMR(600MHz,d 6-DMSO)δ9.88(s,1H),9.03(d,J＝7.7Hz,2H),8.94(s,1H),8.83(s,1H),8.48(s,1H),7.54(s,1H),7.52–7.46(m,1H),7.29(t,J＝6.6Hz,1H),7.26–7.18(m,2H),7.08(d,J＝7.4Hz,1H),6.98(d,J＝8.1Hz,1H),6.71(d,J＝7.4Hz,1H),5.44–5.37(m,2H),5.36–5.27(m,2H),4.37–4.33(m,1H),4.28–4.24(m,1H),4.12–4.07(m,2H),4.05–3.98(m,2H),3.45–3.38(m,4H),3.35–3.26(m,4H),3.25–3.17(m,2H),3.11(d,J＝4.0Hz,2H),3.00(s,2H),2.90–2.83(m,1H),2.25–2.20(m,2H),2.16–2.08(m,1H),2.04(s,3H),1.86(s,3H),1.75–1.68(m,6H),1.64–1.57(m,2H),1.45(s,1H). 1 H NMR (600 MHz, d 6 -DMSO) δ 9.88 (s, 1H), 9.03 (d, J = 7.7 Hz, 2H), 8.94 (s, 1H), 8.83 (s, 1H), 8.48 (s, 1H), 7.54(s,1H), 7.52–7.46(m,1H), 7.29(t,J=6.6Hz,1H), 7.26–7.18(m,2H),7.08(d,J=7.4Hz,1H ), 6.98 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 7.4 Hz, 1H), 5.44 - 5.37 (m, 2H), 5.36 - 5.27 (m, 2H), 4.37 - 4.33 (m, 1H), 4.28–4.24 (m, 1H), 4.12–4.07 (m, 2H), 4.05–3.98 (m, 2H), 3.45–3.38 (m, 4H), 3.35–3.26 (m, 4H), 3.25– 3.17 (m, 2H), 3.11 (d, J = 4.0 Hz, 2H), 3.00 (s, 2H), 2.90 - 2.83 (m, 1H), 2.25 - 2.20 (m, 2H), 2.16 - 2.08 (m, 1H), 2.04 (s, 3H), 1.86 (s, 3H), 1.75 - 1.68 (m, 6H), 1.64 - 1.57 (m, 2H), 1.45 (s, 1H).
实施例36(S)-1-(4-((3'-(3-(2-胺基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1,1'-联苯]-甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐(化合物36)Example 36(S)-1-(4-((3'-(3-(2-Amino-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2-methyl- [1,1'-biphenyl]-methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetic acid Salt (compound 36)
Figure PCTCN2019077582-appb-000088
Figure PCTCN2019077582-appb-000088
步骤1)[2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基]甲醇Step 1) [2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol
将PdCl 2(dppf)(7.28g,9.95mmol)，乙酸钾(29.3g,299mmol)，联硼酸频哪醇酯(37.9g,149mmol)溶于1,4-二氧六环(200.1mL)，加入(3-溴-2-甲基-苯基)甲醇(20.1g,100mmol)，升温至90℃条件下搅拌12h。停止搅拌，冷却至室温，直接柱层析分离(Hexane/EA＝5/1,v/v)得淡绿色固体23.9g，产率为96％。 PdCl 2 (dppf) (7.28 g, 9.95 mmol), potassium acetate (29.3 g, 299 mmol), boronic acid pinacol ester (37.9 g, 149 mmol) was dissolved in 1,4-dioxane (200.1 mL). (3-Bromo-2-methyl-phenyl)methanol (20.1 g, 100 mmol) was added, and the mixture was stirred at 90 ° C for 12 h. The stirring was stopped, cooled to room temperature, and directly subjected to column chromatography (Hexane/EA = 5/1, v/v) to give a pale green solid (23.9 g, yield: 96%).
LC-MS:(pos.ion)m/z：231.1[M-18+1] +； LC-MS: (pos.ion) m/z: 231.1 [M-18+1] + ;
步骤2)1-溴-3-(3-溴丙氧基)苯Step 2) 1-Bromo-3-(3-bromopropoxy)benzene
将3-溴苯酚(5.1g,29mmol)溶于丙酮(60.0mL)，加入碳酸钾(12.0g,86.8mmol)，然后加入1,3-二溴丙烷(7.3mL,72mmol)，氮气保护，升温至60℃回流12h。停止搅拌，冷却室温，抽滤除去碳酸钾并用DCM洗涤，减压浓缩直接柱层析(Hexane)分离得淡黄色油8.3g，产率为96％。3-bromophenol (5.1 g, 29 mmol) was dissolved in acetone (60.0 mL), potassium carbonate (12.0 g, 86.8 mmol) was added, then 1,3-dibromopropane (7.3 mL, 72 mmol) was added. Reflux to 60 ° C for 12 h. Stirring was continued, the mixture was cooled to room temperature, and the mixture was evaporated.
步骤3)(3'-(3-溴丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲醇Step 3) (3'-(3-Bromopropoxy)-2-methyl-[1,1'-biphenyl]-3-yl)methanol
将[2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基]甲醇(4.4g,18mmol)，1-溴-3-(3-溴丙氧基)苯(5.0g,17mmol)溶于THF(160.2mL)和H 2O(40.3mL)的混合溶剂，加入磷酸钾(9.0g,42mmol)，氮气保护，室温搅拌20min，加入Pd(dppf)Cl 2(0.62g,0.85mmol)，氮气保护，升温回流12h。停止搅拌，加水(60mL)稀释，EA(100mL×3)萃取，合并有机相并用无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱 层析(PE/EA＝5/1,v/v)分离得褐色油3.6g，产率为63％。 [2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (4.4 g, 18 mmol) 1-Bromo-3-(3-bromopropoxy)benzene (5.0 g, 17 mmol) was dissolved in a mixed solvent of THF (160.2 mL) and H 2 O (40.3 mL), and potassium phosphate (9.0 g, 42 mmol) The mixture was stirred under nitrogen for 20 min at room temperature. Pd(dppf)Cl 2 (0.62 g, 0.85 mmol) was added. Stirring was continued, and the mixture was diluted with water (60 mL), EtOAc (EtOAc (EtOAc)EtOAc. v) A brown oil of 3.6 g was isolated in a yield of 63%.
LC-MS:(pos.ion)m/z：318.2[M-18+1] +； LC-MS: (pos.ion) m/z: 318.2 [M - 18 + 1] + ;
步骤4)4-((3'-(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基]-5-氯-2-羟基苯甲醛Step 4) 4-((3'-(3-Bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]-5-chloro -2-hydroxybenzaldehyde
0℃将(3'-(3-溴丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲醇(2.0g,6.0mmol)和5-氯-2,4-二羟基苯甲醛(1.1g,6.4mmol)溶于THF(30.1mL)，加入三苯基膦(2.3g,8.8mmol)，氮气保护，缓慢注入DIAD(1.8mL,9.1mmol)，室温条件下搅拌24h。停止搅拌，加水(30mL)稀释，EA(30mL×3)萃取，合并有机相并用无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(PE/EA＝10/1,v/v)分离得黄色固体1.9g，产率为65％。(3'-(3-Bromopropoxy)-2-methyl-[1,1'-biphenyl]-3-yl)methanol (2.0 g, 6.0 mmol) and 5-chloro-2 at 0 °C. 4-Dihydroxybenzaldehyde (1.1 g, 6.4 mmol) was dissolved in THF (30.1 mL), triphenylphosphine (2.3 g, 8.8 mmol) was added, and then filtered, and then, DIDA (1.8 mL, 9.1 mmol) Stir under 24h. Stirring was continued, the mixture was diluted with water (30 mL), EtOAc (30 mL×3) was evaporated, evaporated, evaporated, evaporated, evaporated v) 1.9 g of a yellow solid isolated in 65% yield.
步骤5)(7-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2'-甲基-[1,1'-联苯]-3-基)氧基)丙基)-7-氮杂螺[3.5]壬-2-基)氨基甲酸叔丁酯Step 5) (7-(3-((3)-((2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2'-methyl-[1,1'-biphenyl) Tert-butyl ester of 3-yl)oxy)propyl)-7-azaspiro[3.5]non-2-yl)carbamate
将4-((3'-(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基]-5-氯-2-羟基苯甲醛(0.5g,1mmol)，7-氮杂螺[3.5]壬-2-基氨基甲酸叔丁酯(0.3g,1mmol)溶于DMF(10.1mL)，加入碳酸钾(0.8g,6mmol)，加入NaI(0.2g,1mmol)，升温至75℃搅拌10h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(Hexane/EA＝1/3,v/v)得红色固体0.33g，产率为50％。4-((3'-(3-Bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]-5-chloro-2 -Hydroxybenzaldehyde (0.5 g, 1 mmol), tert-butyl 7-azaspiro[3.5]non-2-ylcarbamate (0.3 g, 1 mmol) dissolved in DMF (10.1 mL). 6mmol), add NaI (0.2g, 1mmol), warmed to 75 ° C and stirred for 10h. Stirring was stopped, cooled to room temperature, diluted with water (30mL), extracted with EA (20mL × 3), the combined organic phase and saturated brine (30mL) The organic layer was dried (MgSO4).
LC-MS:(pos.ion)m/z：650.2[M+1] +； LC-MS: (pos.ion) m/z: 650.2 [M+1] + ;
步骤6)(7-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2'-甲基-[1,1'-联苯]-3-基)氧基)丙基)-7-氮杂-螺[3.5]壬-2-基)氨基甲酸叔丁酯Step 6) (7-(3-((3'-((2-Cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl) -2'-Methyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]non-2-yl)carbamic acid tert-butyl ester
将5-(氯甲基)烟腈盐酸盐(0.12g,0.63mmol)溶于DMF(10.1mL)，加入碳酸铯(0.99g,3.0mmol)，室温搅拌10min。加入(7-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2'-甲基-[1,1'-联苯]-3-基)氧基)丙基)-7-氮杂-螺[3.5]壬-2-基)氨基甲酸叔丁酯(0.33g,0.51mmol)和NaI(15.0mg,0.10mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝90/1,v/v)得黄色固体0.3g，产率为80％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.12 g, 0.63 mmol) was dissolved in DMF (10.1 mL). Add (7-(3-((3)-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2'-methyl-[1,1'-biphenyl]- tert-Butyl 3-yl)oxy)propyl)-7-aza-spiro[3.5]non-2-yl)carbamate (0.33 g, 0.51 mmol) and NaI (15.0 mg, 0.10 mmol) Stir at 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (15 mL), EtOAc (EtOAc) (EtOAc) Separation (DCM / MeOH = 90/1, v / v) afforded 0.3 g of a yellow solid.
LC-MS:(pos.ion)m/z：766.2[M+1] +； LC-MS: (pos.ion) m/z: 766.2 [M+1] + ;
步骤7)(S)-1-(4-((3'-(3-(2-((叔丁氧基羰基)胺基)-7-氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 7) (S)-1-(4-((3'-(3-(2-((tert-butoxycarbonyl))amino)-7-azaspiro[3.5]indole-7-yl) Oxy)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy) Benzyl) piperidine-2-carboxylic acid
将(7-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2'-甲基-[1,1'-联苯]-3-基)氧基)丙基)-7-氮杂-螺[3.5]壬-2-基)氨基甲酸叔丁酯(0.3g,0.4mmol)和D-哌啶酸(0.1g,0.8mmol)溶于DMF(15.0mL)，加入乙酸(0.2mL,3mmol)，加热至60℃搅拌1.5h，冷却至室温，缓慢加入氰基硼氢化钠(0.12g,1.9mmol)，氮气保护，室温搅拌12h，停止搅拌，冷却至室温，加入饱和碳酸氢钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝3/1,v/v)分离得黄色固体0.1g，产率为30％。(7-(3-((3'-((2-Chloropyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2 '-Methyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]non-2-yl)carbamic acid tert-butyl ester (0.3 g, 0.4 mmol) and D-pipecolic acid (0.1 g, 0.8 mmol) were dissolved in DMF (15.0 mL), acetic acid (0.2 mL, 3 mmol) was added, heated to 60 ° C for 1.5 h, cooled to room temperature, slowly added cyano boron Sodium hydride (0.12 g, 1.9 mmol), EtOAc (EtOAc m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated .
LC-MS:(pos.ion)m/z：440.3[0.5(M+1)] +； LC-MS: (pos.ion) m/z: 440.3 [0.5 (M+1)] + ;
步骤8)(S)-1-(4-((3'-(3-(2-胺基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1,1'-联苯]-甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐Step 8) (S)-1-(4-((3'-(3-(2-Amino-7-azaspiro[3.5]fluoren-7-yl)propoxy)-2-methyl- [1,1'-biphenyl]-methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetic acid salt
将(S)-1-(4-((3'-(3-(2-((叔丁氧基羰基)胺基)-7-氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.1g,0.1mmol)溶于DCM(25.1mL)，加入TFA(2.0mL)，室温搅拌4h。减压浓缩体系，送制备分离得白色粘稠固体41.3mg，产率为40％。(S)-1-(4-((3'-(3-(2-((tert-Butoxycarbonyl))amino)-7-azaspiro[3.5]indole-7-yl)propoxy -2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl Piperidine-2-carboxylic acid (0.1 g, 0.1 mmol) was dissolved in EtOAc (EtOAc)EtOAc. The system was concentrated under reduced pressure, and then was taken to yield 41.3 mg of white viscous solid, yield 40%.
LC-MS:(pos.ion)m/z：779.2[M+1] +； LC-MS: (pos.ion) m / z: 779.2 [M + 1] +;
1H NMR(600MHz,d 6-DMSO)δ9.59(s,1H),9.04(d,J＝12.3Hz,2H),8.47(s,1H),8.10(s,2H),7.54(s,1H),7.50(d,J＝6.2Hz,1H),7.43–7.35(m,1H),7.34–7.27(m,1H),7.23(d,J＝7.1Hz,2H),6.97(d,J＝6.6Hz,1H),6.90(d,J＝6.4Hz,1H),6.86(s,1H),5.44–5.38(m,2H),5.36–5.25(m,2H),4.38–4.32(m,1H),4.31–4.20(m,1H),4.13–4.07(s,2H),3.47–3.41(m,4H),3.25–3.19(m,2H),3.02–2.92(m,2H),2.91–2.80(m,2H),2.35–2.28(m,1H),2.25(s,3H),2.18-2.06(m,4H),2.03–1.93(m,2H),1.89–1.85(m,1H),1.85–1.60(m,6H),1.60–1.38(m,2H). 1 H NMR (600MHz, d 6 -DMSO) δ9.59 (s, 1H), 9.04 (d, J = 12.3Hz, 2H), 8.47 (s, 1H), 8.10 (s, 2H), 7.54 (s, 1H), 7.50 (d, J = 6.2 Hz, 1H), 7.43 - 7.35 (m, 1H), 7.34 - 7.27 (m, 1H), 7.23 (d, J = 7.1 Hz, 2H), 6.97 (d, J = 6.6 Hz, 1H), 6.90 (d, J = 6.4 Hz, 1H), 6.86 (s, 1H), 5.44 - 5.38 (m, 2H), 5.36 - 5.25 (m, 2H), 4.38 - 4.32 (m, 1H), 4.31–4.20 (m, 1H), 4.13–4.07 (s, 2H), 3.47–3.41 (m, 4H), 3.25–3.19 (m, 2H), 3.02–2.92 (m, 2H), 2.91– 2.80 (m, 2H), 2.35 - 2.28 (m, 1H), 2.25 (s, 3H), 2.18 - 2.06 (m, 4H), 2.03 - 1.93 (m, 2H), 1.89 - 1.85 (m, 1H), 1.85–1.60 (m, 6H), 1.60–1.38 (m, 2H).
实施例37(S)-1-(4-((3'-(3-(2,7-二氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐(化合物37)Example 37(S)-1-(4-((3'-(3-(2,7-diazaspiro[3.5]fluoren-7-yl)propoxy)-2-methyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoro Acetate (Compound 37)
Figure PCTCN2019077582-appb-000089
Figure PCTCN2019077582-appb-000089
步骤1)7-(3-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2'-甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,7-二氮杂螺[3.5]壬-2-羧酸叔丁酯Step 1) 7-(3-((2-Chloro-4-formyl-5-hydroxyphenoxy)methyl)-2'-methyl-[1,1'-biphenyl]-3-yl) Oxy)propyl)-2,7-diazaspiro[3.5]indole-2-carboxylic acid tert-butyl ester
将4-((3'-(3-溴丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)甲氧基]-5-氯-2-羟基苯甲醛(0.5g,1mmol)，2,7-二氮杂螺[3.5]壬-2-羧酸叔丁酯(0.3g,1mmol)溶于DMF(10.1mL)，加入碳酸钾(0.8g,6mmol)，加入NaI(0.2g,1mmol)，升温至75℃搅拌12h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(Hexane/EA＝1/3,v/v)得红色固体0.4g，产率为60％。4-((3'-(3-Bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy]-5-chloro-2 -Hydroxybenzaldehyde (0.5 g, 1 mmol), 2,7-diazaspiro[3.5]indole-2-carboxylic acid tert-butyl ester (0.3 g, 1 mmol) dissolved in DMF (10.1 mL). g, 6 mmol), EtOAc (0.2 g, 1 mmol) After washing with 30 mL), dried over anhydrous sodium sulfate, filtered, washed, evaporated, evaporated, evaporated.
LC-MS:(pos.ion)m/z：636.2[M+1] +； LC-MS: (pos.ion) m/z: 636.2 [M + 1] + ;
步骤2)7-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2'-甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,7-二氮杂螺[3.5]壬-2-羧酸叔丁酯Step 2) 7-(3-((3'-((2-Chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-) 2'-Methyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]indole-2-carboxylic acid tert-butyl ester
将5-(氯甲基)烟腈盐酸盐(0.14g,0.74mmol)溶于DMF(10.1mL)，加入碳酸铯(1.2g,3.7mmol)，室温搅拌10min。加入7-(3-((3'-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2'-甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,7-二氮杂螺[3.5]壬-2-羧酸叔丁酯(0.4g,0.6mmol)和NaI(19.0mg,0.13mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝10/1,v/v)得黄色固体0.36g，产率为80％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.14 g, 0.74 mmol) was dissolved in DMF (10.1 mL). Add 7-(3-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2'-methyl-[1,1'-biphenyl]-3 -yl)oxy)propyl)-2,7-diazaspiro[3.5]indole-2-carboxylic acid tert-butyl ester (0.4 g, 0.6 mmol) and NaI (19.0 mg, 0.13 mmol), warmed to 75 Stir at °C for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (15 mL), EtOAc (EtOAc) (EtOAc) Separation (DCM / MeOH = 10/1, v / v) afforded 0.36 g as a yellow solid.
LC-MS:(pos.ion)m/z：752.2[M+1] +； LC-MS: (pos.ion) m/z: 752.2 [M + 1] + ;
步骤3)(S)-1-(4-((3'-(3-(2-(叔丁氧基羰基)-2,7-二氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3'-(3-(2-(tert-Butoxycarbonyl)-2,7-diazaspiro[3.5]壬-7-yl)propoxy) 2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl Piperidine-2-carboxylic acid
将7-(3-((3'-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2'-甲基-[1,1'-联苯]-3-基)氧基)丙基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.36g,0.48mmol)和D-哌啶酸(0.12g,0.93mmol)溶于DMF(15.0mL)，加入乙酸(0.2mL,3mmol)，加热至60℃搅拌1.5h，冷却至室温，缓慢加入氰基硼氢化钠(0.15g,2.4mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸氢钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤， 洗涤，减压浓缩，柱层析(DCM/MeOH＝3/1,v/v)分离得黄色固体94.2mg，产率为23％。7-(3-((3'-((2-Chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2' -methyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]decane-2-carboxylic acid tert-butyl ester (0.36 g, 0.48 mmol) and D-pipecolic acid (0.12 g, 0.93 mmol) dissolved in DMF (15.0 mL), added acetic acid (0.2 mL, 3 mmol), heated to 60 ° C for 1.5 h, cooled to room temperature, slowly added cyano boron Sodium hydride (0.15 g, 2.4 mmol). The mixture was stirred and cooled to room temperature. The mixture was stirred with EtOAc EtOAc EtOAc. The mixture was concentrated under reduced pressure and purified (jjjjjjjj
LC-MS:(pos.ion)m/z：432.8[0.5(M+1)] +； LC-MS: (pos.ion) m/z: 432.8 [0.5 (M+1)] + ;
步骤4)(S)-1-(4-((3'-(3-(2,7-二氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐Step 4) (S)-1-(4-((3'-(3-(2,7-diazaspiro[3.5]fluoren-7-yl)propoxy)-2-methyl-[1 ,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoro Acetate
将(S)-1-(4-((3'-(3-(2-(叔丁氧基羰基)-2,7-二氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(94.2mg,0.109mmol)溶于DCM(25.1mL)，加入TFA(2.0mL)，室温搅拌4h。减压浓缩体系，送制备分离得黄色粘稠固体34.4mg，产率为36％。(S)-1-(4-((3'-(3-(2-(tert-Butoxycarbonyl)-2,7-diazaspiro[3.5]fluoren-7-yl)propoxy) -2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl) Piperidine-2-carboxylic acid (94.2 mg, 0.109 mmol) was dissolved in EtOAc (EtOAc)EtOAc. The system was concentrated under reduced pressure, and was taken to give a white solid, 34.4 mg.
LC-MS:(pos.ion)m/z：765.2[M+1] +； LC-MS: (pos.ion) m/z: 765.2 [M+1] + ;
1H NMR(600MHz,d 6-DMSO)δ9.93(s,1H),9.19–8.88(m,4H),8.48(s,1H),7.59–7.46(m,2H),7.42–7.35(m,1H),7.34–7.26(m,1H),7.26–7.16(m,2H),6.96(d,J＝6.9Hz,1H),6.90(d,J＝6.3Hz,1H),6.85(s,1H),5.44–5.38(m,2H),5.36–5.25(m,2H),4.40–4.30(m,1H),4.30–4.19(m,1H),4.10(s,2H),3.85(s,2H),3.76(s,2H),3.44–3.40(m,2H),3.21(s,2H),3.04–2.83(m,4H),2.25(s,3H),2.20(d,J＝13.6Hz,2H),2.15(s,3H),1.95–1.84(m,2H),1.80–1.57(m,4H),1.57–1.38(m,2H). 1 H NMR (600 MHz, d 6 -DMSO) δ 9.93 (s, 1H), 9.19 - 8.88 (m, 4H), 8.48 (s, 1H), 7.59 - 7.46 (m, 2H), 7.42 - 7.35 (m) , 1H), 7.34 - 7.26 (m, 1H), 7.26 - 7.16 (m, 2H), 6.96 (d, J = 6.9 Hz, 1H), 6.90 (d, J = 6.3 Hz, 1H), 6.85 (s, 1H), 5.44–5.38 (m, 2H), 5.36–5.25 (m, 2H), 4.40–4.30 (m, 1H), 4.30–4.19 (m, 1H), 4.10 (s, 2H), 3.85 (s, 2H), 3.76 (s, 2H), 3.44 - 3.40 (m, 2H), 3.21 (s, 2H), 3.04 - 2.83 (m, 4H), 2.25 (s, 3H), 2.20 (d, J = 13.6 Hz) , 2H), 2.15 (s, 3H), 1.95–1.84 (m, 2H), 1.80–1.57 (m, 4H), 1.57–1.38 (m, 2H).
实施例67(2S)-1-(4-((3'-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物67)Example 67(2S)-1-(4-((3'-(3-(2-oxa-7-azaspiro[4.5]fluoren-7-yl)propoxy)-2-methyl- [1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 67)
Figure PCTCN2019077582-appb-000090
Figure PCTCN2019077582-appb-000090
步骤1)4-((3'-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3'-(3-(2-oxa-7-azaspiro[4.5]癸-7-yl)propoxy)-2-methyl-[1,1'-linked Benzyl-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-((3'-(3-溴丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(740mg,1.51mmol)和2-氧杂-7-氮杂螺[4.5]癸烷盐酸盐(402.6mg,2.27mmol)的DMF(20mL)溶液中，依次加入碳酸钾(522mg,3.77mmol)和NaI(339.7mg,2.26mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)，得到黄色油状液体370mg，产率44.52％。To 4-((3'-(3-bromopropoxy)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2 under nitrogen -Hydroxybenzaldehyde (740 mg, 1.51 mmol) and 2-oxa-7-azaspiro[4.5]decane hydrochloride (402.6 mg, 2.27 mmol) in DMF (20 mL) , 3.77 mmol) and NaI (339.7 mg, 2.26 mmol), heated to 70 ° C, and reacted for 16 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc)EtOAc. Purification by chromatography (DCM / MeOH = 10/1, v/v)
LC-MS:(pos.ion)m/z：550.1[M+1] +； LC-MS: (pos.ion) m/z: 550.1 [M+1] + ;
步骤2)5-((5-((3'-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3'-(3-(2-oxa-7-azaspiro[4.5]]-7-yl)propoxy)-2-methyl-[1, 1'-Biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
将4-((3'-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(370mg,067mmol)和5-氯甲基-3-氰基吡啶盐酸盐(148.8mg,0.81mmol)的DMF溶液(20mL)中，依次加入碳酸铯(534.3mg,1.68mmol)和碘化钠(19.66mg,0.13mmol)，N 2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1,v/v)得到黄色油状液体400mg，产率89.27％。 4-((3'-(3-(2-oxa-7-azaspiro[4.5]癸-7-yl)propoxy)-2-methyl-[1,1'-biphenyl]] -3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (370 mg, 067 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (148.8 mg, 0.81 mmol) in DMF ( In 20 mL), cesium carbonate (534.3 mg, 1.68 mmol) and sodium iodide (19.66 mg, 0.13 mmol) were successively added, protected with N 2 and reacted at 75 ° C for 4 h. Stirring was continued, the mixture was cooled to room temperature, diluted with water (20 mL), EtOAc (EtOAc (EtOAc) Separation and purification (DCM / MeOH = 10/1, v/v) afforded 400 mg ofyel.
LC-MS:(pos.ion)m/z：666.2[M+1] +； LC-MS: (pos.ion) m/z: 666.2 [M+1] + ;
步骤3)(2S)-1-(4-((3'-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(4-((3'-(3-(2-oxa-7-azaspiro[4.5]癸-7-yl)propoxy)-2-methyl- [1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((5-((3'-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2-甲基-[1,1'-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(400mg,0.6mmol)和D-哌啶酸(155.1mg,1.2mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，60℃反应1h，冷却至室温，再向反应体系中加入硼***(188.7mg,3mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1,v/v)，得到淡黄色固体92mg，产率19.66％。5-((5-((3'-(3-(2-oxa-7-azaspiro[4.5]癸-7-yl)propoxy)-2-methyl-[1,1') -biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (400 mg, 0.6 mmol) and D-pipecolic acid (155.1 mg, 1.2 mmol) Add acetic acid to the solution of DMF (10mL), adjust the pH to about 5, react at 60 ° C for 1h, cool to room temperature, then add sodium borohydride (188.7mg, 3mmol) to the reaction system, react at room temperature for 3h, then react at 80 °C 16h. Stirring was stopped, saturated potassium carbonate solution was added and stirred for 30 min. Diluted with water (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. MeOH = 4/1, v/v) gave a pale yellow solid (yield:
LC-MS:(pos.ion)m/z：779.2[M+1] +； LC-MS: (pos.ion) m / z: 779.2 [M + 1] +;
1H NMR(400MHz,d 6-DMSO)δ9.04–8.97(m,2H),8.45(s,1H),7.49(d,J＝7.2Hz,1H),7.42(s,1H),7.35(t,J＝7.9Hz,1H),7.28(t,J＝7.5Hz,1H),7.21(d,J＝7.2Hz,1H),7.12(s,1H),6.93(d,J＝8.3Hz,1H),6.88–6.81(m,2H),5.34(s,2H),5.26(s,2H),4.05(t,J＝6.2Hz,2H),3.79(d,J＝13.9Hz,1H),3.66(dd,J＝18.6,11.5Hz,4H),3.55(d,J＝8.1Hz,1H),3.51(s,1H),3.32(d,J＝8.5Hz,2H),3.15(d,J＝4.3Hz,1H),2.34–2.26(m,2H),2.24(s,4H),1.90(d,J＝5.6Hz,2H),1.79(s,1H),1.75–1.67(m,2H),1.56–1.31(m,10H),1.23(s,1H). 1 H NMR (400 MHz, d 6 -DMSO) δ 9.04 - 8.97 (m, 2H), 8.45 (s, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.42 (s, 1H), 7.35 ( t, J = 7.9 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.12 (s, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.88–6.81 (m, 2H), 5.34 (s, 2H), 5.26 (s, 2H), 4.05 (t, J = 6.2 Hz, 2H), 3.79 (d, J = 13.9 Hz, 1H), 3.66 (dd, J = 18.6, 11.5 Hz, 4H), 3.55 (d, J = 8.1 Hz, 1H), 3.51 (s, 1H), 3.32 (d, J = 8.5 Hz, 2H), 3.15 (d, J) =4.3 Hz, 1H), 2.34 - 2.26 (m, 2H), 2.24 (s, 4H), 1.90 (d, J = 5.6 Hz, 2H), 1.79 (s, 1H), 1.75 - 1.67 (m, 2H) , 1.56–1.31 (m, 10H), 1.23 (s, 1H).
本发明化合物的体外抗肿瘤活性测定Determination of in vitro antitumor activity of the compounds of the invention
体外酶学水平的检测方法采用Cisbio公司PD-1/PD-L1 binding assay kit检测试剂盒In vitro enzyme level detection method using Cisbio PD-1/PD-L1 binding assay kit
1.实验原理：1. Experimental principle:
PD-1蛋白带HIS标签，PD-1的配体PD-L1带hFc标签，分别用Eu标记的anti-hFc抗体和XL665标记的anti-HIS抗体与两个标签蛋白结合。激光激发后，能量能够从供体Eu上转移到受体XL665，使得XL665发光。而加入抑制剂后，阻断了PD-1与配体PD-L1的结合，使得Eu和XL665距离较远，能量不能转移，XL665不发光。The PD-1 protein carries the HIS tag, and the PD-1 ligand PD-L1 carries the hFc tag, which binds to the two tagged proteins with the Eu-labeled anti-hFc antibody and the XL665-labeled anti-HIS antibody, respectively. After laser excitation, energy can be transferred from the donor Eu to the acceptor XL665, causing the XL665 to illuminate. After the addition of the inhibitor, the binding of PD-1 to the ligand PD-L1 was blocked, so that Eu and XL665 were far apart, energy could not be transferred, and XL665 did not emit light.
2.实验方法：2. Experimental method:
使用Cisbio Bioassays的HTRF测定试剂盒(目录号64ICP01PEG)进行PD1/PD-L1结合测定,具体操作方法参照试剂盒说明进行。简单叙述如下，使用384孔白色酶标板，将化合物溶于DMSO溶液中,浓度为10mM。首先将化合物储备溶液用稀释剂稀释40倍，然后使用含有2.5％DMSO的试剂盒稀释缓冲液稀释5倍。在每个孔中加入4ul的稀释液或稀释液稀释的目标化合物，最终的DMSO浓度为0.5％。PD1和PD-L1溶液分别以每孔3ul加入，化合物与PD1和PD-L1预孵育10分钟后，将按照产品说明书制备的10ul检测抗体加入到每个孔中。在室温下孵育平板过夜后，通过在PHERAstar FS酶标仪(BMG，德国)中读取平板获得数据。HTRF信号计算为10000×(665/620比率)。将各化合物的计算信号拟合成具有可变斜率的S形剂量-反应曲线，并且通过曲线拟合(GraphPad Prism 7)获得IC  50值。 The PD1/PD-L1 binding assay was performed using the HTRF assay kit (catalog number 64 ICP01 PEG) of Cisbio Bioassays, and the specific method of operation was carried out with reference to the kit instructions. Briefly described below, the compound was dissolved in DMSO at a concentration of 10 mM using a 384-well white ELISA plate. The compound stock solution was first diluted 40-fold with a diluent and then diluted 5 times using a kit dilution buffer containing 2.5% DMSO. A 4 ul dilution or dilution of the target compound was added to each well to give a final DMSO concentration of 0.5%. The PD1 and PD-L1 solutions were added at 3 ul per well, respectively. After pre-incubation of the compound with PD1 and PD-L1 for 10 minutes, 10 ul of the detection antibody prepared according to the manufacturer's instructions was added to each well. After incubating the plates overnight at room temperature, data were obtained by reading the plates in a PHERAstar FS plate reader (BMG, Germany). The HTRF signal is calculated to be 10000 x (665/620 ratio). The calculated signal is fitted to each of Compound S-shaped dose-response with variable slope - response curves and IC 50 values obtained by curve fitting (GraphPad Prism 7).
实验结果如下：The experimental results are as follows:
表2本发明化合物在分子水平对PD-1/PD-L1相互作用的抑制活性评价Table 2 Evaluation of the inhibitory activity of the compounds of the present invention on PD-1/PD-L1 interaction at the molecular level
实施例编号Example number IC 50(nM) IC 50 (nM) 实施例编号Example number IC 50(nM) IC 50 (nM)
22 1.811.81 23twenty three 2.142.14
55 1.931.93 24twenty four 2.142.14
77 2.352.35 2525 1.831.83
88 2.502.50 2626 3.883.88
99 2.112.11 2727 1.501.50
1010 2.992.99 2929 1.601.60
1111 1.101.10 3030 2.712.71
1313 1.501.50 3131 2.622.62
1414 1.371.37 3333 1.301.30
1515 2.432.43 3434 2.002.00
1616 3.853.85 3535 2.592.59
1717 1.681.68 3636 3.373.37
1818 2.652.65 3737 3.163.16
1919 3.043.04 121121 1.501.50
2020 4.014.01 160160 1.891.89
22twenty two 3.103.10    
实验结论：Experimental results:
从表中可见，本发明化合物在分子水平可显著抑制PD-1与PD-L1的相互作用，因此可用于治疗与PD-1/PD-L1的相互作用相关的疾病。As can be seen from the table, the compound of the present invention can significantly inhibit the interaction of PD-1 with PD-L1 at the molecular level, and thus can be used for the treatment of diseases associated with the interaction of PD-1/PD-L1.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of the present specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" and the like means a specific feature described in connection with the embodiment or example. A structure, material or feature is included in at least one embodiment or example of the invention. In the present specification, the schematic representation of the above terms is not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples. In addition, various embodiments or examples described in the specification, as well as features of various embodiments or examples, may be combined and combined.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described, it is understood that the above-described embodiments are illustrative and are not to be construed as limiting the scope of the invention. The embodiments are subject to variations, modifications, substitutions and variations.

Claims (27)

  1. 一种如式(I)所示的化合物a compound as shown in formula (I)
    Figure PCTCN2019077582-appb-100001
    Figure PCTCN2019077582-appb-100001
    或如式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药，其中：Or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug of a compound of formula (I) ,among them:
    R 1为-(CH 2) nAr，其中，Ar为C 6-12芳基或C 5-12杂芳基，所述Ar任选地被1、2、3或4个取代基所取代，所述取代基各自独立地为H、D、氰基、卤素、氨基、甲磺酰基、乙酰氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或C 1-6烷氧基；n为1、2、3或4； R 1 is -(CH 2 ) n Ar, wherein Ar is a C 6-12 aryl group or a C 5-12 heteroaryl group, and the Ar is optionally substituted with 1, 2, 3 or 4 substituents, The substituents are each independently H, D, cyano, halogen, amino, methylsulfonyl, acetylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1 -6 alkoxy; n is 1, 2, 3 or 4;
    A为-CH 2O-、-OCH 2-、-CH 2-CH 2-、-C(O)NH-或-NHC(O)-； A is -CH 2 O-, -OCH 2 -, -CH 2 -CH 2 -, -C(O)NH- or -NHC(O)-;
    R 2为
    Figure PCTCN2019077582-appb-100002
    R 2 is
    Figure PCTCN2019077582-appb-100002
    其中，R 5和R 6各自独立地为H、D、卤素、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；Z为CH或N； Wherein R 5 and R 6 are each independently H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; Z is CH or N;
    R 7为
    Figure PCTCN2019077582-appb-100003
    q为1、2、3或4；     R 7 is
    Figure PCTCN2019077582-appb-100003
    q is 1, 2, 3 or 4;
    R v为
    Figure PCTCN2019077582-appb-100004
    其中，所述R v任选地被0、1、2或3个取代基所取代，所述取代基各自独立地为羟基、氰基、氨基、氧代(＝O)、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或氨基C 1-6烷基；W 1、W 3和W 5各自独立地为CH 2、S、O、S(O) 2或NH，W 2和W 4各自独立地为CH或者N；m1、m2、m3、m4、m5、m6、m7和m8各自独立地为0、1、2或3；     R v is
    Figure PCTCN2019077582-appb-100004
    Wherein R v is optionally substituted by 0, 1, 2 or 3 substituents, each independently being hydroxy, cyano, amino, oxo (=O), C 1-6 alkane a group, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or amino C 1-6 alkyl; W 1 , W 3 and W 5 are each independently CH 2 , S, O, S(O) 2 or NH, W 2 and W 4 are each independently CH or N; m1, m2, m3, m4, m5, m6, m7 and m8 are each independently 0, 1, 2 or 3;
    R 3为C 1-8烷氨基或C 3-9杂环基，其中，所述的C 3-9杂环基中至少含有一个N原子；所述的C 1-8烷氨基或C 3- 9杂环基任选地被0、1、2、3或4个取代基所取代，所述取代基各自独立地为H、D、羟基、卤素、羧基、C 1- 6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基、氨基、氨基C 1-6烷基、乙酰氨基、氰基、磺酰胺基或氧代(＝O)； R 3 is a C 1-8 alkylamino group or a C 3-9 heterocyclic group, wherein the C 3-9 heterocyclic group contains at least one N atom; the C 1-8 alkylamino group or C 3− 9 heterocyclyl are optionally substituted with 0,1, 2,3 or 4 substituents, each substituent independently is H, D, hydroxy, halogen, carboxy, C 1- 6 -alkyl, C 1 -6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, amino, amino C 1-6 alkyl, acetylamino, cyano, sulfonamide or oxo (=O);
    P为0、1、2或3；P is 0, 1, 2 or 3;
    X和Y各自独立地为H、D、C 1-6烷基、C 1-6烷氧基、卤素或氰基。 X and Y are each independently H, D, C 1-6 alkyl, C 1-6 alkoxy, halogen or cyano.
  2. 如权利要求1所述的化合物，其中：The compound of claim 1 wherein:
    Ar为苯基、吡啶基、嘧啶基、吲哚基或喹啉基，所述的Ar任选地被1、2、3或4个取代基取代，所述取代基各自独立地为H、D、氰基、卤素、氨基、甲磺酰基、乙酰氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基或C 1-6烷氧基。 Ar is a phenyl group, a pyridyl group, a pyrimidinyl group, a fluorenyl group or a quinolyl group, and the Ar is optionally substituted by 1, 2, 3 or 4 substituents each independently H, D , cyano, halogen, amino, methylsulfonyl, acetylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy.
  3. 如权利要求1或2所述的化合物，所述的R v为以下结构式形成的基团之一： The compound according to claim 1 or 2, wherein R v is one of the groups formed by the following structural formula:
    Figure PCTCN2019077582-appb-100005
    Figure PCTCN2019077582-appb-100005
    Figure PCTCN2019077582-appb-100006
    Figure PCTCN2019077582-appb-100006
    其中，所述W 1、W 3和W 5各自独立地为CH 2、S、S(O) 2或NH，W 2和W 4各自独立地为CH或者N；R v任选地被0、1、2或3个取代基取代，所述取代基各自独立地为羟基、氰基、氨基、氧代(＝O)、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或氨基C 1-6烷基。 Wherein, W 1 , W 3 and W 5 are each independently CH 2 , S, S(O) 2 or NH, and W 2 and W 4 are each independently CH or N; R v is optionally 0, Substituted by 1, 2 or 3 substituents, each of which is independently hydroxy, cyano, amino, oxo (=O), C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 Haloalkoxy, C 1-6 alkoxy or amino C 1-6 alkyl.
  4. 如权利要求1-3任意一项所述的化合物，所述的R v为以下结构式形成的基团之一： The compound according to any one of claims 1 to 3, wherein R v is one of the groups formed by the following structural formula:
    Figure PCTCN2019077582-appb-100007
    Figure PCTCN2019077582-appb-100007
    Figure PCTCN2019077582-appb-100008
    Figure PCTCN2019077582-appb-100008
    其中，所述R v可任选的被0、1、2或3个取代基取代，所述取代基各自独立地为羟基、氰基、氨基、氧代(＝O)、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或氨基C 1-6烷基。 Wherein R v is optionally substituted by 0, 1, 2 or 3 substituents, each of which is independently hydroxy, cyano, amino, oxo (=O), C 1-6 alkane A C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a C 1-6 alkoxy group or an amino C 1-6 alkyl group.
  5. 如权利要求1-4任意一项所述的化合物，其中：A compound according to any one of claims 1 to 4, wherein:
    R 5和R 6各自独立地为H、D、氟、氯、溴、甲基、乙基、正丙基、异丙基、叔丁基、异丁基、正丁基、三氟甲基、二氟甲基、一氟甲基、甲氧基或乙氧基。 R 5 and R 6 are each independently H, D, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl, n-butyl, trifluoromethyl, Difluoromethyl, monofluoromethyl, methoxy or ethoxy.
  6. 如权利要求1-5任意一项所述的化合物，所述的R 3为如下结构形成的基团之一： The compound according to any one of claims 1 to 5, wherein R 3 is one of the groups formed by the following structure:
    Figure PCTCN2019077582-appb-100009
    Figure PCTCN2019077582-appb-100009
  7. 如权利要求1-6任意一项所述的化合物，其为如式(II)所示的化合物，或其立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，酯，药学上可接受的盐或前药，The compound according to any one of claims 1 to 6, which is a compound represented by the formula (II), or a stereoisomer thereof, a geometric isomer, a tautomer, an oxynitride or a hydrate. , solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug,
    Figure PCTCN2019077582-appb-100010
    Figure PCTCN2019077582-appb-100010
    其中，R 1为-(CH 2) nAr，其中，Ar为苯基、吡啶基、嘧啶基、吲哚基或喹啉基；所述Ar任选地被1、 2、3或4个取代基取代，所述取代基各自独立地为H、D、氰基、卤素、氨基、甲磺酰基、乙酰氨基、C 1- 6烷基或C 1-6烷氧基；n为1、2、3或4。 Wherein R 1 is -(CH 2 ) n Ar, wherein Ar is phenyl, pyridyl, pyrimidinyl, indenyl or quinolyl; said Ar is optionally substituted by 1, 2, 3 or 4 substituted, the substituents are each independently H, D, cyano, halo, amino, methylsulfonyl, acetamido, C 1- 6 alkyl or C 1-6 alkoxy; n is 1,2, 3 or 4.
  8. 如权利要求1-7任意一项所述的化合物，包含以下其中之一的化合物或以下其中之一的化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或前药：The compound according to any one of claims 1 to 7, which comprises a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate of a compound of one of the following compounds or one of the following compounds. , solvate, metabolite, pharmaceutically acceptable salt or prodrug:
    Figure PCTCN2019077582-appb-100011
    Figure PCTCN2019077582-appb-100011
    Figure PCTCN2019077582-appb-100012
    Figure PCTCN2019077582-appb-100012
    Figure PCTCN2019077582-appb-100013
    Figure PCTCN2019077582-appb-100013
    Figure PCTCN2019077582-appb-100014
    Figure PCTCN2019077582-appb-100014
    Figure PCTCN2019077582-appb-100015
    Figure PCTCN2019077582-appb-100015
    Figure PCTCN2019077582-appb-100016
    Figure PCTCN2019077582-appb-100016
    Figure PCTCN2019077582-appb-100017
    Figure PCTCN2019077582-appb-100017
    Figure PCTCN2019077582-appb-100018
    Figure PCTCN2019077582-appb-100018
    Figure PCTCN2019077582-appb-100019
    Figure PCTCN2019077582-appb-100019
    Figure PCTCN2019077582-appb-100020
    Figure PCTCN2019077582-appb-100020
    Figure PCTCN2019077582-appb-100021
    Figure PCTCN2019077582-appb-100021
    Figure PCTCN2019077582-appb-100022
    Figure PCTCN2019077582-appb-100022
    Figure PCTCN2019077582-appb-100023
    Figure PCTCN2019077582-appb-100023
    Figure PCTCN2019077582-appb-100024
    Figure PCTCN2019077582-appb-100024
  9. 一种药物组合物，包含权利要求1-8任一项所述的化合物，及其药学上可接受的辅料或它们的组合。A pharmaceutical composition comprising a compound of any of claims 1-8, and a pharmaceutically acceptable adjuvant thereof, or a combination thereof.
  10. 使用权利要求1-8任一项所述的化合物或权利要求9所述的药物组合物在制备用于防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病的药物的用途。Use of the compound of any one of claims 1-8 or the pharmaceutical composition of claim 9 for the preparation of a medicament for the protection, treatment, treatment or alleviation of a disease associated with a PD-1/PD-L1 signaling pathway in a patient use.
  11. 如权利要求10所述的用途，其中所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。The use according to claim 10, wherein the disease associated with the PD-1/PD-L1 signaling pathway is cancer, an infectious disease or an autoimmune disease.
  12. 如权利要求11所述的用途，其中所述的癌症为器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述自身免疫性疾病为器官特异性自身免 疫病或***性自身免疫病。The use according to claim 11, wherein the cancer is a disease in which an immortalized cell exists in an organ or a body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease or a fungal infectious disease; Autoimmune diseases are organ-specific autoimmune diseases or systemic autoimmune diseases.
  13. 如权利要求12所述的用途，其中所述的器官或体组织中细胞无限增殖的疾病为骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、***区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、***、***癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌***癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、***癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经***(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤或环境诱发的癌症或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。The use according to claim 12, wherein the disease in which the cells in the organ or body tissue are immortalized are bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anus Regional cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, Thyroid cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, solid tumor of children, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) Tumor, primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmental induction a combination of cancer or a disease as described above; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and Lymphocytic leukemia.
  14. 如权利要求12所述的用途，其中所述的病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、***瘤病毒感染和流感。The use according to claim 12, wherein the viral infectious diseases are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection and influenza.
  15. 如权利要求12所述的用途，其中所述的器官特异性自身免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的***性自身免疫病为类风湿关节炎、***性红斑狼疮、***性血管炎、硬皮病、天疱疮、皮肌炎、混合性***病和自身免疫性溶血性贫血。The use according to claim 12, wherein said organ-specific autoimmune disease is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophy Gastritis, pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus , systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease and autoimmune hemolytic anemia.
  16. 一种防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病的方法，所述方法包含给予患者有效治疗剂量的如权利要求1-8任意一项所述的化合物或权利要求9所述的药物组合物。A method of protecting, treating, treating or ameliorating a disease associated with a PD-1/PD-L1 signaling pathway in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound or claim according to any one of claims 1-8 The pharmaceutical composition of claim 9.
  17. 如权利要求16所述的方法，其中所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。The method of claim 16, wherein the disease associated with the PD-1/PD-L1 signaling pathway is cancer, an infectious disease or an autoimmune disease.
  18. 如权利要求17所述的方法，其中所述的癌症为器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述的自身免疫性疾病为器官特异性自身免疫病或***性自身免疫病。The method according to claim 17, wherein said cancer is a disease in which cells are immortalized in an organ or body tissue; said infectious disease is a bacterial infectious disease, a viral infectious disease or a fungal infectious disease; The autoimmune disease is an organ-specific autoimmune disease or a systemic autoimmune disease.
  19. 如权利要求18所述的方法，其中所述的器官或体组织中细胞无限增殖的疾病是指骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、***区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、***、***癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌***癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、***癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经***(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤和环境诱发的癌症，或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、 慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。The method according to claim 18, wherein the disease in which the cells in the organ or body tissue are immortalized refers to bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anus Regional cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, Thyroid cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, solid tumor of children, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) Tumor, primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, and environmental induction Cancer, or a combination of the above; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocyte white blood And chronic lymphocytic leukemia.
  20. 如权利要求18所述的方法，其中所述的病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、***瘤病毒感染和流感。The method according to claim 18, wherein said viral infectious diseases are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection and influenza.
  21. 如权利要求18所述的方法，其中所述的器官特异性自身免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的***性自身免疫病为类风湿关节炎、***性红斑狼疮、***性血管炎、硬皮病、天疱疮、皮肌炎、混合性***病和自身免疫性溶血性贫血。The method according to claim 18, wherein said organ-specific autoimmune disease is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophy Gastritis, pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus , systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease and autoimmune hemolytic anemia.
  22. 如权利要求1-8任意一项所述的化合物或权利要求9所述的药物组合物用于防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病。A compound according to any one of claims 1-8 or a pharmaceutical composition according to claim 9 for use in protecting, treating, treating or ameliorating a disease associated with a PD-1/PD-L1 signaling pathway in a patient.
  23. 如权利要求22所述的用途，其中所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。The use according to claim 22, wherein the disease associated with the PD-1/PD-L1 signaling pathway is cancer, an infectious disease or an autoimmune disease.
  24. 如权利要求23所述的用途，其中所述的癌症为器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述的自身免疫性疾病为器官特异性自身免疫病或***性自身免疫病。The use according to claim 23, wherein the cancer is a disease in which an immortalized cell exists in an organ or a body tissue; the infectious disease is a bacterial infectious disease, a viral infectious disease or a fungal infectious disease; The autoimmune disease is an organ-specific autoimmune disease or a systemic autoimmune disease.
  25. 如权利要求24所述的用途，其中所述的器官或体组织中细胞无限增殖的疾病是指骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、***区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、***、***癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌***癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、***癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经***(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤和环境诱发的癌症，或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。The use according to claim 24, wherein the disease in which the cells in the organ or body tissue are immortalized refers to bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anus Regional cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, Thyroid cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, solid tumor of children, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) Tumor, primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, and environmental induction Cancer, or a combination of the above; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocyte white blood And chronic lymphocytic leukemia.
  26. 如权利要求24所述的用途，其中所述的病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、***瘤病毒感染和流感。The use according to claim 24, wherein the viral infectious diseases are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection and influenza.
  27. 如权利要求24所述的用途，其中所述的器官特异性自身免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的***性自身免疫病为类风湿关节炎、***性红斑狼疮、***性血管炎、硬皮病、天疱疮、皮肌炎、混合性***病和自身免疫性溶血性贫血。The use according to claim 24, wherein said organ-specific autoimmune disease is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophy Gastritis, pulmonary hemorrhagic nephritis syndrome, primary biliary cirrhosis, multiple cerebrospinal sclerosing and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus , systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease and autoimmune hemolytic anemia.
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