WO2017215464A1 - 反吲哚啉环丙胺类化合物及其制备方法、药物组合物和用途 - Google Patents

反吲哚啉环丙胺类化合物及其制备方法、药物组合物和用途 Download PDF

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WO2017215464A1
WO2017215464A1 PCT/CN2017/087081 CN2017087081W WO2017215464A1 WO 2017215464 A1 WO2017215464 A1 WO 2017215464A1 CN 2017087081 W CN2017087081 W CN 2017087081W WO 2017215464 A1 WO2017215464 A1 WO 2017215464A1
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group
substituted
unsubstituted
alkyl
compound
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French (fr)
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柳红
李佳
朱未
周宇波
王江
苏明波
王姝妮
徐威
李淳朴
阚伟娟
蒋华良
陈凯先
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中国科学院上海药物研究所
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Priority to US16/306,751 priority Critical patent/US11873292B2/en
Publication of WO2017215464A1 publication Critical patent/WO2017215464A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to a class of fluorine-substituted cyclopropylamine compounds, a process for the preparation thereof, a pharmaceutical composition containing the same, and as a lysine-specific demethylase 1 (LSD1) Inhibitors, in particular for the preparation of a medicament for the treatment of diseases such as cancer, leukemia and the like.
  • LSD1 lysine-specific demethylase 1
  • Epigenetics is a branch of genetics that studies the heritable changes in gene expression by reversible modification of nucleotides or chromosomes without studying the changes in the DNA sequence of the gene.
  • the regulation mechanisms of epigenetics mainly include DNA methylation, histone modification, non-coding RNA action and the like.
  • epigenetic information is stored by altering the chemical modification of cytosine and histones, which alter the structure of chromatin.
  • Normal epigenetic processes play an important role in life activities such as embryonic development and cell differentiation. Studies have shown that the occurrence of many diseases is related to the abnormality of epigenetic modification.
  • epigenetics has become a research hotspot in the fields of biology and medicine. The research on epigenetics has many processes in the prevention and treatment of many human diseases. The significance of it.
  • LSD1 (also known as BHC110, p110b, and NPAO) was confirmed by Shi's group in 200411 and its structure is highly conserved from yeast to humans. In cells, the demethylation ability of LSD1 is highly specific for genes, substrates, and environments, and produces different (or even opposite) effects on gene expression at different loci. The study found that LSD1 plays an important role in promoting normal cell differentiation, but LSD1 has also been found to be inappropriately inhibited by the abnormal recruitment of downstream abnormal gene targets for leukemia-causing genes (eg, MLL-AF9). In this case, LSD1 maintains the initial damage conferring activity on leukemia stem cells (LSC), and the cellular effects downstream of LSD1 are also significantly different from normal cell states.
  • LSC leukemia stem cells
  • LSD1 can be used as a potential drug for the treatment of leukemia if it can produce controlled and reversible toxicity to normal hematopoietic cells.
  • novel small-molecule LSD1 inhibitors has important research significance for the treatment of diseases such as malignant tumors and leukemia.
  • a fluorine-substituted cyclopropylamine compound having the structure represented by the following formula I, and a racemate, an R-isomer, an S-isomer thereof, and a pharmaceutically thereof thereof Acceptable salts or mixtures thereof:
  • n 1, 2;
  • X is N- or -(CH 2 ) 1-4 , -CH(Ra)(CH 2 ) 0-3 , -C(Ra) 2 (CH 2 ) 0-3 , C3-C6 cycloalkane, carbonyl, or a carbonyl-oxy group, wherein each Ra is independently a C1-C4 alkyl group;
  • Y is a sulfonyl group, a carbonyl group or a carbonyl-oxy group
  • R 1 is selected from -H, a substituted or unsubstituted C1-C12 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3-12 membered heterocyclic group (the heterocyclic group includes Monocyclic, cyclo, spiro or bridged ring), substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heterocyclic group, wherein R1 has 0, 1, 2, or 3 a substituent selected from the group consisting of halogen, aryl, heteroaryl, C1-C6 alkyl, -SO 2 Ra, -NC(O)Ra, -CH 2 C(O)ORa, -C(O) ORa, -C(O)Ra, -C(O)NRaRb, substituted amino, amino, urea, amide, sulfonamide,
  • Each Ra is independently hydrogen, phenyl, phenylmethyl, 3,5-dimethylisoxazol-4-yl, 1,2-dimethyl-1H-imidazol-4-yl, C3-C7 ring Alkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C3 alkylamino or -NHPh;
  • Rb is hydrogen or a C1-C3 alkyl group, or when Ra and Rb are attached to the same atom,
  • Ra and Rb together form a 5- or 6-membered heterocycloalkyl ring
  • R 2 is selected from a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C6-C10 aromatic ring or a substituted or unsubstituted one or four selected from 1 to 4 a 3-12 membered aromatic heterocyclic ring of a hetero atom in oxygen, sulfur, and nitrogen;
  • the substituent is selected from the group consisting of ruthenium, osmium, halogen, unsubstituted or C1-C12 alkyl substituted by 1-3 halogens, C1 unsubstituted or substituted by 1-3 halogen or phenyl -C12 alkoxy, C2-C12 alkenyl unsubstituted or substituted by 1-3 halogens, C3-C6 cycloalkyl unsubstituted or substituted by 1-3 halogens, substituted by C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl substituted by C3-C6 cycloalkyl, hydroxy, cyano, nitro, C1-C6 straight or branched hydroxyalkyl, unsubstituted or from 1-2 a C1-C6 alkyl-substituted amino group, a carboxyl group, a fluorenyl group, or a benzy
  • any two substituents on the alkyl, substituted or unsubstituted cycloalkyl group, the substituted benzene ring or the substituted aromatic heterocyclic ring may be bonded together with its adjacent carbon or hetero atom to contain 1 to 3 From a 5-7 membered heterocyclic ring of a hetero atom in N, O and S, said 5-7 membered heterocyclic ring is optionally substituted with a substituent selected from the group consisting of hydrogen, hydrogen isotope, halogen, and tri Fluoromethyl, methoxy, unsubstituted or Alkyl substituted with 1-3 halogens, C1-C6 straight or branched chain, unsubstituted or substituted with 1-3 halo C1-C6 straight-chain or branched alkoxy, or hydroxy;
  • the halogen is F, Cl, Br or I.
  • the R 1 is selected from a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group, a substituted or unsubstituted 3-10 membered aromatic group.
  • a cyclic group (the heterocyclic group includes a monocyclic, cyclo, spiro or bridged ring), a substituted or unsubstituted C6-C10 aryl group, wherein R1 has 0, 1, 2, or 3 substituents,
  • the substituent is selected from the group consisting of halogen, aryl, heteroaryl, C1-C6 alkyl, -SO 2 Ra, -NC(O)Ra, -CH 2 C(O)ORa, -C(O)ORa, -C (O)Ra, -C(O)NRaRb, substituted amino, amino, urea, amide, sulfonamide, aralkyl and heteroarylalkyl; wherein the heterocyclic group contains 1- 3 heteroatoms: N or O.
  • the heterocyclic group contains 1 or 2 hetero atoms selected from N or O.
  • R 2 is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 3-7 membered cycloalkyl; wherein said substitution refers to One or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C1-4 alkyl, fluoro C1-4 alkyl, C1-4 alkoxy.
  • Y is a sulfonyl group or a carbonyl group.
  • the compound is a compound A1-A72 in the table.
  • a lysine-specific demethylase 1 (LSD1) inhibitor comprising the compound as described in the first aspect of the invention, enantiomerically , diastereomers, racemates and mixtures thereof, as well as pharmaceutically acceptable salts, crystalline hydrates and solvates thereof.
  • a pharmaceutical composition comprising: (A) a therapeutically effective amount of a compound according to the first aspect of the invention, enantiomers, diastereomers, external Racemates and mixtures thereof, and one or more of their pharmaceutically acceptable salts, crystalline hydrates, and solvates; and (B) a pharmaceutically acceptable carrier.
  • a compound, an enantiomer, a diastereomer, a racemate, and mixtures thereof according to the first aspect of the invention, and a pharmaceutically acceptable thereof A salt, a crystalline hydrate, and a solvate for use in the preparation of a medicament for treating or preventing a malignant tumor disease associated with lysine-specific demethylase 1 (LSD1).
  • LSD1 lysine-specific demethylase 1
  • the disease is selected from the group consisting of brain cancer (glioma), glioblastoma, leukemia, Ban-Zhou syndrome, Cowden's disease, cerebellar dysplastic ganglioneuroma , breast cancer, inflammatory breast cancer, Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, kidney cancer , ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, bone and thyroid giant cell tumor.
  • brain cancer glioma
  • glioblastoma leukemia
  • Ban-Zhou syndrome Cowden's disease
  • cerebellar dysplastic ganglioneuroma breast cancer
  • inflammatory breast cancer Wilms tumor
  • Ewing sarcoma rhabdomyosarcoma
  • the anti-porphyrin cyclopropylamine compound can be used as a potent LSD1 inhibitor, and can also be used for the preparation of a therapeutic or prophylactic lysine-specific demethylase. 1 (LSD1) related drugs for malignant tumor diseases. Based on the above findings, the inventors completed the present invention.
  • the halogen is F, Cl, Br or I.
  • C1-C12 alkyl means a straight or branched alkyl group having 1 to 12 carbon atoms, and includes, without limitation, methyl, ethyl, propyl, isopropyl, butyl.
  • Base isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • C1-C6 alkoxy means a straight or branched alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, a methoxy group, an ethoxy group, a propoxy group, Isopropoxy and butoxy groups.
  • C3-C12 cycloalkyl means a cyclic alkyl group having 3 to 12 carbon atoms in the ring, and includes, without limitation, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a ring. Hexyl, cycloheptyl, cyclooctyl and cyclodecyl.
  • C3-C8 cycloalkyl “C3-C7 cycloalkyl”
  • C3-C6 cycloalkyl and the like have similar meanings.
  • C6-C10 aryl means an aromatic ring group having 6 to 10 carbon atoms which does not contain a hetero atom in the ring, such as a phenyl group, a naphthyl group or the like.
  • C6 aryl has a similar meaning.
  • 3-12 membered heterocyclic group means a saturated or unsaturated 3-12 membered ring group having 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, for example, Dioxolyl and the like.
  • 3-7 membered heterocyclic group has a similar meaning.
  • 3-12 membered heterocyclic ring means a cyclic saturated or partially unsaturated non-aromatic group having 3-12 members, including a monocyclic ring, a fused ring, a spiro ring or a bridged ring, wherein the heterocyclic ring There are at least one ring atom selected from the group consisting of O, S and/or N.
  • 5-12 membered aromatic heterocyclic group means a cyclic aromatic group having 5 to 12 members, wherein the heterocyclic ring has at least one ring atom selected from the group consisting of O, S and/or N.
  • substituted means that one or more hydrogen atoms on a particular group are replaced by a specific substituent.
  • Particular substituents are the substituents described above in the corresponding paragraphs, or the substituents which appear in the examples.
  • a substituted group may have a substituent selected from a particular group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • a cyclic substituent, such as a heterocycloalkyl group may be attached to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, for example, two rings having a common carbon atom.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are, for example but not limited to, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic , aryl, heteroaryl, halogen, hydroxy, carboxy (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino, alkoxy and the like.
  • C1-Cn means that the group has 1-n carbon atoms.
  • C1-C12 means that the group has 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11 or 12 carbon atoms;
  • C6-C10 means that the group has 6, 7, 8, 9 or 10 carbon atoms.
  • the term "pharmaceutically acceptable” ingredient means a substance which is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reaction), that is, a reasonable benefit/risk ratio.
  • the term "effective amount" means an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect.
  • the precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount that the clinician can determine.
  • the present invention provides a compound represented by the following formula (I):
  • R 1 , R 2 , X, Y, n are each independently a group as shown in the compounds of Table 1.
  • the compounds of the formula (I) according to the invention are preferably the following specific compounds:
  • the compounds of the invention have asymmetric centers, chiral axes and chiral planes and may exist in the form of racemates, R-isomers or S-isomers. Those skilled in the art will be able to resolve the R-isomer and/or the S-isomer from the racemate by conventional techniques.
  • the invention still further provides pharmaceutically acceptable salts of the compounds of formula I, for example, a compound of formula I is reacted with an inorganic or organic acid to form a conventional pharmaceutically acceptable salt.
  • conventional pharmaceutically acceptable salts can be prepared by reacting a compound of formula I with an inorganic or organic acid, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, and the like, and Organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, and acrylic acid.
  • Acid fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzene Sulfonic acid, 2-acetoxybenzoic acid, isethionate, etc.; or a sodium, potassium, calcium, aluminum or ammonium salt of a compound of formula I with an inorganic base; or a compound of formula I and an organic base A methylamine salt, ethylamine salt or ethanolamine salt formed.
  • Another aspect of the present invention provides a process for the preparation of a compound represented by Formula I, which is carried out according to Scheme 1 below.
  • the compound of the formula (I) can be produced by the method shown in the following Scheme 1.
  • the intermediate (III) is obtained by reacting porphyrin or 1,2,3,4-tetrahydroquinoline (II) with benzenesulfonyl chloride. Subsequent to the acylation of chloropropionyl chloride to give intermediate (IV), which is then nitrated with sodium nitrite to give intermediate (V).
  • the obtained intermediate is reduced by sodium borohydride to obtain an alcohol intermediate (VI), followed by a light delay reaction in a trans molecule to obtain a trans porphyrin nitrocyclopropane intermediate (VII), which is obtained by reduction of zinc hydride powder.
  • Intermediate (VIII) is obtained by reacting porphyrin or 1,2,3,4-tetrahydroquinoline (II) with benzenesulfonyl chloride.
  • intermediate (IV) Subsequent to the acylation of chloropropionyl chloride to give intermediate (IV),
  • Intermediate (VIII) is obtained by reductive amination, coupling and condensation to give intermediate (IX), which is then protected by t-butoxycarbonyl to give intermediate (X). Removal of the benzenesulfonyl group under magnesium reduction conditions affords the intermediate (XI). Finally, it is reacted with an acid chloride and the protecting group is removed in a dioxane hydrochloride solution to obtain the salt-forming target product (I).
  • the compound of the present invention has excellent lysine-specific demethylase 1 (LSD1) inhibitory activity, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates And a pharmaceutical composition containing the compound of the present invention as a main active ingredient for treating, preventing, and alleviating lysine specificity Demethylase 1 (LSD1) activity-related diseases.
  • the compound of the present invention can be used for the prevention and treatment of drugs for metabolic diseases such as hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver deformation, atherosclerosis, obesity and the like.
  • the compounds disclosed herein are also useful for the treatment of brain cancer (glioma), glioblastoma, leukemia, Ban-Zuo syndrome, Cowden's disease, cerebellar dysplastic ganglioneuroma, breast cancer, inflammatory mammary gland Cancer, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, kidney cancer, ovarian cancer, pancreatic cancer, Prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone and thyroid, etc.
  • brain cancer glioma
  • glioblastoma leukemia
  • Ban-Zuo syndrome Cowden's disease
  • cerebellar dysplastic ganglioneuroma breast cancer
  • inflammatory mammary gland Cancer Wilms' tumor
  • Ewing's sarcoma r
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 0.05 to 200 mg of the compound/agent of the invention, more preferably from 0.1 mg to 100 mg of the compound of the invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifier such as Tween
  • a wetting agent such as sodium lauryl sulfate
  • a coloring agent such as a flavoring agent, a stabilizer, an antioxidant, a preservative
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening Agents, flavors and fragrances.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 5 to 500 mg.
  • the compounds and pharmaceutical compositions of the present invention can be administered by oral, nasal, dermal, pulmonary or gastrointestinal routes. Most preferably oral. Most preferably, the daily dose is from 0.01 to 200 mg/kg body weight, taken once, or from 0.01 to 100 mg/kg body weight in divided doses.
  • the optimal dosage for the individual should be based on the particular treatment. Usually starting with a small dose, gradually increase the dose until the most suitable dose is found. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the preparation method has the advantages of mild reaction conditions, abundant raw materials, easy operation and post-treatment, and corresponding Good selectivity and other advantages.
  • the compound has a good lysine-specific demethylase 1 (LSD1) inhibitory activity.
  • LSD1 inhibitor which exhibits excellent LSD1 inhibitory activity and tumor cell inhibitory activity in an in vitro experiment.
  • Triethylamine (163 mL, 1.17 mol) was added to a solution of porphyrin (100 g, 839.18 mmol) in dichloromethane (1 L), and then benzene succinyl chloride (128 mL, 1.01) Mol). After reacting for one hour, it was slowly returned to room temperature and stirred overnight. After the TLC reaction was completed, deionized water (200 mL) was slowly added under ice-cooling. The organic layer was washed once with deionized water (1.0 L), saturated aqueous sodium hydrogen carbonate (1.0 L) and saturated brine (1.0 L).
  • Triphenylphosphine (17.37 g, 66.23 mmol) was dissolved in 200 mL of anhydrous tetrahydrofuran under argon. Under ice-cooling, a solution of DBAD (15.25 g, 66.23 mmol) in tetrahydrofuran (100 mL) was added dropwise to the reaction mixture, and the mixture was stirred for 1 hour to precipitate a white solid. To the reaction solution, a solution of 3-nitro-1-(1-(phenylsulfonyl)indan-5-yl)propan-1-ol (16 g, 44.15 mmol) in tetrahydrofuran (100 mL) was slowly added slowly.
  • N-tert-butoxycarbonylpiperidine-4-carbaldehyde was replaced with 4-tert-butoxycarbonylpiperidineacetaldehyde, and the remaining starting materials, reagents and preparation methods were the same as those in Example 14 to obtain product A16 in a yield of 57%.
  • reaction liquid was placed under cooling at -30 ° C, sodium borohydride (18 mg, 0.45 mmol) was added portionwise, and the mixture was slowly returned to room temperature for 3 hours.
  • the reaction mixture was quenched by the dropwise addition of saturated sodium bicarbonate, and extracted three times with dichloromethane (20 mL). The combined organic layers were washed with EtOAc EtOAc EtOAc EtOAc. 50–1/20) Purified viscous liquid.
  • the obtained product was dissolved in 10 mL of methanol, and a solution of dioxane hydrochloride (5 mL) was slowly added dropwise, and the mixture was stirred overnight.
  • A25 (80 mg, 0.132 mmol) was dispersed in 1M hydrochloric acid (5 mL), and the reaction mixture was heated at 90 ° C for 2 hours. The upper clear solution was poured out while hot, 10 mL of acetonitrile was added, and concentrated under reduced pressure to give a salt product A26 (63 mg, 70%).
  • A27 (960 mg, 1.95 mmol) was dissolved in 30 mL of dichloromethane, and then Boc 2 O (61 4 mg, 2.81 mmol) and triethylamine (390 ⁇ L, 2.81 mmol) were added, and the mixture was stirred at room temperature for eight hours.
  • MATERIALS Human recombinant LSD1, the LSD1 protein fragment of fusion GST (aa158-end) was expressed and purified by E. coli expression system.
  • LSD1 activity detection kit LANCE Ultra LSD1Histone H3-Lysine 4Demethylase Assay, purchased from Perkin Elmer;
  • the H3 polypeptide substrate ARTK(me1)QTARKSTGGKAPRKQLA-GG-K(Biotin)-NH2 was synthesized by Jill Biochemical Company.
  • LSD1 specifically removes the methylation modification at the K4 lysine on the H3 polypeptide substrate, making it a substrate without methylation.
  • the method employs a histone H3 methylated polypeptide (1-24) as a substrate and introduces a biotin label in the C segment of the substrate.
  • the methylation modification on the substrate H3K4 can be removed.
  • the Eu-labeled H3K4 background antibody binds to the substrate by antigen-antibody reaction, while the streptavidin-labeled receptor is bound by the specific interaction of streptavidin and biotin. . This allows the Eu-labeled donor to interact with the streptavidin-labeled receptor.
  • the emission wavelength is 620 nm; the other part of the energy is transferred to the receptor ( On acceptor), the emission wavelength is 665 nm.
  • the 665 nm emission is only produced by the FRET caused by the donor. Therefore, when biomolecules interact, there are two excitation lights of 620 nm and 665 nm; when there is no interaction, there is only one excitation light of 620 nm.
  • the LSD1 demethylation activity can be reflected by detecting the ratio of the fluorescence signals at the two emission wavelengths of 665 nm and 620 nm.
  • a blank control was set to determine the strength of the enzyme activity.
  • the experiment used GSK-2879552 as a positive inhibitor; the structure of GSK-2879552 was as follows:
  • Sample treatment Samples were dissolved in DMSO, stored at low temperature, and the concentration of DMSO in the final system was controlled to a range that did not affect the activity of the assay.
  • the activity of the sample was tested by initial screening at a single concentration, for example 20 ⁇ M.
  • the inhibition rate %Inhibition is greater than 50
  • the active dose-dependent relationship, ie, the IC50 value is obtained by nonlinearly fitting the sample concentration by the sample activity, and the software used for the calculation is Graphpad Prism 5,
  • the model used for the fit was sigmoidal dose-response (varible slope), and for most inhibitor screening models, the bottom and top of the fitted curve were set to 0 and 100.
  • MATERIALS Human recombinant MAOA was purchased from Promega; human recombinant MAOB was purchased from Sigma;
  • the MAOA and MAOB activity assay kit MAO-Glo was purchased from Promega.
  • This method uses a specific luciferin derivative as a substrate.
  • MAOA or MAOB can catalyze the conversion of substrate to luciferin methyl ester.
  • the product luciferin methyl ester is under the action of luciferase.
  • the fluorescence can be poorly generated, so that the activity of MAOA or MAOB can be reflected by the intensity of the fluorescent signal.
  • a blank control was set to determine the strength of the enzyme activity. Tranylcypromine was used as a positive inhibitor in the experiment.
  • Sample treatment Samples were dissolved in DMSO, stored at low temperature, and the concentration of DMSO in the final system was controlled to a range that did not affect the activity of the assay.
  • the activity of the sample was tested by primary screening at a single concentration, for example 100 [mu]M.
  • the inhibition rate %Inhibition is greater than 50
  • the active dose-dependent relationship, ie, the IC 50 value is obtained by nonlinearly fitting the sample concentration by the sample activity, and the software used for calculation is Graphpad Prism 5
  • the model used for fitting is sigmoidal dose-response (varible slope), and for most inhibitor screening models, the bottom and top of the fitted curve are set to 0 and 100.
  • MTS assay detects the growth inhibition of MV (4:11) in leukemia cells by the test compound.
  • the principle is that succinate dehydrogenase in mitochondria in living cells can reduce exogenous thiazole blue to insoluble blue. Color crystalline Formazan.
  • MATERIALS Leukemia cell line MV4-11: pediatric acute lymphoid myeloid leukemia, immune double phenotype, AF4-MLL fusion t(4,11), is a cell growth inhibitory cell line of LSD1 inhibitor (Cancer cell.2012,17 ;21(4): 473-487).
  • test compound at a concentration of 10 mM and the positive compounds ORY-1001 and GSK2879552 were sequentially diluted with DMSO in a concentration gradient of 3 times, each 8 points.
  • the compounds mixed with the medium were separately added to a 96-well plate covered with cells, and three pairs of wells, 20 ⁇ L per well, were mixed.
  • the blank group was added to 200 ⁇ L of IMDM medium, and the DMSO group was added to 180 ⁇ L of the cell-containing medium in DMSO diluted with the medium.

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Abstract

本发明涉及药物化学和药物治疗学领域，具体涉及通式（I）的化合物，其外消旋体、R-异构体、S-异构体、可药用盐及它们的混合物，其制备方法、含此类化合物的药物组合物及作为赖氨酸特异性脱甲基酶1(LSD1)抑制剂的用途。本发明所涉及的环丙胺类化合物在治疗癌症中的用途。

Description

反吲哚啉环丙胺类化合物及其制备方法、药物组合物和用途 技术领域
本发明涉及药物化学和药物治疗学领域，具体涉及一类氟取代的环丙胺类化合物、其制备方法、含此类化合物的药物组合物及作为赖氨酸特异性脱甲基酶1(LSD1)抑制剂，特别是制备用于治疗癌症、白血病等疾病的药物的用途。
背景技术
表观遗传学是研究基因的DNA序列不发生变化的前提下，通过对核苷酸或染色体的可逆性修饰使基因表达可遗传的变化的遗传学分支学科。表观遗传学的调控机制主要包括DNA甲基化、组蛋白修饰、非编码RNA作用等。大多数情况下，表观遗传信息通过改变胞嘧啶和组蛋白的化学修饰而储存起来，这些化学结构的改变调控染色质的结构。正常的表观遗传过程对于胚胎发育、细胞分化等生命活动有着重要作用。研究证明，很多疾病的发生与表观遗传修饰的异常相关，近年来表观遗传学成为生物学、医学等领域内的研究热点，表观遗传学的相关研究在人类许多疾病的防治过程中具有的重要意义。
LSD1(又称为BHC110、p110b和NPAO)由Shi课题组于2004年所确认11，其结构从酵母到人类均高度保守。在细胞中，LSD1的去甲基化能力具有基因、底物专和环境高度专一性，对不同基因位点的基因表达产生出不同(甚至相反)的功效。研究发现LSD1在促进正常细胞分化中起到了重要的作用，但LSD1也被发现会被异常的招募对致白血病的基因受损的下游异常基因目标产生不当的抑制作用(如MLL-AF9)。在这种情况下，LSD1会维持初始损伤赋予白血病干细胞(LSC)的活性，LSD1下游的细胞效应也显著区别于正常的细胞状态。在正常的造血过程中，在最原始造血干细胞(HSC)水平上并未发现基因表达的变化，这与由完全相反的LSD1消耗诱导的血球减少的观察结果相一致。因此，LSD1若能对正常造血细胞产生可控可逆的毒性，可作为潜在治疗白血病的药物作用靶点。
因此，开发结构新颖的小分子LSD1抑制剂，对于治疗恶性肿瘤和白血病等疾病的研究具有重要的研究意义。
发明内容
本发明的目的是提供一种结构新颖的小分子LSD1抑制剂。
本发明的第一方面，提供了一种具有如下通式I所示结构的氟取代的环丙胺类化合物，及其外消旋体、R-异构体、S-异构体、其药学上可接受的盐或它们混合物：
Figure PCTCN2017087081-appb-000001
其中：
n＝1，2；
X为无或-(CH2)1-4、-CH(Ra)(CH2)0-3、-C(Ra)2(CH2)0-3、C3-C6的环烷烃、羰基，或羰基-氧基，其中各个Ra各自独立地为C1-C4烷基；
Y为磺酰基、羰基或羰基-氧基；
R1选自-H、取代或未取代的C1-C12烷基、取代或未取代的C3-C12环烷基、取代或未取代的3-12元杂环基(所述的杂环基包括单环、并环、螺环或桥环)、取代或未取代的C6-C10芳基、取代或未取代的5-12元芳杂环基，其中R1具有0、1、2、或3个取代基，所述取代基选自卤素、芳基、杂芳基、C1-C6烷基、-SO2Ra、-NC(O)Ra、-CH2C(O)ORa、-C(O)ORa、-C(O)Ra、-C(O)NRaRb、取代的氨基、氨基、脲、酰胺、磺酰胺、芳烷基和杂芳烷基；其中，所述的杂环基含有选自下组的1-3个杂原子：N、O或S；
各Ra独立地为氢、苯基、苯基甲基、3,5-二甲基异噁唑-4-基、1,2-二甲基-1H-咪唑-4-基、C3-C7环烷基、C1-C6烷基、C1-C4烷氧基、C1-C3烷基氨基或-NHPh；
Rb为氢或C1-C3烷基，或当Ra和Rb连接至相同原子时，
Ra和Rb一起形成5-或6-元杂环烷基环；
R2选自取代或未取代的C1-C8烷基、取代或未取代的C3-C12环烷基、取代或未取代的C6-C10芳环或者取代或未取代的含有1～4个选自氧、硫和氮中的杂原子的3-12元的芳香杂环；
其中，所述的取代基选自下组：氘、氚、卤素、未取代或由1-3个卤素取代的C1-C12烷基、未取代或由1-3个卤素或苯基取代的C1-C12烷氧基、未取代或由1-3个卤素取代的C2-C12烯基、未取代或由1-3个卤素取代的C3-C6环烷基、由C1-C6烷氧基取代的C1-C6烷基、由C3-C6环烷基取代的C1-C6烷基、羟基、氰基、硝基、C1-C6直链或支链的羟烷基、未取代或由1-2个C1-C6烷基取代的胺基、羧基、巯基，或未取代或被选自下组的一个或多个取代基取代的苄基：羧基、C2-C6的酯基；或者，取代或未取代的烷基、取代或未取代的环烷基、所述取代的苯环或取代的芳香杂环上任意两个取代基可以与其相邻的碳原子或杂原子一起连接成含有1至3个选自N、O和S中的杂原子的5-7元杂环，所述5-7元杂环非必须地被选自如下基团的取代基所取代：氢、氢的同位素、卤素、三氟甲基、甲氧基、未取代或由1-3个卤素取代的C1-C6直链或支链的烷基、未取代或由1-3个卤素取代的C1-C6直链或支链的烷氧基、或羟基；
在本发明中，所述卤素为F、Cl、Br或I。
在另一优选例中，所述的R1选自取代或未取代的C3-C12环烷基、取代或未取代的3-10元杂环基、取代或未取代的3-10元芳杂环基(所述的杂环基包括单环、并环、螺环或桥环)、取代或未取代的C6-C10芳基，其中R1具有0、1、2、或3个取代基，所述取代基选自卤素、芳基、杂芳基、C1-C6烷基、-SO2Ra、-NC(O)Ra、-CH2C(O)ORa、-C(O)ORa、-C(O)Ra、-C(O)NRaRb、取代的氨基、氨基、脲、酰胺、磺酰胺、芳烷基和杂芳烷基；其中，所述的杂环基含有选自下组的1-3个杂原子：N或O。
在另一优选例中，所述的杂环基含有1个或2个选自N或O的杂原子。
在另一优选例中，R2选自下组：取代或未取代的苯基、取代或未取代的萘基、取代或未取代的3-7元环烷基；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基所取代：卤素、C1-4烷基、氟代C1-4烷基、C1-4烷氧基。
在另一优选例中，Y为磺酰基或羰基。
在另一优选例中，所述的化合物为表格中的化合物A1-A72.
本发明的第二方面，提供了一种赖氨酸特异性脱甲基酶1(LSD1)抑制剂，所述的抑制剂包括如本发明第一方面中所述的化合物，其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物。
本发明的第三方面，提供了一种如本发明第一方面所述的式(I)化合物的制备方法，包括步骤：
Figure PCTCN2017087081-appb-000002
(e)在惰性溶剂中，用醇类中间体(VI)与亲核试剂进行光延反应，得到反式的吲哚啉硝基环丙烷中间体(VII)；和
用式(VII)化合物制备式(I)化合物；
其中，各基团的定义如本发明第一方面中所述。
本发明的第四方面，提供了一种如本发明第一方面所述的式(I)化合物的制备方法，所述的制备方法包括步骤：
Figure PCTCN2017087081-appb-000003
(j)在惰性溶剂中，用式(XI)与酰氯反应并脱除保护基，得到目标产物(I)；
其中，各基团的定义如本发明第一方面中所述。
本发明的第五方面，提供了一种药物组合物，包括：(A)治疗有效量的如本发明第一方面所述的化合物，其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物中的一种或多种；和(B)药学上可接受的载体。
本发明的第六方面，提供了一种如本发明第一方面所述的化合物、其对映异构体、非对映异构体、外消旋体及其混合物以及其药学上可接受的盐、结晶水合物及溶剂合物，用于制备治疗或预防与赖氨酸特异性脱甲基酶1(LSD1)相关的恶性肿瘤疾病的药物的用途。
在另一优选例中，所述的疾病选自下组：脑癌(胶质瘤)、成胶质细胞瘤、白血病、班-佐综合征、考登病、小脑发育不良性神经节细胞瘤、乳腺癌、炎性乳腺癌、维尔姆斯瘤、尤因肉瘤、横纹肌肉瘤、室管膜瘤、髓母细胞瘤、结肠癌、头颈癌、肾癌、肺癌、肝癌、黑素瘤、肾癌、卵巢癌、胰腺癌、前列腺癌、肉瘤、骨肉瘤、骨和甲状腺的巨细胞瘤。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地发现，反吲哚啉环丙胺类化合物能够被用作高效的LSD1抑制剂，还能用于制备治疗或预防与赖氨酸特异性脱甲基酶1(LSD1)相关的恶性肿瘤疾病的药物。基于上述发现，发明人完成了本发明。
术语
除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，所述卤素为F、Cl、Br或I。
在本发明中，术语“C1-C12烷基”是指具有1至12个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等；优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本发明中，术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明中，术语“C3-C12环烷基”是指在环上具有3至12个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基等。术语“C3-C8环烷基”、“C3-C7环烷基”、和“C3-C6环烷基”等具有类似的含义。
在本发明中，术语“C6-C10芳基”是指在环上不含杂原子的具有6至10个碳原子的芳香族环基，如苯基、萘基等。术语“C6芳基”具有类似的含义。
在本发明中，术语“3-12元杂环基”是指在环上含有1～3个选自氧、硫和氮中的杂原子的饱和或不饱和的3-12元环基，例如二氧杂环戊基等。术语“3-7元杂环基”具有类似的含义。
术语“3-12元的杂环”指具有3-12元的环状饱和或部分不饱和非芳香性基团，包括单环、并环、螺环或桥环，其中，所述的杂环具有至少1个选自下组的环原子：O、S和/或N。
术语“5-12元芳杂环基”指具有5-12元的环状芳香性基团，其中，所述的杂环具有至少1个选自下组的环原子：O、S和/或N。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环烷基，可以与另一个环相连，例如环烷基，从而形成螺二环系，例如，两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-8醛基、C2-10酰基、C2-10酯基、氨基、烷氧基等。
特别地，形如“C1-Cn”的表述指基团具有1-n个碳原子，例如，“C1-C12”的表述指基团具有1个，2个，3个，4个，5个，6个，7个，8个，9个，10个，11个或12个碳原子；“C6～C10”指基团具有6个，7个，8个，9个或10个碳原子。
本发明中，术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)，即有合理的效益/风险比的物质。
本发明中，术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量，或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此，预先指定准确的有效量是没用的。然而，对于某给定的状况而言，可以用常规实验来确定该有效量，临床医师是能够判断出来的。
式(I)化合物
本发明提供了一种如下式(I)所示的化合物：
Figure PCTCN2017087081-appb-000004
在本发明的一个优选实施例中，R1、R2、X、Y、n各自独立地为表1化合物中所示的基团。
在本发明更优选的实施方案中，本发明的通式(I)的化合物优选为如下具体化合物：
表1
Figure PCTCN2017087081-appb-000005
Figure PCTCN2017087081-appb-000006
Figure PCTCN2017087081-appb-000007
Figure PCTCN2017087081-appb-000008
Figure PCTCN2017087081-appb-000009
Figure PCTCN2017087081-appb-000010
Figure PCTCN2017087081-appb-000011
本发明的化合物具有不对称中心、手性轴和手性平面，并且可以以外消旋体、R-异构体或S-异构体的形式存在。本领域技术人员能够采用常规技术手段由外消旋体拆分获得R-异构体和/或S-异构体。
本发明还进一步提供了通式I化合物的可药用的盐，例如通式I化合物与无机酸或有机酸反应形成常规的可药用盐。例如，常规的可药用盐可通过通式I化合物与无机酸或有机酸反应制得，所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者通式I化合物与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式I化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐。
式I化合物的制备
本发明另一方面提供了一种通式I表示的化合物的制备方法，该制备方法按照如下方案1进行。
式(I)化合物可以通过以下方案1所示的方法制备。以吲哚啉或1,2,3,4-四氢喹啉(II)为原料，通过与苯磺酰氯反应得到中间体(III)。之后与氯丙酰氯发生傅克酰基化反应得到中间体(IV)，再与亚硝酸钠发生硝化反应得到中间体(V)。所得中间体经硼氢化钠还原得到醇类中间体(VI)，接着反式分子内的光延反应得到反式的吲哚啉硝基环丙烷中间体(VII)，并在盐酸锌粉还原下得到中间体(VIII)。中间体(VIII)通过还原胺化、偶联与缩合的方式得到中间体(IX)，再经叔丁氧羰基保护得到中间体(X)。在镁粉还原条件下脱除苯磺酰基得到中间体(XI)。最后与酰氯反应并在盐酸二氧六环溶液中脱除保护基得到成盐的目标产物(I)。
Figure PCTCN2017087081-appb-000012
药物组合物和施用方法
由于本发明化合物具有优异的赖氨酸特异性脱甲基酶1(LSD1)抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与赖氨酸特异性 脱甲基酶1(LSD1)活性相关的疾病。根据现有技术，本发明化合物可用于预防和治疗高脂血症、高胆固醇血症、高甘油三酯血症、脂肪肝变形、动脉粥样硬化、肥胖等代谢性疾病药物中的应用。本文公开的化合物还能用于治疗脑癌(胶质瘤)、成胶质细胞瘤、白血病、班-佐综合征、考登病、小脑发育不良性神经节细胞瘤、乳腺癌、炎性乳腺癌、维尔姆斯瘤、尤因肉瘤、横纹肌肉瘤、室管膜瘤、髓母细胞瘤、结肠癌、头颈癌、肾癌、肺癌、肝癌、黑素瘤、肾癌、卵巢癌、胰腺癌、前列腺癌、肉瘤、骨肉瘤、骨和甲状腺的巨细胞瘤等等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有0.05-200mg本发明化合物/剂，更佳地，含有0.1mg-100mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2017087081-appb-000013
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味 剂、娇味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。本发明的化合物和药物组合物可通过口、鼻、皮肤、肺或者胃肠道等的给药途径。最优选为口服。最优选日剂量为0.01-200mg/kg体重，一次性服用，或0.01-100mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
与现有技术相比，本发明的主要优点包括：
(1)提供了一类结构新颖的赖氨酸特异性脱甲基酶1(LSD1)抑制剂化合物以及衍生物，其制备方法具有反应条件温和、原料丰富易得、操作及后处理简单、对应选择性好等优点。所述的化合物具有很好的赖氨酸特异性脱甲基酶1(LSD1)抑制活性。
(2)提供了一种LSD1抑制剂，该类抑制剂在体外实验中表现出非常优异的LSD1抑制活性和肿瘤细胞抑制活性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1反式-2-(1-(苯磺酰基)吲哚啉-5-基)环丙胺(A1)
Figure PCTCN2017087081-appb-000014
1.1 1-(苯磺酰)二氢吲哚的合成
Figure PCTCN2017087081-appb-000015
在冰浴搅拌的条件下，在吲哚啉(100g,839.18mmol)的二氯甲烷(1L)溶液中加入三乙胺(163mL,1.17mol)，之后慢慢滴加苯环酰氯(128mL,1.01mol)。反应一小时后，慢慢回至室温搅拌过夜。TLC检测反应完全后，在冰浴条件下慢慢加入去离子水(200mL)。有机层依次用去离子水(1.0L)、饱和碳酸氢钠水溶液(1.0L)与饱和食盐水(1.0L)洗一次。 所得有机层用无水硫酸钠干燥，减压浓缩得粗品。最后，粗品在乙醇加热重结晶条件下纯化得到中间体(201g，92％yield)。1H NMR(400MHz,DMSO)δ7.82(d,J＝7.7Hz,2H),7.67(d,J＝7.4Hz,1H),7.57(t,J＝7.7Hz,2H),7.49(d,J＝8.1Hz,1H),7.20(t,J＝7.8Hz,1H),7.15(d,J＝7.4Hz,1H),6.98(t,J＝7.4Hz,1H),3.92(t,J＝8.4Hz,2H),2.89(t,J＝8.4Hz,2H).LRMS[M+H]+:260.0.
1.2 3-氯-1-(1-(苯磺酰)二氢吲哚-5-基)丙烷-1-酮.的合成
Figure PCTCN2017087081-appb-000016
在冰浴搅拌条件下，在三氯化铝(113g,848.36mmol)的1,2-二氯乙烷(1.0L)反应液中慢慢滴加3-氯丙酰氯(81mL,848.36mmol)。反应一小时后，分批加入中间体1-(苯磺酰)二氢吲哚(200g,771.24mmol)，慢慢回至室温反应六小时。TLC检测反应完全后，将反应液缓慢倒入1.0L的冰水混合物中(在此过程中防止温度过高，需添加冰块)。有机层依次用去离子水(1.0L)、饱和碳酸氢钠水溶液(1.0L)与饱和食盐水(1.0L)洗一次。所得有机层用无水硫酸钠干燥，减压浓缩得粗品。最后，粗品碾压粉碎加入乙醇(700mL)中搅拌过夜，过滤得固体3-氯-1-(1-(苯磺酰)二氢吲哚-5-基)丙烷-1-酮(263g,97％yield)。1H NMR(400MHz,DMSO)δ7.91–7.86(m,3H),7.79(s,1H),7.72(t,J＝7.4Hz,1H),7.61(t,J＝7.8Hz,2H),7.56(d,J＝8.5Hz,1H),4.01(t,J＝8.6Hz,2H),3.89(t,J＝6.3Hz,2H),3.46(t,J＝6.3Hz,2H),3.05(t,J＝8.5Hz,2H).LRMS[M+H]+:350.0.
1.3 3-硝基-1-(1-(苯磺酰)二氢吲哚-5-基)丙烷-1-酮的合成
Figure PCTCN2017087081-appb-000017
在室温搅拌条件下，向中间体3-氯-1-(1-(苯磺酰)二氢吲哚-5-基)丙烷-1-酮(260g,743.21mmol)的DMF(750mL)溶液中依次分批加入亚硝酸钠(102.6g,1.49mol)和苯三酚(30.9g,245.26mmol)。反应24小时后，反应过滤得固体，再加入700mL去离子水中搅拌2小时。过滤的固体，烘干得中间体3-硝基-1-(1-(苯磺酰)二氢吲哚-5-基)丙烷-1-酮(258g,96％yield)。1H NMR(400MHz,DMSO)δ7.93–7.89(m,3H),7.81(s,1H),7.72(t,J＝7.4Hz,1H),7.65–7.57(m,3H),4.89–4.78(m,2H),4.01(t,J＝8.6Hz,2H),3.63(t,J＝5.6Hz,2H),3.06(t,J＝8.5Hz,2H).
1.4 3-硝基-1-(1-(苯磺酰)二氢吲哚-5-基)丙烷-1-醇的合成
Figure PCTCN2017087081-appb-000018
将中间体3-硝基-1-(1-(苯磺酰)二氢吲哚-5-基)丙烷-1-酮(250g,693.70mmol)分散于THF(750mL)/H2O(750mL)溶液中。在冰浴搅拌条件下，向反应液中分批加入硼氢化钠(31.5g,832.44mmol)，反应搅拌过夜。TLC检测反应完全后，在冰浴搅拌条件下缓慢加入饱和氯化铵溶液淬灭。反应液用二氯甲烷(750mL)萃取两次，所得有机层合并用饱和 食盐水洗一次，并用无水硫酸钠干燥，减压浓缩得粘稠液体3-硝基-1-(1-(苯磺酰)二氢吲哚-5-基)丙烷-1-醇(231g,92％yield)。1H NMR(400MHz,DMSO)δ7.84–7.78(m,2H),7.68(t,J＝7.4Hz,1H),7.57(t,J＝7.7Hz,2H),7.44(d,J＝8.3Hz,1H),7.16(d,J＝8.3Hz,1H),7.13(s,1H),5.48(d,J＝4.4Hz,1H),4.63–4.49(m,3H),3.92(t,J＝8.4Hz,2H),2.89(t,J＝8.4Hz,2H),2.23–2.06(m,2H).LRMS[M-H]+:361.1.
1.5反式-5-(2-硝基环丙基)-1-(苯磺酰)二氢吲哚的合成
Figure PCTCN2017087081-appb-000019
在氩气保护条件下，将三苯基膦(17.37g,66.23mmol)溶于200mL的无水四氢呋喃中。在冰浴搅拌条件下，慢慢往反液中滴加DBAD(15.25g,66.23mmol)的四氢呋喃溶液(100mL)，反应搅拌1小时，析出白色固体。在此反应液中缓慢加入3-硝基-1-(1-(苯磺酰)二氢吲哚-5-基)丙烷-1-醇(16g,44.15mmol)的四氢呋喃溶液(100mL)，慢慢回至室温反应3小时。TLC检测反应完全后，加入300mL去离子水，并用乙酸乙酯(200mL)萃取三次。所得有机层合并用饱和食盐水洗一次，并用无水硫酸钠干燥，减压浓缩。所得粗品经柱层析(EA/PE＝1/6–1/3)分离、并用异丙醇重结晶纯化白色固体反-5-(2-硝基环丙基)-1-(苯磺酰)二氢吲哚(7.3g,48％)。1H NMR(400MHz,DMSO)δ7.80(dd,J＝8.4,1.2Hz,2H),7.71–7.65(m,1H),7.57(t,J＝7.7Hz,2H),7.39(d,J＝8.3Hz,1H),7.11(dd,J＝8.4,1.6Hz,1H),7.04(s,1H),4.70(ddd,J＝7.1,3.8,3.1Hz,1H),3.90(t,J＝8.4Hz,2H),3.07(ddd,J＝10.9,8.0,2.9Hz,1H),2.87(t,J＝8.4Hz,2H),2.14–2.06(m,1H),1.76(ddd,J＝7.9,7.3,6.3Hz,1H).LRMS[M+H]+:345.1.
1.6反式-2-(1-(苯磺酰基)吲哚啉-5-基)环丙胺(A1)的合成
向反-5-(2-硝基环丙基)-1-(苯磺酰)二氢吲哚(1.0g,2.90mmol)的THF(30mL)中加入锌粉(1.9g,29.04mmol)。在冰浴搅拌条件下，向反应液中慢慢滴加2M盐酸水溶液(15mL)，慢慢回至室温反应搅拌过夜。TLC检测反应完全后，过滤得滤液，并用二氯甲烷清洗滤渣。所得滤液用1M氢氧化钠水溶液(30mL)中和，析出白色固体。再经过滤得滤液，滤渣再用二氯甲烷清洗。所得滤液中加入饱和碳酸氢钠溶液，并用二氯甲烷(80mL)萃取三次。合并有机层用饱和食盐水清洗一次，并用无水硫酸钠干燥，减压浓缩，经柱层析分离(MeOH/DCM＝1/50–1/20)纯化得液体。所得产物溶于10mL的二氧六环溶液中。在室温搅拌条件下，向反应液中慢慢滴加盐酸二氧六环溶液，溶液出现浑浊。搅拌过夜后，反应液中析出固体，过滤得黄色固体A1(670mg,66％yield)。1H NMR(400MHz,DMSO)δ8.60(s,2H),7.81–7.76(m,2H),7.67(t,J＝7.4Hz,1H),7.56(t,J＝7.7Hz,2H),7.38(d,J＝8.3Hz,1H),7.01(d,J＝8.3Hz,1H),6.92(s,1H),3.89(t,J＝8.4Hz,2H),3.56(s,1H),2.84(t,J＝8.4Hz,2H),2.68(dt,J＝7.9,4.1Hz,1H),2.32–2.24(m,1H),1.39–1.31(m,1H),1.10(dd,J＝13.9,6.3Hz,1H).mp 190-193℃.LRMS[M+H]+:315.1.
实施例2反式-N-苯基-2-(1-(苯磺酰基)吲哚啉-5-基)环丙胺(A2)
Figure PCTCN2017087081-appb-000020
将A1(200mg,0.57mmol)分散于二氯甲烷(20mL)中，加入1M氢氧化钠水溶液(20mL)中和。所得液体用二氯甲烷(20mL)萃取三次，合并有机层，用饱和食盐水洗一次。所得有机溶液用无水硫酸钠干燥，并减压浓缩得淡黄色液体。将此液体重新溶入4mL二甲亚砜中，依次加入碘苯(175mg,0.86mmol)、碘化亚铜(11mg,0.057mmol)与L-脯氨酸(13mg,0.114mmol)。在氩气保护下，所得反应液在90度油浴下加热搅拌反应过夜。待TLC检测反应完全后，加入乙酸乙酯与稀释，并用去离子水洗三次。所得有机层用饱和食盐水清洗，并用无水硫酸钠干燥，减压浓缩，经柱层析分离(MeOH/DCM＝1/50–1/20)纯化得粘稠液体。将所得产物溶于10mL甲醇中，缓慢滴加盐酸二氧六环溶液(5mL)，搅拌反应过夜。TLC检测反应完全后，加入20mL乙酸乙酯，在减压浓缩得黄色固体A2(131mg,54％)。1H NMR(500MHz,Deuterium Oxide)δ7.75(dd,J＝7.4,2.1Hz,2H),7.66–7.60(m,1H),7.56(t,J＝7.4Hz,2H),7.09–7.00(m,3H),6.92(dd,J＝7.5,2.0Hz,1H),6.71(tt,J＝7.4,1.9Hz,1H),6.64–6.55(m,3H),4.70(s,1H),4.55(dt,J＝12.5,8.5Hz,1H),4.18(ddd,J＝12.4,9.1,2.3Hz,1H),3.07(ddd,J＝18.9,8.8,2.3Hz,1H),2.94(ddd,J＝18.6,9.1,8.1Hz,1H),2.83(q,J＝7.1Hz,1H),2.02(q,J＝7.0Hz,1H),1.08(td,J＝7.0,5.0Hz,1H),0.78(td,J＝7.1,5.0Hz,1H)..LRMS[M+H]+:391.1.
实施例3反式-N-苄基-2-(1-(苯磺酰基)吲哚啉-5-基)环丙胺(A3)
Figure PCTCN2017087081-appb-000021
将A1(200mg,0.57mmol)分散于二氯甲烷(20mL)中，加入1M氢氧化钠水溶液(20mL)中和。所得液体用二氯甲烷(20mL)萃取三次，合并有机层，用饱和食盐水洗一次。所得有机溶液用无水硫酸钠干燥，并减压浓缩得淡黄色液体。将此液体重新溶入10mL甲醇中，依次加入苯甲醛(41mg,0.38mmol)和冰醋酸(44μL,0.76mmol)。在氩气保护下，所得反应液回流搅拌反应10分钟。待反应液冷却至室温后，慢慢加入氰基硼氢化钠(45mg,0.76mmol)。搅拌反应2小时后，慢慢加入饱和碳酸氢钠溶液淬灭反应，并用二氯甲烷(20mL)萃取三次。合并有机层依次用10％醋酸水溶液(20mL)、1M氢氧化钠水溶液(20mL)与饱和食盐水清洗，并用无水硫酸钠干燥，减压浓缩，经柱层析分离(MeOH/DCM＝1/50–1/20)纯化得粘稠液体。将所得产物溶于10mL甲醇中，缓慢滴加盐酸二氧六环溶液(5mL)，搅拌反应过夜。TLC检测反应完全后，加入20mL乙酸乙酯，在减压浓缩得黄色固体A3(137mg,55％)。1H NMR(400MHz,MeOD)δ7.79(d,J＝7.5Hz,2H),7.63(t,J＝7.5Hz,1H),7.53–7.41(m,8H),6.96(d,J＝7.8Hz,1H),6.85(s,1H),4.35(d,J＝2.4Hz,2H),3.93(t,J＝8.4Hz,2H),2.93–2.87(m,1H),2.84(t,J＝8.4Hz,2H),2.33(ddd,J＝9.7,6.5,3.2Hz,1H),0.91–0.88(m,2H).mp 92-94℃.LRMS[M+H]+:405.0.
实施例4反式-N-(1-苯基乙基)-2-(1-(苯磺酰)二氢吲哚-5-基)环丙胺(A4)
Figure PCTCN2017087081-appb-000022
将苯甲醛替换为苯乙酮，其余所需原料、试剂及制备方法同实施例3，得产物A4，产率为42％。1H NMR(500MHz,Deuterium Oxide)δ7.81(dd,J＝7.4,2.0Hz,4H),7.62(ddt,J＝9.5,6.6,2.2Hz,2H),7.58–7.52(m,4H),7.39–7.26(m,8H),7.22(ddt,J＝7.5,6.0,2.1Hz,2H),7.06–6.98(m,4H),6.58(d,J＝7.4Hz,2H),4.70(s,2H),4.49(ddd,J＝12.6,8.6,2.0Hz,2H),4.17(q,J＝6.9Hz,2H),4.14–4.04(m,2H),3.06(dt,J＝18.8,8.9Hz,2H),3.01–2.93(m,3H),2.92(d,J＝7.0Hz,1H),2.01(q,J＝7.1Hz,2H),1.51(d,J＝6.8Hz,6H),1.04(td,J＝7.0,5.0Hz,2H),0.84(td,J＝7.0,4.9Hz,2H).LRMS[M+H]+:419.2.
实施例5反式-N-(4-二甲胺基-苄基)-2-(1-(苯磺酰基)吲哚啉-5-基)环丙胺(A5)
Figure PCTCN2017087081-appb-000023
将苯甲醛替换为4-N,N-二甲基苯甲醛，其余所需原料、试剂及制备方法同实施例3，得产物A5，产率为41％。1H NMR(400MHz,MeOD)δ7.81(d,J＝7.6Hz,2H),7.70–7.63(m,3H),7.58–7.49(m,5H),6.99(d,J＝8.8Hz,1H),6.91(s,1H),4.43(d,J＝2.4Hz,2H),3.95(t,J＝8.5Hz,2H),3.25(d,J＝1.8Hz,6H),2.97–2.91(m,1H),2.86(t,J＝8.4Hz,2H),2.44–2.37(m,1H),1.52–1.45(m,1H),1.38–1.34(m,1H).mp 145-147℃.LRMS[M+H]+:448.1.
实施例6反式-N-(4-吡啶-亚甲基)-2-(1-(苯磺酰基)吲哚啉-5-基)环丙胺(A6)
Figure PCTCN2017087081-appb-000024
将苯甲醛替换为4-吡啶甲醛，其余所需原料、试剂及制备方法同实施例3，得产物A6，产率为52％。1H NMR(400MHz,MeOD)δ8.98–8.92(m,2H),8.23(d,J＝6.3Hz,2H),7.79(d,J＝7.5Hz,2H),7.63(t,J＝7.5Hz,1H),7.51(dd,J＝13.0,5.3Hz,3H),7.02(d,J＝8.1Hz,1H),6.94(s,1H),4.75(s,2H),3.93(t,J＝8.4Hz,2H),3.07(dt,J＝7.8,3.8Hz,1H),2.85(t,J＝8.4Hz,2H),2.56(ddd,J＝10.4,6.5,3.7Hz,1H),1.66–1.58(m,1H),1.42–1.35(m,1H).mp 80-81℃.LRMS[M+H]+:406.1.
实施例7反式-N-(5-吲哚亚甲基)-2-(1-(苯磺酰基)吲哚啉-5-基)环丙胺(A7)
Figure PCTCN2017087081-appb-000025
将苯甲醛替换为5-吲哚甲醛，其余所需原料、试剂及制备方法同实施例3，得产物A7，产率为57％。1H NMR(400MHz,DMSO)δ9.64(s,1H),9.50(s,1H),7.78(t,J＝6.8Hz,2H),7.71–7.64(m,2H),7.60–7.52(m,3H),7.39(dd,J＝5.4,2.7Hz,1H),7.35(d,J＝8.2Hz,1H),7.21(d,J＝8.3Hz,1H),7.09(d,J＝6.5Hz,1H),6.94(d,J＝8.2Hz,1H),6.81(s,1H),4.28(s,2H),3.89(t,J＝8.4Hz,2H),2.81(t,2H),2.76(d,J＝5.4Hz,1H),2.40–2.33(m,1H),1.47–1.41(m,1H),1.22–1.15(m,1H).mp>300℃.LRMS[M+H]+:444.2.
实施例8反式-N-(3-吲哚亚甲基)-2-(1-(苯磺酰基)吲哚啉-5-基)环丙胺(A8)
Figure PCTCN2017087081-appb-000026
将苯甲醛替换为3-吲哚甲醛，其余所需原料、试剂及制备方法同实施例3，得产物A8，产率为48％。1H NMR(400MHz,MeOD)δ7.81(d,J＝7.6Hz,2H),7.64(d,J＝7.6Hz,1H),7.61(d,J＝7.8Hz,1H),7.55–7.48(m,3H),7.46(s,1H),7.42(d,J＝8.2Hz,1H),7.15(t,J＝7.6Hz,1H),6.98(t,J＝7.6Hz,1H),6.92(d,J＝8.0Hz,1H),6.74(s,1H),4.58(s,2H),3.94(t,J＝8.4Hz,2H),2.91(dt,J＝8.1,4.1Hz,1H),2.83(t,J＝8.4Hz,2H),2.31(ddd,J＝10.2,6.8,3.4Hz,1H),1.48–1.33(m,2H).mp 123-124℃.LRMS[M+H]+:443.8.
实施例9反式-N-(2-(1-(苯磺酰)二氢吲哚-5-基)环丙基)环己胺(A9)
Figure PCTCN2017087081-appb-000027
将苯甲醛替换为环己酮，其余所需原料、试剂及制备方法同实施例3，得产物A9，产率为48％。1H NMR(500MHz,Deuterium Oxide)δ7.81(dd,J＝7.5,2.0Hz,2H),7.66–7.52(m,3H),7.01–6.93(m,2H),6.58(d,J＝7.5Hz,1H),4.49(ddd,J＝12.5,6.0,4.5Hz,1H),4.02(dt,J＝12.6,8.7Hz,1H),3.02–2.95(m,2H),2.79(q,J＝7.0Hz,1H),2.35(p,J＝6.9Hz,1H),2.10(dq,J＝12.7,7.0Hz,2H),1.98(q,J＝7.1Hz,1H),1.74(dt,J＝12.7,7.0Hz,2H),1.60(ddd,J＝12.7,7.0,5.7Hz,2H),1.42(dq,J＝12.6,6.9Hz,2H),1.30(dq,J＝12.7,6.9Hz,2H),1.02(td,J＝7.0,5.0Hz,1H),0.81(td,J＝7.0,5.0Hz,1H).LRMS[M+H]+:397.2.
实施例10反式-N-环己亚甲基-2-(1-(苯磺酰基)吲哚啉-5-基)环丙胺(A10)
Figure PCTCN2017087081-appb-000028
将苯甲醛替换为环己烷甲醛，其余所需原料、试剂及制备方法同实施例3，得产物A10，产率为43％。1H NMR(400MHz,MeOD)δ7.78(d,J＝7.5Hz,2H),7.62(t,J＝7.4Hz,1H),7.54–7.46(m,3H),7.04(d,J＝8.4Hz,1H),6.94(s,1H),3.93(t,J＝8.4Hz,2H),3.02(d,J＝7.2Hz,2H),2.92–2.81(m,3H),2.40(ddd,J＝10.4,6.7,3.6Hz,1H),1.80(d,J＝11.8Hz,4H),1.75–1.67(m,2H),1.48–1.40(m,1H),1.35–1.20(m,4H),1.11–0.98(m,2H).mp 140-145℃.LRMS[M+H]+:411.1.
实施例11反式-N-丁基-2-(1-(苯磺酰)二氢吲哚-5-基)环丙胺(A11)
Figure PCTCN2017087081-appb-000029
将苯甲醛替换为丁醛，其余所需原料、试剂及制备方法同实施例3，得产物A11，产率为39％。1H NMR(500MHz,Deuterium Oxide)δ7.81(dd,J＝7.4,2.0Hz,2H),7.66–7.58(m,1H),7.57(d,J＝7.3Hz,2H),6.98(s,2H),6.61–6.55(m,1H),4.70(s,1H),4.49(ddd,J＝12.6,6.3,4.3Hz,1H),4.02(dt,J＝12.4,8.8Hz,1H),3.03–2.91(m,3H),2.89(ddd,J＝12.4,9.6,2.5Hz,1H),2.76(q,J＝7.0Hz,1H),1.98(q,J＝7.1Hz,1H),1.58–1.42(m,2H),1.37–1.17(m,2H),1.07–0.94(m,4H),0.80(td,J＝7.0,5.0Hz,1H).LRMS[M+H]+:371.2.
实施例12反式-2-(1-(苯磺酰)二氢吲哚-5-基)-N-((四氢-2H-吡喃-4-基)甲基)环丙胺(A12)
Figure PCTCN2017087081-appb-000030
将苯甲醛替换为4-四氢吡喃甲醛，其余所需原料、试剂及制备方法同实施例3，得产物A12，产率为53％。1H NMR(500MHz,Deuterium Oxide)δ7.81(dd,J＝7.4,2.1Hz,2H),7.66–7.52(m,3H),6.97(d,J＝6.7Hz,2H),6.61–6.55(m,1H),4.70(s,1H),4.49(ddd,J＝12.5,6.1,4.2Hz,1H),4.03(dt,J＝12.6,8.8Hz,1H),3.87(dt,J＝11.5,7.0Hz,2H),3.47(dt,J＝11.5,6.9Hz,2H),3.02–2.95(m,2H),2.78(q,J＝7.1Hz,1H),2.47(d,J＝6.7Hz,2H),1.98(q,J＝7.1Hz,1H),1.70–1.53(m,3H),1.25(dq,J＝13.3,6.8Hz,2H),1.01(td,J＝6.9,5.0Hz,1H),0.82(td,J＝7.0,5.0Hz,1H).LRMS[M+H]+:413.2.
实施例13反式-N-(2-(1-(苯磺酰)二氢吲哚-5-基)环丙基)四氢-2H-吡喃-4-胺(A13)
Figure PCTCN2017087081-appb-000031
将苯甲醛替换为4-四氢吡喃酮，其余所需原料、试剂及制备方法同实施例3，得产物A13，产率为48％。1H NMR(500MHz,Deuterium Oxide)δ7.80(dd,J＝7.4,2.1Hz,2H), 7.66–7.52(m,3H),7.03–6.95(m,2H),6.58(d,J＝7.4Hz,1H),4.70(s,1H),4.53(ddd,J＝12.6,9.0,7.6Hz,1H),4.12(ddd,J＝12.3,9.2,2.8Hz,1H),3.88(dt,J＝11.5,7.0Hz,2H),3.49(dt,J＝11.4,7.1Hz,2H),3.07–2.79(m,4H),2.08(dq,J＝14.0,7.1Hz,2H),1.98(q,J＝7.0Hz,1H),1.67(dq,J＝14.0,7.1Hz,2H),1.02(td,J＝7.0,5.0Hz,1H),0.80(td,J＝7.0,4.9Hz,1H).LRMS[M+H]+:399.2.
实施例14反式-N-(4-哌啶亚甲基)-2-(1-(苯磺酰基)吲哚啉-5-基)环丙胺(A14)
Figure PCTCN2017087081-appb-000032
将A27(100mg,0.195mmol)溶于甲醇(5mL)中，在室温搅拌的条件下加入盐酸二氧六环溶液(2mL)。反应搅拌过夜后，加入10mL乙酸乙酯，再加压条件下浓缩得成盐产物A14(78mg,83％)。1H NMR(400MHz,MeOD)δ7.80(d,J＝7.5Hz,2H),7.64(t,J＝7.6Hz,1H),7.55–7.48(m,3H),7.08(d,J＝8.2Hz,1H),6.99(s,1H),3.94(t,J＝8.4Hz,2H),3.46(d,J＝12.7Hz,2H),3.19(d,J＝6.9Hz,2H),3.06(t,J＝11.8Hz,2H),2.97(dt,J＝7.8,4.0Hz,1H),2.87(t,J＝8.4Hz,2H),2.55(ddd,J＝10.3,6.7,3.7Hz,1H),2.21–2.14(m,1H),2.08(d,J＝12.7Hz,2H),1.64–1.50(m,3H),1.39–1.30(m,1H).mp 179-181℃.LRMS[M+H]+:412.1
实施例15反式-N-(4-哌啶基)-2-(1-(苯磺酰基)吲哚啉-5-基)环丙胺(A15)
Figure PCTCN2017087081-appb-000033
将A1(200mg,0.57mmol)分散于二氯甲烷(20mL)中，加入1M氢氧化钠水溶液(20mL)中和。所得液体用二氯甲烷(20mL)萃取三次，合并有机层，用饱和食盐水洗一次。所得有机溶液用无水硫酸钠干燥，并减压浓缩得淡黄色液体。将此液体重新溶入10mL二氯乙烷中，依次加入N-叔丁氧羰基-4-哌啶酮(76mg,0.38mmol)和冰醋酸(44μL,0.76mmol)。在氩气保护下慢慢加入三乙酰氧基硼氢化钠(161mg,0.76mmol)。室温搅拌反应过夜后，慢慢加入饱和碳酸氢钠溶液淬灭反应，并用二氯甲烷(20mL)萃取三次。合并有机层依次用10％醋酸水溶液(20mL)、1M氢氧化钠水溶液(20mL)与饱和食盐水清洗，并用无水硫酸钠干燥，减压浓缩，经柱层析分离(MeOH/DCM＝1/50–1/20)纯化得粘稠液体。将所得产物溶于10mL甲醇中，缓慢滴加盐酸二氧六环溶液(5mL)，搅拌反应过夜。TLC检测反应完全后，加入20mL乙酸乙酯，在减压浓缩得黄色固体A15(81mg,45％)。1H NMR(400MHz,MeOD)δ7.81(d,J＝7.7Hz,2H),7.64(t,J＝7.5Hz,1H),7.56–7.49(m,3H),7.06(d,J＝8.1Hz,1H),6.97(s,1H),3.95(t,J＝8.4Hz,2H),3.23–3.13(m,1H),2.94(dt,J＝7.7,3.9Hz,1H),2.87(t,J＝8.4Hz,2H),2.44(ddd,J＝10.2,6.6,3.7Hz,1H),2.38–2.28(m,2H),2.19(d,J＝11.5Hz,2H),1.66–1.46(m,5H),1.38(dd,J＝14.3,7.0Hz,1H).mp>300℃.LRMS[M+H]+:412.2.
实施例16反式-N-(4-哌啶乙基基)-2-(1-(苯磺酰基)吲哚啉-5-基)环丙胺(A16)
Figure PCTCN2017087081-appb-000034
将N-叔丁氧羰基哌啶-4-甲醛替换为4-叔丁氧羰基哌啶乙醛，其余所需原料、试剂及制备方法同实施例14，得产物A16，产率为57％。1H NMR(400MHz,MeOD)δ7.82–7.78(m,2H),7.64(t,J＝7.2Hz,1H),7.56–7.48(m,3H),7.07(d,J＝8.3Hz,1H),6.98(s,1H),3.94(t,J＝8.4Hz,2H),3.42(d,J＝12.7Hz,3H),3.29–3.21(m,2H),3.01(t,J＝11.9Hz,2H),2.97–2.90(m,1H),2.87(t,J＝8.4Hz,2H),2.48(ddd,J＝10.2,6.6,3.4Hz,1H),2.00(d,J＝10.1Hz,2H),1.90–1.61(m,2H),1.53–1.38(m,3H),1.35(dd,J＝14.1,7.2Hz,1H).mp 64-65℃.LRMS[M+H]+:426.2.
实施例17反式-N-(吖丁啶-3-基甲基)-2-(1-(苯磺酰)二氢吲哚-5-基)环丙胺(A17)
Figure PCTCN2017087081-appb-000035
将N-叔丁氧羰基哌啶-4-甲醛替换为3-叔丁氧羰基吖啶甲醛，其余所需原料、试剂及制备方法同实施例14，得产物A17，产率为48％。1H NMR(400MHz,MeOD)δ7.83–7.77(m,2H),7.64(t,J＝7.4Hz,1H),7.53(dt,J＝13.0,6.7Hz,3H),7.11–7.05(m,1H),7.00(d,J＝6.6Hz,1H),4.26–4.04(m,1H),3.97–3.91(m,3H),3.43(d,J＝5.2Hz,2H),3.24(t,J＝5.9Hz,1H),3.02(dt,J＝25.5,12.8Hz,1H),2.86(t,J＝8.3Hz,2H),2.77(s,1H),2.69–2.50(m,1H),1.68–1.57(m,1H),1.41–1.26(m,2H).mp 145-148℃.LRMS[M+H]+:384.2.
实施例18反式-4-((2-(1-(苯磺酰)二氢吲哚-5-基)环丙基氨基)甲基)环己胺(A18)
Figure PCTCN2017087081-appb-000036
将N-叔丁氧羰基哌啶-4-甲醛替换为1-叔丁氧羰基环己胺-4-甲醛，其余所需原料、试剂及制备方法同实施例14，得产物A18，产率为42％。1H NMR(400MHz,MeOD)δ7.80(d,J＝7.8Hz,2H),7.64(t,J＝7.4Hz,1H),7.57–7.48(m,3H),7.07(d,J＝8.2Hz,1H),6.98(s,1H),3.94(t,J＝8.4Hz,2H),3.10(d,J＝7.0Hz,2H),2.94(dt,J＝7.7,3.9Hz,1H),2.86(t,J＝8.3Hz,2H),2.52(ddd,J＝10.2,6.5,3.6Hz,1H),2.12(d,J＝9.9Hz,2H),2.00(d,J＝11.7Hz,2H),1.89–1.75(m,2H),1.59–1.40(m,3H),1.36–1.18(m,3H).mp 172-175℃.LRMS[M+H]+:426.2.
实施例19反式-N1-(2-(1-(苯磺酰)二氢吲哚-5-基)环丙基)环己烷-1,4-二胺(A19)
Figure PCTCN2017087081-appb-000037
将A1(200mg,0.57mmol)分散于二氯甲烷(20mL)中，加入1M氢氧化钠水溶液(20mL)中和。所得液体用二氯甲烷(20mL)萃取三次，合并有机层，用饱和食盐水洗一次。所得有机溶液用无水硫酸钠干燥，并减压浓缩得淡黄色液体。将此液体重新溶于10mL甲醇中，向此溶液中加入4-N-Boc-氨基环己酮(81mg,0.38mmol)和200mg分子筛，反应搅拌反应10分钟。在冰浴条件下加入冰醋酸(44μL,0.76mmol)，慢慢回至室温反应3小时。之后，反应液置于-30℃冷却条件下，分批加入硼氢化钠(18mg,0.45mmol)，慢慢回至室温反应3小时。想反应液中慢慢加入饱和碳酸氢钠溶液淬灭反应，并用二氯甲烷(20mL)萃取三次。合并有机层依次用10％醋酸水溶液(20mL)、1M氢氧化钠水溶液(20mL)与饱和食盐水清洗，并用无水硫酸钠干燥，减压浓缩，经柱层析分离(MeOH/DCM＝1/50–1/20)纯化得粘稠液体。将所得产物溶于10mL甲醇中，缓慢滴加盐酸二氧六环溶液(5mL)，搅拌反应过夜。TLC检测反应完全后，加入20mL乙酸乙酯，在减压浓缩得黄色固体A19(63mg,34％)。1H NMR(400MHz,MeOD)δ7.81(d,J＝7.5Hz,2H),7.64(t,J＝7.3Hz,1H),7.56–7.49(m,3H),7.06(d,J＝8.2Hz,1H),6.97(s,1H),3.95(t,J＝8.3Hz,2H),3.22–3.14(m,1H),2.98–2.91(m,1H),2.87(t,J＝8.3Hz,2H),2.48–2.41(m,1H),2.39–2.28(m,2H),2.19(d,J＝11.1Hz,2H),1.68–1.47(m,5H),1.45–1.32(m,2H).mp>300℃.LRMS[M+H]+:412.2.
实施例20反式-N-(2-(1-(苯磺酰)二氢吲哚-5-基)环丙基)-7-氮杂螺[3.5]壬烷-2-胺(A20)
Figure PCTCN2017087081-appb-000038
将N-叔丁氧羰基哌啶-4-酮替换为2-氧代-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯，其余所需原料、试剂及制备方法同实施例15，得产物A20，产率为40％。1H NMR(400MHz,CD3OD)δ7.77(dd,J＝8.3,1.1Hz,2H),7.61(t,J＝7.5Hz,1H),7.52–7.45(m,3H),7.03(d,J＝8.3Hz,1H),6.95(s,1H),4.04–3.95(m,1H),3.91(t,J＝8.4Hz,2H),3.19–3.14(m,2H),3.13–3.08(m,2H),2.84(t,J＝8.4Hz,2H),2.81–2.77(m,1H),2.50–2.37(m,3H),2.18(td,J＝12.5,8.6Hz,2H),1.94–1.87(m,4H),1.48(ddd,J＝10.8,6.7,4.4Hz,1H),1.32–1.26(m,1H).mp 161-164℃.LRMS[M+H]+:438.2.
实施例21反式-N-((4-甲基哌啶-4-基)甲基)-2-(1-(苯磺酰)二氢吲哚-5-基)环丙胺(A21)
Figure PCTCN2017087081-appb-000039
将N-叔丁氧羰基哌啶-4-甲醛替换为4-甲基-N-叔丁氧羰基哌啶-4-甲醛，其余所需原料、试剂及制备方法同实施例14，得产物A21，产率为56％。1H NMR(400MHz,MeOD) δ7.80(d,J＝7.5Hz,2H),7.64(t,J＝7.4Hz,1H),7.56–7.49(m,3H),7.09(d,J＝8.4Hz,1H),7.01(s,1H),3.95(t,J＝8.4Hz,2H),3.30(d,J＝5.0Hz,1H),3.27(s,2H),3.26–3.19(m,2H),3.03(dt,J＝7.6,3.9Hz,1H),2.87(t,J＝8.3Hz,2H),2.68–2.58(m,1H),1.91–1.81(m,2H),1.77(dt,J＝9.4,4.4Hz,2H),1.67–1.59(m,1H),1.35(dd,J＝14.1,7.0Hz,1H),1.32–1.20(m,4H).mp 137-138℃.LRMS[M+H]+:426.3.
实施例22反式-4-((2-(1-(苯磺酰)二氢吲哚-5-基)环丙基氨基)甲基)哌啶-4-羧酸(A22)
Figure PCTCN2017087081-appb-000040
将N-叔丁氧羰基哌啶-4-甲醛替换为4-羧酸-N-叔丁氧羰基哌啶-4-甲醛，其余所需原料、试剂及制备方法同实施例14，得产物A22，产率为51％。1H NMR(500MHz,Deuterium Oxide)δ7.84–7.77(m,2H),7.66–7.52(m,3H),7.02–6.94(m,2H),6.58(d,J＝7.5Hz,1H),4.70(s,2H),4.54–4.45(m,1H),4.02(dt,J＝12.5,8.7Hz,1H),3.15(dt,J＝12.4,6.9Hz,2H),3.01–2.94(m,2H),2.92–2.75(m,3H),2.70(s,2H),2.36(dt,J＝13.2,7.2Hz,2H),1.94(q,J＝7.0Hz,1H),1.77(dt,J＝13.3,7.1Hz,2H),1.03(td,J＝7.0,5.0Hz,1H),0.80(td,J＝6.9,5.0Hz,1H).LRMS[M+H]+:456.2.
实施例23反式-N-((1-甲基哌啶-4-基)甲基)-2-(1-(苯磺酰)二氢吲哚-5-基)环丙胺(A23)
Figure PCTCN2017087081-appb-000041
将N-叔丁氧羰基哌啶-4-甲醛替换为N-甲基哌啶-4-甲醛，其余所需原料、试剂及制备方法同实施例14，得产物A23，产率为56％。1H NMR(500MHz,Deuterium Oxide)δ7.81(dd,J＝7.5,2.0Hz,2H),7.66–7.52(m,3H),6.97(d,J＝6.6Hz,2H),6.58(dt,J＝7.5,1.1Hz,1H),4.70(s,1H),4.49(ddd,J＝12.5,6.0,4.5Hz,1H),4.02(dt,J＝12.5,8.7Hz,1H),3.11(dt,J＝12.5,7.1Hz,2H),3.02–2.95(m,2H),2.78(q,J＝7.0Hz,1H),2.47(d,J＝7.0Hz,2H),2.31–2.22(m,2H),2.25(s,4H),1.97(q,J＝6.9Hz,1H),1.73(dq,J＝14.1,7.1Hz,2H),1.42(dq,J＝13.9,7.1Hz,2H),1.23(hept,J＝7.0Hz,1H),1.01(td,J＝7.0,5.0Hz,1H),0.82(td,J＝7.1,5.0Hz,1H).LRMS[M+H]+:426.2.
实施例24反式-N-((1-苯甲基哌啶-4-基)甲基)-2-(1-(苯磺酰)二氢吲哚-5-基)环丙胺(A24)
Figure PCTCN2017087081-appb-000042
制备方法同实施例14，得产物A24，产率为37％。1H NMR(400MHz,MeOD)δ7.80(d,J＝7.5Hz,2H),7.64(t,J＝7.4Hz,1H),7.60–7.56(m,2H),7.55–7.49(m,6H),7.07(d,J＝8.3Hz,1H),6.98(s,1H),4.35(s,2H),3.94(t,J＝8.4Hz,2H),3.55(d,J＝12.6Hz,2H),3.17(d,J＝6.8Hz,2H),3.10(t,J＝11.9Hz,2H),2.96(dt,J＝7.8,4.0Hz,1H),2.86(t, J＝8.4Hz,2H),2.53(ddd,J＝10.1,6.5,3.6Hz,1H),2.11(d,J＝14.4Hz,2H),1.65(dd,J＝26.3,12.8Hz,2H),1.59–1.52(m,1H),1.34(dd,J＝14.1,7.1Hz,1H).mp 181-183℃.LRMS[M+H]+:502.3.
实施例25反式-叔丁基4-((4-((2-(1-(苯磺酰)二氢吲哚-5-基)环丙基氨基)甲基)哌啶-1-基)甲基)苯酸酯(A25)
Figure PCTCN2017087081-appb-000043
制备方法同实施例14，得产物A25，产率为48％。1H NMR(400MHz,MeOD)δ7.93(d,J＝8.0Hz,2H),7.77(d,J＝7.4Hz,2H),7.62(t,J＝7.4Hz,1H),7.52–7.46(m,3H),7.44(d,J＝8.1Hz,2H),6.93(d,J＝8.1Hz,1H),6.81(s,1H),3.91(t,J＝8.3Hz,2H),3.59(s,2H),2.91(d,J＝12.2Hz,2H),2.78(t,J＝8.3Hz,2H),2.58(d,J＝6.8Hz,2H),2.26–2.19(m,1H),2.04(t,J＝11.9Hz,2H),1.85(ddd,J＝9.4,6.2,3.1Hz,1H),1.81–1.70(m,2H),1.61(s,9H),1.56–1.49(m,1H),1.31–1.23(m,2H),1.03(dt,J＝9.5,4.7Hz,1H),0.95(dd,J＝12.6,5.6Hz,1H).mp 62-65℃.LRMS[M+H]+:602.2.
实施例26反式-4-((4-((2-(1-(苯磺酰)二氢吲哚-5-基)环丙基氨基)甲基)哌啶-1-基)甲基)苯甲酸(A26)
Figure PCTCN2017087081-appb-000044
将A25(80mg,0.132mmol)分散于1M盐酸(5mL)中，将此反应液在90℃条件下加热反应2小时。趁热倒出上层澄清溶液，加入10mL乙腈，减压浓缩得成盐产物A26(63mg,70％)。1H NMR(400MHz,CD3OD)δ8.15–8.08(m,3H),7.77(d,J＝7.0Hz,2H),7.70(s,2H),7.61(t,J＝7.2Hz,1H),7.51–7.47(m,2H),7.04(d,J＝7.4Hz,1H),6.96(s,1H),4.41(s,2H),3.91(t,J＝7.3Hz,2H),3.53(s,2H),3.15(s,4H),2.90(s,1H),2.83(t,J＝8.1Hz,1H),2.52(s,1H),2.13–2.01(m,2H),1.66(s,3H),1.54(s,1H),1.32(s,1H).mp 190-192℃.LRMS[M+H]+:546.2
实施例27反式-叔丁基4-((2-(1-(苯磺酰)二氢吲哚-5-基)环丙基氨基)甲基)哌啶-1-羧酸酯(A27)
Figure PCTCN2017087081-appb-000045
将A1(200mg,0.57mmol)分散于二氯甲烷(20mL)中，加入1M氢氧化钠水溶液(20mL)中和。所得液体用二氯甲烷(20mL)萃取三次，合并有机层，用饱和食盐水洗一次。所得有机溶液用无水硫酸钠干燥，并减压浓缩得淡黄色液体。将此液体重新溶入10mL甲醇中，依次加入1-叔丁氧羰基哌啶-4-甲醛(81mg,0.38mmol)和冰醋酸(44μL,0.76 mmol)。在氩气保护下，所得反应液回流搅拌反应10分钟。待反应液冷却至室温后，慢慢加入氰基硼氢化钠(45mg,0.76mmol)。搅拌反应2小时后，慢慢加入饱和碳酸氢钠溶液淬灭反应，并用二氯甲烷(20mL)萃取三次。合并有机层依次用10％醋酸水溶液(20mL)、1M氢氧化钠水溶液(20mL)与饱和食盐水清洗，并用无水硫酸钠干燥，减压浓缩，经柱层析分离(MeOH/DCM＝1/50–1/20)纯化得粘稠液体A22(83mg,43％yield)。1H NMR(400MHz,CDCl3)δ7.77(d,J＝7.5Hz,2H),7.53(dd,J＝14.8,7.8Hz,2H),7.44(d,J＝7.9Hz,2H),6.86(d,J＝8.5Hz,1H),6.74(s,1H),4.09(s,2H),3.89(t,J＝8.4Hz,2H),2.81(t,J＝8.4Hz,2H),2.73–2.62(m,2H),2.59(d,J＝6.7Hz,2H),2.27–2.20(m,1H),1.79(ddd,J＝9.0,5.7,2.9Hz,1H),1.65(s,2H),1.61–1.54(m,1H),1.45(s,9H),1.08(qd,J＝12.5,4.5Hz,2H),1.00(dt,J＝9.3,4.7Hz,1H),0.87(dd,J＝12.3,5.7Hz,1H).mp 60-61℃.LRMS[M+Na]+:534.1.
实施例28反式-苯甲基4-((2-(1-(苯磺酰)二氢吲哚-5-基)环丙基氨基)甲基)哌啶-1-羧酸酯(A28)
Figure PCTCN2017087081-appb-000046
制备方法同实施例14，得产物A28，产率为化合物A28的合成方法与化合物A3类似，产率为46％。1H NMR(400MHz,MeOD)δ7.80(d,J＝7.4Hz,2H),7.63(t,J＝7.5Hz,1H),7.56–7.48(m,3H),7.39–7.30(m,5H),7.06(d,J＝8.5Hz,1H),6.96(s,1H),5.13(s,2H),4.21(d,J＝12.8Hz,2H),3.94(t,J＝8.4Hz,2H),3.11(d,J＝7.0Hz,2H),2.97–2.81(m,5H),2.43(s,1H),1.80(d,J＝12.2Hz,2H),1.53–1.44(m,1H),1.37–1.17(m,4H).mp 90-92℃.LRMS[M+H]+:546.0.
实施例29反式-叔丁基4-(2-(1-(苯磺酰)二氢吲哚-5-基)环丙基氨基甲酰)哌啶-1-羧酸酯(A29)
Figure PCTCN2017087081-appb-000047
将A1(100mg,0.29mmol)、1-叔丁氧羰基-4-哌啶甲酸(98mg,0.43mmol)和HATU(163mg,0.43mmol)分散于8mL二氯甲烷中，再向此反应液中加入三乙胺(120μL,0.86mmol)，室温搅拌反应过夜。待TLC检测反应完全后，反应液用二氯甲烷稀释(20mL)，并依次用10％的醋酸水溶液、去离子水、饱和碳酸氢钠溶液和饱和食盐水洗一次，并用无水硫酸钠干燥。所得有机相减压浓缩，经柱层析(EA/PE＝1/2–1/1)分离纯化得白色固体A29(93mg,62％)。1H NMR(400MHz,CDCl3)δ7.75(d,J＝7.6Hz,2H),7.56–7.50(m,2H),7.42(t,J＝7.7Hz,2H),6.97(d,J＝8.5Hz,1H),6.94(s,1H),4.11(s,2H),3.88(t,J＝8.4Hz,2H),2.81(t,J＝8.4Hz,2H),2.78–2.65(m,3H),2.18(ddd,J＝15.0,7.6,3.6Hz,1H),1.94(ddd,J＝9.5,6.3,3.3Hz,1H),1.77(d,J＝12.7Hz,2H),1.69(s,1H),1.61(ddd,J＝16.5,12.5,4.4Hz,2H),1.44(s,9H),1.15(dd,J＝13.4,6.4Hz,1H),1.11–1.03(m,1H).mp 146-148℃.LRMS[M+Na]+:548.2.
实施例30反式-2-(1-(苯磺酰)二氢吲哚-5-基)-N-(1-(哌啶-4-基)乙基)环丙胺(A30)
Figure PCTCN2017087081-appb-000048
制备方法同实施例14，得产物A30，产率为41％。1H NMR(500MHz,Deuterium Oxide)δ7.84–7.78(m,2H),7.66–7.52(m,3H),6.98(d,J＝6.6Hz,2H),6.58(dt,J＝7.5,1.1Hz,1H),4.70(s,2H),4.49(ddd,J＝12.5,6.1,4.3Hz,1H),4.02(dt,J＝12.4,8.6Hz,1H),3.14(dt,J＝12.5,7.1Hz,2H),3.02–2.95(m,2H),2.85(q,J＝7.1Hz,1H),2.73(dt,J＝12.5,7.0Hz,2H),2.59(p,J＝6.8Hz,1H),2.00(q,J＝6.9Hz,1H),1.72(dq,J＝11.8,6.6,6.1Hz,2H),1.36–1.18(m,6H),1.03(td,J＝7.0,5.0Hz,1H),0.81(td,J＝7.0,5.0Hz,1H).LRMS[M+H]+:426.2.
实施例31反式-2-(1-(苯磺酰)二氢吲哚-5-基)-N-(2-(哌啶-4-基)丙烷-2-基)环丙胺(A31)
Figure PCTCN2017087081-appb-000049
1H NMR(500MHz,Deuterium Oxide)δ7.81(dd,J＝7.5,2.0Hz,2H),7.66–7.52(m,3H),7.04(dd,J＝7.5,2.0Hz,1H),6.97(d,J＝2.0Hz,1H),6.58(d,J＝7.5Hz,1H),4.70(s,2H),4.49(ddd,J＝12.7,6.3,4.3Hz,1H),4.03(dt,J＝12.5,8.7Hz,1H),3.17–2.94(m,5H),2.74(dt,J＝12.5,7.1Hz,2H),1.99(q,J＝7.1Hz,1H),1.81–1.68(m,3H),1.33–1.24(m,2H),1.16(s,6H),0.98(td,J＝7.0,4.9Hz,1H),0.82(td,J＝7.0,5.0Hz,1H).LRMS[M+H]+:440.2.
实施例32反式-2-(1-(联苯基-4-基磺酰)二氢吲哚-5-基)-N-(哌啶-4-基甲基)环丙胺(A32)
Figure PCTCN2017087081-appb-000050
32.1叔-丁基反-4-((叔-丁氧基羰基(2-(1-(苯磺酰)二氢吲哚-5-基)环-丙基)氨基)甲基)哌啶-1-羧酸酯
Figure PCTCN2017087081-appb-000051
将A27(960mg,1.95mmol)溶于30mL二氯甲烷中，依次加入Boc2O(61 4mg,2.81mmol)与三乙胺(390μL,2.81mmol)，室温搅拌反应八小时。TLC检测反应完全后，反应液减压浓缩，经柱层析(EA/PE＝1/8–1/4)分离纯化得白色固体叔-丁基反-4-((叔-丁氧基羰基(2-(1-(苯磺酰)二氢吲哚-5-基)环-丙基)氨基)甲基)哌啶-1-羧酸酯(1.08g,94％yield)。 1H NMR(400MHz,CDCl3)δ7.78(d,J＝7.6Hz,2H),7.59–7.53(m,2H),7.44(t,J＝7.8Hz,2H),6.97(d,J＝8.4Hz,1H),6.83(s,1H),4.17–4.01(m,2H),3.91(t,J＝8.4Hz,2H),3.29(s,1H),3.02(s,1H),2.84(t,J＝8.3Hz,2H),2.74–2.56(m,3H),2.03(s,1H),1.82(s,1H),1.62(t,J＝13.0Hz,2H),1.46(s,9H),1.41(s,9H),1.23–1.08(m,4H).mp 68-70℃.LRMS[M+Na]+:634.2.
32.2叔丁基反-4-((叔-丁氧基羰基(2-(二氢吲哚-5-基)环丙基)氨基)甲基)哌啶-1-羧酸酯
Figure PCTCN2017087081-appb-000052
在冰浴搅拌的条件下，向叔-丁基反-4-((叔-丁氧基羰基(2-(1-(苯磺酰)二氢吲哚-5-基)环-丙基)氨基)甲基)哌啶-1-羧酸酯(1.0g,1.63mmol)的甲醇(50mL)溶液中分批加入镁粉(794mg,32.69mmol)，反应慢慢回至室温搅拌过夜。TLC检测反应完全后，在冰浴搅拌的条件下，慢慢加入饱和氯化铵溶液淬灭反应。反应液用二氯甲烷(50mL)萃取三次后，合并有机层，再依次用饱和碳酸氢钠水溶液与饱和食盐水洗一次。所得有机溶液用无水硫酸钠干燥，减压浓缩得到淡红色的油状物叔丁基反-4-((叔-丁氧基羰基(2-(二氢吲哚-5-基)环丙基)氨基)甲基)哌啶-1-羧酸酯(741mg,96％yield)。1H NMR(400MHz,CDCl3)δ6.86(s,1H),6.77(d,J＝7.9Hz,1H),6.51(d,J＝7.9Hz,1H),4.17–3.96(m,2H),3.48(t,J＝8.3Hz,2H),3.22(bs,1H),3.07(bs,1H),2.94(t,J＝8.3Hz,2H),2.64(bs,2H),2.58–2.53(m,1H),2.06–1.93(m,1H),1.82(bs,1H),1.59(t,J＝9.4Hz,2H),1.43(s,9H),1.41(s,9H),1.18–1.06(m,4H).LRMS[M+H]+:472.2.
32.3反式-2-(1-(联苯基-4-基磺酰)二氢吲哚-5-基)-N-(哌啶-4-基甲基)环丙胺(A32)的合成
在室温条件下，在叔丁基反-4-((叔-丁氧基羰基(2-(二氢吲哚-5-基)环丙基)氨基)甲基)哌啶-1-羧酸酯(150mg,0.32mmol)的二氯甲烷(8mL)溶液中依次加入联苯磺酰氯(121mg,0.48mmol)与三乙胺(66μL,0.48mmol)，反应搅拌反应过夜。TLC检测反应完全后，加入20mL二氯甲烷稀释，并依次用去离子水、饱和碳酸氢钠水溶液和饱和食盐水洗一次。所得有机溶液在无水硫酸钠中干燥并减压浓缩，最后经柱层析(EA/PE＝1/8–1/4)分离纯化。所得固体溶于10mL甲醇中，缓慢滴加盐酸二氧六环溶液(5mL)，搅拌反应过夜。TLC检测反应完全后，加入20mL乙酸乙酯，在减压浓缩得固体产物A32(81mg,52％)。1H NMR(400MHz,CD3OD)δ7.83(d,J＝8.4Hz,2H),7.70(d,J＝8.4Hz,2H),7.59(d,J＝7.1Hz,2H),7.54(d,J＝8.3Hz,1H),7.44(t,J＝7.3Hz,2H),7.38(t,J＝7.2Hz,1H),7.07(d,J＝8.3Hz,1H),6.97(s,1H),3.94(t,J＝8.4Hz,2H),3.43(d,J＝12.8Hz,2H),3.15(d,J＝6.9Hz,2H),3.03(t,J＝12.1Hz,2H),2.94(dt,J＝7.4,3.7Hz,1H),2.88(t,J＝8.4Hz,2H),2.54(ddd,J＝10.0,6.4,3.3Hz,1H),2.16(d,J＝2.9Hz,1H),2.05(d,J＝13.8Hz,2H),1.61–1.48(m,3H),1.31(dd,J＝14.2,7.0Hz,1H).mp 182-185℃.LRMS[M+H]+:488.2.
实施例33反式-2-(1-(萘-2-基磺酰)二氢吲哚-5-基)-N-(哌啶-4-基甲基)环丙胺(A33)
Figure PCTCN2017087081-appb-000053
制备方法同实施例32，得产物A33，产率为41％。1H NMR(400MHz,CD3OD)δ8.40(s,1H),7.98(d,J＝7.8Hz,1H),7.95–7.89(m,2H),7.70(dd,J＝8.7,1.8Hz,1H),7.68–7.56(m,3H),7.07(d,J＝8.4Hz,1H),6.92(s,1H),3.99(t,J＝8.4Hz,2H),3.42(d,J＝12.9Hz,2H),3.14(d,J＝6.9Hz,2H),3.02(t,J＝12.1Hz,2H),2.92(dt,J＝7.6,3.9Hz,1H),2.82(t,J＝8.4Hz,2H),2.51(ddd,J＝10.1,6.5,3.5Hz,1H),2.19–2.08(m,1H),2.04(d,J＝14.0Hz,2H),1.60–1.45(m,3H),1.30(dd,J＝13.1,5.8Hz,1H).mp 162-164℃.LRMS[M+H]+:462.2.
实施例34反式-N-(哌啶-4-基甲基)-2-(1-(4-(三氟甲基)苯磺酰)二氢吲哚-5-基)环丙胺(A34)
Figure PCTCN2017087081-appb-000054
制备方法同实施例32，得产物A34，产率为53％。1H NMR(400MHz,MeOD)δ8.02(d,J＝8.2Hz,2H),7.85(d,J＝8.3Hz,2H),7.55(d,J＝8.3Hz,1H),7.10(d,J＝8.4Hz,1H),7.01(s,1H),4.00(t,J＝8.4Hz,2H),3.46(d,J＝13.1Hz,2H),3.19(d,J＝7.0Hz,2H),3.06(td,J＝12.9,2.1Hz,2H),2.98(dt,J＝7.8,4.1Hz,1H),2.91(t,J＝8.4Hz,2H),2.55(ddd,J＝10.1,6.6,3.5Hz,1H),2.22–2.12(m,1H),2.08(d,J＝14.1Hz,2H),1.65–1.51(m,3H),1.36(dd,J＝14.3,6.8Hz,1H).mp 217-221℃.LRMS[M+H]+:480.2.
实施例35反式-N-(哌啶-4-基甲基)-2-(1-(3-(三氟甲基)苯磺酰)二氢吲哚-5-基)环丙胺(A35)
Figure PCTCN2017087081-appb-000055
制备方法同实施例32，得产物A35，产率为47％。1H NMR(400MHz,MeOD)δ8.09(d,J＝7.6Hz,1H),7.99–7.95(m,2H),7.76(t,J＝7.8Hz,1H),7.56(d,J＝8.1Hz,1H),7.12(d,J＝8.1Hz,1H),7.01(s,1H),3.98(t,J＝8.2Hz,2H),3.46(d,J＝12.1Hz,2H),3.19(d,J＝5.4Hz,2H),3.06(t,J＝12.5Hz,2H),2.98(s,1H),2.86(t,J＝8.2Hz,2H),2.61–2.54(m,1H),2.18(s,1H),2.08(d,J＝13.4Hz,2H),1.58(d,J＝7.6Hz,3H),1.38–1.29(m,1H).mp 200-203℃.LRMS[M+H]+:480.2.
实施例36反式-N-(哌啶-4-基甲基)-2-(1-(2-(三氟甲基)苯磺酰)二氢吲哚-5-基)环丙(A36)
Figure PCTCN2017087081-appb-000056
制备方法同实施例32，得产物A36，产率为38％。1H NMR(500MHz,Deuterium Oxide)δ8.07–8.00(m,1H),7.84–7.76(m,1H),7.69–7.63(m,2H),6.99(d,J＝2.0Hz,1H),6.92(dd,J＝7.5,2.0Hz,1H),6.58(d,J＝7.5Hz,1H),4.70(s,2H),4.55(ddd,J＝12.5,8.4,1.6Hz,1H),4.18(ddd,J＝12.4,9.6,7.9Hz,1H),3.19–3.05(m,3H),2.98(ddd,J＝18.7,8.1,1.7Hz,1H),2.79–2.67(m,3H),2.47(d,J＝6.9Hz,2H),1.92(q,J＝7.0Hz,1H),1.66(dq,J＝14.0,7.0Hz,2H),1.39–1.28(m,2H),1.21(hept,J＝6.9Hz,1H),1.02(td,J＝7.0,5.0Hz,1H),0.79(td,J＝7.1,5.0Hz,1H).LRMS[M+H]+:480.2.
实施例37反式-N-(哌啶-4-基甲基)-2-(1-(m-甲苯磺酰)二氢吲哚-5-基)环丙胺(A37)
Figure PCTCN2017087081-appb-000057
制备方法同实施例32，得产物A37，产率为48％。1H NMR(500MHz,Deuterium Oxide)δ7.78(dt,J＝7.3,2.0Hz,1H),7.71(t,J＝2.0Hz,1H),7.61(dt,J＝7.5,2.0Hz,1H),7.54(t,J＝7.4Hz,1H),7.00–6.94(m,2H),6.58(dt,J＝7.3,1.0Hz,1H),4.70(s,2H),4.49(ddd,J＝12.5,6.1,4.5Hz,1H),4.02(dt,J＝12.5,8.7Hz,1H),3.14(dt,J＝12.5,7.1Hz,2H),3.02–2.95(m,2H),2.82–2.69(m,3H),2.47(d,J＝6.9Hz,2H),2.42(s,3H),1.97(q,J＝7.0Hz,1H),1.69(dq,J＝13.8,7.0Hz,2H),1.39–1.18(m,3H),1.01(td,J＝7.0,5.0Hz,1H),0.81(td,J＝7.1,5.0Hz,1H).LRMS[M+H]+:426.2.
实施例38反式-2-(1-(3-氯苯磺酰)二氢吲哚-5-基)-N-(哌啶-4-基甲基)环丙胺(A38)
Figure PCTCN2017087081-appb-000058
制备方法同实施例32，得产物A38，产率为38％。1H NMR(400MHz,MeOD)δ7.77(t,J＝1.8Hz,1H),7.76–7.73(m,1H),7.66(ddd,J＝8.0,2.0,0.9Hz,1H),7.55–7.50(m,2H),7.11(d,J＝8.4Hz,1H),7.02(s,1H),3.96(t,J＝8.4Hz,2H),3.46(d,J＝13.1Hz,2H),3.19(d,J＝6.9Hz,2H),3.06(t,J＝11.8Hz,2H),2.99(dt,J＝7.7,4.0Hz,1H),2.90(t,J＝8.4Hz,2H),2.58(ddd,J＝10.0,6.4,3.3Hz,1H),2.23–2.14(m,1H),2.09(d,J＝14.9Hz,2H),1.64–1.53(m,3H),1.36(dd,J＝14.2,6.9Hz,1H).mp 165-169℃.LRMS[M+H]+:446.2.
实施例39反式-2-(1-(3-甲氧基苯磺酰)二氢吲哚-5-基)-N-(哌啶-4-基甲基)环丙胺(A39)
Figure PCTCN2017087081-appb-000059
制备方法同实施例32，得产物A39，产率为51％。1H NMR(400MHz,MeOD)δ7.54(d,J＝8.0Hz,1H),7.43(t,J＝7.9Hz,1H),7.36(d,J＝7.5Hz,1H),7.23(s,1H),7.19(d,J＝7.8Hz,1H),7.09(d,J＝7.8Hz,1H),7.00(s,1H),3.93(t,J＝8.1Hz,2H),3.77(s,3H),3.47(d,J＝11.7Hz,2H),3.19(d,J＝4.4Hz,2H),3.06(t,J＝12.6Hz,2H),2.98(s,1H),2.86(t,J＝8.2Hz,2H),2.57(s,1H),2.19(s,1H),2.09(d,J＝13.6Hz,2H),1.65–1.53(m,3H),1.35(dd,J＝11.8,7.6Hz,1H).mp 170-174℃.LRMS[M+H]+:442.2.
实施例40反式-2-(1-(甲磺酰)二氢吲哚-5-基)-N-(哌啶-4-基甲基)环丙胺(A40)
Figure PCTCN2017087081-appb-000060
制备方法同实施例32，得产物A40，产率为48％。1H NMR(400MHz,MeOD)δ7.31(d,J＝8.3Hz,1H),7.14(s,1H),7.07(d,J＝8.3Hz,1H),3.98(t,J＝8.5Hz,2H),3.47(d,J＝13.1Hz,2H),3.21(d,J＝6.9Hz,2H),3.15(t,J＝8.5Hz,2H),3.07(t,J＝11.7Hz,2H),3.06–2.94(m,1H),2.90(s,3H),2.63–2.57(m,1H),2.19(s,1H),2.10(d,J＝14.2Hz,2H),1.66–1.51(m,3H),1.38(dd,J＝14.2,6.9Hz,1H).mp 203-206℃.LRMS[M+H]+:350.1.
实施例41反式-N-(哌啶-4-基甲基)-2-(1-(丙基磺酰)二氢吲哚-5-基)环丙胺(A41)
Figure PCTCN2017087081-appb-000061
制备方法同实施例32，得产物A41，产率为39％。1H NMR(400MHz,MeOD)δ7.29(d,J＝8.3Hz,1H),7.12(s,1H),7.05(d,J＝8.4Hz,1H),4.02(t,J＝8.5Hz,2H),3.47(d,J＝13.0Hz,2H),3.21(d,J＝7.0Hz,2H),3.15(t,J＝8.5Hz,2H),3.12–3.05(m,4H),3.01(dd,J＝7.7,3.9Hz,1H),2.58(dd,J＝7.3,3.1Hz,1H),2.19(ddd,J＝11.2,7.5,3.3Hz,1H),2.10(d,J＝15.3Hz,2H),1.87–1.75(m,2H),1.64–1.52(m,3H),1.38(dd,J＝14.3,6.8Hz,1H),1.03(t,J＝7.5Hz,3H).mp 187-191℃.LRMS[M+H]+:378.2.
实施例42反式-N-(哌啶-4-基甲基)-2-(1-(三氟甲磺酰)二氢吲哚-5-基)环丙胺(A42)
Figure PCTCN2017087081-appb-000062
制备方法同实施例32，得产物A42，产率为41％。1H NMR(400MHz,MeOD)δ7.34(d,J＝8.4Hz,1H),7.20(s,1H),7.12(d,J＝8.4Hz,1H),4.25(t,J＝8.3Hz,2H),3.47(d,J＝13.0Hz,2H),3.27–3.19(m,4H),3.12–3.01(m,3H),2.63(ddd,J＝10.3,6.5,3.5Hz,1H),2.26–2.15(m,1H),2.10(d,J＝14.5Hz,2H),1.68–1.53(m,3H),1.41(dd,J＝14.4,6.9Hz,1H).mp 227-230℃.LRMS[M+H]+:404.2.
实施例43反式-2-(1-(环己基磺酰)二氢吲哚-5-基)-N-(哌啶-4-基甲基)环丙胺(A43)
Figure PCTCN2017087081-appb-000063
制备方法同实施例32，得产物A43，产率为40％。1H NMR(400MHz,MeOD)δ7.27(d,J＝8.3Hz,1H),7.10(s,1H),7.02(d,J＝8.4Hz,1H),4.07(t,J＝8.6Hz,2H),3.47(d,J＝13.2Hz,3H),3.21(d,J＝7.0Hz,2H),3.16(t,J＝8.6Hz,2H),3.07(t,J＝11.6Hz,3H),3.02–2.97(m,1H),2.58(ddd,J＝10.3,6.6,3.6Hz,1H),2.23–2.17(m,1H),2.10(d,J＝14.2Hz,2H),2.03(d,J＝12.9Hz,2H),1.84(d,J＝13.2Hz,2H),1.69(d,J＝11.8Hz,1H),1.57(ddd,J＝12.0,7.2,2.5Hz,5H),1.37(dd,J＝14.4,6.8Hz,1H),1.29(dd,J＝7.7,4.6Hz,2H).mp 205-206℃.LRMS[M+H]+:418.3.
实施例44反式-2-(1-(叔丁基磺酰)二氢吲哚-5-基)-N-(哌啶-4-基甲基)环丙胺(A44)
Figure PCTCN2017087081-appb-000064
制备方法同实施例32，得产物A44，产率为40％。1H NMR(500MHz,Deuterium Oxide)δ7.01–6.93(m,2H),6.58(d,J＝7.5Hz,1H),4.70(s,2H),4.49(ddd,J＝12.5,9.7,8.1Hz,1H),4.27(ddd,J＝12.5,8.3,1.3Hz,1H),3.24–3.10(m,3H),2.91(ddd,J＝18.3,9.7,8.4Hz,1H),2.80–2.68(m,3H),2.47(d,J＝6.8Hz,2H),1.99(q,J＝7.0Hz,1H),1.74–1.63(m,2H),1.49(s,9H),1.39–1.31(m,2H),1.33–1.22(m,2H),1.01(td,J＝7.0,4.9Hz,1H),0.79(td,J＝7.0,4.9Hz,1H).LRMS[M+H]+:392.2.
实施例45反式-苯基(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)甲酮(A45)
Figure PCTCN2017087081-appb-000065
制备方法同实施例32，得产物A45，产率为39％。1H NMR(400MHz,DMSO)δ9.70(s,2H),9.06(s,1H),8.94(s,1H),8.20–7.92(m,1H),7.63–7.42(m,5H),7.14–6.93(m,2H),4.00(t,J＝8.1Hz,2H),3.26(d,J＝11.9Hz,2H),3.05(t,J＝8.1Hz,2H),2.99(s,1H),2.92–2.76(m,3H),2.61(s,1H),2.08(s,1H),1.97(d,J＝14.1Hz,2H),1.61(s,1H),1.45(dd,J＝22.6,10.3Hz,2H),1.27–1.10(m,2H).mp 202-204℃.LRMS[M+H]+:376.1.
实施例46反式-萘-2-基(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)甲酮(A46)
Figure PCTCN2017087081-appb-000066
制备方法同实施例32，得产物A46，产率为41％。1H NMR(500MHz,Deuterium Oxide)δ8.19(t,J＝1.5Hz,1H),7.97(dd,J＝7.5,1.6Hz,1H),7.88(ddt,J＝7.3,3.1,1.5Hz,2H),7.66–7.49(m,4H),7.16–7.09(m,2H),4.70(s,2H),4.16(ddd,J＝12.5,8.3,5.0Hz,1H), 3.90(ddd,J＝12.6,9.0,7.1Hz,1H),3.26(ddd,J＝8.8,6.0,3.8Hz,2H),3.15(dt,J＝12.5,7.0Hz,2H),2.82–2.69(m,3H),2.47(d,J＝6.8Hz,2H),1.97(q,J＝7.0Hz,1H),1.70(dq,J＝13.7,6.9Hz,2H),1.39–1.21(m,3H),1.05(td,J＝6.9,4.9Hz,1H),0.79(td,J＝7.0,4.9Hz,1H).LRMS[M+H]+:426.2.
实施例47反式-联苯基-4-基(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)甲酮(A47)
Figure PCTCN2017087081-appb-000067
制备方法同实施例32，得产物A47，产率为42％。1H NMR(400MHz,DMSO)δ9.65(s,2H),9.00(s,1H),8.85(s,1H),7.79(d,J＝8.0Hz,2H),7.74(d,J＝7.5Hz,2H),7.67(d,J＝7.1Hz,2H),7.51(t,J＝7.5Hz,2H),7.42(t,J＝7.4Hz,1H),7.06(M,2H),4.07(t,J＝8.1Hz,2H),3.26(d,J＝13.1Hz,3H),3.07(t,J＝8.0Hz,2H),2.99(d,J＝4.4Hz,2H),2.91–2.80(m,3H),2.60(s,1H),2.07(s,1H),1.97(d,J＝13.2Hz,2H),1.65–1.56(m,1H),1.44(dd,J＝24.9,13.2Hz,3H).mp 179-180℃.LRMS[M+H]+:452.3.
实施例48反式-(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)(3-(三氟甲基)苯基)甲酮(A48)
Figure PCTCN2017087081-appb-000068
制备方法同实施例32，得产物A48，产率为43％。1H NMR(400MHz,DMSO)δ8.08(s,1H),7.94–7.78(m,3H),7.71(t,J＝7.8Hz,1H),7.15–7.00(m,2H),4.05(s,2H),3.44(d,J＝13.0Hz,2H),3.19(d,J＝6.8Hz,2H),3.14(t,J＝8.2Hz,2H),3.04(t,J＝12.0Hz,3H),2.59(s,1H),2.22–2.12(m,1H),2.09(s,2H),1.64–1.49(m,3H),1.38(dd,J＝12.2,5.9Hz,1H).mp 230-232℃.LRMS[M+H]+:444.1.
实施例49反式-2-苯基-1-(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)乙酮(A49)
Figure PCTCN2017087081-appb-000069
制备方法同实施例32，得产物A49，产率为42％。1H NMR(400MHz,MeOD)δ8.07(d,J＝8.3Hz,1H),7.39–7.24(m,5H),7.09(s,1H),7.03(d,J＝8.4Hz,1H),4.17(t,J＝8.4Hz,2H),3.89(s,2H),3.46(d,J＝13.0Hz,2H),3.23–3.14(m,4H),3.10–2.98(m,3H),2.59(ddd,J＝10.3,6.4,3.5Hz,1H),2.24–2.15(m,1H),2.09(d,J＝14.8Hz,2H),1.65–1.52(m,3H),1.38(dd,J＝14.1,6.9Hz,1H).mp 234-237℃.LRMS[M+H]+:390.1.
实施例50反式-苯甲基5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-羧酸酯(A50)
Figure PCTCN2017087081-appb-000070
制备方法同实施例32，得产物A50，产率为43％。1H NMR(400MHz,CD3OD)δ7.45–7.28(m,6H),7.07–6.93(m,2H),5.22(s,2H),4.02(t,J＝7.70Hz,2H),3.44(d,J＝10.2Hz,2H),3.18(s,2H),3.10(t,J＝7.69Hz,2H),3.05–2.90(m,3H),2.55(s,1H),2.18(s,1H),2.07(d,J＝12.6Hz,2H),1.56(s,3H),1.34(s,1H).mp 215-218℃.LRMS[M+H]+:406.2.
实施例51反式-1-(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)乙酮(A51)
Figure PCTCN2017087081-appb-000071
制备方法同实施例32，得产物A51，产率为43％。1H NMR(500MHz,Deuterium Oxide)δ7.08(dq,J＝4.1,2.0Hz,2H),4.70(s,2H),4.19(td,J＝7.5,2.3Hz,2H),3.32(ddd,J＝9.1,6.3,2.0Hz,2H),3.15(dt,J＝12.6,7.1Hz,2H),2.80–2.68(m,3H),2.47(d,J＝6.8Hz,2H),1.97(s,3H),1.96(q,J＝7.0Hz,1H),1.69(dq,J＝13.6,6.9Hz,2H),1.39–1.20(m,3H),1.04(td,J＝7.0,5.0Hz,1H),0.78(td,J＝7.1,5.0Hz,1H).LRMS[M+H]+:314.2.
实施例52反式-2,2,2-三氟-1-(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)乙酮(A52)
Figure PCTCN2017087081-appb-000072
制备方法同实施例32，得产物A52，产率为34％。1H NMR(500MHz,Deuterium Oxide)δ7.47–7.41(m,1H),7.09(dq,J＝3.5,2.0Hz,2H),4.70(s,2H),4.54(ddd,J＝8.2,6.5,3.3Hz,2H),3.41–3.32(m,2H),3.15(dt,J＝12.6,6.9Hz,2H),2.83–2.68(m,3H),2.47(d,J＝6.4Hz,2H),1.96(q,J＝7.0Hz,1H),1.71(q,J＝6.8Hz,2H),1.39–1.26(m,3H),1.04(td,J＝7.0,5.0Hz,1H),0.78(td,J＝6.9,5.0Hz,1H).LRMS[M+H]+:368.2.
实施例53反式-1-(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)丙烷-1-酮(A53)
Figure PCTCN2017087081-appb-000073
制备方法同实施例32，得产物A53，产率为48％。1H NMR(400MHz,MeOD)δ8.07(d,J＝8.4Hz,1H),7.10(s,1H),7.03(d,J＝8.4Hz,1H),4.13(t,J＝8.5Hz,2H),3.47(d,J＝13.3Hz,2H),3.21(d,J＝7.0Hz,3H),3.11–2.90(m,4H),2.61–2.50(m,3H),2.18(s,1H),2.09(d,J＝14.2Hz,2H),1.65–1.51(m,3H),1.39(dd,J＝14.3,6.8Hz,1H),1.20(t,J＝7.4Hz,3H).mp 250-252℃.LRMS[M+H]+:328.2.
实施例54反式-1-(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)丁烷-1-酮(A54)
Figure PCTCN2017087081-appb-000074
制备方法同实施例32，得产物A54，产率为38％。1H NMR(400MHz,MeOD)δ8.06(d,J＝8.4Hz,1H),7.10(s,1H),7.03(d,J＝8.1Hz,1H),4.15(t,J＝8.4Hz,2H),3.47(d,J＝12.7Hz,2H),3.21(d,J＝7.3Hz,3H),3.11–2.93(m,4H),2.58(s,1H),2.51(t,J＝7.5Hz,2H),2.19(s,1H),2.09(d,J＝15.0Hz,2H),1.69(dt,J＝15.2,7.6Hz,2H),1.64–1.51(m,3H),1.45(dd,J＝15.0,7.5Hz,2H),1.38(dd,J＝13.2,6.1Hz,1H),0.99(t,J＝7.3Hz,3H).mp 215-217℃.LRMS[M+H]+:342.2.
实施例55反式-1-(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)戊烷-1-酮(A55)
Figure PCTCN2017087081-appb-000075
制备方法同实施例32，得产物A55，产率为48％。1H NMR(400MHz,MeOD)δ8.06(d,J＝8.4Hz,1H),7.10(s,1H),7.03(d,J＝8.1Hz,1H),4.15(t,J＝8.4Hz,2H),3.47(d,J＝12.7Hz,2H),3.21(d,J＝7.3Hz,3H),3.11–2.93(m,4H),2.58(s,1H),2.51(t,J＝7.5Hz,2H),2.19(s,1H),2.09(d,J＝15.0Hz,2H),1.69(dt,J＝15.2,7.6Hz,2H),1.64–1.51(m,3H),1.45(dd,J＝15.0,7.5Hz,2H),1.38(dd,J＝13.2,6.1Hz,1H),0.99(t,J＝7.3Hz,3H).mp 216-219℃.LRMS[M+H]+:356.3.
实施例56反式-3-甲氧基-1-(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)丙烷-1-酮(A56)
Figure PCTCN2017087081-appb-000076
制备方法同实施例32，得产物A56，产率为42％。1H NMR(400MHz,MeOD)δ8.08(d,J＝8.3Hz,1H),7.12(s,1H),7.05(d,J＝8.1Hz,1H),4.25(s,2H),4.08(t,J＝8.4Hz,2H),3.50–3.45(m,5H),3.25–3.19(m,4H),3.11–3.01(m,3H),2.59(ddd,J＝10.3,6.6,3.7Hz,1H),2.26–2.15(m,1H),2.10(d,J＝14.6Hz,2H),1.65–1.55(m,3H),1.39(dd,J＝14.4,6.8Hz,1H).mp>300℃.LRMS[M+H]+:344.2.
实施例57反式-2-甲基-1-(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)丙烷-1-酮(A57)
Figure PCTCN2017087081-appb-000077
制备方法同实施例32，得产物A57，产率为41％。1H NMR(500MHz,Deuterium Oxide)δ7.45(d,J＝7.4Hz,1H),7.10–7.02(m,2H),4.70(s,2H),4.35(ddd,J＝12.6,9.2,7.7Hz,1H),3.97(ddd,J＝12.4,9.2,3.0Hz,1H),3.42–3.22(m,2H),3.15(dt,J＝12.4,7.1Hz, 2H),3.05(hept,J＝6.8Hz,1H),2.81–2.68(m,3H),2.47(d,J＝6.9Hz,2H),1.98(q,J＝7.0Hz,1H),1.70(dq,J＝13.8,7.0Hz,2H),1.40–1.31(m,2H),1.33–1.14(m,7H),1.03(td,J＝7.0,4.9Hz,1H),0.80(td,J＝7.0,5.0Hz,1H).LRMS[M+H]+:342.2.
实施例58反式-2,2-二甲基-1-(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)丙烷-1-酮(A58)
Figure PCTCN2017087081-appb-000078
制备方法同实施例32，得产物A58，产率为44％。1H NMR(400MHz,CD3OD)δ8.01(d,J＝8.4Hz,1H),7.08(s,1H),7.00(d,J＝8.4Hz,1H),4.29(t,J＝8.1Hz,2H),3.44(d,J＝13.2Hz,2H),3.18(d,J＝6.9Hz,2H),3.12(t,J＝8.1Hz,2H),3.05–2.96(m,3H),2.58–2.52(m,1H),2.20–2.11(m,1H),2.06(d,J＝14.5Hz,2H),1.60–1.50(m,3H),1.37–1.35(m,10H).mp 231-232℃.LRMS[M+H]+:356.2.
实施例59反式-环己基(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)甲酮(A59)
Figure PCTCN2017087081-appb-000079
制备方法同实施例32，得产物A59，产率为50％。1H NMR(400MHz,CD3OD)δ8.05(d,J＝8.4Hz,1H),7.07(s,1H),7.00(d,J＝8.0Hz,1H),4.19(t,J＝8.3Hz,2H),3.45(d,J＝13.1Hz,2H),3.17(t,J＝7.9Hz,2H),3.05(d,J＝12.6Hz,2H),3.02–2.96(m,2H),2.92(d,J＝6.2Hz,1H),2.05(t,J＝14.6Hz,3H),1.90–1.81(m,6H),1.74(d,J＝12.8Hz,2H),1.53(s,2H),1.50(s,1H),1.42–1.37(m,4H),1.34(d,J＝6.7Hz,1H).mp 166-168℃.LRMS[M+H]+:382.3
实施例60反式-环庚基(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)甲酮(A60)
Figure PCTCN2017087081-appb-000080
制备方法同实施例32，得产物A60，产率为41％。1H NMR(500MHz,Deuterium Oxide)δ7.08(dq,J＝3.7,2.0Hz,2H),4.70(s,2H),4.15(t,J＝7.5Hz,2H),3.40–3.25(m,2H),3.15(dt,J＝12.4,7.1Hz,2H),2.83(q,J＝7.1Hz,1H),2.73(dt,J＝12.5,7.1Hz,2H),2.63(p,J＝6.9Hz,1H),2.57–2.44(m,4H),2.15(dq,J＝13.9,7.1Hz,2H),1.95(q,J＝7.0Hz,1H),1.74(dq,J＝14.1,7.1Hz,2H),1.55–1.27(m,10H),0.78(td,J＝7.0,4.9Hz,1H).LRMS[M+H]+:396.2.
实施例61反式-环戊基(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)甲酮(A61)
Figure PCTCN2017087081-appb-000081
制备方法同实施例32，得产物A61，产率为45％。1H NMR(500MHz,Deuterium Oxide)δ7.42(d,J＝7.4Hz,1H),7.10–7.02(m,2H),4.70(s,2H),4.15(t,J＝7.6Hz,2H),3.32 (qt,J＝19.0,7.6Hz,2H),3.20–3.05(m,3H),2.85–2.69(m,3H),2.47(d,J＝6.8Hz,2H),2.10–1.92(m,3H),1.81–1.66(m,4H),1.57–1.27(m,7H),1.03(td,J＝7.0,4.9Hz,1H),0.78(td,J＝7.0,4.9Hz,1H).LRMS[M+H]+:368.2.
实施例62反式-环丁基(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)甲酮(A62)
Figure PCTCN2017087081-appb-000082
制备方法同实施例32，得产物A62，产率为43％。1H NMR(500MHz,Deuterium Oxide)δ7.08(dq,J＝3.6,2.0Hz,2H),4.70(s,2H),4.15(t,J＝7.7Hz,2H),3.43(p,J＝7.0Hz,1H),3.36–3.28(m,2H),3.14(dt,J＝12.5,7.0Hz,2H),2.80–2.68(m,3H),2.55–2.44(m,4H),2.20–2.09(m,2H),2.06–1.84(m,3H),1.69(dq,J＝13.7,6.9Hz,2H),1.38–1.19(m,3H),1.04(td,J＝7.0,5.0Hz,1H),0.78(td,J＝7.0,5.0Hz,1H).LRMS[M+H]+:354.2.
实施例63反式-环丙基(5-(2-(哌啶-4-基甲基氨基)环丙基)二氢吲哚-1-基)甲酮(A63)
Figure PCTCN2017087081-appb-000083
制备方法同实施例32，得产物A63，产率为41％。1H NMR(500MHz,Deuterium Oxide)δ7.40(d,J＝7.5Hz,1H),7.11–7.02(m,2H),4.70(s,2H),4.15(t,J＝7.6Hz,2H),3.36(t,J＝7.6Hz,2H),3.15(dt,J＝12.5,7.1Hz,2H),2.82–2.68(m,3H),2.47(d,J＝6.9Hz,2H),1.98(q,J＝6.9Hz,1H),1.77–1.63(m,3H),1.40–1.29(m,2H),1.24(hept,J＝6.9Hz,1H),1.16–1.08(m,2H),1.02(td,J＝6.9,5.0Hz,1H),0.93(tt,J＝7.2,4.2Hz,2H),0.80(td,J＝7.0,4.9Hz,1H).LRMS[M+H]+:340.2.
实施例64反式-N-(2-(1-(苯磺酰)-1,2,3,4-四氢喹啉-6-基)环丙基)苯胺(A64)
Figure PCTCN2017087081-appb-000084
制备方法同实施例2，得产物A64，产率为41％。1H NMR(500MHz,Deuterium Oxide)δ7.66–7.58(m,1H),7.60–7.49(m,4H),7.23–7.09(m,3H),6.92–6.87(m,1H),6.85–6.78(m,2H),6.71(tt,J＝7.5,2.0Hz,1H),6.58(d,J＝7.5Hz,1H),4.70(s,1H),4.48(td,J＝12.4,3.4Hz,1H),4.04(ddt,J＝12.4,4.5,1.6Hz,1H),2.86(q,J＝7.0Hz,1H),2.77(dtd,J＝15.5,2.9,1.4Hz,1H),2.53(ddd,J＝16.0,13.0,3.0Hz,1H),2.09(q,J＝7.0Hz,1H),1.93–1.79(m,1H),1.68(dqd,J＝13.2,3.0,1.6Hz,1H),1.09(td,J＝6.9,5.0Hz,1H),0.76(td,J＝7.0,5.0Hz,1H).LRMS[M+H]+:405.2.
实施例65反式-N-苯甲基-2-(1-(苯磺酰)-1,2,3,4-四氢喹啉-6-基)环丙胺(A65)
Figure PCTCN2017087081-appb-000085
制备方法同实施例3，得产物A65，产率为39％。LRMS[M+H]+:419.2.
实施例66反式-N-(2-(1-(苯磺酰)-1,2,3,4-四氢喹啉-6-基)环丙基)哌啶-4-胺(A66)
Figure PCTCN2017087081-appb-000086
制备方法同实施例15，得产物A66，产率为41％。1H NMR(500MHz,Deuterium Oxide)δ7.80(dd,J＝7.5,2.0Hz,2H),7.66–7.52(m,3H),7.00–6.93(m,2H),6.58(d,J＝7.4Hz,1H),4.70(s,2H),4.26(dt,J＝12.5,2.9Hz,1H),3.80–3.70(m,1H),3.13(dt,J＝12.4,7.1Hz,2H),2.95–2.85(m,4H),2.81(q,J＝7.0Hz,1H),2.72(p,J＝7.0Hz,1H),2.08–1.94(m,3H),1.93–1.82(m,2H),1.57(dq,J＝14.0,7.1Hz,2H),1.02(td,J＝6.9,4.9Hz,1H),0.81(td,J＝7.0,5.0Hz,1H).LRMS[M+H]+:412.2.
实施例67反式-2-(1-(苯磺酰)-1,2,3,4-四氢喹啉-6-基)-N-(哌啶-4-基甲基)环丙胺(A67)
Figure PCTCN2017087081-appb-000087
制备方法同实施例14，得产物A67，产率为40％。1H NMR(500MHz,Deuterium Oxide)δ7.80(dd,J＝7.6,2.0Hz,2H),7.66–7.52(m,3H),7.01–6.93(m,2H),6.58(d,J＝7.4Hz,1H),4.70(s,2H),4.25(dt,J＝12.3,2.8Hz,1H),3.78–3.69(m,1H),3.16(dt,J＝12.5,7.1Hz,2H),2.92–2.71(m,5H),2.47(d,J＝6.9Hz,2H),2.02–1.93(m,1H),1.92–1.82(m,2H),1.74(dq,J＝13.9,7.0Hz,2H),1.46(hept,J＝6.9Hz,1H),1.34(dq,J＝14.0,7.1Hz,2H),1.02(td,J＝6.9,4.9Hz,1H),0.82(td,J＝7.0,5.0Hz,1H).LRMS[M+H]+:426.2.
实施例68反式-N-(哌啶-4-基甲基)-2-(1-(丙基磺酰)-1,2,3,4-四氢喹啉-6-基)环丙胺(A68)
Figure PCTCN2017087081-appb-000088
制备方法同实施例32，得产物A68，产率为41％。1H NMR(500MHz,Deuterium Oxide)δ6.97–6.91(m,2H),4.70(s,2H),4.18(ddt,J＝12.6,4.0,1.6Hz,1H),4.08(td,J＝12.3,3.2Hz,1H),3.14(dt,J＝12.5,7.1Hz,2H),3.04(td,J＝12.5,3.6Hz,1H),2.97–2.81(m,2H),2.84–2.65(m,4H),2.47(d,J＝6.9Hz,2H),2.18(ddtd,J＝20.6,12.7,8.0,3.6Hz,1H),2.01–1.93(m,2H),1.93–1.79(m,2H),1.68(dq,J＝13.8,7.0Hz,2H),1.38–1.17(m,3H),1.04–0.91(m,4H),0.81(td,J＝7.1,5.0Hz,1H).LRMS[M+H]+:392.2.
实施例69反式-2-(1-(环己基磺酰)-1,2,3,4-四氢喹啉-6-基)-N-(哌啶-4-基甲基)环丙胺(A69)
Figure PCTCN2017087081-appb-000089
制备方法同实施例32，得产物A69，产率为38％。1H NMR(500MHz,Deuterium Oxide) δ6.94(t,J＝3.8Hz,2H),6.58(d,J＝7.5Hz,1H),4.70(s,2H),3.42(s,2H),3.14(dt,J＝12.4,7.1Hz,2H),2.94(d,J＝15.0Hz,1H),2.83(d,J＝15.0Hz,1H),2.79–2.69(m,3H),2.47(s,2H),2.37(dd,J＝12.4,5.9Hz,2H),1.98(d,J＝12.6Hz,2H),1.88(s,2H),1.81–1.68(m,4H),1.72–1.63(m,2H),1.45–1.28(m,5H),1.24(s,1H),1.00(s,1H),0.81(s,1H).LRMS[M+H]+:432.2.
实施例70反式-苯基(6-(2-(哌啶-4-基甲基氨基)环丙基)-3,4-二氢喹啉-1(2H)-基)甲酮(A70)
制备方法同实施例32，得产物A70，产率为32％。1H NMR(500MHz,Deuterium Oxide)δ7.63(d,J＝7.3Hz,1H),7.35–7.21(m,5H),7.12–7.04(m,2H),4.70(s,2H),3.85–3.75(m,2H),3.15(dt,J＝12.4,7.1Hz,2H),3.00–2.92(m,1H),2.84(q,J＝7.1Hz,1H),2.73(dt,J＝12.4,7.1Hz,2H),2.47(d,J＝6.9Hz,2H),2.02–1.81(m,3H),1.74(dq,J＝13.9,7.0Hz,2H),1.46(hept,J＝6.9Hz,1H),1.34(dt,J＝13.2,7.0Hz,2H),1.02(td,J＝7.0,5.0Hz,1H),0.79(td,J＝7.0,4.9Hz,1H).LRMS[M+H]+:390.2.
实施例71反式-1-(6-(2-(哌啶-4-基甲基氨基)环丙基)-3,4-二氢喹啉-1(2H)-基)丁烷-1-酮(A71)
Figure PCTCN2017087081-appb-000091
制备方法同实施例32，得产物A71，产率为42％。1H NMR(500MHz,Deuterium Oxide)δ7.33(d,J＝7.3Hz,1H),7.07–7.01(m,2H),4.70(s,2H),3.67–3.56(m,1H),3.19–3.03(m,3H),2.98(dddd,J＝18.3,3.6,2.4,1.2Hz,1H),2.79–2.65(m,4H),2.60(td,J＝12.6,2.8Hz,1H),2.47(d,J＝6.9Hz,2H),2.03–1.95(m,2H),1.98–1.85(m,2H),1.69(dq,J＝13.9,7.0Hz,2H),1.41–1.27(m,3H),1.22(hept,J＝6.9Hz,1H),1.07–0.94(m,4H),0.77(td,J＝7.1,5.0Hz,1H).LRMS[M+H]+:356.2.
实施例72反式-环己基(6-(2-(哌啶-4-基甲基氨基)环丙基)-3,4-二氢喹啉-1(2H)-基)甲酮(A72)
Figure PCTCN2017087081-appb-000092
制备方法同实施例32，得产物A72，产率为38％。1H NMR(500MHz,Deuterium Oxide)δ7.14(d,J＝7.5Hz,1H),7.05–6.99(m,2H),4.70(s,2H),4.45(s,2H),3.15(dt,J＝12.4,7.1Hz,2H),3.06(d,J＝16.9Hz,1H),2.96(d,J＝16.9Hz,1H),2.79–2.68(m,3H),2.47(s,2H),2.36(s,1H),2.17–2.09(m,2H),2.10(s,2H),1.95(s,1H),1.87–1.64(m,7H),1.52–1.30(m,5H),1.22(s,1H),1.03(s,1H),0.77(s,1H).LRMS[M+H]+:396.3.
实施例73分子水平活性测试
1.LSD1体外活性实验
筛选方法：赖氨酸特异性脱甲基酶1(LSD1)活性筛选
仪器：酶标仪EnvisionTM(PerkinElmer,USA)。
材料：人源重组LSD1，本实验室利用大肠杆菌表达系统表达并纯化获得的融合GST的LSD1蛋白片断(aa158-end)；
LSD1活性检测试剂盒LANCE Ultra LSD1Histone H3-Lysine 4Demethylase Assay，购自Perkin Elmer公司；
H3多肽底物ARTK(me1)QTARKSTGGKAPRKQLA-GG-K(Biotin)-NH2由吉尔生化公司合成。
原理：LSD1能够特异性去除H3多肽底物上K4位赖氨酸上的甲基化修饰，使其变成无甲基化修饰的底物。本方法采用组蛋白H3甲基化多肽(1-24)作为底物，在底物的C段引入生物素标记。当LSD1在FAD的参与下，启动反应，能够去除底物H3K4上的甲基化修饰。在Eu标记的H3K4本底抗体就能够与底物通过抗原抗体反应而结合在一起，同时链霉亲和素标记的受体通过链霉亲和素与生物素的特异性相互作用而结合在一起。从而使得Eu标记的供体能够与链霉亲和素标记的受体相互作用。在荧光共振能量转移中，当由于生物分子相互作用导致两个荧光基团接近时，在激发时被穴状化合物捕获的部分能量将被释放，发射波长为620nm；另一部分能量转移到受体(acceptor)上，发射波长665nm。665nm的发射光仅由供体(donor)引起的FRET产生。所以，当生物分子相互作用时，有两个激发光620nm和665nm；当不存在相互作用时，只有620nm一个激发光。通过检测665nm和620nm两个发射波长的荧光信号比值能反应LSD1去甲基化活性。同时设置空白对照来判定酶活性的强弱。实验采用GSK-2879552作为阳性抑制剂；GSK-2879552的结构分别如下：
Figure PCTCN2017087081-appb-000093
样品处理：样品用DMSO溶解，低温保存，DMSO在最终体系中的浓度控制在不影响检测活性的范围之内。
初筛选择单浓度条件下，例如20μM，对样品的活性进行测试。对于在一定条件下表现出活性的样品，例如抑制率％Inhibition大于50，测试活性剂量依赖关系，即IC50值，通过样品活性对样品浓度进行非线性拟和得到，计算所用软件为Graphpad Prism 5，拟合所使用的模型为sigmoidal dose-response(varible slope)，对于大多数抑制剂筛选模型，将拟合曲线底部和顶部设定为0和100。
实验结果：
Figure PCTCN2017087081-appb-000094
Figure PCTCN2017087081-appb-000095
2.MAOA和MAOB体外活性实验
筛选方法：单胺氧化酶MAOA和MAOB活性筛选
仪器：酶标仪EnvisionTM(PerkinElmer,USA)。
材料：人源重组MAOA，购自Promega公司；人源重组MAOB，购自Sigma公司；
MAOA和MAOB活性检测试剂盒MAO-Glo购自Promega公司。
原理：本方法采用特异性的一种特性萤光素衍生物作为底物，MAOA或MAOB能够催化底物变为萤光素甲酯，其产物萤光素甲酯在萤光素酶的作用下能够差生萤光，从而能够通过萤光信号的强弱来反应MAOA或MAOB的活性。同时设置空白对照来判定酶活性的强弱。实验采用Tranylcypromine作为阳性抑制剂。
样品处理：样品用DMSO溶解，低温保存，DMSO在最终体系中的浓度控制在不影响检测活性的范围之内。
初筛选择单浓度条件下，例如100μM，对样品的活性进行测试。对于在一定条件下表现出活性的样品，例如抑制率％Inhibition大于50，测试活性剂量依赖关系，即IC50值，通过样品活性对样品浓度进行非线性拟和得到，计算所用软件为Graphpad Prism 5，拟合所使用的模型为sigmoidal dose-response(varible slope)，对于大多数抑制剂筛选模型，将拟合曲线底部和顶部设定为0和100。
实验结果：
Figure PCTCN2017087081-appb-000096
Figure PCTCN2017087081-appb-000097
实施例74MTS方法测试化合物对细胞生长抑制活性
实验原理：MTS法检测受试化合物对白血病细胞MV(4:11)的生长抑制作用，其原理是活细胞内的线粒体中琥珀酸脱氢酶能使外源性的噻唑蓝还原为难溶的蓝色结晶Formazan。
材料：白血病细胞株MV4-11：小儿急性淋巴髓细胞白血病，免疫双表型，AF4-MLL融合性t(4,11)，是LSD1抑制剂细胞生长抑制敏感细胞株(Cancer cell.2012,17；21(4):473-487)。
实验方法：
1.取处于对数生长期的MV4-11细胞，精确计数16000cells/mL，将稀释好的细胞液加入96孔板，每孔90μL。
2.取新鲜的培养基，依次加入铺有细胞液的96孔板，每孔90μL。
3.在化合物板中，取浓度为10mM的待测化合物与阳性化合物ORY-1001和GSK2879552，用DMSO依次做3倍浓度梯度稀释，各8个点。
4.分别取稀释好的化合物2μL，分别加入盛有98μL的空白培养基96孔板中，DMSO组以2μLDMSO加入98μL的空白培养基，混匀待用。
5.将用培养基混匀的化合物分别加入铺有细胞的96孔板中，三副孔，每孔20μL，混匀。空白组加入IMDM培养基200μL，DMSO组以用培养基稀释好的DMSO加入180μL含细胞培养基。
6.恒温箱中37℃，5％CO2孵育10天；
7.10天后，加入MTS，孵育2.5h后读值。
实验结果：
Figure PCTCN2017087081-appb-000098
Figure PCTCN2017087081-appb-000099
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种具有如下通式I所示结构的氟取代的环丙胺类化合物，及其外消旋体、R-异构体、S-异构体、其药学上可接受的盐或它们混合物：
    Figure PCTCN2017087081-appb-100001
    其中：
    n＝1，2；
    X为无或-(CH2)1-4、-CH(Ra)(CH2)0-3、-C(Ra)2(CH2)0-3、C3-C6的环烷烃、羰基，或羰基-氧基，其中各个Ra各自独立地为C1-C4烷基；
    Y为磺酰基、羰基或羰基-氧基；
    R1选自-H、取代或未取代的C1-C12烷基、取代或未取代的C3-C12环烷基、取代或未取代的3-12元杂环基(所述的杂环基包括单环、并环、螺环或桥环)、取代或未取代的C6-C10芳基、取代或未取代的5-12元芳杂环基，其中R1具有0、1、2、或3个取代基，所述取代基选自卤素、芳基、杂芳基、C1-C6烷基、-SO2Ra、-NC(O)Ra、-CH2C(O)ORa、-C(O)ORa、-C(O)Ra、-C(O)NRaRb、取代的氨基、氨基、脲、酰胺、磺酰胺、芳烷基和杂芳烷基；其中，所述的杂环基含有选自下组的1-3个杂原子：N、O或S；
    各Ra独立地为氢、苯基、苯基甲基、3,5-二甲基异噁唑-4-基、1,2-二甲基-1H-咪唑-4-基、C3-C7环烷基、C1-C6烷基、C1-C4烷氧基、C1-C3烷基氨基或-NHPh；
    Rb为氢或C1-C3烷基，或当Ra和Rb连接至相同原子时，
    Ra和Rb一起形成5-或6-元杂环烷基环；
    R2选自取代或未取代的C1-C8烷基、取代或未取代的C3-C12环烷基、取代或未取代的C6-C10芳环或者取代或未取代的含有1～4个选自氧、硫和氮中的杂原子的3-12元的芳香杂环；
    其中，所述的取代基选自下组：氘、氚、卤素、未取代或由1-3个卤素取代的C1-C12烷基、未取代或由1-3个卤素或苯基取代的C1-C12烷氧基、未取代或由1-3个卤素取代的C2-C12烯基、未取代或由1-3个卤素取代的C3-C6环烷基、由C1-C6烷氧基取代的C1-C6烷基、由C3-C6环烷基取代的C1-C6烷基、羟基、氰基、硝基、C1-C6直链或支链的羟烷基、未取代或由1-2个C1-C6烷基取代的胺基、羧基、巯基，或未取代或被选自下组的一个或多个取代基取代的苄基：羧基、C2-C6的酯基；或者，取代或未取代的烷基、取代或未取代的环烷基、所述取代的苯环或取代的芳香杂环上任意两个取代基可以与其相邻的碳原子或杂原子一起连接成含有1至3个选自N、O和S中的杂原子的5-7元杂环，所述5-7元杂环非必须地被选自如下基团的取代基所取代：氢、氢的同位素、卤素、三氟甲基、甲氧基、未取代或由1-3个卤素取代的C1-C6直链或支链的烷基、未取代或由1-3个卤素取代的C1-C6直链或支链的烷氧基、或羟基；
    在本发明中，所述卤素为F、Cl、Br或I。
  2. 如权利要求1所述的化合物，其特征在于，所述的R1选自取代或未取代的C3-C12环烷基、取代或未取代的3-10元杂环基、取代或未取代的3-10元芳杂环基(所述的杂环基包括单环、并环、螺环或桥环)、取代或未取代的C6-C10芳基，其中R1具有0、1、 2、或3个取代基，所述取代基选自卤素、芳基、杂芳基、C1-C6烷基、-SO2Ra、-NC(O)Ra、-CH2C(O)ORa、-C(O)ORa、-C(O)Ra、-C(O)NRaRb、取代的氨基、氨基、脲、酰胺、磺酰胺、芳烷基和杂芳烷基；其中，所述的杂环基含有选自下组的1-3个杂原子：N或O。
  3. 如权利要求1所述的化合物，其特征在于，R2选自下组：取代或未取代的苯基、取代或未取代的萘基、取代或未取代的3-7元环烷基；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基所取代：卤素、C1-4烷基、氟代C1-4烷基、C1-4烷氧基。
  4. 如权利要求1所述的化合物，其特征在于，Y为磺酰基或羰基。
  5. 如权利要求1所述的化合物，其特征在于，所述的化合物选自下组：
    Figure PCTCN2017087081-appb-100002
    Figure PCTCN2017087081-appb-100003
    Figure PCTCN2017087081-appb-100004
    Figure PCTCN2017087081-appb-100005
    Figure PCTCN2017087081-appb-100006
    Figure PCTCN2017087081-appb-100007
    Figure PCTCN2017087081-appb-100008
    Figure PCTCN2017087081-appb-100009
  6. 一种赖氨酸特异性脱甲基酶1(LSD1)抑制剂，其特征在于，所述的抑制剂包括如权利要求1～5中任一所述的化合物，其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物。
  7. 如权利要求1所述的式(I)化合物的制备方法，其特征在于，包括步骤：
    Figure PCTCN2017087081-appb-100010
    (e)在惰性溶剂中，用醇类中间体(VI)与亲核试剂进行光延反应，得到反式的吲哚啉硝基环丙烷中间体(VII)；和
    用式(VII)化合物制备式(I)化合物；
    其中，各基团的定义如权利要求1中所述。
  8. 如权利要求1-5任一所述的式(I)化合物的制备方法，其特征在于，所述的制备方法包括步骤：
    Figure PCTCN2017087081-appb-100011
    (j)在惰性溶剂中，用式(XI)与酰氯反应并脱除保护基，得到目标产物(I)；
    其中，各基团的定义如权利要求1中所述。
  9. 一种药物组合物，其特征在于，包括：(A)治疗有效量的如权利要求1-5任一所述的化合物，其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物中的一种或多种；和(B)药学上可接受的载体。
  10. 如权利要求1所述的化合物、其对映异构体、非对映异构体、外消旋体及其混 合物以及其药学上可接受的盐、结晶水合物及溶剂合物的用途，其特征在于，用于制备治疗或预防与赖氨酸特异性脱甲基酶1(LSD1)相关的恶性肿瘤疾病的药物。
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