WO2020052647A1 - Composé spiro-hétérocyclique agissant en tant qu'inhibiteur de lsd1 et son utilisation - Google Patents

Composé spiro-hétérocyclique agissant en tant qu'inhibiteur de lsd1 et son utilisation Download PDF

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WO2020052647A1
WO2020052647A1 PCT/CN2019/105680 CN2019105680W WO2020052647A1 WO 2020052647 A1 WO2020052647 A1 WO 2020052647A1 CN 2019105680 W CN2019105680 W CN 2019105680W WO 2020052647 A1 WO2020052647 A1 WO 2020052647A1
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compound
mmol
hydrochloride
reaction solution
alkyl
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PCT/CN2019/105680
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Chinese (zh)
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吴凌云
汪秋燕
黎健
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 CN201980058619.9A priority Critical patent/CN112672994B/zh
Publication of WO2020052647A1 publication Critical patent/WO2020052647A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/35—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing only non-condensed rings
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom

Definitions

  • the present invention relates to a class of heterospirocyclic compounds that are lysine-specific demethylase 1 (LSD1) inhibitors, and their use in the preparation of a medicament for treating diseases associated with LSD1. Specifically, it relates to a compound represented by formula (I), an isomer thereof, and a pharmaceutically acceptable salt thereof.
  • LSD1 lysine-specific demethylase 1
  • LSD1 Lysine specific demethylase1
  • KDM1A is the first reported histone lysine demethylase, which regulates the methylation of histone lysine Status, extensive participation in transcriptional regulation, affecting many physiological processes such as cell proliferation and differentiation, and pluripotency of embryonic stem cells.
  • the LSD1 structure includes three main parts: the N-terminal SWIRM domain, the C-terminal aminooxidase domain (AOL), and the central Tower domain. [Ruchi Anand, Ronen Marmorstein, Journal of Biological Chemistry, 2007, 35425–35429].
  • the C-terminal amino oxidase domain includes two active pockets, one is a site for FAD binding, and the other is a site for recognition and binding to substrates [Pete Stavropoulos, Günter Blobel, André Hoelz, Nature Structral & Molecular Biology , 2006, 626-632].
  • the function of the SWIRM domain has not been clearly defined. It does not directly participate in the binding of FAD or substrates, but 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 the conformation. effect. [Yong Chen, Yuting Yang, Feng Wang Wang et al., Biochemistry, 2006, 13956–13961].
  • the Tower domain is the binding domain of LSD1 to other protein factors.
  • LSD1 combines with different protein factors and acts on different substrates, thus playing different roles in regulating histones and gene expression.
  • the combination of LSD1 and CoREST will preferentially act on histone H3K4. By demethylation, the related histone markers will be removed and gene transcription will be inhibited.
  • LSD1 After binding to androgen receptor protein, recombinant LSD1 will preferentially act In H3K9, androgen receptor-related gene transcription is activated by demethylation [Ruchi Anand, Ronen Marmorstein, Journal of Biological Chemistry, 2007, 35425–35429; Eric Metzger, Melanie Wissmann, Na Yin 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 Zhao, Jinlian Ma, Zhiru Wang, Medical Research Reviews, 2015, 1032–1071].
  • LSD1 is a FAD-dependent amino oxidase, in which proton transfer is considered to be its most probable oxidation mechanism [Zheng Y C, Yu B, Chen Z S, et al. Epigenomics, 2016, 8, 651-666.].
  • the N-CH 3 bond of the substrate is converted into an imine bond through proton transfer.
  • This imine ion intermediate undergoes a hydrolysis reaction to generate demethylated amines on one side and formaldehyde on the other.
  • 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 (LSCs). LSD1 is highly expressed in a variety of solid tumors such as lung cancer, breast cancer, prostate cancer, liver cancer and pancreatic cancer, which is closely related to the poor prognosis of the tumor. 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), an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • 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 0, 1, 2, 3, or 4;
  • R is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl
  • the 4-7 membered heterocycloalkyl group comprises 1, 2, 3 or 4 heteroatoms or heteroatoms independently selected from -NH-, -O-, -S- and N;
  • the carbon atoms with "*" are chiral carbon atoms and exist in the form of (R) or (S) single enantiomer or are rich in one enantiomer;
  • Carbon atoms with "#” are chiral carbon atoms and exist in the form of a single enantiomer (R) or (S) or are rich in one enantiomer.
  • the R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CH 3 and -CH 2 CH 3 , and other variables are as defined in the present invention.
  • the R a is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, COOH, Which said It is optionally substituted by 1, 2 or 3 R, other variables are as defined in the present invention.
  • the R a is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, COOH, Other variables are as defined in the present invention.
  • R 1 is selected from the group consisting of NH 2 , CN, COOH, -CH 3 , -CH 2 -CH 3 , Other variables are as defined in the present invention.
  • the present invention provides a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • 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 0, 1, 2, 3, or 4;
  • R a is selected from F, Cl, Br, I, OH, NH 2 , CN, COOH, and C 1-3 alkylamino, wherein the C 1-3 alkylamino is optionally substituted with 1, 2 or 3 R;
  • R is selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • the carbon atoms with "*" are chiral carbon atoms and exist in the form of (R) or (S) single enantiomer or are rich in one enantiomer;
  • Carbon atoms with "#” are chiral carbon atoms and exist in the form of a single enantiomer (R) or (S) or are rich in one enantiomer.
  • Other variables are as defined in the present invention.
  • the R a is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, COOH, and Which said It is optionally substituted by 1, 2 or 3 R, other variables are as defined in the present invention.
  • the R a is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, COOH, and Other variables are as defined in the present invention.
  • R 1 is selected from the group consisting of NH 2 , CN, COOH, CH 3 , Other variables are as defined in the present invention.
  • the present invention provides a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • 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 0, 1, 2, 3, or 4;
  • R a is selected from F, Cl, Br, I, OH, NH 2 , CN, and OOH, wherein the phenyl group is optionally substituted with 1, 2 or 3 R;
  • R is selected from F, Cl, Br, I, OH and NH 2 ;
  • the carbon atoms with "*" are chiral carbon atoms and exist in the form of (R) or (S) single enantiomer or are rich in one enantiomer;
  • Carbon atoms with "#” are chiral carbon atoms and exist in the form of a single enantiomer (R) or (S) or are rich in one enantiomer.
  • R a is selected from F, Cl, Br, I, OH, NH 2, CN and COOH, other variables are as defined in the present invention.
  • R 1 is selected from the group consisting of NH 2 , CN, COOH, CH 3 , Other variables are as defined in the present invention.
  • the aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • g and R 1 are as defined in the present invention.
  • the invention also provides a compound of the formula, an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • the aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • the present invention also provides the aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the hydrochloride salt.
  • the invention also provides the use of the above-mentioned compound, its isomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with LSD1.
  • the compounds of the present invention have significant inhibitory activity on LSD1 and obvious inhibitory activity on NCI-H1417, HL60 and MV-4-11 cell proliferation; meanwhile, they have good pharmacokinetic properties; and CT-26 mouse colon cancer xenograft model combined with PD-L1 monoclonal antibody and MC38 mouse colon cancer xenograft model combined with PD-1 monoclonal antibody have excellent tumor suppressive effect.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of sound 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 a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention.
  • base addition salts can be obtained by contacting a sufficient amount of a base with a neutral form of such compounds in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds 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, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc .; and organic acid salts, such as 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; salts of amino acids such as arginine , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by a conventional chemical method. Generally, such salts are prepared by reacting these compounds in the form of a free acid or base with a stoichiometric appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • This invention contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers Isomers, (D) -isomers, (L) -isomers, and racemic and other mixtures thereof, such as enantiomeric or diastereomeric enriched mixtures, all of which belong to the present invention Within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers in mirror image relationship to each other.
  • cis-trans isomer or “geometric isomer” are caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.
  • diastereomer refers to a stereoisomer in which a molecule has two or more centers of chirality and is in a non-mirror relationship between molecules.
  • wedge solid line key And wedge dashed keys Represents the absolute configuration of a solid center, using straight solid line keys And straight dashed keys Represents the relative configuration of the solid center, with wavy lines Represents a wedge solid line key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid line key And straight dashed keys
  • the following formula (A) indicates 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) Exists in the form of a mixture;
  • the following formula (B) represents that the compound exists as a single isomer of the formula (B-1) or (B-2) or in the form of both (B-1) and (B-2) The isomers exist as a mixture.
  • the following formula (C) represents that the compound exists as a single isomer of the formula (C-1) or (C-2) or in the form of the two isomers of the formula (C-1) and the formula (C-2) It exists as a mixture.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be quickly converted to each other. If tautomers are possible (eg in solution), the chemical equilibrium of the tautomers can be reached.
  • proton tautomers also known as prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include recombination of some bonding electrons for mutual conversion.
  • a specific example of the keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “rich in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enantiomerically enriched” refer to one of the isomers or the The enantiomeric content is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or more 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is 90% and the other isomer or enantiomer is 10%, the isomer or enantiomeric 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 an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then a conventional method known in the art Diastereomeric resolution is performed and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereoisomers is usually accomplished by using chromatography that employs a chiral stationary phase and optionally is combined with chemical derivatization (such as the generation of amino groups from amines) Formate).
  • the compounds of the invention may contain atomic isotopes in unnatural proportions on one or more of the atoms constituting the compound.
  • compounds such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C) can be labeled with radioisotopes.
  • deuterated drugs can be replaced by heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have lower toxicity and increased drug stability , Enhance efficacy, extend the biological half-life of drugs and other advantages. Transformations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • “Optional” or “optionally” refers to events or conditions described later that may, but need not, occur, and that the description includes situations in which the events or conditions occur and situations in which the events or conditions do not occur.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specific atom with a substituent, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • O oxygen
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable such as R
  • its definition in each case is independent.
  • the group may be optionally substituted with at most two R, and R in each case has independent options.
  • combinations of substituents and / or variants 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- , the linking group is a single bond.
  • substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X is vacant in AX, it means that the structure is actually A.
  • a substituent's bond can be cross-linked to two or more 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 may be substituted at any position on the cyclohexyl or cyclohexadiene. .
  • substituents do not indicate which atom is connected to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be passed through any The carbon atom is attached to a substituted group.
  • the intermediate linking group L is -MW-.
  • -MW- can be connected to ring A and ring B in the same direction as the reading order from left to right. You can also connect ring A and ring B in the opposite direction from the reading order from left to right.
  • the number of atoms on a ring is generally defined as the number of rings, for example, a "5-7 member ring” refers to a “ring” arranged around 5-7 atoms.
  • 3-12 membered ring means a cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl group consisting of 3 to 12 ring atoms.
  • the ring includes a single ring, and also includes a double ring or a multi-ring system such as a spiro ring, a parallel ring and a bridge ring.
  • the ring optionally contains 1, 2, or 3 heteroatoms independently selected from O, S, and N.
  • the 3-12 member 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 yuan, 4-7 yuan, 4-6 yuan, 4-5 yuan, 5-10 yuan, 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6- 9 yuan, 6-8 yuan and 6-7 yuan ring, etc.
  • the term "5- to 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 "ring” independently meets the above definition.
  • 5- to 6-membered ring means a cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aromatic group consisting of 5 to 6 ring atoms. Or heteroaryl.
  • the ring includes a single ring, and also includes a double ring system such as a spiro ring, a parallel ring and a bridge ring. Unless otherwise specified, the ring optionally contains 1, 2, or 3 heteroatoms independently selected from O, S, and N.
  • the 5-6 membered ring includes a 5-membered, 6-membered ring, and the like.
  • 5-6 membered ring includes, for example, phenyl, pyridyl, piperidinyl, and the like; on the other hand, the term “5-6 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 "ring” independently meets the above definition.
  • C 1-6 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl 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, etc .; it may Is monovalent (such as methyl), divalent (such as methylene) or polyvalent (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 and the like.
  • C 1-4 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 and C 2-3 alkyl, etc .; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as (Such as methine).
  • Examples of C 1-4 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) and the like.
  • C 1-3 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, and the like; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (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 one 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, isobutyl (Oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), 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 one oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy, 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.
  • C1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino, and the like.
  • Examples of C 1-3 alkylamino include, but are not limited to, -NHCH 3 , -N (CH 3 ) 2 , -NHCH 2 CH 3 , -N (CH 3 ) CH 2 CH 3 , -NHCH 2 CH 2 CH 3 ,- NHCH 2 (CH 3 ) 2 and the like.
  • C 6-10 aromatic ring and “C 6-10 aryl” in the present invention are used interchangeably, and the terms “C 6-10 aromatic ring” or “C 6-10 aryl” mean A cyclic hydrocarbon group with a conjugated ⁇ -electron system consisting of 6 to 10 carbon atoms, which can be a monocyclic, fused bicyclic or fused tricyclic system, where each ring is aromatic. It may be monovalent, divalent, or polyvalent, and C 6-10 aryl includes C 6-9 , C 9 , C 10, and C 6 aryl, and the like. Examples of C 6-10 aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).
  • the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the rest of the molecule.
  • the 4-7 membered heterocycloalkyl includes 5-6 members, 4 members, 5 members, 6 members, 7 members, and the like.
  • 4- to 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.), tetrahydrofuryl (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, dithiazyl, isoxazolidinyl, isothiazolyl
  • a heteroatom may occupy a connection position between the heterocycloalkyl group and the rest of the molecule.
  • the 5- to 6-membered heterocycloalkyl includes 5- and 6-membered heterocycloalkyl.
  • Examples of 5- to 6-membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-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, dithiaalkyl, isoxazolidinyl, isothiazolyl Alkyl, 1,2-oxazinyl, 1,2-thiazinyl
  • 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 , and also include 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.
  • n yuan to n + m means that the number of atoms on the ring is n to n + m.
  • 3-12-membered rings include 3-, 4-, 5-, 6-, 7-, 8-, and 9-membered rings.
  • 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 member ring, 6-7 member ring, 6-8 member ring, and 6-10 member ring, etc.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonic acid. Esters, etc .; acyloxy, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes but is not limited to "amino protecting group", “hydroxy protecting group” or “mercapto 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) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyld
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of a 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 (such as acetyl); aryl methyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and more.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl (such as acetyl)
  • aryl methyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl
  • 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 familiar to those skilled in the art. Equivalent alternatives, preferred embodiments 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, equivalent; CDI stands for Carbonyl diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N, N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate EtOH for ethanol; MeOH for methanol; CBz for benzy
  • the reaction solution was diluted with dichloromethane (80 mL), and then washed with a saturated aqueous sodium hydrogen carbonate solution (100 mL x 3), water (100 mL x 2), and saturated brine (100 mL x 1), and then dried over anhydrous sodium sulfate and filtered.
  • the obtained mother liquor was concentrated to obtain compound 1-4.
  • reaction solution was stirred at 25 ° C for 11.5 hours.
  • the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with ethyl acetate (20 mL ⁇ 3).
  • MS-ESI calculated [M + H] + 568, found 568.
  • the purpose of this test is to detect the inhibitory activity of the compound on LSD1 in vitro.
  • the enzyme used in this test is human-derived LSD1, and the standard substrate is the histone H3K4me peptide (20 ⁇ M).
  • the enzyme-fluorescence coupling method was used to detect the H produced by the reaction of LSD1 by horseradish peroxidase (HPR) and the fluorescent reagent Amplex Red The method of 2 O 2 determines the activity of the compound. 3 fold dilution beginning from 10 ⁇ M, the IC 50 value of 10 concentrations of the test compound.
  • test compounds have LSD1 inhibitory activity, and the results are shown in Table 1.
  • test compounds have inhibitory activity on NCI-H1417 cell proliferation, 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.
  • RPMI-1640 medium, fetal bovine serum, penicillin / streptomycin antibiotics were 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).
  • HL60 cells were seeded in white 384-well plates, each well containing 40 ⁇ L of cell suspension, which contained 600 HL60 cells.
  • Cell plates were cultured overnight in a carbon dioxide incubator. Dilute the test compound 5 times with a row gun to the 10th concentration, that is, dilute from 2mM to 1.024nM, and set up a double well experiment.
  • the cell plate was cultured in a carbon dioxide incubator for 6 days.
  • test compound has HL60 cell proliferation inhibitory activity, and the results are shown in Table 3.
  • Table 3 Test results of HL60 cell proliferation inhibition compounds of the present invention
  • the compound of the present invention has obvious inhibitory activity on HL60 cell proliferation.
  • IMDM medium fetal calf serum, penicillin / streptomycin antibiotics were 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).
  • MV-4-11 cells were seeded in a white 96-well plate, 80 ⁇ L of cell suspension per well, which contained 6000 MV-4-11 cells. Cell plates were cultured overnight in a carbon dioxide incubator.
  • test compound has inhibitory activity on MV-4-11 cell proliferation, 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 Slark
  • Intravenous and oral vehicles are a mixed vehicle of 10% dimethyl sulfoxide and 90% 10% hydroxypropyl ⁇ -cyclodextrin.
  • This project uses four male CD-1 mice and two mice for intravenous administration at a dose of 1 mg / kg, collected for 0 h (before administration) and 0.0833, 0.25, 0.5, 1, 2 after administration , 4,8,24h plasma samples, and two other mice were administered by oral gavage at a dose of 2mg / kg, collected 0h (before administration) and 0.25, 0.5, 1, 2, 4 after administration,
  • the supernatant was sampled by centrifugation with water, and the plasma drug concentration was quantitatively analyzed by LC-MS / MS analysis method, and the pharmacokinetic parameters were calculated, such as peak concentration (C max ), clearance (CL), and half-life (T 1/2 ), Tissue distribution (Vdss), area under the curve (AUC 0-last ), bioavailability (F), etc.
  • the compounds of the present invention have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life, and clearance rate.
  • Age and weight 7 weeks of age, weight 18-23 grams
  • CT-26 mouse colon cancer cell
  • the culture medium was 1640 medium containing 10% fetal bovine serum, and the culture conditions were 37 ° C and 5% carbon dioxide.
  • the passage ratio is 1: 2 to 1: 3, and the passage is performed 2 to 3 times a week.
  • 0.1 mL (3 ⁇ 10 5 ) cells were inoculated subcutaneously on the right back of each mouse. Animals were randomly divided into groups based on body weight on the same day.
  • the solvent used in the experiment was a 0.5% methylcellulose solution.
  • the preparation method was to weigh 5g of methylcellulose, dissolve it in 800mL of ultrapure water, and stir to volume to 1000mL with ultrapure water.
  • the test substance was dissolved in a solvent to prepare a uniform solution with a certain concentration and stored at 4 ° C.
  • the experimental index is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameter was measured twice a week with vernier calipers.
  • T / C% T RTV / C RTV ⁇ 100% (T RTV : RTV in the treatment group; C RTV : RTV in the negative control group).
  • PD-L1 monoclonal antibody source BioXcell.
  • MC38 mouse colon cancer cell
  • the culture medium was 1640 medium containing 10% fetal bovine serum, and the culture conditions were 37 ° C and 5% carbon dioxide.
  • the passage ratio is 1: 2 to 1: 3, and the passage is performed 2 to 3 times a week.
  • 0.1 mL (2 ⁇ 10 5 ) cells were subcutaneously inoculated on the right back of each mouse. Animals were randomly divided into groups based on body weight on the same day.
  • the solvent used in the experiment was a 0.5% methylcellulose solution.
  • the preparation method was to weigh 5g of methylcellulose, dissolve it in 800mL of ultrapure water, and stir to volume to 1000mL with ultrapure water.
  • the test substance was dissolved in a solvent to prepare a uniform solution with a certain concentration and stored at 4 ° C.
  • the experimental index is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameter was measured twice a week with vernier calipers.
  • T / C% T RTV / C RTV ⁇ 100% (T RTV : RTV in the treatment group; C RTV : RTV in the negative control group).
  • PD-1 monoclonal antibody source BioXcell.
  • CONCLUSION The combination of the compound of the present invention and PD-1 monoclonal antibody has excellent antitumor effect on MC38 mouse colon cancer xenograft model.

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Abstract

L'invention concerne une classe de composés spiro-hétérocycliques qui peuvent agir en tant qu'inhibiteurs de la déméthylase 1 spécifique de la lysine (LSD1), et leur utilisation dans la préparation de médicaments pour le traitement de maladies associées à LSD1. L'invention concerne en particulier un composé tel que représenté par la formule (I), et un isomère et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2019/105680 2018-09-13 2019-09-12 Composé spiro-hétérocyclique agissant en tant qu'inhibiteur de lsd1 et son utilisation WO2020052647A1 (fr)

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Cited By (5)

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WO2022214303A1 (fr) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 pour le traitement de cancers myéloïdes
WO2022267495A1 (fr) * 2021-06-22 2022-12-29 南昌弘益药业有限公司 Composé oxa-spirocyclique contenant de l'azote et son utilisation
WO2023217784A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement de tumeurs mutantes nf1 à l'aide d'inhibiteurs de lsd1
WO2023217758A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement d'une tumeur maligne des gaines des nerfs périphériques (tmgnp) à l'aide d'inhibiteurs de lsd1
WO2024110649A1 (fr) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 et d'inhibiteurs de ménine pour le traitement du cancer

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CN104203914A (zh) * 2011-10-20 2014-12-10 奥瑞泽恩基因组学股份有限公司 作为lsd1抑制剂的(杂)芳基环丙胺化合物
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CN102985402A (zh) * 2010-04-20 2013-03-20 罗马大学 反苯环丙胺衍生物作为组蛋白去甲基酶lsd1和/或lsd2的抑制剂
CN103124724A (zh) * 2010-07-29 2013-05-29 奥瑞泽恩基因组学股份有限公司 Lsd1的基于芳基环丙胺的脱甲基酶抑制剂及其医疗用途
CN103857393A (zh) * 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 环丙基胺作为lsd1抑制剂
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022214303A1 (fr) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 pour le traitement de cancers myéloïdes
WO2022267495A1 (fr) * 2021-06-22 2022-12-29 南昌弘益药业有限公司 Composé oxa-spirocyclique contenant de l'azote et son utilisation
WO2023217784A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement de tumeurs mutantes nf1 à l'aide d'inhibiteurs de lsd1
WO2023217758A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement d'une tumeur maligne des gaines des nerfs périphériques (tmgnp) à l'aide d'inhibiteurs de lsd1
WO2024110649A1 (fr) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 et d'inhibiteurs de ménine pour le traitement du cancer

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