CN116924983A - Novel heterocyclic compound - Google Patents

Novel heterocyclic compound Download PDF

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Publication number
CN116924983A
CN116924983A CN202210327578.2A CN202210327578A CN116924983A CN 116924983 A CN116924983 A CN 116924983A CN 202210327578 A CN202210327578 A CN 202210327578A CN 116924983 A CN116924983 A CN 116924983A
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alkyl
membered
cycloalkyl
substituted
amino
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娄振邦
胡玟奇
张权浩
王业柳
商现星
刘爽
史俊芬
王鹤
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Capital Pharmaceutical Holdings Beijing Co ltd
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Capital Pharmaceutical Holdings Beijing Co ltd
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Priority to PCT/CN2023/084314 priority patent/WO2023185811A1/en
Publication of CN116924983A publication Critical patent/CN116924983A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a novel heterocyclic compound; specifically, the invention provides a compound shown in a formula (I) or pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, a pharmaceutical composition containing the compound, and application of the compound in preparation of medicines for treating MAT 2A-related diseases.

Description

Novel heterocyclic compound
Technical Field
The present invention relates to a novel heterocyclic compound or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, a pharmaceutical composition containing the same and use as an MAT2A inhibitor.
Background
Methylthioadenosine phosphorylase (Methylthioadenosine phosphorylase, MTAP) is an enzyme present in all normal tissues and catalyzes the production of Methylthioadenosine (MTA) into methylthioribo-1-phosphate (MTR-1P) and adenine. MTAP gene is located in the region of human chromosome 9p21, and also located in this region are the oncogenes p15INK2A (also known as CDKN 2A) and p15INK4B. About 15% of human cancers have homozygous MTAP gene deletions, such as primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, and the like, and are often accompanied by co-deletions of the cancer suppressor gene CDKN 2A. This co-deletion results in poor prognosis of invasive tumors, lacking effective molecular targeted therapies.
Methionine adenosyltransferase (Methionine adenosyltransferase, MAT), also known as S-adenosylmethionine synthetase, is involved in the rate limiting step of methionine circulation, catalyzing the synthesis of S-adenosylmethionine (S-adenosyl methionine, SAM) from methionine and ATP. SAM is the main methyl donor in cells, used for methylation of DNA, RNA and proteins and other substrates, involved in a variety of biological processes. Methionine adenosyltransferase 2A (Methionine adenosyltransferase a, MAT 2A) is one of the members of the MAT family of proteins, in addition to which the MAT family has two members, MAT1A and MAT 2B. MAT1A is specifically expressed in liver, MAT2A is widely distributed, and MAT1A and MAT2A can catalyze the synthesis of SAM, but the catalytic dynamics and regulation properties of the two are different. MAT2B was not catalytically active and formed dimers with MAT2A as a regulatory subunit, resulting in conformational changes in MAT2A, regulating MAT2A activity by increasing affinity of MAT2A for methionine and SAM.
MAT2A was identified as a synthetic lethal target in MTAP-deleted cancers. It was found that in shRNA screening of approximately 400 cancer cell lines, MAT2A knockdown resulted in more MTAP-deficient cells being inactivated compared to MTAP-expressing cells. Furthermore, inducible knockdown of MAT2A protein reduced tumor growth in vivo, and these results suggest that MAT2A inhibitors may provide a novel treatment for MTAP-deficient cancer patients. Further studies have found that inhibition of MAT2A in MTAP-deleted cells inhibits the activity of the protein arginine N-methyltransferase 5 (Protein arginine methyltransferase, PRMT5). PRMT5 utilizes SAM as a methyl donor, and can methylate various proteins (including histones and nonhistones) to participate in the processes of gene transcription and translation, cell proliferation and the like. MTA, a substrate of MTAP, is a potent inhibitor of PRMT5, and MTA accumulates in large amounts in MTAP-deficient tumor cells, reducing the catalytic activity of PRMT 5. MTAP-deleted cells are more dependent on SAM production and thus MAT2A activity than MTAP-expressing cells. Inhibition of MAT2A activity can reduce intracellular SAM concentration, selectively reducing PRMT5 activity in MTAP-deficient cells. Thus, targeting MAT2A can specifically inhibit proliferation of MTAP-deleted tumor cells by inhibiting PRMT5 activity, thereby producing a synthetic lethal effect.
MAT2A inhibitor may provide a new treatment method for MTAP-deficient cancer patients, and is an innovative field with wide development space. WO2018039972, WO2020123395 and the like disclose MAT2A inhibitor compounds.
The patent describes 4-aminoquinoline derivatives which have good inhibitory activity on MAT2A and also have good inhibitory activity on MTAP-deleted tumor cells. In addition, the compound has excellent oral bioavailability, plasma protein adsorption, pharmacokinetic characteristics and in-vivo efficacy of animals; has low toxicity, CYP-inhibition, etc.
Disclosure of Invention
The invention provides an MAT2A inhibitor which is a compound shown in a general formula (I) or pharmaceutically acceptable salt, solvate, polymorph or isomer thereof. The invention also provides a series of compounds represented by the general formula (I) and pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof, pharmaceutical compositions containing the compounds, methods for treating MAT 2A-related diseases by using the compounds and compositions thereof, and application of the compounds and compositions thereof in preparing medicines for treating MAT 2A-related diseases.
In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof,
wherein,,
l is a bond or CH 2 ，CH 2 Can optionally be C 1-6 Alkyl or 3-8 membered cycloalkyl,
X 1 、X 2 and X 3 Each independently selected from N and CR 4 ，
R 1 Selected from C 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally being substituted by halogen, -CN, -OH, -NH 2 、C 1 - 6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-N (R) -C 1-6 An alkyl group is substituted and a substituent is substituted,
R 2 is a 3-8 membered carbocycle, 3-8 membered heterocycle, benzene ring, or 5-6 membered heteroaryl ring, the carbocycle, heterocycle, benzene ring, and heteroaryl ring optionally being fused to a 3-8 membered carbocycle, 3-8 membered heterocycle, benzene ring, or 5-6 membered heteroaryl ring, the carbocycle, heterocycle, benzene ring, or heteroaryl ring optionally being fused to 1-3R 12 Instead of the above-mentioned,
R 12 each independently selected from halogen, CF 3 、-CN、-OH、-NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl and-N (R) -C 1-6 Alkyl, said alkyl, cycloalkyl and heterocycloalkyl being optionally substituted by halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl, or-N (R) -C 1-6 An alkyl group is substituted and a substituent is substituted,
R 3 selected from H, halogen, CF 3 、-CN、-OH、-NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl, -N (R) -C 1-6 Alkyl groupThe alkyl, cycloalkyl and heterocycloalkyl groups may optionally be substituted with halogen, -CN, -OH, -NH 2 、C 1 - 6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl, or-N (R) -C 1-6 An alkyl group is substituted and a substituent is substituted,
R 4 each independently selected from H, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl and-N (R) -C 1-6 Alkyl, said alkyl, cycloalkyl and heterocycloalkyl being optionally substituted by halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl, or-N (R) -C 1-6 Alkyl substitution
R is each independently selected from C 1-6 Alkyl, 3-8 membered cycloalkyl and 3-8 membered heterocycloalkyl, which alkyl, cycloalkyl and heterocycloalkyl may optionally be halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl,
R 10 and R is 11 Each independently selected from C 1-6 Alkyl and 3-8 membered cycloalkyl groups, which may optionally be substituted with halogen, -CN, -OH, or-NH 2 Instead of the above-mentioned,
with the proviso that the following compounds are excluded:
in certain embodiments, L is a bond;
in certain embodiments, R 1 Selected from C 1-6 Alkyl, 3-8 membered cycloalkyl and 3-8 membered heterocycloalkyl, which alkyl, cycloalkyl and heterocycloalkyl may optionally be halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8Membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-N (R) -C 1-6 Alkyl substitution;
in certain embodiments, R 1 Selected from C 1-6 Alkyl, 3-8 membered cycloalkyl and 3-8 membered heterocycloalkyl, preferably C 1-6 An alkyl group;
in certain embodiments, R3 is selected from H, halogen, CF 3 、-CN、-OH、-NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groupsR 10 And R is 11 As defined above;
in certain embodiments, R 2 Is a benzene ring or a 5-6 membered heteroaromatic ring, which may optionally be fused with a 3-8 membered carbocyclic ring, a 3-8 membered heterocyclic ring, a benzene ring, or a 5-6 membered heteroaromatic ring, which carbocyclic ring, heterocyclic ring, benzene ring, or heteroaromatic ring may optionally be substituted with 1-3R 12 Substituted, R 12 As defined above;
in certain embodiments, R 4 Each independently selected from H, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl and-N (R) -C 1-6 Alkyl, said alkyl, cycloalkyl and heterocycloalkyl optionally being halogen, -CN, -OH, or-NH 2 Substitution;
in certain embodiments, R 4 Each independently selected from H, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl and-N (R) -C 1-6 Alkyl, preferably H, halogen, -CN, -OH, -NH 2 Or C 1-6 An alkyl group;
in certain embodiments, R is selected from C 1-6 Alkyl, 3-8 membered cycloalkyl and 3-8 membered heterocycloalkyl, preferably C 1-6 An alkyl group;
in certain embodiments, R 10 And R is 11 Each independently selected from C 1-6 Alkyl and 3-8 membered cycloalkyl, preferably C 1-6 An alkyl group;
in some embodiments of the invention, the compounds of the invention are selected from:
or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof. In some embodiments, the pharmaceutical compositions of the present invention further comprise pharmaceutically acceptable excipients.
In another aspect, the present invention provides a method of treating a disorder associated with MAT2A, comprising administering to a subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a pharmaceutical composition thereof;
In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disorder associated with MAT 2A.
In some embodiments of the invention, the MAT 2A-related disease is a tumor, preferably a solid tumor.
Detailed Description
In the following detailed description of the invention, exemplary embodiments are set forth that utilize the principles of the present invention. The features and advantages of the present invention may be better understood by reference to the following summary.
It is to be understood that the scope of the various aspects of the invention is defined by the claims, and methods and structures within the scope of these claims, as well as equivalent methods and structures, are within the scope of the claims.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter of the invention. The use of the singular also includes the plural unless specifically stated otherwise. The use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.
Certain chemical terms
The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". And, the optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ) Fully substituted (e.g.: -CF 2 CF 3 ) Monosubstituted (e.g.: -CH 2 CH 2 F) Or any level between mono-and full-substitution (e.g.: -CH 2 CHF 2 、-CF 2 CH 3 、-CFHCHF 2 Etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, nuclear magnetism, high performance liquid chromatography, infrared and ultraviolet/visible spectrometry, and pharmacological methods are employed. Unless specifically defined otherwise, the relevant terms and experimental procedures and techniques herein in analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.
When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH 2 O-is equivalent to-OCH 2 -。
The terms "group", "chemical group" as used herein refer to a particular moiety or functional group of a molecule. Chemical groups are often considered as chemical entities that are embedded or attached to a molecule.
Some of the chemical groups named herein may be represented by shorthand notations for the total number of carbon atoms. For example, C 1-6 Alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated by the shorthand notation does not include carbon atoms on a possible substituent.
The term "halogen", "halo" or "halide" refers to bromine, chlorine, fluorine or iodine.
The compounds of the invention may comprise one or more (e.g., one, two, three or four) isotopic substitutions. For example, in the compounds, H may be in any isotopic form, including 1 H、 2 H (D or deuterium) and 3 h (T or tritium); c may be in any isotopic form, including 12 C、 13 C and C 14 C, performing operation; o may be in any isotopic form, including 16 O and 18 o, etc.
The terms "aromatic", "aromatic ring", "aromatic ring" as used herein refer to a planar ring or ring portion of multiple rings having a delocalized electron conjugated system of 4n+2 electrons, where n is an integer. The aromatic ring may be formed from 5, 6, 7, 8, 9 or more than 9 atoms. The aromatic compound may be optionally substituted and may be monocyclic or polycyclic with fused rings.
The term "heteroatom" or "hetero" as used herein alone or as part of other ingredients refers to atoms other than carbon and hydrogen. The heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different from one another.
The term "fused" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
The term "spiro" or "spiro" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
The term "alkyl" as used herein alone or in combination refers to an optionally substituted straight or optionally substituted branched monovalent saturated hydrocarbon having from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, attached to the rest of the molecule by single bonds, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.
The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched monovalent hydrocarbon radical having one or more c=c double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The double bonds in these groups may be in either cis or trans conformation and should be understood to include both isomers. Examples include, but are not limited to, vinyl (ch=ch 2 ) 1-propenyl (CH) 2 CH＝CH 2 ) Isopropenyl (C (CH) 3 )＝CH 2 ) Butenyl, and 1, 3-butadienyl, and the like. Alkenyl groups as defined herein are present in the numerical range, e.g. "C 2 -C 6 Alkenyl "or" C 2-6 Alkenyl "refers to alkenyl groups that may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkenyl groups herein are also intended to cover instances where no numerical range is specified.
The term "alkynyl", as used herein alone or in combination, refers to an optionally substituted straight or branched chain monovalent hydrocarbon radical having one or more c≡c triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. Alkynyl groups as defined herein are present in the numerical range, e.g. "C 2 -C 6 Alkynyl "or" C 2-6 Alkynyl "refers to an alkynyl group that may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkynyl herein also encompasses cases where no numerical range is specified.
The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, which has 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, and most preferably 6 carbon atoms. Aryl groups may be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "heteroaryl" or "heteroaryl ring" refers to a single ring or fused ring of 5 to 12 ring atoms having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms containing 1, 2, 3 or 4 ring atoms selected from N, O, S, the remaining ring atoms being C and having a fully conjugated pi-electron system. Heteroaryl or heteroaromatic rings may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl, and heteroalicyclic. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazinyl.
The term "cycloalkyl" as used herein, alone or in combination, refers to an optionally substituted monovalent saturated hydrocarbon ring containing from 3 to about 15 ring-forming carbon atoms or from 3 to about 10 ring-forming carbon atoms, and may also include other non-ring-forming carbon atoms as substituents (e.g., methylcyclopropyl).
The term "carbocycle" refers to a structure covalently closed by a carbon, which may be saturated or partially unsaturated. Carbocycles may be formed from 3, 4, 5, 6, 7, 8, 9 or more than 9 atoms. The distinction between the terms carbocycle and heterocycle is that the ring backbone of a heterocycle contains at least one atom different from carbon. "carbocycles" herein may be monocyclic or polycyclic, and polycyclic carbocycles include spiro, fused and bridged rings. The carbocycle may be optionally substituted. "carbocycle" herein preferably comprises about 5 to about 20 or 5 to 10 or 5-8 or 5-6 backbone ring atoms.
The terms "heterocycle", "heterocycloalkyl", as used herein, alone or in combination, refer to an aliphatic heterocycle, which may be saturated or partially unsaturated. Where the number of carbon atoms of the heterocyclic ring is referred to herein (e.g. C 3-6 Heterocyclic ring) in which at least one non-carbon atom (heteroatom) is necessarily present. For example "C 3-6 The designation "heterocycle" refers only to the number of carbon atoms in the ring, and not to the total number of atoms in the ring. The designation "4-6 membered heterocyclic ring" refers to the total number of atoms contained in the ring (i.e., a four, five, or six membered ring in which at least one atom is a carbon atom, at least one atom is a heteroatom, and the remaining 2-4 atoms are carbon atoms or heteroatoms). For heterocycles having two or more heteroatoms, the two or more heteroatoms may be the same as or different from each other. The "heterocycle" herein may be a single ring or multiple rings, and the multiple ring heterocycle includes spiro rings, condensed rings and bridged rings. The heterocycle may be optionally substituted. The "heterocycle" herein preferably contains from about 5 to about 20 or 5 to 10 or 5-8 or 5-6 backbone ring atoms.
The term "polymorph" or "polymorphism" as used herein means that the compounds of the present invention have a variety of lattice morphologies. Some compounds of the invention may have more than one crystal form, and the invention encompasses all polymorphs or mixtures thereof.
Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.
Unless otherwise specified, olefinic double bonds contained in the compounds of the present invention include the E and Z isomers.
It will be appreciated that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in the R or S configuration. Some of the compounds of the present invention may also exhibit cis-properties. The phenomenon of isomerism, which is obvious to a person skilled in the art. It is to be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers as well as mixtures thereof, including racemic mixtures. These isomers may be separated from their mixtures by performing or modifying known methods, such as chromatography techniques and recrystallization techniques, or they may be prepared separately from the appropriate isomers of their intermediates.
The term "pharmaceutically acceptable salt" as used herein includes both acid and base addition salts.
"pharmaceutically acceptable salts of acids" refers to those salts that retain the biological effectiveness and properties of the free base of the compound, are not biologically or otherwise undesirable, are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, decanoic acid, hexanoic acid, carbonic acid, cinnamic acid, citric acid, and the like. By "pharmaceutically acceptable salts of bases" is meant those salts which retain the biological effectiveness and properties of the free acid of the compound, are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reaction with inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.
The organic bases forming salts include, but are not limited to, primary, secondary, tertiary, cyclic amines and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, caffeine and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
Crystallization often yields solvates of the compounds of the present invention. The term "solvate" as used herein refers to a complex of one or more molecules of a compound of the invention and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent is also possible. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may only occasionally retain water or a mixture of water with some other solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The term "pharmaceutical composition" as used herein refers to a formulation that is mixed with a compound of the present invention and a medium that is generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human. Such a medium comprises all pharmaceutically acceptable carriers.
The term "acceptable" in relation to a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
"pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administration for use in humans and domestic animals.
The terms "subject," "patient," "subject," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.
The term "treatment" as used herein refers to the treatment of a related disease or condition in a mammal, particularly a human, including
(i) Preventing a disease or condition in a mammal, particularly a mammal that has been previously exposed to a disease or condition but has not been diagnosed with the disease or condition, from developing the corresponding disease or condition;
(ii) Inhibiting the disease or disorder, i.e., controlling its progression;
(iii) Alleviating the disease or condition, i.e., causing regression of the disease or condition;
(iv) Relieving symptoms caused by diseases or symptoms.
The terms "disease" and "disorder" as used herein may be used interchangeably or differently and, because some specific diseases or disorders have not yet been known to cause a disease (and therefore the cause of the disease is not yet known), they cannot be considered as a disease but rather can be considered as an unwanted condition or syndrome, more or less specific symptoms of which have been confirmed by clinical researchers.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The anti-cancer treatments described herein may be useful as monotherapy or may include conventional surgery, radiation therapy or chemotherapy in addition to administration of a compound having formula (I); or a combination of such additional therapies. Such conventional surgery, radiation therapy or chemotherapy may be administered simultaneously, sequentially or separately with the compound having formula (I) for treatment.
Preparation of the Compounds of the invention
The following schemes show the methods for preparing the compounds of the present invention.
It will be appreciated that in the following description, combinations of substituents and/or variables of the formula are only allowed in the case of stable compounds.
Those skilled in the art will also appreciate that in the schemes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. These functional groups include hydroxyl, amino, mercapto and carboxyl groups. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., t-butylmethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable amino, amidino and guanidine protecting groups include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto groups include-C (O) -R "(R" represents alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or arylalkyl esters. The protecting groups may be added or removed by standard techniques known to those skilled in the art.
Examples
The following non-limiting examples are illustrative only and do not limit the invention in any way.
Unless otherwise indicated, temperatures are degrees celsius. Reagents were purchased from commercial suppliers of national pharmaceutical group chemicals Beijing Co., ltd, alfa Aesar (Alfa Aesar), or Beijing carboline technologies Co., ltd, and these reagents were used directly without further purification unless otherwise indicated.
Unless otherwise indicated, the following reactions were carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or argon, or using dry tubes; the reaction flask is provided with a rubber diaphragm, so that a substrate and a reagent are added through a syringe; glassware drying and/or heat drying.
Column chromatography purification uses 200-300 mesh silica gel from the Qingdao marine chemical plant unless otherwise indicated; preparation of thin layer chromatography A thin layer chromatography silica gel prefabricated plate (HSGF 254) manufactured by Kagaku chemical industry research institute of tobacco, inc.; the MS was determined using a Thermo LCQ sheet type (ESI) liquid chromatograph-mass spectrometer; the polarimeter SGW-3 was used for polarimeter, shanghai Shen Guang instruments and meters Inc.
Nuclear magnetic data [ ] 1 H NMR) was run at 400MHz using a Varian apparatus. The solvent used in the nuclear magnetic data is CDCl 3 、CD 3 OD、D 2 O, DMSO-d6, etc., in four waysMethylsilane (0.00 ppm) or residual solvent (CDCl) 3 ：7.26ppm；CD 3 OD：3.31ppm；D 2 O:4.79ppm; d6—dmso:2.50 ppm). When peak shape diversity is indicated, the following abbreviations represent the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet). If the coupling constant is given, it is in Hertz (Hz).
Synthesis method
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Embodiments of the present application can be prepared according to the routes described in schemes 1-4. Wherein examples 1-14 can be prepared according to the scheme described in scheme 1, examples 15, 16, 17, 19, 20, 22, 23, 25 and 26 can be prepared according to the scheme described in scheme 2, examples 27-40 can be prepared according to the scheme described in scheme 3, examples 44 and 45 can be prepared according to the scheme described in scheme 4, and examples 49-53 can be prepared according to the scheme described in scheme 5.
In scheme 1, raw material 1 undergoes ullmann reaction with amine in the presence of copper catalyst and appropriate base to produce intermediate 2; reacting the intermediate 2 with triphosgene to generate an intermediate 3; intermediate 3 reacts with ethyl cyanoacetate in the presence of a suitable base to form intermediate 4; the intermediate 4 and phosphorus oxychloride undergo chlorination reaction to generate an intermediate 5; the intermediate 5 and ammonia methanol solution undergo substitution reaction to produce a product 6.
In scheme 2, raw material 1 undergoes ullmann reaction with amine in the presence of copper catalyst and appropriate base to produce intermediate 2; reacting the intermediate 2 with triphosgene to generate an intermediate 3; intermediate 3 reacts with dimethyl malonate in the presence of a suitable base to form intermediate 4; the intermediate 4 and phosphorus oxychloride undergo chlorination reaction to generate an intermediate 5; the intermediate 5 and ammonia methanol solution undergo substitution reaction to produce a product 6.
In the flow 3, the raw material 1 reacts with triphosgene to generate an intermediate 2; the intermediate 2 and alcohol undergo a photo-delay reaction to generate an intermediate 3; intermediate 3 reacts with dimethyl malonate in the presence of a suitable base to form intermediate 4; the intermediate 4 and phosphorus oxychloride undergo chlorination reaction to generate an intermediate 5; the intermediate 5 and ammonia methanol solution undergo substitution reaction to produce a product 6.
In the flow 4, the raw material 1 and amine are subjected to ammonolysis reaction to generate an intermediate 2; the intermediate 2 and phosphorus oxychloride undergo chlorination reaction to generate an intermediate 3; the intermediate 3 and ammonia methanol solution undergo substitution reaction to produce a product 4.
In scheme 5, raw material 1 undergoes hydrolysis in the presence of a suitable base to form intermediate 2; intermediate 2 and cyclopropyl alcohol undergo condensation reaction to produce product 3.
Example 1
4-amino-7-chloro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carbonitrile
According to the preparation route shown in the scheme 1, the specific synthesis steps are as follows:
step 1: 4-chloro-2- (phenylamino) benzoic acid (intermediate 1-2)
2, 4-dichlorobenzoic acid (1.90 g), copper powder (64 mg), cuprous oxide (72. 72 mg) and potassium carbonate (1.66 g) were charged into a three-necked flask under nitrogen atmosphere, N-dimethylformamide (50 mL) was added thereto, and after stirring at room temperature for 30 minutes, a solution of aniline (1.12 g) in N, N-dimethylformamide (5 mL) was slowly added, and then heated to 130℃and stirred for 12 hours. The reaction solution was cooled to room temperature, filtered, 3mol/L hydrochloric acid (10 mL) and water (100 mL) were added to the filtrate, extracted with dichloromethane (100 ml×3), the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give the objective compound 1-2 (1.24 g).
Step 2: 7-chloro-1-phenyl-2, 4-dihydro-1H-3, 1-benzoxazine-2, 4-dione (intermediate 1-3)
Intermediate 1-2 (1.24 g) was dissolved in methylene chloride (30 mL), N-diisopropylethylamine (1.29 g) was added, triphosgene (1.78 g) was slowly added with ice-bath cooling and stirred for 30 minutes, then stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting with methylene chloride) to give the objective compound 1-3 (1.23 g).
Step 3: 7-chloro-4-hydroxy-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carbonitrile (intermediate 1-4)
Intermediate 1-3 (1.23 g) and ethyl cyanoacetate (945 mg) were dissolved in dry N, N-dimethylformamide (20 mL), sodium hydride (540 mg) was slowly added with ice-bath cooling, and the mixture was allowed to warm to room temperature and stirred overnight. To the reaction solution were added 3mol/L hydrochloric acid (10 mL) and water (40 mL), filtered, and the cake was washed with water (30 mL. Times.3) to give the objective compound 15-4 (912 mg).
Step 4:4, 7-dichloro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carbonitrile (intermediate 1-5)
To intermediate 1-4 (900 mg) was added phosphorus oxychloride (20 mL) and the mixture was stirred at 100℃for 12 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium bicarbonate solution (30 mL) was added to the residue, the extract was extracted with dichloromethane (100 ml×3), the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20:1) to give the objective compound 1-5 (858 mg).
Step 5: 4-amino-7-chloro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carbonitrile (example 1)
Methanol (20 mL) and 7mol/L ammonia methanol solution (10 mL) were added to intermediate 1-5 (850 mg), heated to 50deg.C and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=10:1) to give a product (704 mg).
1 H NMR(400MHz，DMSO-d6)δ8.27(d，J＝8.8Hz，1H)，7.95-8.26(brs，2H)，7.57-7.60(m，2H)，7.50-7.54(m，1H)，7.28-7.33(m，3H)，6.33(d，J＝2.0Hz，1H)。
Example 2
4-amino-7-methyl-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carbonitrile
The procedure of example 1 was followed using 2-bromo-4-methylbenzoic acid and aniline as starting materials to give the product according to the preparation scheme of example 1.
1 H NMR(400MHz，DMSO-d6)δ8.12(d，J＝8.4Hz，1H)，7.76-8.06(brs，2H)， 7.54..7.60(m，2H)，7.48-7.52(m，1H)，7.22-7.26(m，2H)，7.06(dd，J＝8.4Hz，1.2Hz， 1H)，6.22(s，1H)，2.18(s，3H)。
Example 3
4-amino-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carbonitrile
The procedure of example 1 was followed using 2-bromobenzoic acid and aniline as starting materials to give the product.
1 H NMR(400MHz，DMSO-d6)δ8.23(d，J＝7.2Hz，1H)，7.84-8.15(brs，2H)， 7.54-7.58(m，2H)，7.44-7.51(m，2H)，7.19-7.27(m，3H)，6.44(d，J＝8.8Hz，1H)。
Example 4
4-amino-7-iodo-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carbonitrile
The procedure of example 1 was followed using 2-bromo-4-iodobenzoic acid and aniline as starting materials to give the product according to the preparation scheme of example 1.
1 H NMR(400MHz，DMSO-d6)δ8.20(d，J＝8.4Hz，1H)，8.00-8.15(brs，2H)， 7.57-7.59(m，2H)，7.52-7.54(m，1H)，7.27-7.30(m，3H)，6.33(d，J＝2.0Hz，1H)。
Example 5
4-amino-7-trifluoromethyl-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carbonitrile
The procedure of example 1 was followed using 2-bromo-4-trifluoromethylbenzoic acid and aniline as starting materials to give the product.
1 H NMR(400MHz，CDCl 3 )δ8.48(d，J＝8.8Hz，1H)，8.00-8.10(brs，2H)， 7.52-7.62(m，4H)，7.33(d，J＝8.4Hz，2H)，6.61(s，1H)。
Example 6
4-amino-8-fluoro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carbonitrile
The procedure of example 1 was followed using 2-bromo-3-fluorobenzoic acid and aniline as starting materials to give the product.
1 H NMR(400MHz，DMSO-d6)δ7.98-8.26(m，3H)，7.34-7.43(m，4H)， 7.21-7.28(m，3H)。
Example 7
4-amino-6, 7-difluoro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carbonitrile
The procedure of example 1 was followed using 2-bromo-4, 5-difluorobenzoic acid and aniline as starting materials to give the product.
1 H NMR(400MHz，CD 3 OD+CDCl 3 )δ7.96(dd，J＝11.2Hz，8.4Hz，1H)， 7.48-7.57(m，3H)，7.16-7.18(m，2H)，6.40(dd，J＝12.0Hz，6.8Hz，1H)。
Example 8
4-amino-5-fluoro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carbonitrile
The procedure of example 1 was followed using 2-bromo-5-fluorobenzoic acid and aniline as starting materials to give the product.
1 H NMR(400MHz，CD 3 OD+CDCl 3 )δ7.46-7.56(m，3H)，7.32-7.38(m，1H)，7.14-7.18(m，2H)，6.93(dd，J＝13.2Hz，8.0Hz，1H)，6.43(d，J＝9.2Hz，1H)。
Example 9
4-amino-7-chloro-1- (3-methylphenyl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile
The procedure of example 1 was followed using 2, 4-dichlorobenzoic acid and 3-methylaniline as starting materials to give the product.
1 H NMR(400MHz，DMSO-d6)δ8.26(d，J＝8.8Hz，1H)，7.96-8.21(brs，2H)， 7.46(t，J＝7.6Hz，1H)，7.30-7.34(m，2H)，7.10(s，1H)，7.08(d，J＝8.0Hz，1H)， 6.37(d，J＝1.6Hz，1H)，2.47(s，3H)。
Example 10
4-amino-6, 7-dichloro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carbonitrile
The procedure of example 1 was followed using 4, 5-dichlorobenzoic acid and aniline as starting materials to give the product.
1 H NMR(400MHz，DMSO-d6)δ8.60(s，1H)，7.94-8.38(brs，2H)，7.51-7.61(m， 3H)，7.30(d，J＝7.2Hz，2H)，6.49(s，1H)。
Example 11
4-amino-7-chloro-2-oxo-1- (pyridin-3-yl) -1, 2-dihydroquinoline-3-carbonitrile
The procedure of example 1 was followed using 2, 4-dichlorobenzoic acid and 3-aminopyridine as starting materials to give the product.
1 H NMR(400MHz，DMSO-d6)δ8.72(d，J＝4.8Hz，1.6Hz，1H)，8.53(d，J＝ 2.4Hz，1H)，8.29(d，J＝8.8Hz，1H)，8.01-8.28(brs，2H)，7.83-7.86(m，1H)，7.64(dd， J＝8.8Hz，4.8Hz，1H)，7.36(dd，J＝8.8Hz，2.0Hz，1H)，6.39(d，J＝2.0Hz，1H)。
Example 12
4-amino-7-chloro-2-oxo-1-phenyl-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
The procedure of example 1 was followed using 2, 6-dichloronicotinic acid and aniline as starting materials to give the product.
1 H NMR(400MHz，CD 3 OD+CDCl 3 )δ8.22(d，J＝8.4Hz，1H)，7.34-7.43(m， 3H)，7.07-7.10(m，3H)。
Example 13
4-amino-7-chloro-2-oxo-1, 2-dihydroquinoline-3-carbonitrile
The procedure of scheme 1 was followed, starting from step 2, with 2-amino-4-chlorobenzoic acid as intermediate 2, with reference to the preparation procedure of example 1, to give the product.
1 H NMR(400MHz，DMSO-d6)δ11.31(s，1H)，8.12(d，J＝8.4Hz，1H)， 7.78-8.08(brs，2H)，7.20-7.23(m，2H)。
Example 14
4-amino-7-chloro-1-methyl-2-oxo-1, 2-dihydroquinoline-3-carbonitrile
Following the preparation route of scheme 1, starting from step 2 with 4-chloro-2-methylaminobenzoic acid as intermediate 2, the product is obtained with reference to the preparation procedure of example 1.
1 H NMR(400MHz，DMSO-d6)δ8.20(d，J＝8.4Hz，1H)，7.80-8.04(brs，2H)， 7.53(d，J＝2.0Hz，1H)，7.32(dd，J＝8.4Hz，2.0Hz，1H)，3.46(s，3H)。
Example 15
4-amino-7-chloro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The preparation route according to scheme 2:
step 1: 4-chloro-2- (phenylamino) benzoic acid (intermediate 1-2)
Refer to step 1 of example 1.
Step 2: 7-chloro-1-phenyl-2, 4-dihydro-1H-3, 1-benzoxazine-2, 4-dione (intermediate 1-3)
Refer to step 2 of example 1.
Step 3: 7-chloro-4-hydroxy-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester (intermediate 15-4)
Intermediate 1-3 (1.23 g) and dimethyl malonate (763 mg) were dissolved in dry N, N-dimethylformamide (20 mL), sodium hydride (540 mg) was slowly added under ice-bath cooling, and the mixture was allowed to warm to room temperature and stirred overnight. To the reaction solution were added 3mol/L hydrochloric acid (10 mL) and water (40 mL), filtered, and the cake was washed with water (30 mL. Times.3) to give the objective compound 15-4 (937 mg).
Step 4: 7-chloro-4-chloro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester (intermediate 15-5)
To intermediate 15-4 (937 mg) was added phosphorus oxychloride (20 mL), and the mixture was heated to 100 ℃ and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate (30 mL) was added to the residue, the extract was extracted with dichloromethane (100 ml. Times.3), the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20:1) to give the objective compound 15-5 (911 mg).
Step 5: 4-amino-7-chloro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester (example 15)
Methanol (20 mL) and 7mol/L ammonia in methanol (10 mL) were added to intermediate 15-5 (900 mg), heated to 50deg.C and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=10:1) to give a product (804 mg).
1 H NMR(400MHz，CD 3 OD+CDCl 3 )δ7.95(d，J＝8.8Hz，1H)，7.52-7.56(m， 2H)，7.45-7.49(m，1H)，7.17-7.19(m，2H)，7.14(dd，J＝8.8Hz，1.6Hz，1H)，6.49(d， J＝1.6Hz，1H)，3.81(s，3H)。
Example 16
4-amino-7-iodo-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-bromo-4-iodobenzoic acid and aniline as starting materials to give the product according to the preparation scheme of scheme 2.
1 H NMR(400MHz，DMSO-d6)δ8.36(s，2H)，7.97(d，J＝8.4Hz，1H)， 7.48-7.59(m，4H)，7.22-7.25(m，2H)，6.65(d，J＝1.6Hz，1H)，3.68(s，3H)。
Example 17
4-amino-7-trifluoromethyl-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 2 was followed using 2-bromo-4-trifluoromethylbenzoic acid and aniline as starting materials to give the product.
1 H NMR(400MHz，DMSO-d6)δ8.46(d，J＝8.8Hz，1H)，8.40(s，2H)， 7.50-7.60(m，4H)，7.27-7.29(m，2H)，6.55(s，1H)，3.71(s，3H)。
Example 18
4-amino-7- ((dimethyl (oxy) subunit) -lambda 6 -thioylidene) amino) -2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
To a mixture of example 15 (80 mg), dimethyl sulfimide (35 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (21 mg), cesium carbonate (121 mg) and tris (dibenzylideneacetone) dipalladium (10 mg) under nitrogen gas was added 1, 4-dioxane (10 mL), and the mixture was heated to 100℃and stirred for 12 hours. The reaction solution was cooled to room temperature, filtered, water (100 mL) was added, extracted with dichloromethane (100 mL x 3), the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20:1) to give the product (2 mg).
1 H NMR(400MHz，CDCl 3 )δ7.48-7.53(m，3H)，7.41-7.45(m，1H)，7.20-7.23 (m，2H)，6.94(dd，J＝8.8Hz，2.0Hz，1H)，6.16(d，J＝2.0Hz，1H)，3.87(s，3H)，3.08 (s，6H)。
Example 19
4-amino-7-iodo-1- (2-methylphenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-bromo-4-iodobenzoic acid and 2-methylaniline as starting materials to give the product according to the preparation scheme of scheme 2.
1 H NMR(400MHz，DMSO-d6)δ8.42(s，2H)，8.02(d，J＝9.2Hz，1H)，7.55(dd， J＝8.4Hz，1.2Hz，1H)，7.35-7.46(m，3H)，7.13(dd，J＝7.2Hz，1.2Hz，1H)，6.56(d， J＝1.2Hz，1H)，3.69(s，3H)，1.87(s，3H)。
Example 20
4-amino-7-iodo-1- (2-chlorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-bromo-4-iodobenzoic acid and 2-chloroaniline as starting materials to give the product.
1 H NMR(400MHz，DMSO-d6)δ8.53(s，2H)，8.03(d，J＝8.8Hz，1H)， 7.71-7.73(m，1H)，7.54-7.59(m，3H)，7.42-7.45(m，1H)，6.55(s，1H)，3.69(s，3H)。
Example 21
4-amino-1- (3- (hydroxymethyl) phenyl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
Step 1:2- ((3- (Dimethoxymethyl) phenyl) amino) -4- (trifluoromethyl) benzoic acid
2-amino-4- (trifluoromethyl) benzoic acid (1.0 g), 1-bromo-3- (dimethoxymethyl) benzene (2.23 g), copper powder (31 mg), copper oxide (35 mg) and potassium carbonate (808 mg) were mixed in N, N-dimethylformamide (20 mL) under nitrogen, heated to 150℃and stirred overnight, the reaction solution was cooled to room temperature, filtered through celite, the filtrate was acidified with 1mol/L hydrochloric acid to adjust pH to 6 to 7, extracted with dichloromethane, the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the product (352 mg).
Step 2:1- (3- (dimethoxymethyl) phenyl) -7- (trifluoromethyl) -2H-benzo [ d ] [1,3] oxazine-2, 4 (1H) -dione
2- ((3- (dimethoxymethyl) phenyl) amino) -4- (trifluoromethyl) benzoic acid (310 mg) and N, N-diisopropylethylamine (258 mg) were dissolved in dichloromethane (10 mL), triphosgene (327 mg) was added, and stirred overnight at room temperature. The reaction was quenched with water, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (271 mg) which was directly used for the next reaction.
Step 3:1- (3- (dimethoxymethyl) phenyl) -4-hydroxy-2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
1- (3- (dimethoxymethyl) phenyl) -7- (trifluoromethyl) -2H-benzo [ d ] [1,3] oxazine-2, 4 (1H) -dione (271 mg) and dimethyl 1, 3-malonate (188 mg) were dissolved in N, N-dimethylformamide (5 mL) under nitrogen, cooled to 0 ℃, sodium t-butoxide (137 mg) was added in portions, and the mixture was stirred overnight after returning to room temperature. The reaction was quenched with water, citric acid (500 mg) was added, solids precipitated, and the solids were filtered and collected to give the product (198 mg).
Step 4: 4-chloro-1- (3-formylphenyl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
1- (3- (dimethoxymethyl) phenyl) -4-hydroxy-2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester (190 mg) was dissolved in phosphorus oxychloride (10 mL), heated to reflux and stirred for 2 hours, cooled to room temperature, and concentrated under reduced pressure to give a solid product (148 mg).
Step 5: 4-chloro-1- (3- (hydroxymethyl) phenyl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
Methyl 4-chloro-1- (3-formylphenyl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylate (140 mg) was dissolved in methanol (10 mL), cooled to 0℃and sodium borohydride (15 mg) was added in portions, stirred at room temperature for 4 hours, quenched with water, extracted with dichloromethane, the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the product (119 mg).
Step 6: 4-amino-1- (3- (hydroxymethyl) phenyl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
Methyl 4-chloro-1- (3- (hydroxymethyl) phenyl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylate (110 mg) was dissolved in 7mol/L ammonia methanol solution (5 mL), heated to reflux and stirred overnight, cooled to room temperature, and concentrated under reduced pressure to give the product (18 mg).
1 H NMR(400MHz，CDCl 3 )δ7.82(d，J＝8.4Hz，1H)，7.60-7.69(brs，3H)， 7.50-7.57(m，3H)，7.39(d，J＝8.8Hz，1H)，7.14(d，J＝7.2Hz，1H)，6.85(s，1H)， 4.76(s，2H)，3.89(s，3H)。
Example 22
4-amino-7-bromo-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2, 4-dibromobenzoic acid and aniline as starting materials to give the product according to the preparation scheme of scheme 2.
1 H NMR(400MHz，DMSO-d 6 )δ8.37(s，2H)，8.16(d，J＝8.8Hz，1H)， 7.56-7.59(m，2H)，7.48-7.52(m，1H)，7.40(dd，J＝8.8Hz，2.0Hz，1H)，7.24(d，J＝ 7.6Hz，2H)，6.44(d，J＝2.0Hz，1H)，3.69(s，3H)。
Example 23
4-amino-7-trifluoromethyl-1- (2-methylphenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-bromo-4-trifluoromethylbenzoic acid and 2-methylaniline as starting materials to give the product.
1 H NMR(400MHz，CDCl 3 )δ7.54-8.10(m，3H)，7.34-7.41(m，4H)，7.12(d，J＝ 7.6Hz，1H)，6.73(s，1H)，3.90(s，3H)，2.00(s，3H)。
Example 24
4-amino-7-vinyl-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
To a mixture of example 15 (50 mg), potassium vinyltrifluoroborate (48 mg), [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (13 mg) and cesium carbonate (85 mg) under nitrogen gas was added 1, 4-dioxane (10 mL) and water (2 mL), and the mixture was heated to 120℃and stirred for 12 hours. The reaction solution was cooled to room temperature, filtered, water (100 mL) was added, extracted with dichloromethane (100 mL x 3), the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20:1) to give the product (22 mg).
1 H NMR(400MHz，CDCl 3 )δ7.60(d，J＝8.8Hz，1H)，7.52-7.56(m，2H)， 7.45-7.49(m，1H)，7.27(dd，J＝8.8Hz，1.6Hz，1H)，7.22-7.25(m，2H)，6.54(dd，J＝ 17.6Hz，10.8Hz，1H)，6.52(d，J＝1.6Hz，1H)，5.68(d，J＝17.6Hz，1H)，5.31(d，J＝ 10.8Hz，1H)，3.88(s，3H)。
Example 25
4-amino-1- (4-methoxyphenyl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-bromo-4-trifluoromethylbenzoic acid and 4-methoxyaniline as starting materials to give the product according to the preparation scheme of scheme 2.
1 H NMR(400MHz，DMSO-d6)δ8.44(d，J＝8.4Hz，1H)，8.34(s，2H)，7.53(d， J＝8.0Hz，1H)，7.18(d，J＝8.8Hz，2H)，7.10(d，J＝8.8Hz，2H)，6.64(s，1H)，3.82 (s，3H)，3.71(s，3H)。
Example 26
4-amino-1- (naphthalen-2-yl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-bromo-4-trifluoromethylbenzoic acid and 2-naphthylamine as starting materials to give the product.
1 H NMR(400MHz，CDCl 3 )δ8.04(d，J＝8.4Hz，1H)，7.94(d，J＝8.0Hz，1H)， 7.85(d，J＝7.6Hz，1H)，7.79(d，J＝8.8Hz，1H)，7.77(s，1H)，7.52-7.60(m，2H)， 7.39(d，J＝8.4Hz，1H)，7.29(dd，J＝8.8Hz，1.6Hz，1H)，6.89(s，1H)，3.90(s，3H)。
Example 27
4-amino-1-benzyl-7-chloro-2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
According to the preparation route of the scheme 3, the specific synthesis steps are as follows:
step 1: 7-chloro-2, 4-dihydro-1H-3, 1-benzoxazine-2, 4-dione (intermediate 27-2)
2-amino-4-chlorobenzoic acid 27-1 (3.0 g) was dissolved in dry tetrahydrofuran (30 mL), triphosgene (2.084 g) was added, and stirred overnight at room temperature. Filtration and washing of the filter cake with tetrahydrofuran (10 ml x 3) gave the target compound 27-2 (1.42 g).
Step 2: 1-benzyl-7-chloro-2, 4-dihydro-1H-3, 1-benzoxazine-2, 4-dione (intermediate 27-3)
Triphenylphosphine (1.132 g) was dissolved in dichloromethane (10 mL), a solution of diisopropyl azodicarboxylate (872 mg) in dichloromethane (3 mL) was slowly added under ice-bath cooling, stirred under ice-bath cooling for 30 min, intermediate 27-2 (800 mg) was added, stirred for 5 min, and a solution of benzyl alcohol (434 mg) in dichloromethane (5 mL) was added. Stir at room temperature overnight. Filtration and washing of the filter cake with dichloromethane (10 ml x 3) gave the title compound 27-3 (749 mg).
Step 3: 1-benzyl-7-chloro-4-hydroxy-2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester (intermediate 27-4)
Intermediate 27-3 (200 mg) and dimethyl malonate (111 mg) were dissolved in dry N, N-dimethylformamide (20 mL), sodium hydride (84 mg) was slowly added thereto under ice-bath cooling, and the mixture was allowed to warm to room temperature and stirred overnight. 3mol/L hydrochloric acid (10 mL) and water (40 mL) were added, filtered, and the filter cake was washed with water (30 mL. Times.3) to give the title compound 27-4 (165 mg).
Step 4: 1-benzyl-7-chloro-4-chloro-2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester (intermediate 27-5)
To intermediate 27-4 (160 mg) was added phosphorus oxychloride (10 mL), and the mixture was heated to 100 ℃ and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution (20 mL) was added to the residue, extracted with dichloromethane (30 ml. Times.3), the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20:1) to give the objective compound 27-5 (128 mg).
Step 5: 4-amino-1-benzyl-7-chloro-2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester (example 27)
Methanol (20 mL) and 7mol/L ammonia in methanol (10 mL) were added to intermediate 27-5 (120 mg), heated to 50deg.C and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=10:1) to give a product (52 mg).
1 H NMR(400MHz，CDCl 3 )δ7.56(d，J＝8.8Hz，1H)，7.20-7.31(m，6H)，7.13 (dd，J＝8.8Hz，2.0Hz，1H)，544(s，2H)，3.95(s，3H)。
Example 28
4-amino-1-benzyl-7-iodo-2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 27 was followed using 2-amino-4-iodobenzoic acid and benzyl alcohol as starting materials to give the product according to the preparation scheme of scheme 3.
1 H NMR(400MHz，CD 3 OD+CDCl 3 )δ7.58-7.64(m，1H)，7.53(s，1H)，7.45(d， J＝8.4Hz，1H)，7.24-7.28(m，2H)，7.14-7.20(m，3H)，5.38(s，2H)，3.85(s，3H)。
Example 29
4-amino-1-benzyl-2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 27 was followed using 2-amino-4-trifluoromethylbenzoic acid and benzyl alcohol as starting materials to give the product according to the preparation scheme of scheme 3.
1 H NMR(400MHz，CD 3 OD+CDCl 3 )δ8.10(d，J＝8.8Hz，1H)，7.42(s，1H)，7.36(d， J＝8.8Hz，1H)，7.23-7.27(m，2H)，7.17-7.19(m，3H)，5.46(s，2H)，3.88(s，3H)。
Example 30
4-amino-1-benzyl-7-bromo-2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 27 was followed using 2-amino-4-bromobenzoic acid and benzyl alcohol as starting materials to give the product according to the preparation scheme of scheme 3.
1 H NMR(400MHz，CDCl 3 )δ7.40-7.72(m，3H)，7.38(d，J＝2.0Hz，1H)， 7.19-7.32(m，6H)，5.43(s，2H)，3.95(s，3H)。
Example 31
4-amino-1-benzyl-7-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 27 was followed using 2-amino-4-methylbenzoic acid and benzyl alcohol as starting materials to give the product according to the preparation scheme of scheme 3.
1 H NMR(400MHz，CDCl 3 )δ7.52(d，J＝7.2Hz，1H)，7.17-7.29(m，5H)，6.99 (s，1H)，6.97(d，J＝8.8Hz，1H)，5.46(s，2H)，3.93(s，3H)，2.33(s，3H)。
Example 32
4-amino-7-chloro-2-oxo-1- (pyridin-2-ylmethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
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The procedure of example 27 was followed using 2-amino-4-chlorobenzoic acid and 2-hydroxymethylpyridine as starting materials to give the product.
1 H NMR(400MHz，CDCl 3 )δ8.56(d，J＝4.8Hz，1H)，7.56-7.92(m，4H)，7.43 (d，J＝1.6Hz，1H)，7.15-7.21(m，2H)，7.10(dd，J＝8.4Hz，2.0Hz，1H)，5.54(s，2H)， 3.93(s，3H)。
Example 33
4-amino-7-bromo-2-oxo-1- (pyridin-2-ylmethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 27 was followed using 2-amino-4-bromobenzoic acid and 2-hydroxymethylpyridine as starting materials to give the product according to the preparation scheme of scheme 3.
1 H NMR(400MHz，CDCl 3 )δ8.57(d，J＝4.4Hz，1H)，7.52-7.85(m，4H)，7.49 (d，J＝8.8Hz，1H)，7.25(dd，J＝8.8Hz，1.6Hz，1H)，7.21(d，J＝8.4Hz，1H)， 7.15-7.18(m，1H)，5.54(s，2H)，3.93(s，3H)。
Example 34
4-amino-7-iodo-2-oxo-1- (pyridin-2-ylmethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 27 was followed using 2-amino-4-iodobenzoic acid and 2-hydroxymethylpyridine as starting materials to give the product according to the preparation scheme of scheme 3.
1 H NMR(400MHz，CD 3 OD+CDCl 3 )δ8.52(d，J＝4.0Hz，1H)，7.61-7.67(m， 2H)，7.60(s，1H)，7.48-7.52(m，1H)，7.23-7.26(m，1H)，7.06-7.11(m，1H)，5.50(s， 2H)，3.85(s，3H)。
Example 35
4-amino-2-oxo-1- (pyridin-2-ylmethyl) -7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 27 was followed using 2-amino-4-trifluoromethylbenzoic acid and 2-hydroxymethylpyridine as starting materials to give the product according to the preparation scheme of scheme 3.
1 H NMR(400MHz，CD 3 OD+CDCl 3 )δ8.42(d，J＝4.8Hz，1H)，7.97(d，J＝7.6 Hz，1H)，7.47-7.54(m，2H)，7.30(d，J＝7.6Hz，1H)，7.05-7.12(m，2H)，5.49(s，2H)， 3.81(s，3H)。
Example 36
4-amino-7-methyl-2-oxo-1- (pyridin-2-ylmethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 27 was followed using 2-amino-4-methylbenzoic acid and 2-hydroxymethylpyridine as starting materials to give the product.
1 H NMR(400MHz，CDCl3)δ8.57(d，J＝4.4Hz，1H)，7.30-7.92(m，4H)， 7.12-7.17(m，3H)，6.99(d，J＝8.0Hz，1H)，5.58(s，2H)，3.95(s，3H)，2.35(s，3H)。
Example 37
4-amino-7-iodo-2-oxo-1- (1-phenylethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 27 was followed using 2-amino-4-iodobenzoic acid and 1-phenylethanol as starting materials to give the product according to the preparation scheme of scheme 3.
1 H NMR(400MHz，CDCl 3 )δ7.47-7.68(brs，2H)，7.45(d，J＝1.2Hz，1H)， 7.21-7.36(m，7H)，7.10(q，J＝7.2Hz，1H)，3.95(s，3H)，1.84(d，J＝7.6Hz，3H)。
Example 38
4-amino-7-iodo-1- ((2-methylphenyl) methyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 27 was followed using 2-amino-4-iodobenzoic acid and 2-methylbenzyl alcohol as starting materials to give the product according to the preparation scheme of scheme 3.
1 H NMR(400MHz，DMSO-d6)δ8.24(s，2H)，7.95(d，J＝8.4Hz，1H)，7.55(dd， J＝8.4Hz，1.2Hz，1H)，7.83(d，J＝1.2Hz，1H)，7.22(d，J＝7.2Hz，1H)，7.11(t，J＝ 7.6Hz，1H)，6.99(t，J＝7.6Hz，1H)，6.43(d，J＝7.6Hz，1H)，5.27(s，2H)，3.71(s， 3H)，2.39(s，3H)。
Example 39
4-amino-1- ((2-chlorophenyl) methyl) -7-iodo-2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
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The procedure of example 27 was followed using 2-amino-4-iodobenzoic acid and 2-chlorobenzyl alcohol as starting materials to give the product according to the preparation scheme of scheme 3.
1 H NMR(400MHz，DMSO-d6)δ8.31(s，2H)，7.97(d，J＝8.4Hz，1H)，7.57(dd， J＝8.4Hz，1.2Hz，1H)，7.52(d，J＝8.0Hz，1H)，7.40(d，J＝1.2Hz，1H)，7.27(td，J ＝7.6Hz，1.2Hz，1H)，7.19(td，J＝7.6Hz，1.2Hz，1H)，6.66(dd，J＝8.0Hz，1.2Hz， 1H)，5.36(s，2H)，3.71(s，3H)。
Example 40
4-amino-1- (3H-imidazol-4-ylmethyl) -7-iodo-2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 27 was followed using 2-amino-4-iodobenzoic acid and 4- (hydroxymethyl) imidazole as starting materials to give the product according to the preparation scheme of scheme 3.
1 H NMR(400MHz，DMSO-d6)δ12.80-13.50(brs，1H)，8.22(s，2H)， 8.00-8.09(m，1H)，7.96(s，1H)，7.92(d，J＝8.8Hz，1H)，7.55(d，J＝8.4Hz，1H)， 7.06(s，1H)，5.24(s，2H)，3.72(s，3H)。
Example 41
4-amino-7-chloro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid
Example 15 (100 mg) was dissolved in tetrahydrofuran (10 mL), a solution of lithium hydroxide (22 mg) in water (3 mL) was added, and the mixture was heated to 70℃and stirred overnight. Cooled to room temperature, concentrated under reduced pressure, water (30 mL) was added to the residue, which was washed with dichloromethane (20 mL x 3), then 3mol/L hydrochloric acid (10 mL) was added, a white solid precipitated, filtered, and the filter cake was washed with water to give the product (78 mg).
1 H NMR(400MHz，CD 3 OD+CDCl 3 )δ8.07(d，J＝8.8Hz，1H)，7.54-7.63(m，3H)，7.22-7.27(m，3H)，6.61(s，1H)。
Example 42
4-amino-7-chloro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxamide
Methanol (20 mL) and 7mol/L ammonia methanol solution (10 mL) were added to intermediate 15-5 (850 mg), heated to 50deg.C and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=10:1) to give a product (43 mg).
1 H NMR(400MHz，CD 3 OD+CDCl 3 )δ7.97(d，J＝8.4Hz，1H)，7.57-7.60(m， 2H)，7.50-7.54(m，1H)，7.19-7.22(m，2H)，7.17(dd，J＝9.2Hz，2.0Hz，1H)，6.50(d， J＝2.0Hz，1H).
Example 43
4-amino-1-benzyl-2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxamide
The procedure of example 29 was followed to give the product.
1 H NMR(400MHz，DMSO-d6)δ10.78-11.38(brs，1H)，9.64(s，1H)，8.30-8.60 (m，2H)，7.51-7.58(m，2H)，7.43(d，J＝2.8Hz，1H)，7.27-7.30(m，2H)，7.16-7.22(m， 3H)，5.54(s，2H)。
Example 44
4-amino-7-chloro-N-methyl-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxamide
According to the preparation route of the scheme 3, the specific synthesis steps are as follows:
step 1: 7-chloro-4-hydroxy-N-methyl-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxamide (intermediate 44-1)
Methyl 7-chloro-4-hydroxy-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylate (intermediate 1-5) (200 mg) was dissolved in acetonitrile (20 mL), methylamine hydrochloride (300 mg) was added, heated to 90 ℃ and stirred overnight, cooled to room temperature, filtered, the filtrate concentrated under reduced pressure, water (30 mL) was added, extracted with dichloromethane (30 mL x 3), the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound 44-1 (188 mg).
Step 2: 7-chloro-4-chloro-N-methyl-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxamide (intermediate 44-2)
To intermediate 44-1 (180 mg) was added phosphorus oxychloride (10 mL), and the mixture was heated to 100℃and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution (30 mL) was added to the residue, the extract was extracted with dichloromethane (30 ml. Times.3), the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20:1) to give the objective compound 44-2 (112 mg).
Step 3: 4-amino-7-chloro-N-methyl-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxamide (example 44)
Methanol (5 mL) and 7mol/L ammonia methanol solution (5 mL) were added to intermediate 44-2 (100 mg), heated to 50deg.C and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=10:1) to give a product (81 mg).
1 H NMR(400MHz，DMSO-d 6 )δ10.80-11.20(brs，1H)，10.02(q，J＝4.4Hz， 1H)，8.16-8.42(m，2H)，7.57-7.60(m，2H)，7.50-7.54(m，1H)，7.34(dd，J＝8.4Hz，1.6Hz，1H)，7.29(d，J＝7.6Hz，2H)，6.33(d，J＝1.2Hz，1H)，2.72(d，J＝4.4Hz， 3H)。
Example 45
4-amino-7-chloro-N, N-dimethyl-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxamide
Referring to the preparation procedure of example 44, the methylamine hydrochloride in step 1 was replaced with 1mol/L dimethylamine tetrahydrofuran solution to give the product (62 mg).
1 H NMR(400MHz，CDCl 3 )δ7.47-7.58(m，4H)，7.20(d，J＝7.2Hz，2H)，7.15 (dd，J＝8.4Hz，2.0Hz，1H)，6.64(d，J＝1.6Hz，1H)，5.76(s，2H)，3.09(s，3H)，3.02 (s，3H)。
Example 46
4-amino-7-chloro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid ethyl ester
Referring to the preparation procedure of example 1, dimethyl malonate in step 3 was substituted for diethyl malonate to obtain the product.
1 H NMR(400MHz，CDCl 3 )δ7.51-7.84(m，5H)，7.46-7.50(m，1H)，7.21-7.23 (m，2H)，7.13(dd，J＝8.8Hz，2.0Hz，1H)，6.56(d，J＝2.0Hz，1H)，4.36(q，J＝7.2 Hz，2H)，1.37(t，J＝7.2Hz，3H)。
Example 47
4-amino-7-chloro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid 2-ethoxyethyl ester
Acetonitrile (20 mL) and ethylene glycol monoethyl ether (1 mL) were added to example 45 (100 mg), heated to 90 ℃ and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=10:1) to give a product (11 mg).
1 H NMR(400MHz，CDCl 3 )δ7.40-7.60(m，6H)，7.20-7.22(m，2H)，7.13(dd，J ＝8.8Hz，1.6Hz，1H)，6.55(d，J＝2.0Hz，1H)，4.45(t，J＝5.6Hz，2H)，3.75(t，J＝ 5.6Hz，2H)，3.53(q，J＝7.2Hz，2H)，1.17(t，J＝7.2Hz，3H)。
Example 48
4-amino-7-chloro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid propan-2-yl ester
Acetonitrile (20 mL) and isopropanol (1 mL) were added to example 45 (100 mg), heated to 90 ℃ and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=10:1) to give a product (14 mg).
1 H NMR(400MHz，DMSO-d6)δ8.29(s，2H)，8.23(d，J＝8.8Hz，1H)，7.55-7.59(m，2H)，7.48-7.52(m，1H)，7.25-7.28(m，3H)，6.27(d，J＝2.0Hz，1H)， 5.02-5.10(m，1H)，1.21(d，J＝6.0Hz，6H)。
Example 49
4-amino-7-chloro-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid cyclopropyl ester
Example 41 (50 mg) was dissolved in N, N-dimethylformamide (5 mL), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (91 mg) and N, N-diisopropylethylamine (62 mg) were added, and heated to 60℃and stirred overnight. The reaction was cooled to room temperature, water (20 mL) was added, extracted with dichloromethane (30 mL x 3), the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (dichloromethane/methanol=20:1) to give the product (8 mg).
1 H NMR(400MHz，DMSO-d6)δ8.47(s，2H)，8.25(d，J＝8.8Hz，1H)， 7.55-7.58(m，2H)，7.48-7.51(m，1H)，7.26(dd，J＝9.2Hz，2.0Hz，1H)，7.24(d，J＝ 8.0Hz，2H)，6.26(d，J＝2.0Hz，1H)，4.15-4.19(m，1H)，0.66-0.71(m，2H)， 0.60-0.64(m，2H)。
Example 50
4-amino-7-iodo-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid cyclopropyl ester
According to the preparation route of the scheme 4, the specific synthesis steps are as follows:
step 1: 4-amino-7-iodo-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid (intermediate 50-1)
Referring to the procedure for the preparation of example 41, the end product of example 1 was replaced with the end product of example 16 to give the title compound 50-1 (80 mg).
Step 2: 4-amino-7-iodo-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid cyclopropyl ester (example 50)
Referring to the preparation procedure of example 49, starting from intermediate 50-1, the product (10 mg) was obtained.
1 H NMR(400MHz，DMSO-d 6 )δ8.45(s，2H)，7.98(d，J＝8.8Hz，1H)， 7.49-7.58(m，4H)，7.21-7.25(m，2H)，6.63(d，J＝1.6Hz，1H)，4.14-4.20(m，1H)， 0.66-0.72(m，2H)，0.58-0.65(m，2H)。
Example 51
4-amino-2-oxo-1-phenyl-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid cyclopropyl ester
Following the preparation route of scheme 4, referring to the preparation procedure of example 50 using example 17 as starting material, the product (12 mg) was obtained.
1 H NMR(400MHz，DMSO-d 6 )δ8.48(s，2H)，8.46(d，J＝8.8Hz，1H)， 7.49-7.60(m，4H)，7.27(d，J＝6.8Hz，2H)，6.54(s，1H)，4.17-4.22(m，1H)， 0.68-0.73(m，2H)，0.61-0.65(m，2H)。
Example 52
4-amino-7-iodo-1- (2-methylphenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid cyclopropyl ester
Following the preparation route of scheme 4, referring to the preparation procedure of example 50 using example 19 as starting material, product 52 (10 mg) was obtained.
1 H NMR(400MHz，CD 3 OD+CDCl 3 )δ7.63(d，J＝8.8Hz，1H)，7.47(dd，J＝ 8.8Hz，1.2Hz，1H)，7.29-7.41(m，3H)，7.04(d，J＝7.6Hz，1H)，6.74(d，J＝1.6Hz， 1H)，4.15-4.22(m，1H)，1.93(s，3H)，0.80-0.84(m，2H)，0.67-0.71(m，2H)。
Example 53
4-amino-7-iodo-1- ((2-methylphenyl) methyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid cyclopropyl ester
Following the preparation route of scheme 4, the product was obtained by reference to the preparation procedure of example 50, using example 38 as starting material.
1 H NMR(400MHz，CDCl 3 )δ7.42-7.78(m，3H)，7.31-7.34(m，2H)，7.19(d，J＝ 7.6Hz，1H)，7.12(t，J＝7.6Hz，1H)，7.01(t，J＝7.6Hz，1H)，6.63(d，J＝8.0Hz，1H)， 5.32(s，2H)，4.25-4.30(m，1H)，2.44(s，3H)，0.91-0.94(m，2H)，0.76-0.81(m，2H)。
Example 54
4-amino-7-chloro-3- (hydroxymethyl) -1-phenyl-1, 2-dihydro-quinolin-2-one
Example 15 (100 mg) was dissolved in dry tetrahydrofuran (20 mL) under nitrogen, 1mol/L lithium aluminum hydride toluene solution (0.9 mL) was slowly added under ice-bath cooling, stirred under ice-bath cooling for 30 minutes, and then stirred at room temperature overnight. The reaction was poured into ice water (30 mL), extracted with ethyl acetate (30 mL x 3), the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20:1) to give the product (52 mg).
1 H NMR(400MHz，DMSO-d6)δ8.09(d，J＝8.4Hz，1H)，7.55-7.59(m，2H)， 7.48-7.52(m，1H)，7.20-7.24(m，3H)，6.66(s，2H)，6.31(d，J＝1.6Hz，1H)，4.73(t，J ＝5.2Hz，1H)，4.52(d，J＝5.6Hz，2H)。
Example 55
tert-butyl-N- (4-amino-7-chloro-2-oxo-1-phenyl-1, 2-dihydroquinolin-3-yl) -carbamic acid ester
The final product of example 41 (150 mg) was dissolved in t-butanol (10 mL), diphenyl azide phosphate (176 mg) and di-t-butyl dicarbonate (94 mg) were added, and the mixture was heated to 100℃and stirred overnight. Cooled to room temperature, water (20 mL) was added, extracted with dichloromethane (30 mL x 3), the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=4:1) to give the product (28 mg).
1 H NMR(400MHz，CDCl 3 )δ7.93(d，J＝8.4Hz，1H)，7.55-7.59(m，2H)， 7.48-7.52(m，1H)，7.24-7.26(m，2H)，7.14(dd，J＝8.4Hz，2.0Hz，1H)，6.58(d，J＝ 2.0Hz，1H)，1.59(s，9H)。
Example 56
4-amino-7-chloro-3- (3-methyl-1, 2, 4-oxadiazol-5-yl) -1-phenyl-1, 2-dihydroquinolin-2-one
The final product of example 15 (20 mg) was dissolved in 1, 4-dioxane (5 mL), N-hydroxyacetamide (9 mg) and cesium carbonate (20 mg) were added, and the mixture was heated to 110℃and stirred for 40 hours. Cooled to room temperature, water was added, the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography (dichloromethane/methanol=20:1) to give a product (11 mg).
1 H NMR(400MHz，DMSO-d6)δ8.56-9.75(brs，2H)，8.34(d，J＝8.8Hz，1H)， 7.59-7.63(m，2H)，7.52-7.56(m，1H)，7.37(dd，J＝8.8Hz，2.0Hz，1H)，7.32(d，J＝ 8.0Hz，2H)，6.35(d，J＝2.0Hz，1H)，2.41(s，3H)。
Example 57
4-amino-7-chloro-3- (5-methyl-1, 3, 4-oxadiazol-2-yl) -1-phenyl-1, 2-dihydroquinolin-2-one
The final product of example 15 (300 mg) was dissolved in anhydrous methanol (10 mL), and 85% hydrazine hydrate solution (2 mL) was added and stirred at room temperature for 24 hours. The resulting crude product was filtered, dissolved in methylene chloride (5 mL), acetyl chloride (24 mg) was slowly added and stirred at room temperature for 3 hours. 1mol/L hydrochloric acid (5 mL) was added, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was separated by column chromatography (dichloromethane/methanol=10:1) to give a white solid, which was dissolved in acetonitrile (6 mL), phosphorus oxychloride (6 drops) and a catalytic amount of 4-dimethylaminopyridine were added, refluxed overnight, cooled to room temperature, concentrated under reduced pressure, and the residue was separated by column chromatography (dichloromethane/methanol=20:1) to give the product (74 mg).
1 H NMR(400MHz，DMSO-d6)δ8.54-8.80(brs，2H)，8.31(d，J＝8.8Hz，1H)， 7.58-7.62(m，2H)，7.51-7.55(m，1H)，7.34(d，J＝8.8Hz，1H)，7.31(d，J＝7.6Hz， 2H)，6.36(s，1H)，2.48(s，3H)。
Example 58
4-amino-7-bromo-3- (3-methyl-1, 2, 4-oxadiazol-5-yl) -1-phenyl-1, 2-dihydroquinolin-2-one
The procedure of example 56 was followed using the final product of example 22 as starting material to give the product.
1 H NMR(400MHz，DMSO-d6)δ8.50-9.72(brs，2H)，8.25(d，J＝8.8Hz，1H)， 7.59-7.63(m，2H)，7.52-7.55(m，1H)，7.49(dd，J＝8.8Hz，1.6Hz，1H)，7.32(d，J＝ 7.6Hz，2H)，6.50(d，J＝2.0Hz，1H)，2.41(s，3H)。
Example 59
4-amino-1- (2, 3-dihydro-1-benzofuran-4-yl) -7-iodo-2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-bromo-4-iodobenzoic acid and 2, 3-dihydro-1-benzofuran-4-amine as starting materials to give the product according to the preparation scheme of scheme 2.
1 H NMR(400MHz，DMSO-d6)δ8.42(s，2H)，8.01(d，J＝8.6Hz，1H)，7.59(dd， J＝8.5，1.7Hz，1H)，7.29(t，J＝7.9Hz，1H)，6.91(d，J＝8.0Hz，1H)，6.81(d，J＝1.6 Hz，1H)，6.69(d，J＝7.8Hz，1H)，4.54(t，J＝8.8Hz，2H)，3.72(s，3H)，2.87(dt，J＝ 17.1，8.8Hz，1H)，2.75(dt，J＝16.3，8.6Hz，1H)。
Example 60
4-amino-2-oxo-1- (pyridin-2-yl) -7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-bromopyridine and 2-amino-4- (trifluoromethyl) benzoic acid as starting materials to give the product.
1 H NMR(400MHz，CD 3 OD)δ8.74(s，1H)，8.34(d，J＝9.2Hz，1H)，8.16(t，J ＝8.4Hz，1H)，7.66(d，J＝6.8Hz，1H)，7.52-7.56(m，2H)，6.58(s，1H)，3.82(s，3H)。
Example 61
4-amino-2-oxo-1- (pyrimidin-2-yl) -7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-bromopyrimidine and 2-amino-4- (trifluoromethyl) benzoic acid as starting materials to give the product.
1 H NMR(400MHz，CD 3 OD)δ9.27(d，J＝8.8Hz，1H)，8.40(d，J＝8.4Hz，1H)， 8.34(dd，J＝7.2Hz，2.0Hz，1H)，7.82-8.07(m，2H)，6.54(t，J＝7.2Hz，1H)，3.85(s， 3H)。
Example 62
4-amino-7- (trifluoromethyl) -1- (4- (trifluoromethoxy) phenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 2 was followed using 2-bromo-4-trifluoromethylbenzoic acid and para-trifluoromethoxyaniline as starting materials to give the product.
1 H NMR(400MHz，DMSO-d6)δ8.46-8.48(m，3H)，7.55-7.59(m，3H)，7.45(d， J＝8.4Hz，2H)，6.56(s，1H)，3.72(s，3H)。
Example 63
4-amino-1- (4- (difluoromethoxy) phenyl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 2 was followed using 2-bromo-4-trifluoromethylbenzoic acid and p-difluoromethoxybenzene as starting materials to give the product.
1 H NMR(400MHz，DMSO-d6)δ8.46(d，J＝8.8Hz，1H)，8.41(s，2H)，7.56(dd， J＝8.8Hz，1.6Hz，1H)，7.37(t，J＝73.6Hz，1H)，7.37(s，4H)，6.60(s，1H)，3.72(s， 3H)。
Example 64
4-amino-1- (4-hydroxyphenyl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
Example 25 (50 mg) was dissolved in methylene chloride (10 mL), and boron tribromide (1 mL) was slowly added dropwise under ice-bath cooling, followed by stirring for 2 hours under ice-bath cooling. The reaction solution was filtered, water (20 mL) was added to the filtrate, extracted with dichloromethane (20 ml×3), the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=15:1) to give a product (32 mg).
1 H NMR(400MHz，DMSO-d6)δ10.12(s，1H)，9.15(s，1H)，8.61(d，J＝8.8Hz， 1H)，7.74(d，J＝8.8Hz，1.2Hz，1H)，7.31-7.35(m，2H)，7.14-7.17(m，2H)，6.79(s， 1H)，3.84(s，3H)。
Example 65
4-amino-7- (trimethylsilyl) ethynyl-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
Example 16 (50 mg), trimethylsilylacetylene (48 mg), bis (diphenylphosphinophenyl ether) palladium (II) dichloride (8 mg), triethylamine (60 mg) and tetrahydrofuran (5 mL) were heated in a lock tube to 90℃for reaction for 12 hours under nitrogen. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=25:1) to give a product (55 mg).
1 H NMR(400MHz，CDCl 3 )δ7.42-7.84(m，6H)，7.21-7.24(m，3H)，6.67(d，J＝ 1.2Hz，1H)，3.88(s，3H)，0.19(s，9H)。
Example 66
4-amino-7-cyclopropyl-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
A solution of example 16 (50 mg), cyclopropylboronic acid (31 mg), [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (9 mg) and sodium carbonate (64 mg) in 1, 4-dioxane (10 mL) and water (2 mL) was heated to 90℃under nitrogen and stirred for 12 hours. The reaction was cooled to room temperature, filtered, water (100 mL) was added to the filtrate, extracted with dichloromethane (100 mL x 3), the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=25:1) to give the product (18 mg).
1 H NMR(400MHz，CDCl 3 )δ7.34-7.74(m，6H)，7.22-7.24(m，2H)，6.80(d，J＝ 7.2Hz，1H)，6.32(s，1H)，3.90(s，3H)，1.72-1.80(m，1H)，0.94-0.99(m，2H)， 0.58-0.63(m，2H)。
Example 67
4-amino-7-ethynyl-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
Example 65 (53 mg) was dissolved in methanol (10 mL), tetrabutylammonium fluoride trihydrate (135 mg) was added, and the mixture was heated to 60℃and stirred for 3 hours. Cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20:1) to give the product (22 mg).
1 H NMR(400MHz，CDCl 3 )δ7.75(d，J＝8.8Hz，1H)，7.47-7.51(m，2H)， 7.40-7.44(m，1H)，7.18(dd，J＝8.8Hz，1.6Hz，1H)，7.13-7.15(m，2H)，6.61(s，1H)， 3.79(s，3H)，3.12(s，1H)。
Example 68
4-amino-7-morpholin-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
Example 16 (50 mg), morpholine (52 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (10 mg), cesium carbonate (79 mg) and 1, 4-dioxane (10 mL) were heated in a closed tube to 110 ℃ for reaction for 12 hours under nitrogen. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20:1) to give a product (20 mg).
1 H NMR(400MHz，CDCl 3 )δ7.49-7.54(m，3H)，7.42-7.46(m，1H)，7.22-7.24 (m，2H)，6.72(dd，J＝8.8Hz，2.4Hz，1H)，5.83(d，J＝2.4Hz，1H)，3.87(s，3H)， 3.72-3.74(m，4H)，3.02-3.04(m，4H)。
Example 69
4-amino-1- (2-chlorophenyl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-bromo-4-trifluoromethylbenzoic acid and 2-chloroaniline as starting materials to give the product.
1 H NMR(399MHz，DMSO-d 6 )δ8.59(s，2H)，8.54(d，J＝8.5Hz，1H)，7.82-7.72(m，1H)，7.66-7.57(m，3H)，7.55-7.48(m，1H)，6.46(d，J＝1.7Hz，1H)， 3.75(s，3H)。
Example 70
4-amino-2-oxo-1- (pyridin-3-yl) -7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
Following the preparation route of scheme 2, with 3-bromopyridine and 2-amino-4- (trifluoromethyl) benzoic acid as starting materials, the preparation procedure of example 15 was referenced to give the product.
1 H NMR(400MHz，CD 3 OD)δ8.74(d，J＝4.0Hz，1H)，8.53(s，1H)，8.35(d，J ＝8.4Hz，1H)，7.86-7.89(m，1H)，7.71(dd，J＝8.4Hz，4.8Hz，1H)，7.55(dd，J＝8.4 Hz，1.6Hz，1H)，6.72(s，1H)，3.82(s，3H)。
Example 71
4-amino-2-oxo-1- (pyridin-4-yl) -7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
Following the preparation route of scheme 2, with 4-bromopyridine and 2-amino-4- (trifluoromethyl) benzoic acid as starting materials, the preparation procedure of example 15 was referenced to give the product.
1 H NMR(400MHz，CDCl 3 )δ8.72(d，J＝5.6Hz，2H)，8.17(d，J＝8.8Hz，1H)， 7.39-7.44(brs，2H)，7.29(d，J＝8.2Hz，1H)，7.13(d，J＝5.6Hz，2H)，6.60(s，1H)， 3.75(s，3H)。
Example 72
4-amino-2-oxo-1- (3, 4,5, 6-tetrahydro-2H-pyran-4-yl) -7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-bromo-4-trifluoromethylbenzoic acid and 4-aminotetrahydropyran as starting materials to give the product according to the preparation scheme of scheme 2.
1 H NMR(400MHz，DMSO-d 6 )δ8.37(d，J＝8.5Hz，1H)，7.99(s，2H)，7.90(s， 1H)，7.57(d，J＝8.5Hz，1H)，4.92(s，1H)，3.95(dd，J＝11.4，4.5Hz，2H)，3.76(s， 3H)，3.53(td，J＝11.8，2.0Hz，2H)，2.74(qd，J＝12.2，4.7Hz，2H)，1.56(dd，J＝13.1， 4.0Hz，2H)。
Example 73
4-amino-7-cyclopropyl-1- (4-methoxyphenyl) -2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
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Using example 79 as a starting material, the reaction procedure was followed using the synthesis method of example 66 to give the product (10 mg).
1 H NMR(400MHz，CDCl 3 )δ7.51(d，J＝8.4Hz，1H)，7.13(d，J＝8.8Hz，2H)， 7.04(d，J＝8.8Hz，2H)，6.75(d，J＝8.4Hz，1H)，6.38(d，J＝1.2Hz，1H)，3.87(s，6H)，1.74-1.80(m，1H)，0.93-0.98(m，2H)，0.59-0.63(m，2H)。
Example 74
4-amino-7-carboxylic acid methyl ester-2-oxo-1-phenyl-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
Example 16 (50 mg), [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride (9 mg) and triethylamine (60 mg) were dissolved in methanol (15 mL), carbon monoxide was exchanged three times, and heated to 60℃and stirred for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20:1) to give a product (20 mg).
1 H NMR(400MHz，CDCl 3 )δ7.79(dd，J＝8.8Hz，1.6Hz，1H)，7.71(d，J＝8.8 Hz，1H)，7.54-7.58(m，2H)，7.47-7.51(m，1H)，7.28(d，J＝1.6Hz，1H)，7.22-7.24(m， 2H)，3.90(s，3H)，3.83(s，3H)。
Example 75
4-amino-1- (2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-iodo-4- (trifluoromethyl) benzoic acid and 2, 2-difluorobenzo [ d ] [1,3] dioxolan-5-amine as starting materials according to the preparation route of scheme 2, to give the product.
1 H NMR(400MHz，DMSO-d6)δ8.41-8.52(m，3H)，7.56-7.61(m，2H)，7.52(s， 1H)，7.17(d，J＝7.6Hz，1H)，6.69(s，1H)，3.71(s，3H)。
Example 76
4-amino-1- (3H-benzo [ d ] imidazol-5-yl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed, using 2-amino-4- (trifluoromethyl) benzoic acid and 6-bromo-1H-benzo [ d ] imidazole as starting materials, to give the product.
1 H NMR(400MHz，DMSO-d6)δ12.44-13.12(brs，1H)，8.46(d，J＝8.8Hz，1H)， 8.37(s，3H)，7.75(d，J＝8.8Hz，1H)，7.52-7.54(m，2H)，7.04(dd，J＝8.4Hz，2.0Hz， 1H)，6.60(s，1H)，3.71(s，3H)。
Example 77
4-amino-1-cyclohexyl-2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-iodo-4- (trifluoromethyl) benzoic acid and cyclohexylamine as starting materials, according to the preparation route of scheme 2, to give the product.
1 H NMR(400MHz，DMSO-d6)δ8.33(d，J＝8.4Hz，1H)，7.94(s，2H)，7.78(s，1H)，7.52(d，J＝8.4Hz，1H)，4.48-4.86(m，1H)，3.72(s，3H)，2.33-2.46(m，2H)， 1.74-1.84(m，2H)，1.56-1.70(m，3H)，1.35-1.50(m，2H)，1.08-1.22(m，1H)。
Example 78
4-amino-7-bromo-1- (4-fluorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2, 4-dibromobenzoic acid and 4-fluoroaniline as starting materials to give the product.
1 H NMR(400MHz，DMSO-d 6 )δ8.43(s，2H)，8.19(d，J＝8.8Hz，1H)， 7.47-7.39(m，3H)，7.37-7.30(m，2H)，6.50(d，J＝1.9Hz，1H)，3.71(s，3H)。
Example 79
4-amino-7-iodo-1- (4-methoxyphenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-bromo-4-iodobenzoic acid and 4-methoxyaniline as starting materials to give the product according to the preparation scheme of scheme 2.
1 H NMR(399MHz，DMSO-d 6 )δ8.34(s，2H)，7.98(d，J＝8.5Hz，1H)，7.55(d， J＝8.6Hz，1H)，7.14(q，J＝8.9Hz，4H)，6.75(d，J＝1.6Hz，1H)，3.85(s，3H)，3.71 (s，3H)。
Example 80
4-amino-1- (4-methoxy-2-methylphenyl) -2-oxo-7- (trifluoromethyl) 1, 2-dihydroquinoline-3-carboxylic acid methyl ester
The procedure of example 15 was followed using 2-bromo-4-trifluoromethylbenzoic acid and 4-methoxy-2-methylaniline as starting materials to give the product.
1 H NMR(400MHz，DMSO-d 6 )δ8.46(d，J＝8.4Hz，1H)，8.40(s，2H)，7.56(d， J＝9.6Hz，1H)，7.08(d，J＝8.4Hz，1H)，7.02(d，J＝2.8Hz，1H)，6.92(dd，J＝8.8 Hz，2.8Hz，1H)，6.53(s，1H)，3.81(s，3H)，3.72(s，3H)，1.83(s，3H)。
Biological testing
1. In vitro enzymatic inhibition activity detection of MAT2A by Compounds
The enzymatic activity of MAT2A (semi-inhibitory concentration IC50 value of test compound) was determined using the phosphate assay kit PicolorLockTM (ab 270004, available from Abcam). The method utilizes the principle that purified human MAT2A enzyme catalyzes L-methionine and ATP to release free phosphate in the process of generating S-adenosylmethionine (SAM), and spectrophotometry is used for determining the enzymatic activity of MAT 2A. Compounds were taken in 100% DMSO starting from 1mM10-fold gradient dilutions (total of 8 concentrations) were performed, each concentration taking 2. Mu.L of compound added to 48. Mu.L of reaction buffer (50 mM Tris-HCl pH 7.5, 50mM KCl,10mM MgCl) 2 0.01% brij-35,0.01%BSA,1mM DTT) was diluted and mixed. The final diluted compound, MAT2A enzyme (final concentration 10 nM), ATP (final concentration 50. Mu.M) and L-methionine (final concentration 100. Mu.M) were added 5. Mu.L each to 384 well plates (# 3701, available from CorNING). After the 384 well plates were placed in an incubator at 23℃for 6 hours, 5. Mu.L of the PicolorLock reagent diluted Accelerator (dilution ratio 1:100) was added to each well, and the reaction was terminated by incubating in the incubator at 23℃for 5 minutes. The IC50 value of this compound was calculated using GraphPad Prism software by adding 2. Mu.L of Stabiliser, reading the light absorbance at 630nm on BMG CLARIOstar.
Experimental results:
under the present experimental conditions, the inhibition of MAT2A by the test compound can be expressed as an IC50 value for the inhibition of the level of phosphate production during the enzymatic reaction. The MAT2A inhibitory activity of the above-described partial examples is shown in table 1.
TABLE 1
2. Animal pharmacokinetic studies of examples:
the study used 3 healthy adult male rats, from beijing vernalia laboratory animal technologies limited.
The experimental administration mode is SD rat oral single gastric lavage administration, the administration dosage is 5mg/kg, the administration volume is 5mL/kg, and the administration concentration is 1mg/mL.
The test sample in this item is typically suspended in an aqueous solution of 0.5% hydroxypropyl methylcellulose, 0.1% Tween 80 (W/V/V), at a concentration of 1mg/mL.
The animals dosed by gavage were fasted overnight prior to the experiment, with the fasted time ranging from 10 hours prior to dosing to 4 hours post dosing. Sequentially according to the following time after administration: blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours. Animals were shallowly anesthetized by isoflurane, and about 0.3mL of whole blood was collected in the orbital venous plexus with a glass blood collection tube, placed in a heparin sodium anticoagulation tube, the samples were centrifuged at 4200rpm for 5min at 4 ℃, and the plasma transferred to a centrifuge tube and stored at-80 ℃ until analysis.
Plasma sample analysis the acetonitrile protein precipitation method was used to extract the compounds to be tested and internal standard (warfarin or propranolol) from rat plasma and the extracts were analyzed by LC/MS. Plasma concentration-time data from individual animals were analyzed using a non-compartmental model of WinNonlin (version 5.2.1; pharsight) software to obtain the corresponding pharmacokinetic parameters: maximum (peak) plasma drug concentration C max The method comprises the steps of carrying out a first treatment on the surface of the Peak time T max The method comprises the steps of carrying out a first treatment on the surface of the Half-life T 1/2 And the area under the plasma concentration-time curve, AUC0-inf, extrapolated to an infinitely long time.
The experimental results of some examples are shown in table 3.
TABLE 3 Table 3
The test used 0.5% HPMC,0.1% Tween80 as an adjuvant.

Claims (9)

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof
Wherein,,
l is a bond or CH 2 ，CH 2 Can optionally be C 1-6 Alkyl or 3-8 membered cycloalkyl,
X 1 、X 2 and X 3 Each independently selected from N and CR 4 ，
R 1 Selected from C 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally being substituted by halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-N (R) -C 1-6 An alkyl group is substituted and a substituent is substituted,
R 2 is a 3-8 membered carbocycle, 3-8 membered heterocycle, benzene ring, or 5-6 membered heteroaryl ring, the carbocycle, heterocycle, benzene ring, and heteroaryl ring optionally being fused to a 3-8 membered carbocycle, 3-8 membered heterocycle, benzene ring, or 5-6 membered heteroaryl ring, the carbocycle, heterocycle, benzene ring, or heteroaryl ring optionally being fused to 1-3R 12 Instead of the above-mentioned,
R 12 each independently selected from halogen, CF 3 、-CN、-OH、-NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl and-N (R) -C 1-6 Alkyl, said alkyl, cycloalkyl and heterocycloalkyl being optionally substituted by halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl, or-N (R) -C 1-6 An alkyl group is substituted and a substituent is substituted,
R 3 selected from H, halogen, CF 3 、-CN、-OH、-NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl, -N (R) -C 1-6 Alkyl groupThe alkyl, cycloalkyl and heterocycloalkyl groups may optionally be substituted with halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl, or-N (R) -C 1-6 An alkyl group is substituted and a substituent is substituted,
R 4 each independently selected from H, halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl group、C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl and-N (R) -C 1-6 Alkyl, said alkyl, cycloalkyl and heterocycloalkyl being optionally substituted by halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -O-C 1-6 Alkyl, or-N (R) -C 1-6 An alkyl group is substituted and a substituent is substituted,
r is each independently selected from C 1-6 Alkyl, 3-8 membered cycloalkyl and 3-8 membered heterocycloalkyl, which alkyl, cycloalkyl and heterocycloalkyl may optionally be halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl,
R 10 and R is 11 Each independently selected from C 1-6 Alkyl and 3-8 membered cycloalkyl groups, which may optionally be substituted with halogen, -CN, -OH, or-NH 2 Instead of the above-mentioned,
with the proviso that the following compounds are excluded:
2. the compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein L is a bond, R 1 Selected from C 1-6 Alkyl, 3-8 membered cycloalkyl and 3-8 membered heterocycloalkyl, which alkyl, cycloalkyl and heterocycloalkyl may optionally be halogen, -CN, -OH, -NH 2 、C 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-C 1-6 Alkyl, or-N (R) -C 1-6 Alkyl substitution.
3. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R 3 Selected from H, halogen, CF 3 、-CN、-OH、-NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groupsR 10 And R is 11 As defined in claim 1.
4. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R 2 Is a benzene ring or a 5-6 membered heteroaromatic ring, which may optionally be fused with a 3-8 membered carbocyclic ring, a 3-8 membered heterocyclic ring, a benzene ring, or a 5-6 membered heteroaromatic ring, which carbocyclic ring, heterocyclic ring, benzene ring, or heteroaromatic ring may optionally be substituted with 1-3R 12 Substituted, R 12 As defined in claim 1.
5. The compounds or pharmaceutically acceptable salts, solvates, polymorphs, or isomers thereof
6. A pharmaceutical composition comprising a compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and optionally a pharmaceutically acceptable adjuvant.
7. Use of a compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a pharmaceutical composition according to claim 6, in the manufacture of a medicament for the treatment of a MAT 2A-related disease.
8. The use of claim 7, wherein the MAT 2A-associated disease is a tumor.
9. The use of claim 7, wherein the MAT 2A-related disease is a solid tumor.
CN202210327578.2A 2022-03-29 2022-03-29 Novel heterocyclic compound Pending CN116924983A (en)

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