WO2021058024A1 - Lsd1 inhibitor - Google Patents

Lsd1 inhibitor Download PDF

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Publication number
WO2021058024A1
WO2021058024A1 PCT/CN2020/118824 CN2020118824W WO2021058024A1 WO 2021058024 A1 WO2021058024 A1 WO 2021058024A1 CN 2020118824 W CN2020118824 W CN 2020118824W WO 2021058024 A1 WO2021058024 A1 WO 2021058024A1
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WIPO (PCT)
Prior art keywords
compound
reaction solution
pharmaceutically acceptable
alkyl
isomer
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PCT/CN2020/118824
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French (fr)
Chinese (zh)
Inventor
吴凌云
展震
钱薏
王君为
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202080068659.4A priority Critical patent/CN114502561B/en
Publication of WO2021058024A1 publication Critical patent/WO2021058024A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to a class of heterospiro compounds as inhibitors of lysine-specific demethylase 1 (LSD1), and its application in preparing medicines for treating diseases related to LSD1. Specifically, it relates to the compound represented by formula (I), its isomers and pharmaceutically acceptable salts thereof.
  • Post-translational modifications of histones include methylation, acetylation, phosphorylation, ubiquitination and other processes, which are important regulatory means of epigenetics, which affect gene expression by changing the structure of chromatin [Xueshun Wang, Boshi Huang, Takayoshi Suzuki et al. al., Epigenomics, 2015, 1379-1396;]. Although these modifications do not change the basic sequence of DNA, this epigenetic change may persist throughout the cell life cycle or cell iteration process through cell division [Adrian Bird, Nature, 2007, 396-398]. Therefore, the abnormal function of epigenetics is closely related to the pathological process of various diseases [James T Lynch, William J Harris& Tim C P Somervaille, Expert Opin. Ther.
  • LSD1A Lysine specific demethylase
  • the LSD1 structure includes three main parts: the N-terminal SWIRM domain, the C-terminal amino oxidase domain (AOL) and the central Tower domain. [Ruchi Anand, Ronen Marmorstein, Journal of Biological Chemistry, 2007, 35425–35429].
  • the C-terminal aminooxidase domain includes two active pockets, one is the site for FAD binding, and the other is the site for recognition and binding to the substrate [Pete Stavropoulos, Günter Blobel, André Hoelz, Nature Structral&Molecular Biology, 2006,626-632].
  • SWIRM domain It does not directly participate in the binding of FAD or substrates. However, mutation or removal of this region will reduce the activity of LSD1. Therefore, it is speculated that this region may affect the active region by adjusting its conformation. effect. [Yong Chen, Yuting Yang, Feng Wang et al., Biochemistry, 2006, 13956–13961].
  • Tower domain is the binding domain of LSD1 and other protein factors.
  • LSD1 After LSD1 is combined with different protein factors, it acts on different substrates, thus playing different regulatory effects on histone and gene expression. For example, after LSD1 is combined with CoREST, it will preferentially act on histone H3K4, through demethylation, remove activation-related histone markers, and inhibit gene transcription; and after binding with androgen receptor protein, recombinant LSD1 will act preferentially In H3K9, activation of androgen receptor-related gene transcription through demethylation [Ruchi Anand, Ronen Marmorstein, Journal of Biological Chemistry, 2007, 35425–35429; Eric Metzger, Melanie Wissmann, Na Yin et al., Nature, 2005 ,436-439.].
  • LSD1 also regulates the methylation status of some non-histone substrates, including the tumor suppressor gene p53 and DNA methyltransferase 1 (DNMT1), etc. [Yi Chao Zheng, Jinlian Ma, Zhiru Wang, Medicinal Research Reviews, 2015, 1032–1071].
  • LSD1 is a FAD-dependent amino oxidase, in which proton transfer is considered the most likely oxidation mechanism [Zheng Y C, Yu B, Chen Z S, et al. Epigenomics, 2016, 8, 651-666.].
  • proton transfer the N-CH 3 bond of the substrate is converted into an imine bond.
  • This imine ion intermediate undergoes a hydrolysis reaction to generate demethylated amine on one side and formaldehyde on the other side.
  • LSD1 is abnormally expressed in many different types of tumors. LSD1 is highly expressed in acute myeloid leukemia (AML) subtypes and is an important factor in maintaining the potential of leukemia stem cells (LSC). LSD1 is highly expressed in a variety of solid tumors such as lung cancer, breast cancer, prostate cancer, liver cancer and pancreatic cancer, and is closely related to the poor prognosis of tumors. LSD1 inhibits the expression of cadherin and is closely related to tumor invasion and epithelial-mesenchymal transition (EMT) [Hosseini A, Minucci S. Epigenomics, 2017, 9, 1123-1142.].
  • EMT epithelial-mesenchymal transition
  • the present invention provides a compound of formula (I), its isomers or pharmaceutically acceptable salts thereof,
  • R 1 is C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1- 3- alkyl-4-7 membered heterocycloalkyl, -C 1-3 alkyl-phenyl or -C 1-3 alkyl-5-6 membered heteroaryl, wherein the C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1-3 alkyl-phenyl or -C 1 -3 -5-6 membered heteroaryl group optionally substituted with 1, 2 or 3 R a;
  • R 2 is H or C 1-3 alkyl
  • R 1 and R 2 are connected with the N atom to which they are connected to form a structural unit
  • D 1 is a single bond, O, N(R d11 ) or C(R d12 ) 2 ;
  • D 2 is O, N(R d21 ) or C(R d22 ) 2 ;
  • D 4 is O, N(R d41 ) or C(R d42 ) 2 ;
  • D 5 is a single bond, O, N (R d51 ) or C (R d52 ) 2 ;
  • R d11 , R d21 , R d31 , R d41 and R d51 are each independently H or C 1-3 alkyl;
  • R d12, R d22, R d32 , R d42 and R d52 are each independently H, F, Cl, Br, I, OH, NH 2, CN, COOH or C 1-3 alkyl;
  • R a is F, Cl, Br, I, OH, NH 2 , CN, COOH, Or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R;
  • R is selected from F, Cl, Br, I, OH and NH 2 ;
  • n 0, 1 or 2;
  • n 0, 1, or 2, and m and n cannot be 0 at the same time;
  • r is 0 or 1;
  • q is 0 or 1
  • g is 1, 2 or 3;
  • the 5-6 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N;
  • the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
  • the carbon atom with "#" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the present invention also provides a compound of formula (I), its isomers or pharmaceutically acceptable salts thereof,
  • R 1 is C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1- 3- alkyl-4-7 membered heterocycloalkyl, -C 1-3 alkyl-phenyl or -C 1-3 alkyl-5-6 membered heteroaryl, wherein the C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1-3 alkyl-phenyl or -C 1 -3 -5-6 membered heteroaryl group optionally substituted with 1, 2 or 3 R a;
  • R 2 is H or C 1-3 alkyl
  • R 1 and R 2 are connected with the N atom to which they are connected to form a structural unit
  • D 1 is a single bond, O, N(R d11 ) or C(R d12 ) 2 ;
  • D 2 is O, N(R d21 ) or C(R d22 ) 2 ;
  • D 3 is O, N(R d31 ) or C(R d32 ) 2 ;
  • D 4 is O, N(R d41 ) or C(R d42 ) 2 ;
  • D 5 is a single bond, O, N (R d51 ) or C (R d52 ) 2 ;
  • R d11 , R d21 , R d31 , R d41 and R d51 are each independently H or C 1-3 alkyl;
  • R d12, R d22, R d32 , R d42 and R d52 are each independently H, F, Cl, Br, I, OH, NH 2, CN, COOH or C 1-3 alkyl;
  • R a is F, Cl, Br, I, OH, NH 2 , CN, COOH, Or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R;
  • R is selected from F, Cl, Br, I, OH and NH 2 ;
  • n 0, 1 or 2;
  • n 0, 1, or 2, and m and n cannot be 0 at the same time;
  • r is 0 or 1;
  • q is 0 or 1
  • g is 1, 2 or 3;
  • the 5-6 membered heteroaryl group and the 4-7 membered heterocycloalkyl group respectively contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N ;
  • the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
  • the carbon atom with "#" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • R a is F, Cl, Br, I, OH, NH 2, CN, COOH, CH 3 or CF 3 and other variables are as defined in the present invention.
  • R 1 is CH 3 , -CH 2 -CH 3 , Wherein said CH 3 , -CH 2 -CH 3 , Optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
  • R 1 is CH 3 , -CH 2 -COOH, Other variables are as defined in the present invention.
  • R 2 is H or CH 3 , and other variables are as defined in the present invention.
  • R d11, R d21, R d31 , R d41 and R d51 are each independently H or CH 3, the other variables are as defined in the present invention.
  • R d12, R d22, R d32 , R d42 and R d52 are each independently H, F, Cl, Br, I, OH, NH 2, CN, COOH or CH 3, other variables As defined in the present invention.
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • R 1 and R 2 are as defined in the present invention.
  • the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
  • the carbon atom with "#" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • R 1 and R 2 are as defined in the present invention.
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • R 1 and R 2 are as defined in the present invention.
  • the present invention also provides a compound of the following formula, its isomers or a pharmaceutically acceptable salt thereof,
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • the above-mentioned pharmaceutically acceptable salt is hydrochloride.
  • the present invention also provides the use of the above-mentioned compound, its isomer or pharmaceutically acceptable salt in the preparation of a medicine for treating LSD1 related disorders.
  • the compound of the present invention has significant inhibitory activity on LSD1; and has obvious inhibitory activity on the proliferation of NCI-H1417 cells, HL60 cells and MV-4-11 cells; in addition, the compounds of the present invention have good pharmacokinetics. Kinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate, etc.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from the compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate the double bond or the single bond of the ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror mirror image.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a solid center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the following formula (A) means that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2)
  • the following formula (B) means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of two of formula (B-1) and formula (B-2) A mixture of isomers exists.
  • the following formula (C) represents that the compound exists as a single isomer of formula (C-1) or formula (C-2) or as two isomers of formula (C-1) and formula (C-2) Exist as a mixture.
  • the compound of the present invention may be specific.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomer also called prototropic tautomer
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformation.
  • keto-enol tautomerization is the tautomerization between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterium can be substituted for hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • “Optional” or “optionally” means that the event or condition described later may but not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X in AX is vacant, it means that the structure is actually A.
  • the bond of a substituent can be cross-connected to more than two atoms on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. .
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • the number of atoms in a ring is generally defined as the number of ring members.
  • “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
  • 3-12 membered ring means a cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl composed of 3 to 12 ring atoms.
  • the ring includes a single ring, as well as a bicyclic or polycyclic ring system such as a spiro ring, a fused ring and a bridged ring.
  • the ring optionally contains 1, 2, or 3 heteroatoms independently selected from O, S, and N.
  • the 3-12 membered ring includes 3-10 members, 3-9 members, 3-8 members, 3-7 members, 3-6 members, 3-5 members, 4-10 members, 4-9 members, 4- 8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6 9-membered, 6-8-membered and 6-7-membered rings, etc.
  • 5-7 membered heterocycloalkyl includes piperidinyl and the like, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which independently meets the above definition.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl examples include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-4 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent ( Such as methine).
  • Examples of C 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl) and so on.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy, etc. .
  • C 1-6 alkoxy examples include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) Oxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
  • C 3-7 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 7 carbon atoms, which includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spirocyclic, fused, and Bridge ring.
  • the C 3-7 cycloalkyl group includes C 3-6 , C 3-5 , C 4-7 , C 4-6 , C 4-5 , C 5-7 or C 5-6 cycloalkyl group, etc.; It can be one price, two price, or multiple price.
  • C 3-8 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] dicyclooctane and the like.
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group.
  • Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazo
  • the term "4-7 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 7 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 4-7 membered heterocycloalkyl group includes 5-6 membered, 4-membered, 5-membered, 6-membered, 7-membered heterocycloalkyl and the like.
  • 4-7 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolidiny
  • C 6-10 aromatic ring and “C 6-10 aryl” can be used interchangeably in the present invention.
  • C 6-10 aromatic ring or “C 6-10 aryl” means that A cyclic hydrocarbon group with a conjugated ⁇ -electron system composed of 6 to 10 carbon atoms, which can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. It may be monovalent, divalent or multivalent, and C 6-10 aryl groups include C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.).
  • 5-6 membered heteroaryl ring and “5-6 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-6 membered heteroaryl group” means a ring consisting of 5 to 6 ring atoms. It is composed of a monocyclic group with a conjugated ⁇ -electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; similarly, from n to n +m means the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, and 9-membered ring
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl group, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent and equivalent; CDI stands for Carbonyl diimidazole; Pd(PPh 3 ) 4 stands for palladium tetraphenylphosphine; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethyl Formamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for eth
  • Compound 2 (203mg, 0.549mmol) was subjected to supercritical fluid extraction (column: Chiralcel OD-3 50 ⁇ 4.6mm ID, 3 ⁇ m; mobile phase: A: carbon dioxide B: methanol (0.05% diethylamine); gradient: B From 5% to 40% in A; flow rate: 3 mL/min; column temperature: 35° C.; column pressure: 100 Bar) to obtain compound 19 (retention time: 1.610 minutes).
  • the purpose of this test is to test the compound's in vitro inhibitory activity on LSD1.
  • the enzyme used in this test is human LSD1
  • the standard substrate is histone H3K4me peptide (20 ⁇ M)
  • test compounds have inhibitory activity against LSD1, and the results are shown in Table 1.
  • the compound of the present invention has obvious inhibitory activity on LSD1.
  • Experimental purpose to detect the inhibitory activity of the test compound on the proliferation of NCI-H1417 cells.
  • Experimental method Dissolve the compound to 10mM, dilute the compound 5 times with DMSO in the compound plate.
  • the compound is initially 2mM, and the compound is diluted three times with Bravo, 10 concentrations, and 250nL of the Echo plate is used to reach the upper and lower sides of the blank 384 cell plate.
  • Double duplicate wells add 250nL DMSO/compound to each well/1000 cells/50 ⁇ L of cell suspension, the compound is diluted 200 times, that is, the initial concentration is 10 ⁇ M.
  • the cell plate was placed in a carbon dioxide incubator for 10 days. Add 25 ⁇ L of Promega CellTiter-Glo reagent per well to the cell plate and shake at room temperature for 10 minutes to stabilize the luminescence signal. Use PerkinElmer Envision multi-label analyzer to read.
  • test compound has inhibitory activity against the proliferation of NCI-H1417 cells, and the results are shown in Table 2.
  • the compound of the present invention has obvious inhibitory activity on the proliferation of NCI-H1417 cells.
  • the purpose of the experiment to detect the inhibitory activity of the test compound on the proliferation of HL60 cells.
  • RPMI-1640 medium fetal bovine serum
  • penicillin/streptomycin antibiotics purchased from Vicente.
  • CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega.
  • the HL60 cell line was purchased from Nanjing Kebai Life Technology Co., Ltd. Nivo multi-label analyzer (PerkinElmer).
  • Plant HL60 cells in a white 384-well plate 40 ⁇ L of cell suspension per well, which contains 600 HL60 cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 5-fold to the 10th concentration with a discharge gun, that is, diluted from 2mM to 1.024nM, and a double-well experiment was set up.
  • the cell plate was placed in a carbon dioxide incubator for 6 days.
  • test compound has an inhibitory activity on the proliferation of HL60 cells, and the results are shown in Table 3.
  • Table 3 Test results of the compound of the present invention for inhibiting the proliferation of HL60 cells
  • the compound of the present invention has obvious inhibitory activity on the proliferation of HL60 cells.
  • IMDM medium fetal bovine serum, penicillin/streptomycin antibiotics purchased from Vicente.
  • CellTiter-Glo cell viability chemiluminescence detection reagent
  • the MV-4-11 cell line was purchased from Nanjing Kebai Life Technology Co., Ltd. Nivo multi-label analyzer (PerkinElmer).
  • Plant MV-4-11 cells in a white 96-well plate 80 ⁇ L of cell suspension per well, which contains 6000 MV-4-11 cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 5-fold to the 8th concentration with a discharge gun, that is, diluted from 2mM to 25.6nM, and a double-well experiment was set up.
  • the cell plate was placed in a carbon dioxide incubator for 6 days. Another cell plate is prepared, and the signal value is read as the maximum value (Max value in the following equation) on the day of drug addition to participate in data analysis.
  • Add 25 ⁇ L of cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Using multi-marker analyzer readings.
  • test compound has an inhibitory activity on the proliferation of MV-4-11 cells, and the results are shown in Table 4.
  • the compound of the present invention has obvious inhibitory activity on the proliferation of MV-4-11 cells.
  • CD-1 mice male, 7-9 weeks old, Shanghai Slack
  • the rodent pharmacokinetic characteristics of the compound after intravenous injection and oral administration were tested by standard protocols.
  • the candidate compound was prepared into a clear solution and given to mice by a single intravenous injection and oral administration.
  • the solvent for intravenous injection and oral administration is a mixed solvent of 10% dimethyl sulfoxide and 90% 10% hydroxypropyl ⁇ cyclodextrin.
  • This project uses four male CD-1 mice, two mice are administered intravenously, the dosage is 1mg/kg, and the collection is 0h (before administration) and 0.0833, 0.25, 0.5, 1, 2 after administration.
  • mice were orally administered by gavage at a dose of 2mg/kg, collected 0h (before administration) and after administration 0.25, 0.5, 1, 2, 4, 8,24h plasma samples, collect whole blood samples within 24 hours, centrifuge at 3000g for 15 minutes, separate the supernatant to obtain the plasma sample, add 4 times the volume of the acetonitrile solution containing the internal standard to precipitate the protein, centrifuge to take the supernatant and add the same volume The water was centrifuged to take the supernatant and sample, and the blood drug concentration was quantitatively analyzed by LC-MS/MS analysis method, and the pharmacokinetic parameters were calculated, such as peak concentration (C max ), clearance rate (CL), half-life (T 1/2 ), tissue distribution (Vdss), area under the drug-time curve (AUC 0-last ), bioavailability (F), etc.
  • C max peak concentration
  • CL clearance rate
  • T 1/2 tissue distribution
  • Vdss tissue distribution
  • AUC 0-last area under the drug-
  • the compound of the present invention has good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.

Abstract

Provided are a class of heterospirocyclic compound which act as a lysine-specific demethylase 1 (LSD1) inhibitor, and a use thereof in the preparation of a drug for treating diseases associated with LSD1. The heterospirocyclic compounds are compounds as shown in formula (I), and an isomer and pharmaceutically acceptable salt thereof.

Description

LSD1抑制剂LSD1 inhibitor
本申请主张如下优先权：This application claims the following priority:
CN201910935182.4，申请日：2019.09.29；CN201910935182.4, application date: 2019.09.29;
CN202010838523.9，申请日：2020.08.19。CN202010838523.9, application date: 2020.08.19.
技术领域Technical field
本发明涉及一类作为赖氨酸特异性去甲基化酶1(LSD1)抑制剂的杂螺环化合物，及其在制备治疗与LSD1相关疾病的药物中的应用。具体涉及式(Ⅰ)所示化合物、其异构体及其药学上可接受的盐。The present invention relates to a class of heterospiro compounds as inhibitors of lysine-specific demethylase 1 (LSD1), and its application in preparing medicines for treating diseases related to LSD1. Specifically, it relates to the compound represented by formula (I), its isomers and pharmaceutically acceptable salts thereof.
背景技术Background technique
组蛋白翻译后修饰包括甲基化、乙酰化、磷酸化、泛素化等过程，是表观遗传学的重要调控手段，通过改变染色质结构影响基因表达[Xueshun Wang,Boshi Huang,Takayoshi Suzuki et al.,Epigenomics,2015,1379-1396；]。尽管这些修饰并不改变DNA的基础序列，但这种表观遗传的变化可能通过细胞分裂在整个细胞生命周期或者细胞迭代过程持续存在[Adrian Bird,Nature,2007,396-398]。因此表观遗传学功能异常与各种疾病的病理过程密切相关[James T Lynch,William J Harris&Tim C P Somervaille,Expert Opin.Ther.Targets,2012,1239-1249]，比如各种实体瘤，血液瘤，病毒感染，神经系统异常等疾病。因此，表观遗传学现在成为药物研发领域的研究热点。组蛋白的甲基化状态由组蛋白甲基转移酶和组蛋白去甲基化酶共同调控。赖氨酸特异性去甲基化酶(Lysine specific demethylase 1，LSD1，又名KDM1A)是第一个被报道的组蛋白赖氨酸去甲基化酶，通过调控组蛋白赖氨酸的甲基化状态，广泛参与转录调控，影响细胞增殖和分化、胚胎干细胞多能性等诸多生理过程。[Yujiang Shi,Fei Lan,Caitlin Matson et al.,Cell,2004,941–953][Daniel P.Mould,Alison E.McGonagle,Daniel H.Wiseman et al.,Medicinal Research Reviews,2015,586–618]。LSD1结构包括三个主要部分：N-末端的SWIRM结构域，C-末端的氨基氧化酶结构域(AOL)和中央的Tower域。[Ruchi Anand,Ronen Marmorstein,Journal of Biological Chemistry,2007,35425–35429]。C-末端的氨基氧化酶结构域包括两个活性口袋，一个是FAD结合的位点，另一个是用于识别并与底物结合的位点[Pete Stavropoulos,Günter Blobel,AndréHoelz,Nature Structral&Molecular Biology,2006,626-632]。SWIRM结构域的功能还没有明确的结论，它不直接参与FAD或者底物的结合，但是这个区域的突变或者是去除都会降低LSD1的活性，因此推测该区域可能是通过调整构象，影响活性区域的作用。[Yong Chen,Yuting Yang,Feng Wang et al.,Biochemistry,2006,13956–13961]。Tower结构域是LSD1与其他蛋白因子的结合域。LSD1与不同蛋白因子相结合后，作用于不同底物，从而对组蛋白以及基因表达起到不同的调控作用。比如LSD1与CoREST相结合后，会优先作用于组蛋白H3K4，通过去甲基化，去除激活相关的组蛋白标记，抑制基因转录；而与雄激素受体蛋白结合后，重组的LSD1会优先作用于H3K9，通过去甲基化激活雄激素受体相关的基因转录[Ruchi Anand,Ronen Marmorstein,Journal of Biological Chemistry,2007,35425–35429；Eric Metzger, Melanie Wissmann,Na Yin et al.,Nature,2005,436-439.]。此外，LSD1还调控部分非组蛋白底物的甲基化状态，包括抑癌基因p53和DNA甲基转移酶1(DNA methyltransferase 1，DNMT1)等[Yi Chao Zheng,Jinlian Ma,Zhiru Wang,Medicinal Research Reviews,2015,1032–1071]。Post-translational modifications of histones include methylation, acetylation, phosphorylation, ubiquitination and other processes, which are important regulatory means of epigenetics, which affect gene expression by changing the structure of chromatin [Xueshun Wang, Boshi Huang, Takayoshi Suzuki et al. al., Epigenomics, 2015, 1379-1396;]. Although these modifications do not change the basic sequence of DNA, this epigenetic change may persist throughout the cell life cycle or cell iteration process through cell division [Adrian Bird, Nature, 2007, 396-398]. Therefore, the abnormal function of epigenetics is closely related to the pathological process of various diseases [James T Lynch, William J Harris& Tim C P Somervaille, Expert Opin. Ther. Targets, 2012, 1239-1249], such as various solid tumors, hematomas , Virus infection, nervous system abnormalities and other diseases. Therefore, epigenetics has now become a research hotspot in the field of drug development. The methylation status of histones is regulated by histone methyltransferase and histone demethylase. Lysine specific demethylase (LSD1, also known as KDM1A) is the first reported histone lysine demethylase, which regulates the methylation of histone lysine It is widely involved in transcriptional regulation, affecting cell proliferation and differentiation, embryonic stem cell pluripotency, and many other physiological processes. [Yujiang Shi, Fei Lan,Caitlin Matson et al.,Cell,2004,941–953][Daniel P.Mould,Alison E.McGonagle,Daniel H.Wiseman et al.,Medicinal ResearchReviews,2015,586–618] . The LSD1 structure includes three main parts: the N-terminal SWIRM domain, the C-terminal amino oxidase domain (AOL) and the central Tower domain. [Ruchi Anand, Ronen Marmorstein, Journal of Biological Chemistry, 2007, 35425–35429]. The C-terminal aminooxidase domain includes two active pockets, one is the site for FAD binding, and the other is the site for recognition and binding to the substrate [Pete Stavropoulos, Günter Blobel, André Hoelz, Nature Structral&Molecular Biology, 2006,626-632]. There is no clear conclusion about the function of the SWIRM domain. It does not directly participate in the binding of FAD or substrates. However, mutation or removal of this region will reduce the activity of LSD1. Therefore, it is speculated that this region may affect the active region by adjusting its conformation. effect. [Yong Chen, Yuting Yang, Feng Wang et al., Biochemistry, 2006, 13956–13961]. Tower domain is the binding domain of LSD1 and other protein factors. After LSD1 is combined with different protein factors, it acts on different substrates, thus playing different regulatory effects on histone and gene expression. For example, after LSD1 is combined with CoREST, it will preferentially act on histone H3K4, through demethylation, remove activation-related histone markers, and inhibit gene transcription; and after binding with androgen receptor protein, recombinant LSD1 will act preferentially In H3K9, activation of androgen receptor-related gene transcription through demethylation [Ruchi Anand, Ronen Marmorstein, Journal of Biological Chemistry, 2007, 35425–35429; Eric Metzger, Melanie Wissmann, Na Yin et al., Nature, 2005 ,436-439.]. In addition, LSD1 also regulates the methylation status of some non-histone substrates, including the tumor suppressor gene p53 and DNA methyltransferase 1 (DNMT1), etc. [Yi Chao Zheng, Jinlian Ma, Zhiru Wang, Medicinal Research Reviews, 2015, 1032–1071].
LSD1是FAD依赖的氨基氧化酶，其中质子转移被认为是其最可能的氧化机理[Zheng Y C,Yu B,Chen Z S,et al.Epigenomics,2016,8,651-666.]。首先通过质子转移，将底物的N-CH 3键转化成亚胺键，这个亚胺离子中间体发生水解反应，一边生成去甲基的胺，另一边生成甲醛。在这个催化循环过程中，FAD被还原成FADH2，随后又被一分子的氧气氧化回到FAD，同时生成一分子H2O2[Yujiang Shi,Fei Lan,Caitlin Matson,Cell,2004,941–953]。 LSD1 is a FAD-dependent amino oxidase, in which proton transfer is considered the most likely oxidation mechanism [Zheng Y C, Yu B, Chen Z S, et al. Epigenomics, 2016, 8, 651-666.]. First, through proton transfer, the N-CH 3 bond of the substrate is converted into an imine bond. This imine ion intermediate undergoes a hydrolysis reaction to generate demethylated amine on one side and formaldehyde on the other side. During this catalytic cycle, FAD is reduced to FADH2, which is then oxidized by a molecule of oxygen back to FAD, and at the same time a molecule of H2O2 is generated [Yujiang Shi, Fei Lan, Caitlin Matson, Cell, 2004, 941–953].
LSD1在多种不同类型的肿瘤中异常表达。LSD1在急性髓性白血病(acute myeloid leukemia，AML)亚型中高表达，是维持白血病干细胞(leukemia stem cell，LSC)潜能的重要因素。LSD1在多种实体瘤如肺癌、乳腺癌、前列腺癌、肝癌和胰腺癌中高表达，与肿瘤的预后不良密切相关。LSD1抑制钙粘蛋白的表达，与肿瘤的侵袭和上皮-间质转移(epithelial-mesenchymal transition,EMT)密切相关[Hosseini A,Minucci S.Epigenomics,2017,9,1123-1142.]。LSD1 is abnormally expressed in many different types of tumors. LSD1 is highly expressed in acute myeloid leukemia (AML) subtypes and is an important factor in maintaining the potential of leukemia stem cells (LSC). LSD1 is highly expressed in a variety of solid tumors such as lung cancer, breast cancer, prostate cancer, liver cancer and pancreatic cancer, and is closely related to the poor prognosis of tumors. LSD1 inhibits the expression of cadherin and is closely related to tumor invasion and epithelial-mesenchymal transition (EMT) [Hosseini A, Minucci S. Epigenomics, 2017, 9, 1123-1142.].
LSD1抑制剂目前没有药物获批上市，已有8个药物处于临床研究阶段，主要用于血液肿瘤、小细胞肺癌和尤文氏肉瘤等疾病的治疗。然而，面对巨大的未满足市场，该领域仍然需要活性更好，药代动力学参数更优的候选化合物推进临床试验，以满足治疗需求。There are currently no drugs approved for LSD1 inhibitors, and 8 drugs are in the clinical research stage, mainly for the treatment of diseases such as hematological tumors, small cell lung cancer and Ewing's sarcoma. However, in the face of a huge unsatisfied market, this field still needs candidate compounds with better activity and better pharmacokinetic parameters to promote clinical trials to meet the therapeutic needs.
发明内容Summary of the invention
本发明提供了式(Ⅰ)化合物、其异构体或其药学上可接受的盐，The present invention provides a compound of formula (I), its isomers or pharmaceutically acceptable salts thereof,
Figure PCTCN2020118824-appb-000001
Figure PCTCN2020118824-appb-000001
其中，among them,
R 1为C 1-3烷基、C 3-7环烷基、4-7元杂环烷基、苯基、-C 1-3烷基-C 3-7环烷基、-C 1-3烷基-4-7元杂环烷基、-C 1-3烷基-苯基或-C 1-3烷基-5-6元杂芳基，其中所述C 1-3烷基、C 3-7环烷基、4-7元杂环烷基、苯基、-C 1-3烷基-C 3-7环烷基、-C 1-3烷基-苯基或-C 1-3烷基-5-6元杂芳基任选被1、2或3个R a取代； R 1 is C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1- 3- alkyl-4-7 membered heterocycloalkyl, -C 1-3 alkyl-phenyl or -C 1-3 alkyl-5-6 membered heteroaryl, wherein the C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1-3 alkyl-phenyl or -C 1 -3 -5-6 membered heteroaryl group optionally substituted with 1, 2 or 3 R a;
R 2为H或C 1-3烷基； R 2 is H or C 1-3 alkyl;
或者，R 1和R 2与其所连接的N原子连接一起形成结构单元
Figure PCTCN2020118824-appb-000002
Alternatively, R 1 and R 2 are connected with the N atom to which they are connected to form a structural unit
Figure PCTCN2020118824-appb-000002
D 1为单键、O、N(R d11)或C(R d12) 2； D 1 is a single bond, O, N(R d11 ) or C(R d12 ) 2 ;
D 2为O、N(R d21)或C(R d22) 2； D 2 is O, N(R d21 ) or C(R d22 ) 2 ;
D 3为O、S(＝O) 2、N(R d31)或C(R d32) 2； D 3 is O, S(=O) 2 , N(R d31 ) or C(R d32 ) 2 ;
D 4为O、N(R d41)或C(R d42) 2； D 4 is O, N(R d41 ) or C(R d42 ) 2 ;
D 5为单键、O、N(R d51)或C(R d52) 2； D 5 is a single bond, O, N (R d51 ) or C (R d52 ) 2 ;
R d11、R d21、R d31、R d41和R d51分别独立地为H或C 1-3烷基； R d11 , R d21 , R d31 , R d41 and R d51 are each independently H or C 1-3 alkyl;
R d12、R d22、R d32、R d42和R d52分别独立地为H、F、Cl、Br、I、OH、NH 2、CN、COOH或C 1-3烷基； R d12, R d22, R d32 , R d42 and R d52 are each independently H, F, Cl, Br, I, OH, NH 2, CN, COOH or C 1-3 alkyl;
R a为F、Cl、Br、I、OH、NH 2、CN、COOH、
Figure PCTCN2020118824-appb-000003
或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R取代； R a is F, Cl, Br, I, OH, NH 2 , CN, COOH,
Figure PCTCN2020118824-appb-000003
Or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R;
R选自F、Cl、Br、I、OH和NH 2； R is selected from F, Cl, Br, I, OH and NH 2 ;
m为0、1或2；m is 0, 1 or 2;
n为0、1或2，且m和n不能同时为0；n is 0, 1, or 2, and m and n cannot be 0 at the same time;
r为0或1；r is 0 or 1;
q为0或1；q is 0 or 1;
g为1、2或3；g is 1, 2 or 3;
所述5-6元杂芳基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团；The 5-6 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N;
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；The carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
带“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atom with "#" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
本发明还提供了式(Ⅰ)化合物、其异构体或其药学上可接受的盐，The present invention also provides a compound of formula (I), its isomers or pharmaceutically acceptable salts thereof,
Figure PCTCN2020118824-appb-000004
Figure PCTCN2020118824-appb-000004
其中，among them,
R 1为C 1-3烷基、C 3-7环烷基、4-7元杂环烷基、苯基、-C 1-3烷基-C 3-7环烷基、-C 1-3烷基-4-7元杂环烷基、-C 1-3烷基-苯基或-C 1-3烷基-5-6元杂芳基，其中所述C 1-3烷基、C 3-7环烷基、4-7元杂环烷基、苯基、-C 1-3烷基-C 3-7环烷基、-C 1-3烷基-苯基或-C 1-3烷基-5-6元杂芳基任选被1、2或3个R a取代； R 1 is C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1- 3- alkyl-4-7 membered heterocycloalkyl, -C 1-3 alkyl-phenyl or -C 1-3 alkyl-5-6 membered heteroaryl, wherein the C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1-3 alkyl-phenyl or -C 1 -3 -5-6 membered heteroaryl group optionally substituted with 1, 2 or 3 R a;
R 2为H或C 1-3烷基； R 2 is H or C 1-3 alkyl;
或者，R 1和R 2与其所连接的N原子连接一起形成结构单元
Figure PCTCN2020118824-appb-000005
Alternatively, R 1 and R 2 are connected with the N atom to which they are connected to form a structural unit
Figure PCTCN2020118824-appb-000005
D 1为单键、O、N(R d11)或C(R d12) 2； D 1 is a single bond, O, N(R d11 ) or C(R d12 ) 2 ;
D 2为O、N(R d21)或C(R d22) 2； D 2 is O, N(R d21 ) or C(R d22 ) 2 ;
D 3为O、N(R d31)或C(R d32) 2； D 3 is O, N(R d31 ) or C(R d32 ) 2 ;
D 4为O、N(R d41)或C(R d42) 2； D 4 is O, N(R d41 ) or C(R d42 ) 2 ;
D 5为单键、O、N(R d51)或C(R d52) 2； D 5 is a single bond, O, N (R d51 ) or C (R d52 ) 2 ;
R d11、R d21、R d31、R d41和R d51分别独立地为H或C 1-3烷基； R d11 , R d21 , R d31 , R d41 and R d51 are each independently H or C 1-3 alkyl;
R d12、R d22、R d32、R d42和R d52分别独立地为H、F、Cl、Br、I、OH、NH 2、CN、COOH或C 1-3烷基； R d12, R d22, R d32 , R d42 and R d52 are each independently H, F, Cl, Br, I, OH, NH 2, CN, COOH or C 1-3 alkyl;
R a为F、Cl、Br、I、OH、NH 2、CN、COOH、
Figure PCTCN2020118824-appb-000006
或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R取代； R a is F, Cl, Br, I, OH, NH 2 , CN, COOH,
Figure PCTCN2020118824-appb-000006
Or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R;
R选自F、Cl、Br、I、OH和NH 2； R is selected from F, Cl, Br, I, OH and NH 2 ;
m为0、1或2；m is 0, 1 or 2;
n为0、1或2，且m和n不能同时为0；n is 0, 1, or 2, and m and n cannot be 0 at the same time;
r为0或1；r is 0 or 1;
q为0或1；q is 0 or 1;
g为1、2或3；g is 1, 2 or 3;
所述5-6元杂芳基和4-7元杂环烷基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团；The 5-6 membered heteroaryl group and the 4-7 membered heterocycloalkyl group respectively contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N ；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；The carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
带“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atom with "#" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
本发明的一些方案中，上述R a为F、Cl、Br、I、OH、NH 2、CN、COOH、
Figure PCTCN2020118824-appb-000007
CH 3或CF 3，其他变量如本发明所定义。 Some aspects of the present invention, the above R a is F, Cl, Br, I, OH, NH 2, CN, COOH,
Figure PCTCN2020118824-appb-000007
CH 3 or CF 3 and other variables are as defined in the present invention.
本发明的一些方案中，上述R 1为CH 3、-CH 2-CH 3、
Figure PCTCN2020118824-appb-000008
Figure PCTCN2020118824-appb-000009
其中所述CH 3、-CH 2-CH 3、
Figure PCTCN2020118824-appb-000010
Figure PCTCN2020118824-appb-000011
任选被1、2或3个R a取代，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 1 is CH 3 , -CH 2 -CH 3 ,
Figure PCTCN2020118824-appb-000008
Figure PCTCN2020118824-appb-000009
Wherein said CH 3 , -CH 2 -CH 3 ,
Figure PCTCN2020118824-appb-000010
Figure PCTCN2020118824-appb-000011
Optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
本发明的一些方案中，上述R 1为CH 3、-CH 2-COOH、
Figure PCTCN2020118824-appb-000012
Figure PCTCN2020118824-appb-000013
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 1 is CH 3 , -CH 2 -COOH,
Figure PCTCN2020118824-appb-000012
Figure PCTCN2020118824-appb-000013
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 2为H或CH 3，其他变量如本发明所定义。 In some aspects of the present invention, the above R 2 is H or CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R d11、R d21、R d31、R d41和R d51分别独立地为H或CH 3，其他变量如本发明所定义。 Some aspects of the present invention, the above-described R d11, R d21, R d31 , R d41 and R d51 are each independently H or CH 3, the other variables are as defined in the present invention.
本发明的一些方案中，上述R d12、R d22、R d32、R d42和R d52分别独立地为H、F、Cl、Br、I、OH、NH 2、CN、COOH或CH 3，其他变量如本发明所定义。 Some aspects of the present invention, the above-described R d12, R d22, R d32 , R d42 and R d52 are each independently H, F, Cl, Br, I, OH, NH 2, CN, COOH or CH 3, other variables As defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020118824-appb-000014
为
Figure PCTCN2020118824-appb-000015
Figure PCTCN2020118824-appb-000016
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020118824-appb-000014
for
Figure PCTCN2020118824-appb-000015
Figure PCTCN2020118824-appb-000016
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020118824-appb-000017
为
Figure PCTCN2020118824-appb-000018
Figure PCTCN2020118824-appb-000019
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020118824-appb-000017
for
Figure PCTCN2020118824-appb-000018
Figure PCTCN2020118824-appb-000019
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020118824-appb-000020
为
Figure PCTCN2020118824-appb-000021
Figure PCTCN2020118824-appb-000022
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020118824-appb-000020
for
Figure PCTCN2020118824-appb-000021
Figure PCTCN2020118824-appb-000022
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020118824-appb-000023
为
Figure PCTCN2020118824-appb-000024
Figure PCTCN2020118824-appb-000025
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020118824-appb-000023
for
Figure PCTCN2020118824-appb-000024
Figure PCTCN2020118824-appb-000025
Other variables are as defined in the present invention.
本发明还有一些方案是由上述各变量任意组合而来。There are also some schemes of the present invention that come from any combination of the above-mentioned variables.
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020118824-appb-000026
Figure PCTCN2020118824-appb-000026
其中，R 1和R 2如本发明所定义； Wherein, R 1 and R 2 are as defined in the present invention;
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；The carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
带“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atom with "#" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020118824-appb-000027
Figure PCTCN2020118824-appb-000027
其中，R 1和R 2如本发明所定义。 Wherein, R 1 and R 2 are as defined in the present invention.
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020118824-appb-000028
Figure PCTCN2020118824-appb-000028
其中，R 1和R 2如本发明所定义。 Wherein, R 1 and R 2 are as defined in the present invention.
本发明还提供了下式化合物、其异构体或其药学上可接受的盐，The present invention also provides a compound of the following formula, its isomers or a pharmaceutically acceptable salt thereof,
Figure PCTCN2020118824-appb-000029
Figure PCTCN2020118824-appb-000029
Figure PCTCN2020118824-appb-000030
Figure PCTCN2020118824-appb-000030
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020118824-appb-000031
Figure PCTCN2020118824-appb-000031
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020118824-appb-000032
Figure PCTCN2020118824-appb-000032
本发明的一些方案中，上述药学上可接受的盐为盐酸盐。In some aspects of the present invention, the above-mentioned pharmaceutically acceptable salt is hydrochloride.
本发明还提供了上述化合物、其异构体或其药学上可接受的盐在制备治疗LSD1相关病症的药物上的应用。The present invention also provides the use of the above-mentioned compound, its isomer or pharmaceutically acceptable salt in the preparation of a medicine for treating LSD1 related disorders.
技术效果Technical effect
作为新型的LSD1抑制剂，本发明的化合物对LSD1具有显著的抑制活性；并且对NCI-H1417细胞、HL60细胞以及MV-4-11细胞增殖抑制活性明显；另外，本发明化合物具有良好的药代动力学性质,包括良好的口服生物利用度,口服暴露量,半衰期和清除率等。As a new type of LSD1 inhibitor, the compound of the present invention has significant inhibitory activity on LSD1; and has obvious inhibitory activity on the proliferation of NCI-H1417 cells, HL60 cells and MV-4-11 cells; in addition, the compounds of the present invention have good pharmacokinetics. Kinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate, etc.
定义和说明Definition and description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered uncertain or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is prepared from the compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts. When the compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, which can be converted into any base or acid addition salt.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与 化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise specified, the term "cis-trans isomer" or "geometric isomer" is caused by the inability to freely rotate the double bond or the single bond of the ring-forming carbon atom.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise specified, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror mirror image.
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。Unless otherwise specified, "(D)" or "(+)" means dextrorotation, "(L)" or "(-)" means levorotatory, and "(DL)" or "(±)" means racemic.
除非另有说明，用楔形实线键
Figure PCTCN2020118824-appb-000033
和楔形虚线键
Figure PCTCN2020118824-appb-000034
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020118824-appb-000035
和直形虚线键
Figure PCTCN2020118824-appb-000036
表示立体中心的相对构型，用波浪线
Figure PCTCN2020118824-appb-000037
表示楔形实线键
Figure PCTCN2020118824-appb-000038
或楔形虚线键
Figure PCTCN2020118824-appb-000039
或用波浪线
Figure PCTCN2020118824-appb-000040
表示直形实线键
Figure PCTCN2020118824-appb-000041
和直形虚线键
Figure PCTCN2020118824-appb-000042
Unless otherwise specified, use wedge-shaped solid line keys
Figure PCTCN2020118824-appb-000033
And wedge-shaped dashed key
Figure PCTCN2020118824-appb-000034
Represents the absolute configuration of a solid center, with a straight solid line key
Figure PCTCN2020118824-appb-000035
And straight dashed key
Figure PCTCN2020118824-appb-000036
Indicates the relative configuration of the three-dimensional center, using wavy lines
Figure PCTCN2020118824-appb-000037
Represents a wedge-shaped solid line key
Figure PCTCN2020118824-appb-000038
Or wedge-shaped dashed key
Figure PCTCN2020118824-appb-000039
Or use wavy lines
Figure PCTCN2020118824-appb-000040
Represents a straight solid line key
Figure PCTCN2020118824-appb-000041
And straight dashed key
Figure PCTCN2020118824-appb-000042
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2020118824-appb-000043
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。 Unless otherwise specified, when there is a double bond structure in the compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (including a nitrogen atom) In the double bond, a lone pair of electrons on the nitrogen atom is regarded as a substituent connected), if the atom on the double bond in the compound and its substituent are separated by a wavy line
Figure PCTCN2020118824-appb-000043
Linked means the (Z) isomer, (E) isomer or a mixture of two isomers of the compound. For example, the following formula (A) means that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2) The following formula (B) means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of two of formula (B-1) and formula (B-2) A mixture of isomers exists. The following formula (C) represents that the compound exists as a single isomer of formula (C-1) or formula (C-2) or as two isomers of formula (C-1) and formula (C-2) Exist as a mixture.
Figure PCTCN2020118824-appb-000044
Figure PCTCN2020118824-appb-000044
Figure PCTCN2020118824-appb-000045
Figure PCTCN2020118824-appb-000045
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。The compound of the present invention may be specific. Unless otherwise specified, the term "tautomer" or "tautomeric form" means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached. For example, proton tautomer (also called prototropic tautomer) includes interconversion through proton migration, such as keto-enol isomerization and imine-ene Amine isomerization. Valence isomers (valence tautomer) include some recombination of bonding electrons to carry out mutual transformation. A specific example of keto-enol tautomerization is the tautomerization between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise specified, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in enantiomers" refer to one of the isomers or pairs of The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise stated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。 The optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate). The compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For another example, deuterium can be substituted for hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. "Optional" or "optionally" means that the event or condition described later may but not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着 两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of. When the substituent is oxygen (i.e. =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (such as R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group can optionally be substituted with up to two Rs, and R has independent options in each case. In addition, combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups connected are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基的键可以交叉连接到一个环上的两一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2020118824-appb-000046
表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。 When a substituent is vacant, it means that the substituent is absent. For example, when X in AX is vacant, it means that the structure is actually A. When the bond of a substituent can be cross-connected to more than two atoms on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit
Figure PCTCN2020118824-appb-000046
It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. . When the listed substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom. For example, a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2020118824-appb-000047
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2020118824-appb-000048
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2020118824-appb-000049
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example,
Figure PCTCN2020118824-appb-000047
The middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right
Figure PCTCN2020118824-appb-000048
It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right
Figure PCTCN2020118824-appb-000049
Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members. For example, "5-7 membered ring" refers to a "ring" in which 5-7 atoms are arranged around.
除非另有规定，“3-12元环”表示由3至12个环原子组成的环烷基、杂环烷基、环烯基或杂环烯基。所述的环包括单环，也包括螺环、并环和桥环等双环或多环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述3-12元环包括3-10元、3-9元、3-8元、3-7元、3-6元、3-5元、4-10元、4-9元、4-8元、4-7元、4-6元、4-5元、5-10元、5-9元、5-8元、5-7元、5-6元、6-10元、6-9元、6-8元和6-7元环等。术语“5-7元杂环烷基”包括哌啶基等，但不包括苯基。术语“环”还包 括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。Unless otherwise specified, "3-12 membered ring" means a cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl composed of 3 to 12 ring atoms. The ring includes a single ring, as well as a bicyclic or polycyclic ring system such as a spiro ring, a fused ring and a bridged ring. Unless otherwise specified, the ring optionally contains 1, 2, or 3 heteroatoms independently selected from O, S, and N. The 3-12 membered ring includes 3-10 members, 3-9 members, 3-8 members, 3-7 members, 3-6 members, 3-5 members, 4-10 members, 4-9 members, 4- 8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6 9-membered, 6-8-membered and 6-7-membered rings, etc. The term "5-7 membered heterocycloalkyl" includes piperidinyl and the like, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which independently meets the above definition.
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。 Unless otherwise specified, the term "C 1-6 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C 1-6 alkyl include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
除非另有规定，术语“C 1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C 1-4烷基包括C 1-2、C 1-3和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-4烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)等。 Unless otherwise specified, the term "C 1-4 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 4 carbon atoms. The C 1-4 alkyl group includes C 1-2 , C 1-3 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent ( Such as methine). Examples of C 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl) and so on.
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。 Unless otherwise specified, the term "C 1-3 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
除非另有规定，术语“C 1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C 1-6烷氧基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4和C 3烷氧基等。C 1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。 Unless otherwise specified, the term "C 1-6 alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an oxygen atom. The C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy, etc. . Examples of C 1-6 alkoxy include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) Oxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy and the like.
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。 Unless otherwise specified, the term "C 1-3 alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
除非另有规定，“C 3-7环烷基”表示由3至7个碳原子组成的饱和环状碳氢基团，其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。所述C 3-7环烷基包括C 3-6、C 3-5、C 4-7、C 4-6、C 4-5、C 5-7或C 5-6环烷基等；其可以是一价、二价或者多价。C 3-8环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷等。 Unless otherwise specified, "C 3-7 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 7 carbon atoms, which includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spirocyclic, fused, and Bridge ring. The C 3-7 cycloalkyl group includes C 3-6 , C 3-5 , C 4-7 , C 4-6 , C 4-5 , C 5-7 or C 5-6 cycloalkyl group, etc.; It can be one price, two price, or multiple price. Examples of C 3-8 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] dicyclooctane and the like.
除非另有规定，术语“3-6元杂环烷基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-6元杂环烷基包括4-6元、5-6元、4元、5元和6元杂环烷基等。3-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡 喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。 Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms. Are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings. In addition, for the "3-6 membered heterocycloalkyl group", a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule. The 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperazinyl Pyridyl and so on.
除非另有规定，术语“4-7元杂环烷基”本身或者与其他术语联合分别表示由4至7个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“4-7元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-7元杂环烷基包括5-6元、4元、5元、6元和7元杂环烷基等。4-7元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。 Unless otherwise specified, the term "4-7 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 7 ring atoms, with 1, 2, 3 or 4 ring atoms. Are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings. In addition, with regard to the "4-7 membered heterocycloalkyl group", a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule. The 4-7 membered heterocycloalkyl group includes 5-6 membered, 4-membered, 5-membered, 6-membered, 7-membered heterocycloalkyl and the like. Examples of 4-7 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperyl Pyridyl and so on.
除非另有规定，本发明术语“C 6-10芳环”和“C 6-10芳基”可以互换使用，术语“C 6-10芳环”或“C 6-10芳基”表示由6至10个碳原子组成的具有共轭π电子体系的环状碳氢基团，它可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其可以是一价、二价或者多价，C 6-10芳基包括C 6-9、C 9、C 10和C 6芳基等。C 6-10芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)。 Unless otherwise specified, the terms "C 6-10 aromatic ring" and "C 6-10 aryl" can be used interchangeably in the present invention. The term "C 6-10 aromatic ring" or "C 6-10 aryl" means that A cyclic hydrocarbon group with a conjugated π-electron system composed of 6 to 10 carbon atoms, which can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. It may be monovalent, divalent or multivalent, and C 6-10 aryl groups include C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.).
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。 Unless otherwise specified, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl group" can be used interchangeably in the present invention. The term "5-6 membered heteroaryl group" means a ring consisting of 5 to 6 ring atoms. It is composed of a monocyclic group with a conjugated π-electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, etc.) , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2 -Pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n 至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。 Unless otherwise specified, C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; similarly, from n to n +m means the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, and 9-membered ring , 10-membered ring, 11-membered ring, and 12-membered ring, including any range from n to n+m, for example, 3-12 membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring Ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, 6-10 membered ring, etc.
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl group, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and so on. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxyl group. Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；Pd(PPh 3) 4代表四三苯基膦钯；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；本发明化合物的盐酸盐，加入饱和碳酸氢钠溶液调节pH到中性，经过高效液相色谱法分离(中性,碳酸氢铵体系)得到化合物的游离碱。 The solvent used in the present invention is commercially available. The present invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent and equivalent; CDI stands for Carbonyl diimidazole; Pd(PPh 3 ) 4 stands for palladium tetraphenylphosphine; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethyl Formamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl, which is an amine protecting group; BOC stands for tert-butoxycarbonyl, which is an amine protecting group Group; HOAc stands for acetic acid; NaCNBH 3 stands for sodium cyanoborohydride; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc 2 O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for Diisopropylethylamine; the hydrochloride salt of the compound of the present invention is added with saturated sodium bicarbonate solution to adjust the pH to neutral, and separated by high performance liquid chromatography (neutral, ammonium bicarbonate system) to obtain the free base of the compound.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020118824-appb-000050
软件命名，市售化合物采用供应商目录名称。 Compounds are based on conventional naming principles in the field or used
Figure PCTCN2020118824-appb-000050
The software is named, and the commercially available compounds use the supplier catalog name.
具体实施方式detailed description
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围 的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The following examples describe the present invention in detail, but they are not meant to impose any disadvantageous restriction on the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Will be obvious.
实施例1Example 1
Figure PCTCN2020118824-appb-000051
Figure PCTCN2020118824-appb-000051
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000052
Figure PCTCN2020118824-appb-000052
第一步first step
将化合物1-1(20.0g,70.1mmol)溶于水(200mL)中,用冰水浴将反应液降温至0℃,向反应液中加入氢氧化钠溶液(1mol/L,280mL),反应液在25℃下搅拌反应0.5小时。反应液用乙酸乙酯(300mL x 2)萃取。合并有机相用水(300mL x 1)洗涤,饱和食盐水(300mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩除去溶剂后得到化合物1-2。 1H NMR(400MHz,CDCl 3)δ7.29-7.25(m,2H),7.18-7.15(m,1H),7.05-7.04(m,2H),2.59-2.55(m,1H),1.91-1.87(m,1H),1.08-0.99(m,2H)。 Compound 1-1 (20.0g, 70.1mmol) was dissolved in water (200mL), the reaction solution was cooled to 0℃ with an ice water bath, sodium hydroxide solution (1mol/L, 280mL) was added to the reaction solution, the reaction solution The reaction was stirred at 25°C for 0.5 hour. The reaction solution was extracted with ethyl acetate (300 mL x 2). The combined organic phase was washed with water (300 mL x 1), saturated brine (300 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain compound 1-2. 1 H NMR (400MHz, CDCl 3 ) δ 7.29-7.25 (m, 2H), 7.18-7.15 (m, 1H), 7.05-7.04 (m, 2H), 2.59-2.55 (m, 1H), 1.91-1.87 (m, 1H), 1.08-0.99 (m, 2H).
第二步Second step
将化合物1-3(19.2g,75.2mmol)和化合物1-2(9.11g,68.4mmol)溶于无水二氯甲烷(200mL)中,向反应液中加入醋酸硼氢化钠(36.2g,171mmol),反应液在25℃下继续搅拌12小时。反应液用二氯甲烷(100mL)稀释后依次用饱和碳酸氢钠水溶液(200mL x 2),饱和食盐水(200mL x 1)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到化合物1-4。 1H NMR(400MHz,CDCl 3)δ7.18-7.16(m,2H),7.11-7.17(m, 1H),6.96-6.94(m,2H),3.92-3.89(m,1H),3.61-3.55(m,1H),3.52-3.48(m,3H),3.27-3.23(m,2H),2.24-2.21(m,1H),1.99-1.94(m,1H),1.85-1.79(m,1H),1.55-1.47(m,6H),1.38(s,9H),1.01-0.90(m,2H)。MS-ESI计算值[M+H] +373,实测值373。 Compound 1-3 (19.2g, 75.2mmol) and compound 1-2 (9.11g, 68.4mmol) were dissolved in anhydrous dichloromethane (200mL), and sodium acetate borohydride (36.2g, 171mmol) was added to the reaction solution. ), the reaction solution was continuously stirred at 25°C for 12 hours. The reaction solution was diluted with dichloromethane (100mL) and washed with saturated aqueous sodium bicarbonate (200mL x 2), saturated brine (200mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-4 . 1 H NMR (400MHz, CDCl 3 ) δ 7.18-7.16 (m, 2H), 7.11-7.17 (m, 1H), 6.96-6.94 (m, 2H), 3.92-3.89 (m, 1H), 3.61-3.55 (m,1H),3.52-3.48(m,3H),3.27-3.23(m,2H),2.24-2.21(m,1H),1.99-1.94(m,1H),1.85-1.79(m,1H) , 1.55-1.47 (m, 6H), 1.38 (s, 9H), 1.01-0.90 (m, 2H). MS-ESI calculated value [M+H] + 373, measured value 373.
第三步third step
将化合物1-4(3.80g,10.2mmol)溶于二氯甲烷(40mL)中,在0℃下向反应液中加入N,N-二异丙基乙胺(2.64g,20.4mmol)和化合物1-5(1.48g,12.2mmol)。反应液在15℃下搅拌1小时。加水(100mL),用二氯甲烷(100mL x 3)萃取,有机相用饱和氯化钠(100mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过薄层层析法分离(1：1石油醚/乙酸乙酯,Rf＝0.44)得到化合物1-6。MS-ESI计算值[M+H-100] +357,[M+H-56] +401,实测值357,401。 Compound 1-4 (3.80g, 10.2mmol) was dissolved in dichloromethane (40mL), and N,N-diisopropylethylamine (2.64g, 20.4mmol) and compound were added to the reaction solution at 0°C 1-5 (1.48g, 12.2mmol). The reaction solution was stirred at 15°C for 1 hour. Water (100 mL) was added, extracted with dichloromethane (100 mL x 3), the organic phase was washed with saturated sodium chloride (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (1:1 petroleum ether/ethyl acetate, Rf=0.44) to obtain compound 1-6. MS-ESI calculated value [M+H-100] + 357, [M+H-56] + 401, measured value 357,401.
第四步the fourth step
将化合物1-6(4.03g,8.83mmol)溶于乙酸乙酯(20mL)中,向反应液中加入盐酸乙酸乙酯(4mol/L,22.1mL)。反应液在10℃下搅拌0.5小时。将反应液直接浓缩,得到粗产物化合物1-7。MS-ESI计算值[M+H] +357,实测值357。 Compound 1-6 (4.03 g, 8.83 mmol) was dissolved in ethyl acetate (20 mL), and ethyl hydrochloric acid ethyl acetate (4 mol/L, 22.1 mL) was added to the reaction solution. The reaction solution was stirred at 10°C for 0.5 hour. The reaction solution was directly concentrated to obtain the crude product compound 1-7. MS-ESI calculated value [M+H] + 357, measured value 357.
第五步the fifth step
将化合物1-7(3.15g,8.84mmol)溶于乙腈(30mL)中,向反应液中加入三乙胺(2.24g,22.1mmol)和化合物1-8(2.21g,13.3mmol)。反应液在50℃下搅拌12小时。加水(100mL),用乙酸乙酯(100mL x 3)萃取,有机相用饱和氯化钠(100mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。得到粗产品化合物1-9。MS-ESI计算值[M+H] +443,实测值443。 Compound 1-7 (3.15 g, 8.84 mmol) was dissolved in acetonitrile (30 mL), and triethylamine (2.24 g, 22.1 mmol) and compound 1-8 (2.21 g, 13.3 mmol) were added to the reaction solution. The reaction solution was stirred at 50°C for 12 hours. Water (100 mL) was added, extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated sodium chloride (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product compound 1-9 was obtained. MS-ESI calculated value [M+H] + 443, measured value 443.
第六步Sixth step
将化合物1-9(3.73g,8.43mmol)溶于四氢呋喃(30mL)和水(30mL)中,向反应液中加入氢氧化钠(674mg,16.9mmol)。反应液在50℃下搅拌12小时。将反应液直接浓缩,加水(80mL)并用乙酸乙酯(80mL x 3)萃取,水相用盐酸(1mol/L)调节pH至5,再用乙酸乙酯(100mL x 3)萃取,有机相用饱和氯化钠(50mL x 2)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。得到粗产品化合物1-10。MS-ESI计算值[M+H] +415,实测值415。 Compound 1-9 (3.73 g, 8.43 mmol) was dissolved in tetrahydrofuran (30 mL) and water (30 mL), and sodium hydroxide (674 mg, 16.9 mmol) was added to the reaction solution. The reaction solution was stirred at 50°C for 12 hours. The reaction solution was directly concentrated, water (80mL) was added and extracted with ethyl acetate (80mL x 3), the aqueous phase was adjusted to pH 5 with hydrochloric acid (1mol/L), and then extracted with ethyl acetate (100mL x 3), and the organic phase was extracted with Wash with saturated sodium chloride (50mL x 2), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product compound 1-10 was obtained. MS-ESI calculated value [M+H] + 415, measured value 415.
第七步Seventh step
将化合物1-10(200mg,0.483mmol)溶于N,N-二甲基甲酰胺(4mL)中,向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(275mg,0.724mmol),N,N-二异丙基乙胺(125mg,0.965mmol)和化合物1-11(26.1mg,0.579mmol)。反应液在25℃下搅拌12小时。加水(10mL),用乙酸乙酯(10mL x 3)萃取,有机相用饱和氯化钠(20mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过薄层层析法分离(10：1二氯甲烷/甲醇,Rf＝0.20)得到化合物1-12。MS-ESI计算值[M+H] +442,实测值442。 Compound 1-10 (200mg, 0.483mmol) was dissolved in N,N-dimethylformamide (4mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution. N,N,N,N-tetramethylurea hexafluorophosphate (275mg, 0.724mmol), N,N-diisopropylethylamine (125mg, 0.965mmol) and compound 1-11 (26.1mg, 0.579mmol) ). The reaction solution was stirred at 25°C for 12 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated sodium chloride (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (10:1 dichloromethane/methanol, Rf=0.20) to obtain compound 1-12. MS-ESI calculated value [M+H] + 442, measured value 442.
第八步Eighth step
将化合物1-12(147mg,0.314mmol)溶于四氢呋喃(2mL)中,向反应液中加Pd(PPh 3) 4(36.3mg,31.4μmol)和二乙胺(230mg,3.14mmol)。反应液在80℃下搅拌反应3小时,减压浓缩除去溶剂。用高效液相色谱法(酸性,盐酸体系)制备得到化合物1的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.35-7.31(m,2H),7.25-7.22(m,3H),4.39-4.30(m,2H),4.25-4.18(m,3H),3.60-3.54(m,2H),3.39-3.30(m,2H),3.08-3.00(m,7H),2.70-2.66(m,1H),2.49-2.43(m,1H),2.24-2.10(m,4H),2.04-2.00(m,1H),1.70-1.65(m,1H),1.43-1.42(m,1H)。MS-ESI计算值[M+H] +358,实测值358。 Compound 1-12 (147 mg, 0.314 mmol) was dissolved in tetrahydrofuran (2 mL), and Pd(PPh 3 ) 4 (36.3 mg, 31.4 μmol) and diethylamine (230 mg, 3.14 mmol) were added to the reaction solution. The reaction solution was stirred and reacted at 80°C for 3 hours, and concentrated under reduced pressure to remove the solvent. The hydrochloride of compound 1 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (400MHz, CD 3 OD) δ7.35-7.31 (m, 2H), 7.25-7.22 (m, 3H), 4.39-4.30 (m, 2H), 4.25-4.18 (m, 3H), 3.60- 3.54 (m, 2H), 3.39-3.30 (m, 2H), 3.08-3.00 (m, 7H), 2.70-2.66 (m, 1H), 2.49-2.43 (m, 1H), 2.24-2.10 (m, 4H) ), 2.04-2.00 (m, 1H), 1.70-1.65 (m, 1H), 1.43-1.42 (m, 1H). MS-ESI calculated value [M+H] + 358, measured value 358.
实施例2Example 2
Figure PCTCN2020118824-appb-000053
Figure PCTCN2020118824-appb-000053
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000054
Figure PCTCN2020118824-appb-000054
第一步first step
将化合物1-10(200mg,0.483mmol)溶于N,N-二甲基甲酰胺(4mL)中,向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(275mg,0.724mmol),N,N-二异丙基乙胺(125mg,0.965mmol)和化合物2-1(33.1mg,0.579mmol)。反应液在25℃下搅拌12小时。加水(10mL),用乙酸乙酯(10mL x 3)萃取,有机相用饱和氯化钠(20mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过薄层层析法分离(10：1二氯甲烷/甲醇,Rf＝0.26)得到化合物2-2。MS-ESI计算值[M+H] +454,实测值454。 Compound 1-10 (200mg, 0.483mmol) was dissolved in N,N-dimethylformamide (4mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution. N,N,N,N-tetramethylurea hexafluorophosphate (275mg, 0.724mmol), N,N-diisopropylethylamine (125mg, 0.965mmol) and compound 2-1 (33.1mg, 0.579mmol) ). The reaction solution was stirred at 25°C for 12 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated sodium chloride (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (10:1 dichloromethane/methanol, Rf=0.26) to obtain compound 2-2. MS-ESI calculated value [M+H] + 454, measured value 454.
第二步Second step
将化合物2-2(150mg,0.262mmol)溶于四氢呋喃(2mL)中,向反应液中加Pd(PPh 3) 4(30.3mg,26.3μmol)和二乙胺(192mg,2.62mmol)。反应液在80℃下搅拌反应3小时,减压浓缩除去溶剂。用高效液相色谱法(酸性,盐酸体系)制备得到化合物2的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.35-7.31(m,2H),7.26-7.21(m,3H),4.26-4.16(m,3H),4.05-3.93(m,2H),3.57-3.50(m,2H),3.42-3.58(m,2H),3.06-3.03(m,1H),2.77-2.73(m,1H),2.70-2.66(m,1H),2.49-2.42(m,1H),2.27-2.09(m,4H),2.03-1.99(m, 1H),1.70-1.65(m,1H),1.45-1.39(m,1H),0.80-0.75(m,2H),0.60-0.57(m,2H)。MS-ESI计算值[M+H] +370,实测值370。 Compound 2-2 (150 mg, 0.262 mmol) was dissolved in tetrahydrofuran (2 mL), and Pd(PPh 3 ) 4 (30.3 mg, 26.3 μmol) and diethylamine (192 mg, 2.62 mmol) were added to the reaction solution. The reaction solution was stirred and reacted at 80°C for 3 hours, and concentrated under reduced pressure to remove the solvent. The hydrochloride of compound 2 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (400MHz, CD 3 OD) δ7.35-7.31 (m, 2H), 7.26-7.21 (m, 3H), 4.26-4.16 (m, 3H), 4.05-3.93 (m, 2H), 3.57- 3.50 (m, 2H), 3.42-3.58 (m, 2H), 3.06-3.03 (m, 1H), 2.77-2.73 (m, 1H), 2.70-2.66 (m, 1H), 2.49-2.42 (m, 1H) ), 2.27-2.09 (m, 4H), 2.03-1.99 (m, 1H), 1.70-1.65 (m, 1H), 1.45-1.39 (m, 1H), 0.80-0.75 (m, 2H), 0.60-0.57 (m, 2H). MS-ESI calculated value [M+H] + 370, measured value 370.
实施例3Example 3
Figure PCTCN2020118824-appb-000055
Figure PCTCN2020118824-appb-000055
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000056
Figure PCTCN2020118824-appb-000056
第一步first step
将化合物1-10(200mg,0.483mmol)溶于N,N-二甲基甲酰胺(4mL)中,向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(275mg,0.724mmol),N,N-二异丙基乙胺(125mg,0.965mmol)和化合物3-1(41.2mg,0.579mmol)。反应液在25℃下搅拌12小时。加水(10mL),用乙酸乙酯(10mL x 3)萃取,有机相用饱和氯化钠(20mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过薄层层析法分离(10：1二氯甲烷/甲醇,Rf＝0.28)得到化合物3-2。MS-ESI计算值[M+H] +468,实测值468。 Compound 1-10 (200mg, 0.483mmol) was dissolved in N,N-dimethylformamide (4mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution. N,N,N,N-tetramethylurea hexafluorophosphate (275mg, 0.724mmol), N,N-diisopropylethylamine (125mg, 0.965mmol) and compound 3-1 (41.2mg, 0.579mmol) ). The reaction solution was stirred at 25°C for 12 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated sodium chloride (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (10:1 dichloromethane/methanol, Rf=0.28) to obtain compound 3-2. MS-ESI calculated value [M+H] + 468, measured value 468.
第二步Second step
将化合物3-2(164mg,0.343mmol)溶于四氢呋喃(2mL)中,向反应液中加Pd(PPh 3) 4(39.7mg,34.3μmol)和二乙胺(251mg,3.43mmol)。反应液在80℃下搅拌反应3小时,减压浓缩除去溶剂。用高效液相色谱法(酸性,盐酸体系)制备得到化合物3的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.35-7.31(m,2H),7.26-7.21(m,3H),4.29-4.20(m,5H),3.75-3.59(m,2H),3.51-3.48(m,4H),3.41-3.32(m,2H),3.06-3.03(m,1H),2.68-2.67(m,1H),2.49-2.38(m,1H),2.25-2.10(m,4H),2.03-2.02(m,3H),1.95-1.91(m,2H),1.67-1.66(m,1H),1.44-1.42(m,1H)。MS-ESI计算值[M+H] +384,实测值384。 Compound 3-2 (164 mg, 0.343 mmol) was dissolved in tetrahydrofuran (2 mL), and Pd(PPh 3 ) 4 (39.7 mg, 34.3 μmol) and diethylamine (251 mg, 3.43 mmol) were added to the reaction solution. The reaction solution was stirred and reacted at 80°C for 3 hours, and concentrated under reduced pressure to remove the solvent. The hydrochloride of compound 3 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (400MHz, CD 3 OD) δ7.35-7.31 (m, 2H), 7.26-7.21 (m, 3H), 4.29-4.20 (m, 5H), 3.75-3.59 (m, 2H), 3.51- 3.48 (m, 4H), 3.41-3.32 (m, 2H), 3.06-3.03 (m, 1H), 2.68-2.67 (m, 1H), 2.49-2.38 (m, 1H), 2.25-2.10 (m, 4H) ), 2.03-2.02 (m, 3H), 1.95-1.91 (m, 2H), 1.67-1.66 (m, 1H), 1.44-1.42 (m, 1H). MS-ESI calculated value [M+H] + 384, measured value 384.
实施例4Example 4
Figure PCTCN2020118824-appb-000057
Figure PCTCN2020118824-appb-000057
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000058
Figure PCTCN2020118824-appb-000058
第一步first step
将化合物1-10(200mg,0.483mmol)溶于N,N-二甲基甲酰胺(4mL)中,向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(275mg,0.724mmol),N,N-二异丙基乙胺(125mg,0.965mmol)和化合物4-1(50.4mg,0.579mmol)。反应液在25℃下搅拌12小时。加水(10mL),用乙酸乙酯(10mL x 3)萃取,有机相用饱和氯化钠(20mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过薄层层析法分离(10：1二氯甲烷/甲醇,Rf＝0.26)得到化合物4-2。MS-ESI计算值[M+H] +484,实测值484。 Compound 1-10 (200mg, 0.483mmol) was dissolved in N,N-dimethylformamide (4mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution. N,N,N,N-tetramethylurea hexafluorophosphate (275mg, 0.724mmol), N,N-diisopropylethylamine (125mg, 0.965mmol) and compound 4-1 (50.4mg, 0.579mmol) ). The reaction solution was stirred at 25°C for 12 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated sodium chloride (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (10:1 dichloromethane/methanol, Rf=0.26) to obtain compound 4-2. MS-ESI calculated value [M+H] + 484, measured value 484.
第二步Second step
将化合物4-2(156mg,0.311mmol)溶于四氢呋喃(2mL)中,向反应液中加Pd(PPh 3) 4(35.9mg,31.1μmol)和二乙胺(227mg,3.11mmol)。反应液在80℃下搅拌反应3小时,减压浓缩除去溶剂。用高效液相色谱法(酸性,盐酸体系)制备得到化合物4的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.35-7.31(m,2H),7.26-7.21(m,3H),4.50-4.34(m,2H),4.25-4.18(m,3H),3.73-3.68(m,4H),3.63-3.44(m,6H),3.34-3.32(m,2H),3.06-3.03(m,1H),2.70-2.66(m,1H),2.46-2.44(m,1H),2.26-2.10(m,4H),2.01-1.97(m,1H),1.69-1.66(m,1H),1.45-1.42(m,1H)。MS-ESI计算值[M+H] +400,实测值400。 Compound 4-2 (156 mg, 0.311 mmol) was dissolved in tetrahydrofuran (2 mL), and Pd(PPh 3 ) 4 (35.9 mg, 31.1 μmol) and diethylamine (227 mg, 3.11 mmol) were added to the reaction solution. The reaction solution was stirred and reacted at 80°C for 3 hours, and concentrated under reduced pressure to remove the solvent. The hydrochloride of compound 4 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (400MHz, CD 3 OD) δ7.35-7.31 (m, 2H), 7.26-7.21 (m, 3H), 4.50-4.34 (m, 2H), 4.25-4.18 (m, 3H), 3.73 3.68(m,4H),3.63-3.44(m,6H),3.34-3.32(m,2H),3.06-3.03(m,1H),2.70-2.66(m,1H),2.46-2.44(m,1H) ), 2.26-2.10 (m, 4H), 2.01-1.97 (m, 1H), 1.69-1.66 (m, 1H), 1.45-1.42 (m, 1H). MS-ESI calculated value [M+H] + 400, measured value 400.
实施例5Example 5
Figure PCTCN2020118824-appb-000059
Figure PCTCN2020118824-appb-000059
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000060
Figure PCTCN2020118824-appb-000060
第一步first step
将化合物1-10(200mg,0.483mmol)溶于N,N-二甲基甲酰胺(4mL)中,向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(275mg,0.724mmol),N,N-二异丙基乙胺(125mg,0.965mmol)和化合物5-1(87.8mg,0.579mmol)。反应液在25℃下搅拌12小时。加水(10mL),用乙酸乙酯(10mL x 3)萃取,有机相用饱和氯化钠(20mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过薄层层析法分离(20：1二氯甲烷/甲醇,Rf＝0.27)得到化合物5-2。MS-ESI计算值[M+H] +512,实测值512。 Compound 1-10 (200mg, 0.483mmol) was dissolved in N,N-dimethylformamide (4mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution. N,N,N,N-tetramethylurea hexafluorophosphate (275mg, 0.724mmol), N,N-diisopropylethylamine (125mg, 0.965mmol) and compound 5-1 (87.8mg, 0.579mmol) ). The reaction solution was stirred at 25°C for 12 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated sodium chloride (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (20:1 dichloromethane/methanol, Rf=0.27) to obtain compound 5-2. MS-ESI calculated value [M+H] + 512, measured value 512.
第二步Second step
将化合物5-2(204mg,0.387mmol)溶于四氢呋喃(2mL)中,在氮气保护下向反应液中加入四三苯基磷钯(44.7mg,38.7μmol)和二乙基胺(283mg,3.87mmol)。反应液在80℃下搅拌3小时。将反应液直接浓缩,得到粗产品化合物5-3。MS-ESI计算值[M+H] +428,实测值428。 Compound 5-2 (204mg, 0.387mmol) was dissolved in tetrahydrofuran (2mL), and palladium tetrakistriphenylphosphorus (44.7mg, 38.7μmol) and diethylamine (283mg, 3.87) were added to the reaction solution under nitrogen protection. mmol). The reaction solution was stirred at 80°C for 3 hours. The reaction solution was directly concentrated to obtain the crude product compound 5-3. MS-ESI calculated value [M+H] + 428, measured value 428.
第三步third step
将化合物5-3(165mg,0.386mmol)溶于四氢呋喃(2mL)和水(2mL)中,向反应液中加氢氧化钠(15.4mg,0.386mmol)。反应液在50℃下搅拌反应1小时,减压浓缩除去溶剂,加盐酸(1mol/L)调节pH至5。用高效液相色谱法(酸性,盐酸体系)制备得到化合物5的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.35-7.31(m,2H),7.26-7.21(m,3H),4.51-4.43(m,1H),4.40-4.36(m,1H),4.28-4.16(m,5H),4.05(s,2H),4.64-4.52(m,3H),3.39-3.29(m,2H),3.06-3.02(m,1H),2.67-2.66(m,1H),2.45-2.43(m,1H),2.22-2.12(m,4H),2.02-1.95(m,1H),1.68-1.63(m,1H),1.45-1.42(m,1H)。MS-ESI计算值[M+H] +414,实测值414。 Compound 5-3 (165 mg, 0.386 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL), and sodium hydroxide (15.4 mg, 0.386 mmol) was added to the reaction solution. The reaction solution was stirred and reacted at 50°C for 1 hour, concentrated under reduced pressure to remove the solvent, and hydrochloric acid (1mol/L) was added to adjust the pH to 5. The hydrochloride of compound 5 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (400MHz, CD 3 OD) δ7.35-7.31 (m, 2H), 7.26-7.21 (m, 3H), 4.51-4.43 (m, 1H), 4.40-4.36 (m, 1H), 4.28- 4.16(m,5H),4.05(s,2H),4.64-4.52(m,3H),3.39-3.29(m,2H),3.06-3.02(m,1H),2.67-2.66(m,1H), 2.45-2.43 (m, 1H), 2.22-2.12 (m, 4H), 2.02-1.95 (m, 1H), 1.68-1.63 (m, 1H), 1.45-1.42 (m, 1H). MS-ESI calculated value [M+H] + 414, measured value 414.
实施例6Example 6
Figure PCTCN2020118824-appb-000061
Figure PCTCN2020118824-appb-000061
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000062
Figure PCTCN2020118824-appb-000062
第一步first step
将化合物1-4(1.10g,2.95mmol)溶于无水二氯甲烷中(20mL),加入三乙胺(448mg,4.43mmol)和三氟乙酸酐(930mg,4.43mmol)。反应液在15℃下搅拌反应12小时。向反应液中加入二氯甲烷(50mL),有机相用盐酸(1M,50mL x 1)和饱和食盐水(50mL x 1)洗涤,无水硫酸钠干燥,过滤,母液浓缩,粗产物经过硅胶柱层析法分离(5/1二氯甲烷/甲醇,Rf＝0.38)得到化合物6-1。MS-ESI计算值[M-56+H] +413,[M-Boc+H] +369,实测值413,369。 Compound 1-4 (1.10 g, 2.95 mmol) was dissolved in dry dichloromethane (20 mL), and triethylamine (448 mg, 4.43 mmol) and trifluoroacetic anhydride (930 mg, 4.43 mmol) were added. The reaction solution was stirred and reacted at 15°C for 12 hours. Dichloromethane (50mL) was added to the reaction solution, the organic phase was washed with hydrochloric acid (1M, 50mL x 1) and saturated brine (50mL x 1), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated. The crude product was passed through a silica gel column. Chromatographic separation (5/1 dichloromethane/methanol, Rf=0.38) to obtain compound 6-1. MS-ESI calculated value [M-56+H] + 413, [M-Boc+H] + 369, measured value 413,369.
第二步Second step
将化合物6-1(600mg,1.28mmol)溶于无水二氯甲烷(6mL)中,在20℃下加入三氟乙酸(4.62g,40.5mmol)。反应液在20℃下搅拌反应2小时,减压浓缩除去溶剂,剩余物溶于二氯甲烷(6mL)中,再向其中加入三乙胺(250μL)后在室温下搅拌半小时,减压浓缩除去溶剂,得到化合物6-2。MS-ESI计算值[M+H] +369,实测值369。 Compound 6-1 (600 mg, 1.28 mmol) was dissolved in anhydrous dichloromethane (6 mL), and trifluoroacetic acid (4.62 g, 40.5 mmol) was added at 20°C. The reaction solution was stirred and reacted at 20°C for 2 hours, concentrated under reduced pressure to remove the solvent, and the residue was dissolved in dichloromethane (6mL), then triethylamine (250μL) was added to it, and stirred at room temperature for half an hour, then concentrated under reduced pressure The solvent was removed to obtain compound 6-2. MS-ESI calculated value [M+H] + 369, measured value 369.
第三步third step
将化合物6-2(200mg,0.543mmol)和化合物6-3(136mg,0.814mmol)溶于乙腈(4mL)中,向反应液中加入三乙胺(137mg,1.36mmol)。反应液在50℃下搅拌12小时。加水(10mL),用乙酸乙酯(10mL x 3)萃取,有机相用饱和氯化钠(20mL x 1)洗涤,再用无水硫酸钠干燥,浓缩,粗产物经过薄层层析法分离(1：1石油醚/乙酸乙酯,Rf＝0.35)得到化合物6-4。MS-ESI计算值[M+H] +455,实测值455。 Compound 6-2 (200 mg, 0.543 mmol) and compound 6-3 (136 mg, 0.814 mmol) were dissolved in acetonitrile (4 mL), and triethylamine (137 mg, 1.36 mmol) was added to the reaction solution. The reaction solution was stirred at 50°C for 12 hours. Add water (10mL), extract with ethyl acetate (10mL x 3), wash the organic phase with saturated sodium chloride (20mL x 1), then dry with anhydrous sodium sulfate, concentrate, and separate the crude product by thin layer chromatography ( 1:1 petroleum ether/ethyl acetate, Rf=0.35) to obtain compound 6-4. MS-ESI calculated value [M+H] + 455, measured value 455.
第四步the fourth step
将化合物6-4(150mg,0.328mmol)溶于四氢呋喃(2mL)和水(2mL)中,向反应液中加氢氧化钠(19.7mg,0.492mmol)。反应液在50℃下搅拌反应12小时,减压浓缩,并用盐酸水溶液(1mol/L)调节PH至5。用高效液相色谱法(酸性,盐酸体系)制备得到化合物6的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.35-7.31(m,2H),7.25-7.21(m,3H),4.24-4.13(m,5H),3.65-3.60(m,2H),3.37-3.36(m,1H),3.33-3.32(m,1H),3.06-3.05(m,1H),2.66-2.65(m,1H),2.48-2.47(m,1H),2.19-2.17(m,4H),2.14-2.11(m,1H),1.67-1.65(m,1H),1.44-1.42(m,1H)。MS-ESI计算值[M+H] +331,实测值331。 Compound 6-4 (150 mg, 0.328 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL), and sodium hydroxide (19.7 mg, 0.492 mmol) was added to the reaction solution. The reaction solution was stirred and reacted at 50°C for 12 hours, concentrated under reduced pressure, and adjusted to pH 5 with aqueous hydrochloric acid (1mol/L). The hydrochloride of compound 6 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (400MHz, CD 3 OD) δ7.35-7.31 (m, 2H), 7.25-7.21 (m, 3H), 4.24-4.13 (m, 5H), 3.65-3.60 (m, 2H), 3.37- 3.36 (m, 1H), 3.33-3.32 (m, 1H), 3.06-3.05 (m, 1H), 2.66-2.65 (m, 1H), 2.48-2.47 (m, 1H), 2.19-2.17 (m, 4H) ), 2.14-2.11 (m, 1H), 1.67-1.65 (m, 1H), 1.44-1.42 (m, 1H). MS-ESI calculated value [M+H] + 331, measured value 331.
实施例7Example 7
Figure PCTCN2020118824-appb-000063
Figure PCTCN2020118824-appb-000063
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000064
Figure PCTCN2020118824-appb-000064
第一步first step
将化合物6-2(2.50g,6.79mmol)和化合物7-1(1.59g,8.15mmol)溶于乙腈(25mL)中,向反应液中加入三乙胺(1.37g,13.6mmol)。反应液在50℃下搅拌12小时。加水(100mL),用乙酸乙酯(100mL x 2)萃取,合并有机相用饱和氯化钠(100mL x 1)洗涤,有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法分离(2：1石油醚/乙酸乙酯,Rf＝0.27)得到化合物7-2。 1H NMR(400MHz,CD 3OD)δ7.26-7.22(m,2H),7.18-7.15(m,1H),7.00-6.99(m,2H),4.57-4.56(m,1H),4.03-4.02(m,1H),3.88-3.84(m,1H),3.04-3.02(m,2H),2.55-2.50(m,4H),2.47-2.46(m,1H),2.12-2.11(m,1H),1.98-1.97(m,1H),1.74-1.72(m,1H),1.70-1.69(m,2H),1.68-1.67(m,2H),1.40-1.39(m,9H),1.22-1.16(m,2H)。MS-ESI计算值[M+H] +483,实测值483。 Compound 6-2 (2.50 g, 6.79 mmol) and compound 7-1 (1.59 g, 8.15 mmol) were dissolved in acetonitrile (25 mL), and triethylamine (1.37 g, 13.6 mmol) was added to the reaction solution. The reaction solution was stirred at 50°C for 12 hours. Water (100 mL) was added, extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with saturated sodium chloride (100 mL x 1), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (2:1 petroleum ether/ethyl acetate, Rf=0.27) to obtain compound 7-2. 1 H NMR (400MHz, CD 3 OD) δ7.26-7.22 (m, 2H), 7.18-7.15 (m, 1H), 7.00-6.99 (m, 2H), 4.57-4.56 (m, 1H), 4.03- 4.02 (m, 1H), 3.88-3.84 (m, 1H), 3.04-3.02 (m, 2H), 2.55-2.50 (m, 4H), 2.47-2.46 (m, 1H), 2.12-2.11 (m, 1H) ),1.98-1.97(m,1H),1.74-1.72(m,1H),1.70-1.69(m,2H),1.68-1.67(m,2H),1.40-1.39(m,9H),1.22-1.16 (m, 2H). MS-ESI calculated value [M+H] + 483, measured value 483.
第二步Second step
将化合物7-2(2.80g,5.80mmol)溶于乙酸乙酯(28mL)中,向反应液中加盐酸乙酸乙酯(14.5mL,4M)。反应液在25℃下搅拌反应3小时,减压浓缩除去溶剂,得到化合物7-3。MS-ESI计算值[M+H] +427,实测值427。 Compound 7-2 (2.80 g, 5.80 mmol) was dissolved in ethyl acetate (28 mL), and ethyl hydrochloric acid ethyl acetate (14.5 mL, 4M) was added to the reaction solution. The reaction solution was stirred and reacted at 25°C for 3 hours, and concentrated under reduced pressure to remove the solvent to obtain compound 7-3. MS-ESI calculated value [M+H] + 427, measured value 427.
第三步third step
将化合物7-3(200mg,0.469mmol)溶于N,N-二甲基甲酰胺(4mL)中,向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(214mg,0.563mmol),N,N-二异丙基乙胺(90.9mg,0.704mmol)。反应液在25℃下搅拌1小时。再向反应液中加入化合物7-4(55.3mg,0.516mmol),反应液在25℃ 下搅拌12小时。加水(10mL),用乙酸乙酯(10mL x 3)萃取,合并有机相用饱和氯化钠(10mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过薄层层析法分离(1：1石油醚/乙酸乙酯,Rf＝0.31)得到化合物7-5。MS-ESI计算值[M+H] +516,实测值516。 Compound 7-3 (200mg, 0.469mmol) was dissolved in N,N-dimethylformamide (4mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution. N,N,N,N-tetramethylurea hexafluorophosphate (214mg, 0.563mmol), N,N-diisopropylethylamine (90.9mg, 0.704mmol). The reaction solution was stirred at 25°C for 1 hour. Compound 7-4 (55.3 mg, 0.516 mmol) was added to the reaction solution, and the reaction solution was stirred at 25° C. for 12 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated sodium chloride (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (1:1 petroleum ether/ethyl acetate, Rf=0.31) to obtain compound 7-5. MS-ESI calculated value [M+H] + 516, measured value 516.
第四步the fourth step
将化合物7-5(80.0mg,0.155mmol)溶于四氢呋喃(1mL)和水(1mL)中,向反应液中加氢氧化钠(12.4mg,0.310mmol)。反应液在60℃下搅拌反应12小时,减压浓缩除去溶剂,加盐酸(1mol/L)调节pH至5。用高效液相色谱法(酸性,盐酸体系)制备得到化合物7的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.35-7.30(m,5H),7.27-7.26(m,2H),7.22-7.20(m,3H),4.45(s,2H),4.23-4.22(m,1H),4.16-4.14(m,2H),4.01-4.00(m,2H),3.55-3.50(m,2H),3.37-3.35(m,1H),3.04-3.03(m,1H),2.62-2.61(m,1H),2.50-2.48(m,1H),2.17-2.11(m,5H),2.10-1.96(m,1H),1.64-1.62(m,1H),1.45-1.43(m,1H)。MS-ESI计算值[M+H] +420,实测值420。 Compound 7-5 (80.0 mg, 0.155 mmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and sodium hydroxide (12.4 mg, 0.310 mmol) was added to the reaction solution. The reaction solution was stirred and reacted at 60°C for 12 hours, concentrated under reduced pressure to remove the solvent, and hydrochloric acid (1mol/L) was added to adjust the pH to 5. The hydrochloride of compound 7 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (400MHz, CD 3 OD) δ 7.35-7.30 (m, 5H), 7.27-7.26 (m, 2H), 7.22-7.20 (m, 3H), 4.45 (s, 2H), 4.23-4.22 ( m,1H),4.16-4.14(m,2H),4.01-4.00(m,2H),3.55-3.50(m,2H),3.37-3.35(m,1H),3.04-3.03(m,1H), 2.62-2.61 (m, 1H), 2.50-2.48 (m, 1H), 2.17-2.11 (m, 5H), 2.10-1.96 (m, 1H), 1.64-1.62 (m, 1H), 1.45-1.43 (m ,1H). MS-ESI calculated value [M+H] + 420, measured value 420.
实施例8Example 8
Figure PCTCN2020118824-appb-000065
Figure PCTCN2020118824-appb-000065
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000066
Figure PCTCN2020118824-appb-000066
第一步first step
将化合物7-3(200mg,0.469μmol)溶于N,N-二甲基甲酰胺(4mL)中,向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(214mg,563μmol),N,N-二异丙基乙胺(90.9mg,0.704mmol)。反应液在25℃下搅拌1小时。再向反应液中加入化合物8-1(58.4mg,0.516mmol),反应液在25℃下搅拌12小时。加水(10mL),用乙酸乙酯(10mL x 3)萃取,合并有机相用饱和氯化钠(10mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过薄层层析法分离(1：1石油醚/乙酸乙酯,Rf＝0.37)得到化合物8-2。MS-ESI计算值[M+H] +522,实测值522。 Compound 7-3 (200mg, 0.469μmol) was dissolved in N,N-dimethylformamide (4mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution. N,N,N,N-tetramethylurea hexafluorophosphate (214mg, 563μmol), N,N-diisopropylethylamine (90.9mg, 0.704mmol). The reaction solution was stirred at 25°C for 1 hour. Compound 8-1 (58.4 mg, 0.516 mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 12 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated sodium chloride (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (1:1 petroleum ether/ethyl acetate, Rf=0.37) to obtain compound 8-2. MS-ESI calculated value [M+H] + 522, measured value 522.
第二步Second step
将化合物8-2(80.0mg,0.153mmol)溶于四氢呋喃(1mL)和水(1mL)中,向反应液中加氢氧化钠 (12.3mg,0.307mmol)。反应液在60℃下搅拌反应12小时,减压浓缩除去溶剂,加盐酸(1mol/L)调节pH至5。用高效液相色谱法(酸性,盐酸体系)制备得到化合物8的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.34-7.30(m,2H),7.24-7.21(m,1H),7.20-7.19(m,2H),4.17-4.13(m,3H),3.91(s,2H),3.78-3.77(m,1H),3.37-3.30(m,2H),3.12-3.10(m,2H),3.07-3.04(m,1H),2.96-2.95(m,1H),2.54-2.51(m,1H),2.50-2.47(m,1H),2.13-2.08(m,4H),2.03-1.96(m,1H),1.77-1.75(m,4H),1.74-1.73(m,1H),1.60-1.50(m,2H),1.45-1.40(m,1H),1.39-1.24(m,3H),0.99-0.96(m,2H)。MS-ESI计算值[M+H] +426,实测值426。 Compound 8-2 (80.0 mg, 0.153 mmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and sodium hydroxide (12.3 mg, 0.307 mmol) was added to the reaction solution. The reaction solution was stirred and reacted at 60°C for 12 hours, concentrated under reduced pressure to remove the solvent, and hydrochloric acid (1mol/L) was added to adjust the pH to 5. The hydrochloride of compound 8 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (400MHz, CD 3 OD) δ 7.34-7.30 (m, 2H), 7.24-7.21 (m, 1H), 7.20-7.19 (m, 2H), 4.17-4.13 (m, 3H), 3.91 ( s, 2H), 3.78-3.77 (m, 1H), 3.37-3.30 (m, 2H), 3.12-3.10 (m, 2H), 3.07-3.04 (m, 1H), 2.96-2.95 (m, 1H), 2.54-2.51 (m, 1H), 2.50-2.47 (m, 1H), 2.13-2.08 (m, 4H), 2.03-1.96 (m, 1H), 1.77-1.75 (m, 4H), 1.74-1.73 (m , 1H), 1.60-1.50 (m, 2H), 1.45-1.40 (m, 1H), 1.39-1.24 (m, 3H), 0.99-0.96 (m, 2H). MS-ESI calculated value [M+H] + 426, measured value 426.
实施例9Example 9
Figure PCTCN2020118824-appb-000067
Figure PCTCN2020118824-appb-000067
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000068
Figure PCTCN2020118824-appb-000068
第一步first step
将化合物7-3(300mg,0.704mmol)溶于N,N-二甲基甲酰胺(4mL)中,向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(401mg,1.06mmol),N,N-二异丙基乙胺(182mg,1.41mmol)。反应液在25℃下搅拌1小时。再向反应液中加入化合物9-1(136mg,0.774mmol),反应液在25℃下搅拌12小时。加水(10mL),用乙酸乙酯(10mL x 3)萃取,合并有机相用饱和氯化钠(10mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过薄层层析法分离(1：1石油醚/乙酸乙酯,Rf＝0.41)得到化合物9-2。MS-ESI计算值[M+H] +584,实测值584。 Compound 7-3 (300mg, 0.704mmol) was dissolved in N,N-dimethylformamide (4mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution. N,N,N,N-tetramethylurea hexafluorophosphate (401mg, 1.06mmol), N,N-diisopropylethylamine (182mg, 1.41mmol). The reaction solution was stirred at 25°C for 1 hour. Compound 9-1 (136 mg, 0.774 mmol) was added to the reaction solution, and the reaction solution was stirred at 25° C. for 12 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated sodium chloride (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (1:1 petroleum ether/ethyl acetate, Rf=0.41) to obtain compound 9-2. MS-ESI calculated value [M+H] + 584, measured value 584.
第二步Second step
将化合物9-2(30.0mg,51.4μmol)溶于四氢呋喃(1mL)和水(1mL)中，向反应液中加氢氧化钠(4.11mg,0.103mmol)。反应液在50℃下搅拌反应2小时，减压浓缩除去溶剂，加盐酸(1mol/L)调节pH至5。用高效液相色谱法(酸性,盐酸体系)制备得到化合物9的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.65-7.64(m,1H),7.61-7.59(m,2H),7.58-7.57(m,1H),7.35-7.31(m,2H),7.25-7.24(m,1H), 7.22-7.20(m,2H),4.54(s,2H),4.24-4.22(m,1H),4.20-4.04(m,4H),3.54-3.51(m,2H),3.37-3.36(m,2H),3.04-3.02(m,1H),2.64-2.61(m,1H),2.55-2.50(m,1H),2.19-1.96(m,5H),1.65-1.60(m,1H),1.45-1.43(m,1H)。MS-ESI计算值[M+H] +488,实测值488。 Compound 9-2 (30.0 mg, 51.4 μmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and sodium hydroxide (4.11 mg, 0.103 mmol) was added to the reaction solution. The reaction solution was stirred and reacted at 50°C for 2 hours, concentrated under reduced pressure to remove the solvent, and adjusted to pH 5 by adding hydrochloric acid (1mol/L). The hydrochloride of compound 9 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (400MHz, CD 3 OD) δ 7.65-7.64 (m, 1H), 7.61-7.59 (m, 2H), 7.58-7.57 (m, 1H), 7.35-7.31 (m, 2H), 7.25 7.24(m,1H), 7.22-7.20(m,2H),4.54(s,2H),4.24-4.22(m,1H), 4.20-4.04(m,4H),3.54-3.51(m,2H), 3.37-3.36(m,2H),3.04-3.02(m,1H),2.64-2.61(m,1H),2.55-2.50(m,1H),2.19-1.96(m,5H),1.65-1.60(m ,1H),1.45-1.43(m,1H). MS-ESI calculated value [M+H] + 488, measured value 488.
实施例10Example 10
Figure PCTCN2020118824-appb-000069
Figure PCTCN2020118824-appb-000069
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000070
Figure PCTCN2020118824-appb-000070
第一步first step
将化合物7-3(300mg,0.704mmol)溶于N,N-二甲基甲酰胺(5mL)中，向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(401mg,1.06mmol)，N,N-二异丙基乙胺(182mg,1.41mmol)。反应液在25℃下搅拌1小时。再向反应液中加入化合物10-1(72.1mg,0.774mmol)，反应液在25℃下搅拌12小时。加水(10mL)，用乙酸乙酯(10mL x 3)萃取，合并有机相用饱和氯化钠(10mL x 1)洗涤，用无水硫酸钠干燥，过滤，减压浓缩。粗产物经过薄层层析法分离(1：1石油醚/乙酸乙酯,Rf＝0.43)得到化合物10-2。MS-ESI计算值[M+H] +502,实测值502。 Compound 7-3 (300mg, 0.704mmol) was dissolved in N,N-dimethylformamide (5mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution. N,N,N,N-tetramethylurea hexafluorophosphate (401mg, 1.06mmol), N,N-diisopropylethylamine (182mg, 1.41mmol). The reaction solution was stirred at 25°C for 1 hour. Compound 10-1 (72.1 mg, 0.774 mmol) was added to the reaction solution, and the reaction solution was stirred at 25° C. for 12 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated sodium chloride (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (1:1 petroleum ether/ethyl acetate, Rf=0.43) to obtain compound 10-2. MS-ESI calculated value [M+H] + 502, measured value 502.
第二步Second step
将化合物10-2(35.0mg,69.8μmol)溶于四氢呋喃(1mL)和水(1mL)中，向反应液中加氢氧化钠(5.58mg,0.140mmol)。反应液在50℃下搅拌反应2小时,减压浓缩除去溶剂，加盐酸(1mol/L)调节pH至5。用高效液相色谱法(酸性,盐酸体系)制备得到化合物10的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.62-7.60(m,2H),7.38-7.36(m,4H),7.34-7.32(m,1H),7.26-7.21(m,2H),7.17-7.16(m,1H),4.25-4.15(m,5H),3.62-3.57(m,2H),3.42-3.39(m,2H),3.06-3.04(m,1H),2.60-2.59(m,1H),2.50-2.47(m,1H),2.28-2.24(m,1H),2.16-2.11(m,3H),1.96-1.95(m,1H),1.62-1.61(m,1H),1.47-1.43(m,1H)。MS-ESI计算值[M+H] +406,实测值406。 Compound 10-2 (35.0 mg, 69.8 μmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and sodium hydroxide (5.58 mg, 0.140 mmol) was added to the reaction solution. The reaction solution was stirred and reacted at 50°C for 2 hours, concentrated under reduced pressure to remove the solvent, and hydrochloric acid (1mol/L) was added to adjust the pH to 5. The hydrochloride of compound 10 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (400MHz, CD 3 OD) δ 7.62-7.60 (m, 2H), 7.38-7.36 (m, 4H), 7.34-7.32 (m, 1H), 7.26-7.21 (m, 2H), 7.17- 7.16(m,1H),4.25-4.15(m,5H),3.62-3.57(m,2H),3.42-3.39(m,2H),3.06-3.04(m,1H),2.60-2.59(m,1H) ), 2.50-2.47 (m, 1H), 2.28-2.24 (m, 1H), 2.16-2.11 (m, 3H), 1.96-1.95 (m, 1H), 1.62-1.61 (m, 1H), 1.47-1.43 (m,1H). MS-ESI calculated value [M+H] + 406, measured value 406.
实施例11Example 11
Figure PCTCN2020118824-appb-000071
Figure PCTCN2020118824-appb-000071
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000072
Figure PCTCN2020118824-appb-000072
第一步first step
将化合物7-3(300mg,0.704mmol)溶于N,N-二甲基甲酰胺(5mL)中，向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(401mg,1.06mmol)，N,N-二异丙基乙胺(182mg,1.41mmol)。反应液在25℃下搅拌1小时。再向反应液中加入化合物11-1(166mg,774μmol)，反应液在25℃下搅拌12小时。加水(10mL),用乙酸乙酯(10mL x 3)萃取，合并有机相用饱和氯化钠(10mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过薄层层析法分离(1：1石油醚/乙酸乙酯,Rf＝0.33)得到化合物11-2。MS-ESI计算值[M+H] +623,实测值623。 Compound 7-3 (300mg, 0.704mmol) was dissolved in N,N-dimethylformamide (5mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution. N,N,N,N-tetramethylurea hexafluorophosphate (401mg, 1.06mmol), N,N-diisopropylethylamine (182mg, 1.41mmol). The reaction solution was stirred at 25°C for 1 hour. Compound 11-1 (166 mg, 774 μmol) was added to the reaction solution, and the reaction solution was stirred at 25° C. for 12 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated sodium chloride (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (1:1 petroleum ether/ethyl acetate, Rf=0.33) to obtain compound 11-2. MS-ESI calculated value [M+H] + 623, measured value 623.
第二步Second step
将化合物11-2(40.0mg,64.2μmol)溶于四氢呋喃(1mL)和水(1mL)中，向反应液中加氢氧化钠(5.14mg,0.128mmol)。反应液在50℃下搅拌反应3小时，减压浓缩除去溶剂得到化合物11-3。MS-ESI计算值[M+H] +527,实测值527。 Compound 11-2 (40.0 mg, 64.2 μmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and sodium hydroxide (5.14 mg, 0.128 mmol) was added to the reaction solution. The reaction solution was stirred and reacted at 50°C for 3 hours, and concentrated under reduced pressure to remove the solvent to obtain compound 11-3. MS-ESI calculated value [M+H] + 527, measured value 527.
第三步third step
将化合物11-3(30.0mg,57.0μmol)溶于甲醇(1mL)中,向反应液中加盐酸甲醇(142μL,4mol/L)。反应液在25℃下搅拌反应2小时，减压浓缩除去溶剂。用高效液相色谱法(酸性,盐酸体系)制备得到化合物11的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.36-7.32(m,2H),7.27-7.26(m,1H),7.23-7.21(m,2H),4.71-4.68(m,1H),4.53-4.50(m,1H),4.34-4.32(m,1H),4.24-4.17(m,3H),4.02-3.99(m,1H),3.61-3.57(m,3H),3.40-3.36(m,3H),3.34-3.33(m,1H),3.04-3.01(m,1H),2.80-2.77(m,1H),2.62-2.61(m,1H),2.51-2.48(m,1H),2.15-2.11(m,4H),2.01-1.99(m,1H),1.60-1.58(m,1H),1.45-1.40(m,7H)。MS-ESI计 算值[M+H] +427,实测值427。 Compound 11-3 (30.0mg, 57.0μmol) was dissolved in methanol (1mL), and hydrochloric acid methanol (142μL, 4mol/L) was added to the reaction solution. The reaction solution was stirred and reacted at 25°C for 2 hours, and concentrated under reduced pressure to remove the solvent. The hydrochloride of compound 11 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (400MHz, CD 3 OD) δ7.36-7.32 (m, 2H), 7.27-7.26 (m, 1H), 7.23-7.21 (m, 2H), 4.71-4.68 (m, 1H), 4.53- 4.50(m,1H),4.34-4.32(m,1H),4.24-4.17(m,3H),4.02-3.99(m,1H),3.61-3.57(m,3H),3.40-3.36(m,3H) ),3.34-3.33(m,1H),3.04-3.01(m,1H),2.80-2.77(m,1H),2.62-2.61(m,1H),2.51-2.48(m,1H),2.15-2.11 (m, 4H), 2.01-1.99 (m, 1H), 1.60-1.58 (m, 1H), 1.45-1.40 (m, 7H). MS-ESI calculated value [M+H] + 427, measured value 427.
实施例12Example 12
Figure PCTCN2020118824-appb-000073
Figure PCTCN2020118824-appb-000073
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000074
Figure PCTCN2020118824-appb-000074
第一步first step
将化合物7-3(200mg,0.469mmol)溶于N,N-二甲基甲酰胺(5mL)中，向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(268mg,0.704mmol)，N,N-二异丙基乙胺(182mg,1.41mmol)。反应液在27℃下搅拌1小时。再向反应液中加入化合物12-1(64.0mg,0.563mmol)，反应液在27℃下搅拌12小时。加水(20mL)，用乙酸乙酯(20mL x 2)萃取，合并有机相用饱和氯化钠(50mL x 1)洗涤，有机相用无水硫酸钠干燥，过滤,减压浓缩。粗产物经过硅胶柱层析法分离(1：2石油醚/乙酸乙酯,Rf＝0.09)得到化合物12-2。MS-ESI计算值[M+H] +522,实测值522。 Compound 7-3 (200mg, 0.469mmol) was dissolved in N,N-dimethylformamide (5mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution. N,N,N,N-tetramethylurea hexafluorophosphate (268mg, 0.704mmol), N,N-diisopropylethylamine (182mg, 1.41mmol). The reaction solution was stirred at 27°C for 1 hour. Compound 12-1 (64.0 mg, 0.563 mmol) was added to the reaction solution, and the reaction solution was stirred at 27° C. for 12 hours. Water (20 mL) was added, extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated sodium chloride (50 mL x 1), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (1:2 petroleum ether/ethyl acetate, Rf=0.09) to obtain compound 12-2. MS-ESI calculated value [M+H] + 522, measured value 522.
第二步Second step
将化合物12-2(85.0mg,0.163mmol)溶于四氢呋喃(1mL),乙醇(0.5mL)和水(1mL)中，向反应液中加氢氧化钠(13.0mg,0.326mmol)。反应液在50℃下搅拌反应3小时，减压浓缩除去溶剂，加盐酸(1mol/L)调节pH至7。用高效液相色谱法(酸性,盐酸体系)制备得到化合物12的盐酸盐。 1H NMR(CD 3OD,400MHz)δ7.36-7.31(m,2H),7.27-7.20(m,3H),4.56(s,2H),4.23-4.14(m,4H),4.03(s,2H),3.71-3.56(m,2H),3.51-3.35(m,1H),3.05-3.03(m,1H),2.62-2.59(m,4H),2.55-2.45(m,1H),2.17-2.10(m,4H),2.01-1.92(m,1H),1.62-1.61(m,1H),1.46-1.44(m,1H)。MS-ESI计算值[M+H] +426,实测值426。 Compound 12-2 (85.0 mg, 0.163 mmol) was dissolved in tetrahydrofuran (1 mL), ethanol (0.5 mL) and water (1 mL), and sodium hydroxide (13.0 mg, 0.326 mmol) was added to the reaction solution. The reaction solution was stirred and reacted at 50°C for 3 hours, concentrated under reduced pressure to remove the solvent, and hydrochloric acid (1mol/L) was added to adjust the pH to 7. The hydrochloride of compound 12 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (CD 3 OD, 400MHz) δ7.36-7.31 (m, 2H), 7.27-7.20 (m, 3H), 4.56 (s, 2H), 4.23-4.14 (m, 4H), 4.03 (s, 2H),3.71-3.56(m,2H),3.51-3.35(m,1H),3.05-3.03(m,1H),2.62-2.59(m,4H),2.55-2.45(m,1H),2.17- 2.10 (m, 4H), 2.01-1.92 (m, 1H), 1.62-1.61 (m, 1H), 1.46-1.44 (m, 1H). MS-ESI calculated value [M+H] + 426, measured value 426.
实施例13Example 13
Figure PCTCN2020118824-appb-000075
Figure PCTCN2020118824-appb-000075
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000076
Figure PCTCN2020118824-appb-000076
第一步first step
将化合物7-3(200mg,0.469mmol)溶于N,N-二甲基甲酰胺(5mL)中,向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(268mg,0.703mmol),N,N-二异丙基乙胺(182mg,1.41mmol)。反应液在27℃下搅拌1小时。再向反应液中加入化合物13-1(61.0mg,0.563mmol),反应液在27℃下搅拌12小时。加水(20mL),用乙酸乙酯(20mL x 2)萃取,合并有机相用饱和氯化钠(50mL x 1)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗产物经过薄层层析法分离(1：2石油醚/乙酸乙酯,Rf＝0.2)得到化合物13-2。MS-ESI计算值[M+H] +517,实测值517。 Compound 7-3 (200mg, 0.469mmol) was dissolved in N,N-dimethylformamide (5mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution N,N,N,N-tetramethylurea hexafluorophosphate (268mg, 0.703mmol), N,N-diisopropylethylamine (182mg, 1.41mmol). The reaction solution was stirred at 27°C for 1 hour. Compound 13-1 (61.0 mg, 0.563 mmol) was added to the reaction solution, and the reaction solution was stirred at 27°C for 12 hours. Water (20 mL) was added, extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated sodium chloride (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (1:2 petroleum ether/ethyl acetate, Rf=0.2) to obtain compound 13-2. MS-ESI calculated value [M+H] + 517, measured value 517.
第二步Second step
将化合物13-2(145mg,0.281mmol)溶于四氢呋喃(2mL),乙醇(1mL)和水(2mL)中,向反应液中加氢氧化钠(22.0mg,0.561mmol)。反应液在50℃下搅拌反应3小时,减压浓缩除去溶剂,加盐酸(1mol/L)调节pH至7。用高效液相色谱法(酸性,盐酸体系)制备得到化合物13的盐酸盐。 1H NMR(CD 3OD,400MHz)δ8.82-8.62(m,1H),8.60-8.58(m,1H),8.09-8.07(m,1H),8.02-7.99(m,1H),7.36-7.31(m,2H),7.26-7.20(m,3H),4.22-4.15(m,6H),3.72-3.45(m,4H),3.05-3.03(m,1H),2.75-2.58(m,2H),2.15-2.07(m,6H),1.61-1.45(m,1H),1.12-1.19(m,1H)。MS-ESI计算值[M+H] +421,实测值421。 Compound 13-2 (145 mg, 0.281 mmol) was dissolved in tetrahydrofuran (2 mL), ethanol (1 mL) and water (2 mL), and sodium hydroxide (22.0 mg, 0.561 mmol) was added to the reaction solution. The reaction solution was stirred and reacted at 50°C for 3 hours, concentrated under reduced pressure to remove the solvent, and hydrochloric acid (1mol/L) was added to adjust the pH to 7. The hydrochloride of compound 13 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (CD 3 OD, 400MHz) δ 8.82-8.62 (m, 1H), 8.60-8.58 (m, 1H), 8.09-8.07 (m, 1H), 8.02-7.99 (m, 1H), 7.36 7.31(m,2H),7.26-7.20(m,3H),4.22-4.15(m,6H),3.72-3.45(m,4H),3.05-3.03(m,1H),2.75-2.58(m,2H) ), 2.15-2.07 (m, 6H), 1.61-1.45 (m, 1H), 1.12-1.19 (m, 1H). MS-ESI calculated value [M+H] + 421, measured value 421.
实施例14Example 14
Figure PCTCN2020118824-appb-000077
Figure PCTCN2020118824-appb-000077
合成路线synthetic route
Figure PCTCN2020118824-appb-000078
Figure PCTCN2020118824-appb-000078
第一步first step
将化合物7-3(200mg,0.469mmol)溶于N,N-二甲基甲酰胺(5mL)中,向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(0.232mg,0.610mmol),N,N-二异丙基乙胺(121mg,0.938mmol)。反应液在27℃下搅拌1小时。再向反应液中加入化合物14-1(70.0mg,0.563mmol),反应液在27℃下搅拌12小时。加水(10mL),用乙酸乙酯(10mL x 2)萃取,合并有机相用饱和氯化钠(10mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过薄层层析法分离(1：2石油醚/乙酸乙酯,Rf＝0.16)得到化合物14-2。MS-ESI计算值[M+H] +534,实测值534。 Compound 7-3 (200mg, 0.469mmol) was dissolved in N,N-dimethylformamide (5mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution N,N,N,N-tetramethylurea hexafluorophosphate (0.232mg, 0.610mmol), N,N-diisopropylethylamine (121mg, 0.938mmol). The reaction solution was stirred at 27°C for 1 hour. Compound 14-1 (70.0 mg, 0.563 mmol) was added to the reaction solution, and the reaction solution was stirred at 27°C for 12 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated sodium chloride (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (1:2 petroleum ether/ethyl acetate, Rf=0.16) to obtain compound 14-2. MS-ESI calculated value [M+H] + 534, measured value 534.
第二步Second step
将化合物14-2(50.0mg,94.0μmol)溶于四氢呋喃(1mL),乙醇(0.5mL)和水(1mL)中,向反应液中加氢氧化钠(7.50mg,0.187mmol)。反应液在50℃下搅拌反应3小时,减压浓缩除去溶剂,加盐酸(1mol/L)调节pH至7。用高效液相色谱法(酸性,盐酸体系)制备得到化合物14的盐酸盐。 1H NMR(CD 3OD,400MHz)δ7.35-7.33(m,4H),7.32-7.30(m,1H),7.19-7.17(m,2H),7.08-7.04(m,2H),4.42(s,2H),4.8-4.25(m,1H),4.15-4.11(m,2H),3.97-3.96(m,2H),3.48-3.47(m,2H),3.27-3.26(m,1H),3.03-3.01(m,1H),2.60-2.55(m,2H),2.11-1.93(m,6H),1.57-1.56(m,1H),1.45-1.43(m,1H)。MS-ESI计算值[M+H] +438,实测值438。 Compound 14-2 (50.0 mg, 94.0 μmol) was dissolved in tetrahydrofuran (1 mL), ethanol (0.5 mL) and water (1 mL), and sodium hydroxide (7.50 mg, 0.187 mmol) was added to the reaction solution. The reaction solution was stirred and reacted at 50°C for 3 hours, concentrated under reduced pressure to remove the solvent, and hydrochloric acid (1mol/L) was added to adjust the pH to 7. The hydrochloride of compound 14 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (CD 3 OD, 400MHz) δ7.35-7.33 (m, 4H), 7.32-7.30 (m, 1H), 7.19-7.17 (m, 2H), 7.08-7.04 (m, 2H), 4.42 ( s, 2H), 4.8-4.25 (m, 1H), 4.15-4.11 (m, 2H), 3.97-3.96 (m, 2H), 3.48-3.47 (m, 2H), 3.27-3.26 (m, 1H), 3.03-3.01 (m, 1H), 2.60-2.55 (m, 2H), 2.11-1.93 (m, 6H), 1.57-1.56 (m, 1H), 1.45-1.43 (m, 1H). MS-ESI calculated value [M+H] + 438, measured value 438.
实施例15Example 15
Figure PCTCN2020118824-appb-000079
Figure PCTCN2020118824-appb-000079
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000080
Figure PCTCN2020118824-appb-000080
第一步first step
将化合物7-3(200mg,0.469mmol)溶于N,N-二甲基甲酰胺(5mL)中,向反应液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(0.232g,0.601mmol),N,N-二异丙基乙胺(121mg,0.938mmol)。反应液在27℃下搅拌1小时。再向反应液中加入化合物15-1(34.0mg,0.563mmol),反应液在27℃下搅拌12小时。加水(10mL),用乙酸乙酯(10mL x 2)萃取,合并有机相用饱和氯化钠(10mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过薄层层析法分离(1：2石油醚/乙酸乙酯,Rf＝0.13)得到化合物15-2。MS-ESI计算值[M+H] +470,实测值470。 Compound 7-3 (200mg, 0.469mmol) was dissolved in N,N-dimethylformamide (5mL), and O-(7-azabenzotriazol-1-yl)- was added to the reaction solution N,N,N,N-tetramethylurea hexafluorophosphate (0.232g, 0.601mmol), N,N-diisopropylethylamine (121mg, 0.938mmol). The reaction solution was stirred at 27°C for 1 hour. Compound 15-1 (34.0 mg, 0.563 mmol) was added to the reaction solution, and the reaction solution was stirred at 27° C. for 12 hours. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated sodium chloride (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin layer chromatography (1:2 petroleum ether/ethyl acetate, Rf=0.13) to obtain compound 15-2. MS-ESI calculated value [M+H] + 470, measured value 470.
第二步Second step
将化合物15-2(30.0mg,59.0μmol)溶于四氢呋喃(1mL),乙醇(0.5mL)和水(1mL)中,向反应液中加氢氧化钠(5.00mg,0.119mmol)。反应液在50℃下搅拌反应3小时,减压浓缩除去溶剂,加盐酸(1mol/L)调节pH至4。用高效液相色谱法(酸性,盐酸体系)制备得到化合物15的盐酸盐。 1H NMR(CD 3OD,400MHz)δ7.34-7.30(m,2H),7.26-7.24(m,1H),7.22-7.18(m,2H),4.22-4.14(m,3H),3.93(s,2H),3.63-3.61(m,4H),3.39-3.37(m,2H),3.31-3.30(m,2H),3.03-3.01(m,1H),2.58-2.56(m,1H),2.54-2.42(m,1H),2.30-2.20(m,5H),1.60-1.58(m,1H),1.44-1.42(m,1H)。MS-ESI计算值[M+H] +374,实测值374。 Compound 15-2 (30.0 mg, 59.0 μmol) was dissolved in tetrahydrofuran (1 mL), ethanol (0.5 mL) and water (1 mL), and sodium hydroxide (5.00 mg, 0.119 mmol) was added to the reaction solution. The reaction solution was stirred and reacted at 50°C for 3 hours, concentrated under reduced pressure to remove the solvent, and adjusted to pH 4 by adding hydrochloric acid (1mol/L). The hydrochloride of compound 15 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR (CD 3 OD, 400MHz) δ 7.34-7.30 (m, 2H), 7.26-7.24 (m, 1H), 7.22-7.18 (m, 2H), 4.22-4.14 (m, 3H), 3.93 ( s, 2H), 3.63-3.61 (m, 4H), 3.39-3.37 (m, 2H), 3.31-3.30 (m, 2H), 3.03-3.01 (m, 1H), 2.58-2.56 (m, 1H), 2.54-2.42 (m, 1H), 2.30-2.20 (m, 5H), 1.60-1.58 (m, 1H), 1.44-1.42 (m, 1H). MS-ESI calculated value [M+H] + 374, measured value 374.
实施例16Example 16
Figure PCTCN2020118824-appb-000081
Figure PCTCN2020118824-appb-000081
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000082
Figure PCTCN2020118824-appb-000082
第一步first step
将化合物7-3(50.0mg,117μmol)溶于N,N-二甲基甲酰胺(2mL)中,向反应液中加入三正丙基磷酸酐(50％乙酸乙酯溶液,56.0mg,176μmol),N,N-二异丙基乙胺(30.3mg,235μmol)反应液在25℃下搅拌1小时。再向其中加入化合物16-1(9.86mg,176μmol)。反应液在25℃下搅拌12小时。加水(10mL),用乙酸乙酯(10mL x 3)萃取,有机相用饱和氯化钠(10mL x 1)洗,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到化合物16-2。MS-ESI计算值[M+H] +465,实测值465。 Compound 7-3 (50.0mg, 117μmol) was dissolved in N,N-dimethylformamide (2mL), and tri-n-propyl phosphoric anhydride (50% ethyl acetate solution, 56.0mg, 176μmol) was added to the reaction solution. ), N,N-diisopropylethylamine (30.3mg, 235μmol) reaction solution was stirred at 25°C for 1 hour. Compound 16-1 (9.86 mg, 176 μmol) was added to it. The reaction solution was stirred at 25°C for 12 hours. Add water (10mL), extract with ethyl acetate (10mL x 3), wash the organic phase with saturated sodium chloride (10mL x 1), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 16-2 . MS-ESI calculated value [M+H] + 465, measured value 465.
第二步Second step
将化合物16-2(54.0mg,116μmol)溶于四氢呋喃(1mL)和水(1mL)中,向反应液中加入一水合氢氧化锂(9.76mg,233μmol)。反应液在55℃下搅拌反应12小时,减压浓缩除去溶剂。用高效液相色谱法(中性体系)分离纯化,向得到的馏分中加浓盐酸(20μL)后处理得到化合物16的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.33-7.31(m,2H),7.26-7.21(m,3H),4.28(s,2H),4.20-4.16(m,3H),4.01-4.00(m,2H),3.41-3.37(m,3H),3.28-3.24(m,1H),3.03-3.00(m,1H),2.65-2.64(m,1H),2.48-2.47(m,1H),2.17-2.04(m,5H),1.66-1.65(m,1H),1.42-1.40(m,1H)。MS-ESI计算值[M+H] +369,实测值369。 Compound 16-2 (54.0 mg, 116 μmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and lithium hydroxide monohydrate (9.76 mg, 233 μmol) was added to the reaction solution. The reaction solution was stirred and reacted at 55°C for 12 hours, and concentrated under reduced pressure to remove the solvent. It was separated and purified by high performance liquid chromatography (neutral system). Concentrated hydrochloric acid (20μL) was added to the obtained fraction for post-treatment to obtain the hydrochloride of compound 16. 1 H NMR (400MHz, CD 3 OD) δ7.33-7.31 (m, 2H), 7.26-7.21 (m, 3H), 4.28 (s, 2H), 4.20-4.16 (m, 3H), 4.01-4.00 ( m, 2H), 3.41-3.37 (m, 3H), 3.28-3.24 (m, 1H), 3.03-3.00 (m, 1H), 2.65-2.64 (m, 1H), 2.48-2.47 (m, 1H), 2.17-2.04 (m, 5H), 1.66-1.65 (m, 1H), 1.42-1.40 (m, 1H). MS-ESI calculated value [M+H] + 369, measured value 369.
实施例17Example 17
Figure PCTCN2020118824-appb-000083
Figure PCTCN2020118824-appb-000083
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000084
Figure PCTCN2020118824-appb-000084
第一步first step
将化合物7-3(150mg,352μmol)溶于N,N-二甲基甲酰胺(3mL)中,向反应液中加入三正丙基磷酸酐(50％乙酸乙酯溶液,168mg,528μmol),N,N-二异丙基乙胺(90.9mg,704μmol),再向其中加入化合物17-1(153mg,704μmol)。反应液在25℃下搅拌12小时。加水(10mL),用乙酸乙酯(20mL x 3)萃取,有机相用饱和氯化钠(10mL x 1)洗涤,用无水硫酸钠干燥,过滤,滤液减压浓缩得到化合物17-2。MS-ESI计算值[M+H] +626,实测值626。 Compound 7-3 (150mg, 352μmol) was dissolved in N,N-dimethylformamide (3mL), and tri-n-propyl phosphoric anhydride (50% ethyl acetate solution, 168mg, 528μmol) was added to the reaction solution. N,N-diisopropylethylamine (90.9 mg, 704 μmol), and compound 17-1 (153 mg, 704 μmol) was added to it. The reaction solution was stirred at 25°C for 12 hours. Water (10 mL) was added, extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated sodium chloride (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 17-2. MS-ESI calculated value [M+H] + 626, measured value 626.
第二步Second step
将化合物17-2(120mg,192μmol)溶于四氢呋喃(2mL)和水(1mL)中,向反应液中加一水合氢氧化锂(16.1mg,384μmol)。反应液在55℃下搅拌反应12小时,用盐酸(1mol/L)调节pH至7,减压浓缩除去溶剂,得到粗产物化合物17-3。MS-ESI计算值[M+H] +530,实测值530。 Compound 17-2 (120mg, 192μmol) was dissolved in tetrahydrofuran (2mL) and water (1mL), and lithium hydroxide monohydrate (16.1mg, 384μmol) was added to the reaction solution. The reaction solution was stirred and reacted at 55°C for 12 hours. The pH was adjusted to 7 with hydrochloric acid (1mol/L), and the solvent was removed by concentration under reduced pressure to obtain the crude compound 17-3. MS-ESI calculated value [M+H] + 530, measured value 530.
第三步third step
将化合物17-3(50.0mg,94.4mmol)溶于二氯甲烷(2mL)中,0℃下向反应液中加入三甲基溴硅烷(145mg,944μmol)。反应液在25℃下搅拌12小时。将反应液减压浓缩。用高效液相色谱法(中性体系)分离纯化,向得到的馏分中加浓盐酸(20μL)后处理得到化合物17的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.55-7.54(m,1H),7.43-7.40(m,1H),7.35-7.31(m,2H),7.26-7.25(m,1H),7.23-7.21(m,2H),4.23-4.21(m,3H),4.18-4.16(m,2H),4.03-3.92(m,2H),3.56-3.55(m,2H),3.47-3.45(m,2H),3.05-3.04(m,1H),2.67-2.66(m,1H),2.49-2.48(m,1H),2.19-2.07(m,5H),1.67-1.66(m,1H),1.43-1.41(m,1H)。MS-ESI计算值[M+H] +474,实测值474。 Compound 17-3 (50.0 mg, 94.4 mmol) was dissolved in dichloromethane (2 mL), and bromotrimethylsilane (145 mg, 944 μmol) was added to the reaction solution at 0°C. The reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure. It was separated and purified by high performance liquid chromatography (neutral system), and then concentrated hydrochloric acid (20μL) was added to the obtained fraction to obtain the hydrochloride of compound 17. 1 H NMR (400MHz, CD 3 OD) δ7.55-7.54 (m, 1H), 7.43-7.40 (m, 1H), 7.35-7.31 (m, 2H), 7.26-7.25 (m, 1H), 7.23 7.21 (m, 2H), 4.23-4.21 (m, 3H), 4.18-4.16 (m, 2H), 4.03-3.92 (m, 2H), 3.56-3.55 (m, 2H), 3.47-3.45 (m, 2H) ), 3.05-3.04 (m, 1H), 2.67-2.66 (m, 1H), 2.49-2.48 (m, 1H), 2.19-2.07 (m, 5H), 1.67-1.66 (m, 1H), 1.43-1.41 (m,1H). MS-ESI calculated value [M+H] + 474, measured value 474.
实施例18Example 18
Figure PCTCN2020118824-appb-000085
Figure PCTCN2020118824-appb-000085
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000086
Figure PCTCN2020118824-appb-000086
第一步first step
将化合物7-3(300mg,0.648mmol)溶于N,N-二甲基甲酰胺(5mL),加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟膦酸盐(370mg,0.972mmol)和N,N-二异丙基乙胺(251mg,1.94mmol),反应液在30℃下搅拌1小时,再向反应液中加入化合物18-1(133mg,0.778mmol),反应液在30℃搅拌12小时。向反应液中加入水(10mL),用乙酸乙酯(10mL×3)萃取,合并有机相用饱和食盐水(10mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗产物经过薄层层析法(10：1二氯甲烷/甲醇,Rf＝0.31)分离纯化得到化合物18-2。MS-ESI计算值[M+H] +544,实测值544。 Compound 7-3 (300mg, 0.648mmol) was dissolved in N,N-dimethylformamide (5mL), and O-(7-azabenzotriazol-1-yl)-N,N,N was added , N-tetramethylurea hexafluorophosphonate (370mg, 0.972mmol) and N,N-diisopropylethylamine (251mg, 1.94mmol), the reaction solution was stirred at 30°C for 1 hour, and then added to the reaction solution Compound 18-1 (133 mg, 0.778 mmol) was added, and the reaction solution was stirred at 30°C for 12 hours. Water (10mL) was added to the reaction solution, extracted with ethyl acetate (10mL×3), and the combined organic phases were washed with saturated brine (10mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After separation and purification by thin layer chromatography (10:1 dichloromethane/methanol, Rf=0.31), compound 18-2 was obtained. MS-ESI calculated value [M+H] + 544, measured value 544.
第二步Second step
将化合物18-2(140mg,0.258mmol)溶于四氢呋喃(2mL),乙醇(1mL)和H 2O(1mL)的混合溶液,向溶液中加入氢氧化钠(20.6mg,0.515mmol),反应液在50℃下搅拌3小时,反应液减压浓缩,加入H 2O(2mL)稀释,用稀盐酸(1mol/L)调节反应液pH至4,用乙酸乙酯(5mL×3)萃取,合并有机相,依次用水(20mL×3)和饱和食盐水(30mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经过制备高效液相色谱法分离纯化得到化合物18的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.34-7.30(m,2H),7.25-7.24(m,1H),7.21-7.19(m,2H),4.42(s,2H),4.24-4.09(m,5H),3.93-3.87(m,2H),3.66-3.54(m,2H),3.30-3.25(m,4H),3.20-3.19(m,2H),3.04-3.01(m,1H),2.64-2.60(m,1H),2.47-2.42(m,1H),2.23-1.95(m,5H),1.64-1.59(m,1H),1.45-1.39(m,1H)。MS-ESI计算值[M+H] +448,实测值448。 Compound 18-2 (140mg, 0.258mmol) was dissolved in a mixed solution of tetrahydrofuran (2mL), ethanol (1mL) and H 2 O (1mL), sodium hydroxide (20.6mg, 0.515mmol) was added to the solution, the reaction solution Stir at 50°C for 3 hours, concentrate the reaction solution under reduced pressure, add H 2 O (2mL) to dilute, adjust the pH of the reaction solution to 4 with dilute hydrochloric acid (1mol/L), extract with ethyl acetate (5mL×3), and combine The organic phase was washed successively with water (20mL×3) and saturated brine (30mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was separated and purified by preparative high performance liquid chromatography to obtain the salt of compound 18. Acid salt. 1 H NMR (400MHz, CD 3 OD) δ 7.34-7.30 (m, 2H), 7.25-7.24 (m, 1H), 7.21-7.19 (m, 2H), 4.42 (s, 2H), 4.24-4.09 ( m,5H),3.93-3.87(m,2H),3.66-3.54(m,2H), 3.30-3.25(m,4H), 3.20-3.19(m,2H),3.04-3.01(m,1H), 2.64-2.60 (m, 1H), 2.47-2.42 (m, 1H), 2.23-1.95 (m, 5H), 1.64-1.59 (m, 1H), 1.45-1.39 (m, 1H). MS-ESI calculated value [M+H] + 448, measured value 448.
实施例19,20Examples 19, 20
Figure PCTCN2020118824-appb-000087
Figure PCTCN2020118824-appb-000087
合成路线:synthetic route:
Figure PCTCN2020118824-appb-000088
Figure PCTCN2020118824-appb-000088
将化合物2(203mg,0.549mmol)经超临界流体萃取法(柱:Chiralcel OD-3 50×4.6mm I.D.,3μm；流动相:A:二氧化碳B:甲醇(0.05％二乙胺)；梯度:B在A中从5％到40％；流量:3mL/min；柱温:35℃；柱压:100Bar)分离纯化得到化合物19(保留时间：1.610分钟)。 1H NMR(400MHz,CD 3OD)δ7.24-7.20(m,2H),7.14-7.10(m,1H),7.05-7.03(m,2H),3.98-3.94(m,1H),3.62-3.54(m,2H),2.98-2.96(m,2H),2.67-2.64(m,1H),2.66-2.46(m,4H),2.30-2.26(m,1H),2.12-2.07(m,1H),1.94-1.90(m,1H),1.79-1.76(m, 2H),1.70-1.60(m,3H),1.07-0.99(m,2H),0.76-0.71(m,2H),0.53-0.49(m,2H)。MS-ESI计算值[M+H] +370,实测值370。 Compound 2 (203mg, 0.549mmol) was subjected to supercritical fluid extraction (column: Chiralcel OD-3 50×4.6mm ID, 3μm; mobile phase: A: carbon dioxide B: methanol (0.05% diethylamine); gradient: B From 5% to 40% in A; flow rate: 3 mL/min; column temperature: 35° C.; column pressure: 100 Bar) to obtain compound 19 (retention time: 1.610 minutes). 1 H NMR (400MHz, CD 3 OD) δ 7.24-7.20 (m, 2H), 7.14-7.10 (m, 1H), 7.05-7.03 (m, 2H), 3.98-3.94 (m, 1H), 3.62- 3.54 (m, 2H), 2.98-2.96 (m, 2H), 2.67-2.64 (m, 1H), 2.66-2.46 (m, 4H), 2.30-2.26 (m, 1H), 2.12-2.07 (m, 1H) ),1.94-1.90(m,1H),1.79-1.76(m,2H),1.70-1.60(m,3H),1.07-0.99(m,2H),0.76-0.71(m,2H),0.53-0.49 (m, 2H). MS-ESI calculated value [M+H] + 370, measured value 370.
化合物20(保留时间：1.973分钟)。 1H NMR(400MHz,CD 3OD)δ7.24-7.20(m,2H),7.14-7.10(m,1H),7.05-7.03(m,2H),3.98-3.94(m,1H),3.66-3.54(m,2H),2.97-2.96(m,2H),2.67-2.64(m,1H),2.60-2.44(m,4H),2.30-2.26(m,1H),2.12-2.07(m,1H),1.90-1.86(m,1H),1.78-1.75(m,2H),1.70-1.56(m,3H),1.08-1.01(m,2H),0.76-0.71(m,2H),0.53-0.49(m,2H)。MS-ESI计算值[M+H] +370,实测值370。 Compound 20 (retention time: 1.973 minutes). 1 H NMR (400MHz, CD 3 OD) δ 7.24-7.20 (m, 2H), 7.14-7.10 (m, 1H), 7.05-7.03 (m, 2H), 3.98-3.94 (m, 1H), 3.66- 3.54(m,2H),2.97-2.96(m,2H),2.67-2.64(m,1H),2.60-2.44(m,4H),2.30-2.26(m,1H),2.12-2.07(m,1H) ),1.90-1.86(m,1H),1.78-1.75(m,2H),1.70-1.56(m,3H),1.08-1.01(m,2H),0.76-0.71(m,2H),0.53-0.49 (m, 2H). MS-ESI calculated value [M+H] + 370, measured value 370.
生物化学检测：Biochemical testing:
实验例1：酶活性评价Experimental example 1: Evaluation of enzyme activity
本试验目的是检测化合物对LSD1的体外抑制活性。本试验采用的酶为人源LSD1，标准底物为组蛋白H3K4me肽(20μM)，采用酶荧光偶联法，通过辣根过氧化酶(HPR)和荧光试剂Amplex Red联合检测LSD1反应后生成的H 2O 2的方法测定化合物的活性。从10μM开始3倍稀释，检测化合物的10个浓度下IC 50值。化合物在加入底物开始反应前，酶和底物共孵化30分钟。荧光检测器：EnVision，激发波长：Ex/Em＝530/590nM。 The purpose of this test is to test the compound's in vitro inhibitory activity on LSD1. The enzyme used in this test is human LSD1, the standard substrate is histone H3K4me peptide (20μM), and the enzyme fluorescence coupling method is used to detect the H produced by the reaction of LSD1 through the combination of horseradish peroxidase (HPR) and the fluorescent reagent Amplex Red. 2 O 2 method to determine the activity of the compound. Start the 3-fold dilution from 10 μM, and detect the IC 50 value of the compound at 10 concentrations. Before the compound was added to the substrate to start the reaction, the enzyme and the substrate were incubated for 30 minutes. Fluorescence detector: EnVision, excitation wavelength: Ex/Em=530/590nM.
测试化合物对LSD1抑制活性，结果如表1所示。The test compounds have inhibitory activity against LSD1, and the results are shown in Table 1.
表1：本发明化合物体外酶活性筛选试验结果Table 1: In vitro enzyme activity screening test results of the compounds of the present invention
化合物编号Compound number IC 50(nM) IC 50 (nM) 化合物编号Compound number IC 50(nM) IC 50 (nM)
化合物1的盐酸盐Compound 1 hydrochloride 17.7417.74 化合物6的盐酸盐Compound 6 hydrochloride 120.7120.7
化合物2的盐酸盐Compound 2 Hydrochloride 19.9919.99 化合物10的盐酸盐Compound 10 hydrochloride 37.3537.35
化合物3的盐酸盐Compound 3 hydrochloride 33.8633.86 化合物11的盐酸盐Compound 11 hydrochloride 13.1413.14
化合物4的盐酸盐Compound 4 hydrochloride 18.1318.13 化合物13的盐酸盐Compound 13 hydrochloride 36.3236.32
化合物5的盐酸盐Compound 5 hydrochloride 100.6100.6 化合物18的盐酸盐Compound 18 hydrochloride 112.3112.3
结论：本发明化合物对LSD1抑制活性明显。Conclusion: The compound of the present invention has obvious inhibitory activity on LSD1.
实验例2：对NCI-H1417细胞增殖抑制活性评价：Experimental Example 2: Evaluation of NCI-H1417 cell proliferation inhibitory activity:
实验目的：检测待测化合物对NCI-H1417细胞增殖抑制活性。Experimental purpose: to detect the inhibitory activity of the test compound on the proliferation of NCI-H1417 cells.
实验材料：RPMI 1640培养基，胎牛血清，Promega CellTiter-Glo试剂。NCI-H1417细胞系购自ATCC。Envision多标记分析仪(PerkinElmer)。Experimental materials: RPMI 1640 medium, fetal bovine serum, Promega CellTiter-Glo reagent. The NCI-H1417 cell line was purchased from ATCC. Envision multi-label analyzer (PerkinElmer).
实验方法：将化合物溶解到10mM,在化合物板里用DMSO 5倍稀释化合物，化合物起始为2mM，用Bravo进行三倍稀释，10个浓度，用Echo转板250nL到空白的384细胞板的上下双复孔，往转了250nL DMSO/化合物里面加入每孔/1000个细胞/50μL的细胞悬液，化合物稀释了200倍，即起始作用浓度是10μM。细胞板置于二氧化碳培养箱中培养10天。向细胞板中加入每孔25μL的Promega CellTiter-Glo试剂，室温振荡10分钟使发光信号稳定。采用PerkinElmer Envision多标记分析仪读数。Experimental method: Dissolve the compound to 10mM, dilute the compound 5 times with DMSO in the compound plate. The compound is initially 2mM, and the compound is diluted three times with Bravo, 10 concentrations, and 250nL of the Echo plate is used to reach the upper and lower sides of the blank 384 cell plate. Double duplicate wells, add 250nL DMSO/compound to each well/1000 cells/50μL of cell suspension, the compound is diluted 200 times, that is, the initial concentration is 10μM. The cell plate was placed in a carbon dioxide incubator for 10 days. Add 25μL of Promega CellTiter-Glo reagent per well to the cell plate and shake at room temperature for 10 minutes to stabilize the luminescence signal. Use PerkinElmer Envision multi-label analyzer to read.
数据分析：利用方程式(Max-Ratio)/(Max-Min)*100％将原始数据换算成抑制率，IC 50的值即可通过四参 数进行曲线拟合得出。(XLFIT5中205模式得出，iDBS)。 Data analysis: Using the equation (Max-Ratio)/(Max-Min)*100% to convert the original data into the inhibition rate, the IC 50 value can be obtained by curve fitting with four parameters. (The 205 mode in XLFIT5 is derived, iDBS).
测试化合物对NCI-H1417细胞增殖抑制活性，结果如表2所示。The test compound has inhibitory activity against the proliferation of NCI-H1417 cells, and the results are shown in Table 2.
表2：本发明化合物对NCI-H1417细胞增殖抑制试验结果Table 2: The results of the compound of the present invention inhibiting the proliferation of NCI-H1417 cells
化合物编号Compound number IC 50(nM) IC 50 (nM) 化合物编号Compound number IC 50(nM) IC 50 (nM)
化合物1的盐酸盐Compound 1 hydrochloride 4.514.51 化合物5的盐酸盐Compound 5 hydrochloride 33.1033.10
化合物2的盐酸盐Compound 2 Hydrochloride 3.223.22 化合物6的盐酸盐Compound 6 hydrochloride 28.1828.18
化合物4的盐酸盐Compound 4 hydrochloride 4.764.76 --- ---
结论：本发明化合物对NCI-H1417细胞增殖抑制活性明显。Conclusion: The compound of the present invention has obvious inhibitory activity on the proliferation of NCI-H1417 cells.
实验例3：对HL60细胞增殖抑制活性评价：Experimental example 3: Evaluation of HL60 cell proliferation inhibitory activity:
实验目的：检测待测化合物对HL60细胞增殖抑制活性。The purpose of the experiment: to detect the inhibitory activity of the test compound on the proliferation of HL60 cells.
实验材料：RPMI-1640培养基，胎牛血清，盘尼西林/链霉素抗生素购自维森特。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。HL60细胞系购自南京科佰生命科技有限公司。Nivo多标记分析仪(PerkinElmer)。Experimental materials: RPMI-1640 medium, fetal bovine serum, penicillin/streptomycin antibiotics purchased from Vicente. CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega. The HL60 cell line was purchased from Nanjing Kebai Life Technology Co., Ltd. Nivo multi-label analyzer (PerkinElmer).
实验方法：将HL60细胞种于白色384孔板中，40μL细胞悬液每孔，其中包含600个HL60细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进行5倍稀释至第10个浓度，即从2mM稀释至1.024nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移10μL每孔到细胞板中。细胞板置于二氧化碳培养箱中培养6天。另准备一块细胞板，在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入20μL细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。Experimental method: Plant HL60 cells in a white 384-well plate, 40μL of cell suspension per well, which contains 600 HL60 cells. The cell plate was placed in a carbon dioxide incubator for overnight culture. The compound to be tested was diluted 5-fold to the 10th concentration with a discharge gun, that is, diluted from 2mM to 1.024nM, and a double-well experiment was set up. Add 78 μL of culture medium to the middle plate, and then transfer 2 μL of each well of the gradient dilution compound to the middle plate according to the corresponding position, and transfer 10 μL of each well to the cell plate after mixing. The cell plate was placed in a carbon dioxide incubator for 6 days. In addition, prepare a cell plate, and read the signal value as the maximum value (Max value in the following equation) on the day of dosing to participate in data analysis. Add 20μL of cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate for 10 minutes at room temperature to stabilize the luminescence signal. Using multi-marker analyzer readings.
数据分析：利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。 Data analysis: Using the equation (Sample-Min)/(Max-Min)*100% to convert the original data into inhibition rate, the value of IC 50 can be obtained by four-parameter curve fitting ("log(inhibitor in GraphPad Prism) )vs.response--Variable slope" model).
测试化合物对HL60细胞增殖抑制活性，结果如表3所示。The test compound has an inhibitory activity on the proliferation of HL60 cells, and the results are shown in Table 3.
表3：本发明化合物对HL60细胞增殖抑制试验结果Table 3: Test results of the compound of the present invention for inhibiting the proliferation of HL60 cells
化合物编号Compound number IC 50(nM) IC 50 (nM) 化合物编号Compound number IC 50(nM) IC 50 (nM)
化合物1的盐酸盐Compound 1 hydrochloride 1.731.73 化合物5的盐酸盐Compound 5 hydrochloride 4.514.51
化合物2的盐酸盐Compound 2 Hydrochloride 2.342.34 化合物6的盐酸盐Compound 6 hydrochloride 2.342.34
化合物4的盐酸盐Compound 4 hydrochloride 2.352.35 --- ---
结论：本发明化合物对HL60细胞增殖抑制活性明显。Conclusion: The compound of the present invention has obvious inhibitory activity on the proliferation of HL60 cells.
实验例4：对MV-4-11细胞增殖抑制活性评价：Experimental Example 4: Evaluation of MV-4-11 cell proliferation inhibitory activity:
实验目的：检测待测化合物对MV-4-11细胞增殖抑制活性。Experimental purpose: To detect the inhibitory activity of the test compound on the proliferation of MV-4-11 cells.
实验材料：IMDM培养基，胎牛血清，盘尼西林/链霉素抗生素购自维森特。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。MV-4-11细胞系购自南京科佰生命科技有限公司。Nivo多标记分析仪(PerkinElmer)。Experimental materials: IMDM medium, fetal bovine serum, penicillin/streptomycin antibiotics purchased from Vicente. CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega. The MV-4-11 cell line was purchased from Nanjing Kebai Life Technology Co., Ltd. Nivo multi-label analyzer (PerkinElmer).
实验方法：将MV-4-11细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含6000个MV-4-11细胞。细胞板置于二氧化碳培养箱中过夜培养。Experimental method: Plant MV-4-11 cells in a white 96-well plate, 80μL of cell suspension per well, which contains 6000 MV-4-11 cells. The cell plate was placed in a carbon dioxide incubator for overnight culture.
将待测化合物用排枪进行5倍稀释至第8个浓度，即从2mM稀释至25.6nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。细胞板置于二氧化碳培养箱中培养6天。另准备一块细胞板，在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入25μL细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。The compound to be tested was diluted 5-fold to the 8th concentration with a discharge gun, that is, diluted from 2mM to 25.6nM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL of each well of the gradient dilution compound to the middle plate according to the corresponding position. After mixing, transfer 20 μL of each well to the cell plate. The cell plate was placed in a carbon dioxide incubator for 6 days. Another cell plate is prepared, and the signal value is read as the maximum value (Max value in the following equation) on the day of drug addition to participate in data analysis. Add 25μL of cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Using multi-marker analyzer readings.
数据分析：利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。 Data analysis: Using the equation (Sample-Min)/(Max-Min)*100% to convert the original data into inhibition rate, the value of IC 50 can be obtained by four-parameter curve fitting ("log(inhibitor in GraphPad Prism) )vs.response--Variable slope" model).
测试化合物对MV-4-11细胞增殖抑制活性，结果如表4所示。The test compound has an inhibitory activity on the proliferation of MV-4-11 cells, and the results are shown in Table 4.
表4：本发明化合物对MV-4-11细胞增殖抑制试验结果Table 4: Inhibition test results of the compounds of the present invention on the proliferation of MV-4-11 cells
化合物编号Compound number IC 50(nM) IC 50 (nM) 化合物编号Compound number IC 50(nM) IC 50 (nM)
化合物1的盐酸盐Compound 1 hydrochloride 2.12.1 化合物5的盐酸盐Compound 5 hydrochloride 6.936.93
化合物2的盐酸盐Compound 2 Hydrochloride 0.910.91 化合物6的盐酸盐Compound 6 hydrochloride 34.734.7
化合物4的盐酸盐Compound 4 hydrochloride 1.381.38 --- ---
结论：本发明化合物对MV-4-11细胞增殖抑制活性明显。Conclusion: The compound of the present invention has obvious inhibitory activity on the proliferation of MV-4-11 cells.
实验例5：化合物药代动力学评价Experimental Example 5: Evaluation of Compound Pharmacokinetics
实验目的：测试化合物在CD-1小鼠体内的药代动力学Experimental purpose: To test the pharmacokinetics of the compound in CD-1 mice
实验材料：Experimental Materials:
CD-1小鼠(雄性,7～9周龄,上海斯莱克)CD-1 mice (male, 7-9 weeks old, Shanghai Slack)
实验操作：Experimental operation:
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征,实验中候选化合物配成澄清溶液,给予小鼠单次静脉注射及口服给药。静注及口服溶媒为10％二甲基亚砜与90％的10％的羟丙基β环糊精配成的混合溶媒。该项目使用四只雄性CD-1小鼠,两只小鼠进行静脉注射给药,给药剂量为1mg/kg,收集0h(给药前)和给药后0.0833,0.25,0.5,1,2,4,8,24h的血浆样品,另外两只小鼠口服灌胃给药,给药剂量为2mg/kg,收集0h(给药前)和给药后0.25、0.5,1,2,4,8,24h的血浆样品,收集24小时内的全血样品,3000g离心15分钟,分离上清得血浆样品,加入4倍体积含内标的乙腈溶液沉淀蛋白,离心取上清液加入等倍体积的水再离心取上清进样,以LC-MS/MS分析方法定量分析血药浓度,并计算药代参 数,如达峰浓度(C max),清除率(CL),半衰期(T 1/2),组织分布(Vdss),药时曲线下面积(AUC 0-last),生物利用度(F)等。 The rodent pharmacokinetic characteristics of the compound after intravenous injection and oral administration were tested by standard protocols. In the experiment, the candidate compound was prepared into a clear solution and given to mice by a single intravenous injection and oral administration. The solvent for intravenous injection and oral administration is a mixed solvent of 10% dimethyl sulfoxide and 90% 10% hydroxypropyl β cyclodextrin. This project uses four male CD-1 mice, two mice are administered intravenously, the dosage is 1mg/kg, and the collection is 0h (before administration) and 0.0833, 0.25, 0.5, 1, 2 after administration. ,4,8,24h plasma samples, the other two mice were orally administered by gavage at a dose of 2mg/kg, collected 0h (before administration) and after administration 0.25, 0.5, 1, 2, 4, 8,24h plasma samples, collect whole blood samples within 24 hours, centrifuge at 3000g for 15 minutes, separate the supernatant to obtain the plasma sample, add 4 times the volume of the acetonitrile solution containing the internal standard to precipitate the protein, centrifuge to take the supernatant and add the same volume The water was centrifuged to take the supernatant and sample, and the blood drug concentration was quantitatively analyzed by LC-MS/MS analysis method, and the pharmacokinetic parameters were calculated, such as peak concentration (C max ), clearance rate (CL), half-life (T 1/2 ), tissue distribution (Vdss), area under the drug-time curve (AUC 0-last ), bioavailability (F), etc.
实验结果如表5所示：The experimental results are shown in Table 5:
表5本发明化合物药代动力学测试结果Table 5 Pharmacokinetic test results of the compounds of the present invention
Figure PCTCN2020118824-appb-000089
Figure PCTCN2020118824-appb-000089
结论：本发明化合物具有良好的药代动力学性质,包括良好的口服生物利用度,口服暴露量,半衰期和清除率等。Conclusion: The compound of the present invention has good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.

Claims (17)

  1. 式(Ⅰ)化合物、其异构体或其药学上可接受的盐，The compound of formula (I), its isomers or pharmaceutically acceptable salts thereof,
    Figure PCTCN2020118824-appb-100001
    Figure PCTCN2020118824-appb-100001
    其中，among them,
    R 1为C 1-3烷基、C 3-7环烷基、4-7元杂环烷基、苯基、-C 1-3烷基-C 3-7环烷基、-C 1-3烷基-4-7元杂环烷基、-C 1-3烷基-苯基或-C 1-3烷基-5-6元杂芳基，其中所述C 1-3烷基、C 3-7环烷基、4-7元杂环烷基、苯基、-C 1-3烷基-C 3-7环烷基、-C 1-3烷基-苯基或-C 1-3烷基-5-6元杂芳基任选被1、2或3个R a取代； R 1 is C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1- 3- alkyl-4-7 membered heterocycloalkyl, -C 1-3 alkyl-phenyl or -C 1-3 alkyl-5-6 membered heteroaryl, wherein the C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1-3 alkyl-phenyl or -C 1 -3 -5-6 membered heteroaryl group optionally substituted with 1, 2 or 3 R a;
    R 2为H或C 1-3烷基； R 2 is H or C 1-3 alkyl;
    或者，R 1和R 2与其所连接的N原子连接一起形成结构单元
    Figure PCTCN2020118824-appb-100002
    Alternatively, R 1 and R 2 are connected with the N atom to which they are connected to form a structural unit
    Figure PCTCN2020118824-appb-100002
    D 1为单键、O、N(R d11)或C(R d12) 2； D 1 is a single bond, O, N(R d11 ) or C(R d12 ) 2 ;
    D 2为O、N(R d21)或C(R d22) 2； D 2 is O, N(R d21 ) or C(R d22 ) 2 ;
    D 3为O、S(＝O) 2、N(R d31)或C(R d32) 2； D 3 is O, S(=O) 2 , N(R d31 ) or C(R d32 ) 2 ;
    D 4为O、N(R d41)或C(R d42) 2； D 4 is O, N(R d41 ) or C(R d42 ) 2 ;
    D 5为单键、O、N(R d51)或C(R d52) 2； D 5 is a single bond, O, N (R d51 ) or C (R d52 ) 2 ;
    R d11、R d21、R d31、R d41和R d51分别独立地为H或C 1-3烷基； R d11 , R d21 , R d31 , R d41 and R d51 are each independently H or C 1-3 alkyl;
    R d12、R d22、R d32、R d42和R d52分别独立地为H、F、Cl、Br、I、OH、NH 2、CN、COOH或C 1-3烷基；R a为F、Cl、Br、I、OH、NH 2、CN、COOH、
    Figure PCTCN2020118824-appb-100003
    或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R取代；     R d12 , R d22 , R d32 , R d42 and Rd52 are each independently H, F, Cl, Br, I, OH, NH 2 , CN, COOH or C 1-3 alkyl; R a is F, Cl , Br, I, OH, NH 2 , CN, COOH,
    Figure PCTCN2020118824-appb-100003
    Or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R;
    R选自F、Cl、Br、I、OH和NH 2； R is selected from F, Cl, Br, I, OH and NH 2 ;
    m为0、1或2；m is 0, 1 or 2;
    n为0、1或2，且m和n不能同时为0；n is 0, 1, or 2, and m and n cannot be 0 at the same time;
    r为0或1；r is 0 or 1;
    q为0或1；q is 0 or 1;
    g为1、2或3；g is 1, 2 or 3;
    所述5-6元杂芳基和4-7元杂环烷基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团；The 5-6 membered heteroaryl group and the 4-7 membered heterocycloalkyl group respectively contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N ；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；The carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
    带“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atom with "#" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  2. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R a为F、Cl、Br、I、OH、NH 2、CN、COOH、
    Figure PCTCN2020118824-appb-100004
    CH 3或CF 3。     The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 1, wherein Ra is F, Cl, Br, I, OH, NH 2 , CN, COOH,
    Figure PCTCN2020118824-appb-100004
    CH 3 or CF 3 .
  3. 根据权利要求1或2所述的化合物、其异构体或其药学上可接受的盐，其中，R 1为CH 3、-CH 2-CH 3、
    Figure PCTCN2020118824-appb-100005
    其中所述CH 3、-CH 2-CH 3、
    Figure PCTCN2020118824-appb-100006
    任选被1、2或3个R a取代。     The compound, its isomer, or a pharmaceutically acceptable salt according to claim 1 or 2, wherein R 1 is CH 3 , -CH 2 -CH 3 ,
    Figure PCTCN2020118824-appb-100005
    Wherein said CH 3 , -CH 2 -CH 3 ,
    Figure PCTCN2020118824-appb-100006
    Optionally substituted with 1,2 or 3 substituents R a.
  4. 根据权利要求3所述的化合物、其异构体或其药学上可接受的盐，其中，R 1为CH 3、-CH 2-COOH、
    Figure PCTCN2020118824-appb-100007
    The compound according to claim 3, its isomer or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 , -CH 2 -COOH,
    Figure PCTCN2020118824-appb-100007
  5. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R 2为H或CH 3。 The compound, its isomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is H or CH 3 .
  6. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R d11、R d21、R d31、R d41和R d51分别独立地为H或CH 3。 The compound according to claim 1, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein, R d11, R d21, R d31, R d41 and R d51 are each independently H or CH 3.
  7. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R d12、R d22、R d32、R d42和R d52分别独立地为H、F、Cl、Br、I、OH、NH 2、CN、COOH或CH 3。 The compound according to claim 1, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein, R d12, R d22, R d32, R d42 and R d52 are each independently H, F, Cl, Br, I, OH, NH 2 , CN, COOH or CH 3 .
  8. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2020118824-appb-100008
    为
    Figure PCTCN2020118824-appb-100009
    The compound, its isomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit
    Figure PCTCN2020118824-appb-100008
    for
    Figure PCTCN2020118824-appb-100009
  9. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2020118824-appb-100010
    为
    Figure PCTCN2020118824-appb-100011
    The compound, its isomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit
    Figure PCTCN2020118824-appb-100010
    for
    Figure PCTCN2020118824-appb-100011
  10. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其选自The compound according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, which is selected from
    Figure PCTCN2020118824-appb-100012
    Figure PCTCN2020118824-appb-100012
    其中，R 1和R 2如权利要求1所定义， Wherein, R 1 and R 2 are as defined in claim 1,
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；The carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
    带“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atom with "#" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  11. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其选自The compound according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, which is selected from
    Figure PCTCN2020118824-appb-100013
    Figure PCTCN2020118824-appb-100013
    其中，R 1和R 2如权利要求1所定义。 Wherein, R 1 and R 2 are as defined in claim 1.
  12. 根据权利要求11所述的化合物、其异构体或其药学上可接受的盐，其选自The compound according to claim 11, its isomer or a pharmaceutically acceptable salt thereof, which is selected from
    Figure PCTCN2020118824-appb-100014
    Figure PCTCN2020118824-appb-100014
    其中，R 1和R 2如权利要求11所定义。 Wherein, R 1 and R 2 are as defined in claim 11.
  13. 下式化合物、其异构体或其药学上可接受的盐，The compound of the following formula, its isomer or its pharmaceutically acceptable salt,
    Figure PCTCN2020118824-appb-100015
    Figure PCTCN2020118824-appb-100015
    Figure PCTCN2020118824-appb-100016
    Figure PCTCN2020118824-appb-100016
  14. 根据权利要求13所述的化合物、其异构体或其药学上可接受的盐，其选自The compound according to claim 13, its isomer or a pharmaceutically acceptable salt thereof, which is selected from
    Figure PCTCN2020118824-appb-100017
    Figure PCTCN2020118824-appb-100017
  15. 根据权利要求14所述的化合物、其异构体或其药学上可接受的盐，其选自The compound according to claim 14, its isomer or a pharmaceutically acceptable salt thereof, which is selected from
    Figure PCTCN2020118824-appb-100018
    Figure PCTCN2020118824-appb-100018
  16. 根据权利要求1-15任意一项所述的化合物、其异构体或其药学上可接受的盐，其中所述药学上可接受的盐为盐酸盐。The compound, its isomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-15, wherein the pharmaceutically acceptable salt is hydrochloride.
  17. 根据权利要求1-16任意一项所述的化合物、其异构体或其药学上可接受的盐在制备治疗LSD1相关病症的药物上的应用。The use of the compound, its isomer or its pharmaceutically acceptable salt according to any one of claims 1-16 in the preparation of a medicament for the treatment of LSD1 related disorders.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022214303A1 (en) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors for treating myeloid cancers
WO2023217758A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors
WO2023217784A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating nf1-mutant tumors using lsd1 inhibitors

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103857393A (en) * 2011-03-25 2014-06-11 葛兰素史密斯克莱知识产权（第2号）有限公司 Cyclopropylamines as LSD1 inhibitors
CN104203914A (en) * 2011-10-20 2014-12-10 奥瑞泽恩基因组学股份有限公司 (hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
WO2015123408A1 (en) * 2014-02-13 2015-08-20 Incyte Corporation Cyclopropylamines as lsd1 inhibitors
CN109153636A (en) * 2016-05-09 2019-01-04 朱比连特比利斯有限公司 Cyclopropyl-amide compound as dual LSD1/HDAC inhibitor
WO2019025588A1 (en) * 2017-08-03 2019-02-07 Oryzon Genomics, S.A. Methods of treating behavior alterations
US20190211014A1 (en) * 2014-02-13 2019-07-11 Incyte Corporation Cyclopropylamines as lsd1 inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110248926B (en) * 2017-01-24 2022-12-06 石药集团中奇制药技术（石家庄）有限公司 LSD1 inhibitor and preparation method and application thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103857393A (en) * 2011-03-25 2014-06-11 葛兰素史密斯克莱知识产权（第2号）有限公司 Cyclopropylamines as LSD1 inhibitors
CN104203914A (en) * 2011-10-20 2014-12-10 奥瑞泽恩基因组学股份有限公司 (hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
WO2015123408A1 (en) * 2014-02-13 2015-08-20 Incyte Corporation Cyclopropylamines as lsd1 inhibitors
US20190211014A1 (en) * 2014-02-13 2019-07-11 Incyte Corporation Cyclopropylamines as lsd1 inhibitors
CN109153636A (en) * 2016-05-09 2019-01-04 朱比连特比利斯有限公司 Cyclopropyl-amide compound as dual LSD1/HDAC inhibitor
WO2019025588A1 (en) * 2017-08-03 2019-02-07 Oryzon Genomics, S.A. Methods of treating behavior alterations

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022214303A1 (en) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors for treating myeloid cancers
WO2023217758A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors
WO2023217784A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating nf1-mutant tumors using lsd1 inhibitors

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