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WO2022007866A1 - Fused tricyclic derivative, preparation method therefor, and pharmaceutical application thereof - Google Patents

Fused tricyclic derivative, preparation method therefor, and pharmaceutical application thereof Download PDF

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WO2022007866A1
WO2022007866A1 PCT/CN2021/105088 CN2021105088W WO2022007866A1 WO 2022007866 A1 WO2022007866 A1 WO 2022007866A1 CN 2021105088 W CN2021105088 W CN 2021105088W WO 2022007866 A1 WO2022007866 A1 WO 2022007866A1
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mmol
tert
reaction
room temperature
synthesis
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PCT/CN2021/105088
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French (fr)
Chinese (zh)
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吴俊军
陆银锁
肖瑛
吴建立
洪泽新
段振芳
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深圳信立泰药业股份有限公司
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Priority to CN202180044456.6A priority Critical patent/CN115720578A/en
Publication of WO2022007866A1 publication Critical patent/WO2022007866A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon 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

Definitions

  • the invention belongs to the technical field of chemical drugs, and relates to a tricyclic derivative, a preparation method thereof and its application in medicine.
  • the derivatives are inhibitors of proteoglycanase 2 (ADAMTS-5, Aggrecanase-2).
  • the present invention also relates to pharmaceutical compositions containing these compounds and their use in medicines for treating diseases such as osteoarthritis.
  • Osteoarthritis also known as degenerative arthritis, is a degenerative disease with joint pain as the main symptom caused by multi-factor articular cartilage fibrosis, chapped, ulcers, and loss. Loss of mobility and pain, often resulting in the need for total joint replacement, is the most prevalent disease among the elderly and obese.
  • the pathogenesis of OA has not been clearly studied. Its main causes include age, obesity and joint damage. Under the action of these factors, cell metabolism in joint tissue is disordered, cell signal transduction is disordered, and catabolic pathways are activated.
  • Articular cartilage is mainly composed of chondrocytes and cartilage matrix, of which articular cartilage cells only account for a small part of the total volume of articular cartilage, and most of them are composed of extracellular matrix.
  • the extracellular matrix consists of two macromolecular structures: collagen and proteoglycans.
  • the main cause of articular cartilage degeneration in osteoarticular diseases is the degradation of collagen and proteoglycans of the articular cartilage extracellular matrix.
  • proteoglycanase is the development of OA. Potential targets for therapeutic drugs.
  • Aggrecanases are members of the ADAMTS family, which are disintegrins and metalloproteases with a thrombospondin (TS) motif, and consist of secreted zinc metalloproteases.
  • Aggrecanase is the major protease responsible for the cleavage of aggrecan during the early stages of cartilage remodeling, and matrix metalloproteinases (MMPs) become involved in this process during disease development and continue the degradation of collagen. Therefore, aggrecanase activity is considered to be a marker of cartilage degeneration during inflammatory joint diseases such as OA.
  • the ADAMTS family of secreted zinc metalloproteinases includes nineteen members known to bind and degrade extrachondral matrix (ECM) components.
  • ECM extrachondral matrix
  • ADAMTS-1, -4, -5, -8, -9, -15, -16 and -18 members of the ADAMTS family have been found to cleave the major proteoglycan component of cartilage, aggrecan: ADAMTS-1, -4, -5, -8, -9, -15, -16 and -18. Since ADAMTS-1, -8, -9, -15, -16 and -18 expression and/or aggrecanase degrading activity are rather low, it is believed that ADAMTS-4 (aggrecanase-1) and ADAMTS -5 (Aggrecanase-2) are the two main functional aggrecanases.
  • Aggrecanase 1 (ADAMTS-4) and aggrecanase 2 (ADAMTS-5) are two different aggrecanases isolated from cartilage successively. These two proteases specifically cleave the aggrecanase Glu373-Ala374 bond in the IGD region of the aggrecan core protein. Therefore, these proteases have received the most attention in the pathology of arthritic arthropathy as they are the most potent aggrecanases in vitro. The activity of these aggrecanases is critical for the metabolic balance between synthesis and breakdown of aggrecan.
  • TIM-3 tissue inhibitor of matrix metalloproteinases
  • the present invention aims to discover new ADAMTS inhibitors, especially new compounds with inhibitory activity to ADAMTS-5 and ADAMTS-4 and good biological properties, which can be safely applied to the human body.
  • the present invention provides a series of tricyclic derivatives, their preparation methods and their applications in medicine.
  • the present invention provides a series of natricyclic derivatives of formulae selected from the group consisting of natricyclic derivatives of formula (I), (II), (III), (VI) or stereoisomers thereof Conforms, tautomers, pharmaceutically acceptable salts:
  • X is selected from carbon, nitrogen;
  • Y is selected from carbon, nitrogen, oxygen
  • Z is selected from carbon, nitrogen, oxygen
  • T 1 , T 2 , T 3 and T 4 are respectively selected from carbon, nitrogen and sulfur;
  • R 1 is selected from:
  • R 2 is selected from:
  • phenyl fused to a 5-6 membered monocyclic heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or the heterocycloalkyl is optionally substituted by one or more O substitution, or
  • R 3 is selected from:
  • a 4-7 membered monocyclic heterocycloalkyl containing one or more heteroatoms independently selected from N, S and O, or the monocyclic heterocycloalkyl optionally substituted by one or more halogen or -C( O)OC 1-6 alkyl substitution,
  • R 4 is selected from:
  • R 5a , R 5b , R 5c , R 5d or R 5e are independently selected from:
  • R 6a or R 6b are independently selected from:
  • R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g or R 7h are independently selected from H or C 1-6 alkyl;
  • n 0 ⁇ 2 natural numbers
  • the derivatives are selected from the tricyclic derivatives of formula (Ia), (IIa), (IIIa), (VIa) or their stereoisomers, tautomers body, a pharmaceutically acceptable salt,
  • Y, Z, T 1 , T 2 , T 3 , T 4 , R 1 , m, and n are as defined above.
  • the derivatives are selected from the tricyclic derivatives of formula (Ib), (IIb), (IIIb), (VIb) or their stereoisomers, tautomers body, a pharmaceutically acceptable salt,
  • Y, Z, T 1 , T 2 , T 3 , T 4 , R 1 , m, and n are as defined above.
  • the derivative is selected from the group consisting of formula (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (IIc), ( IId), (IIIc) and tricyclic derivatives or stereoisomers, tautomers, pharmaceutically acceptable salts thereof,
  • R 1 and m are as defined above, and R 8 is independently selected from H or C 1-6 alkyl.
  • the derivatives are selected from the tricyclic derivatives of formula (Ij), (Ik) or their stereoisomers, tautomers and pharmaceutically acceptable salts ,
  • R 1 , m are as defined above.
  • the halogen is fluorine, chlorine, bromine and iodine
  • the C 1-6 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, new Amyl, sec-amyl, tert-amyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl;
  • the C 1-6 alkoxy is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-butoxy pentyloxy, isopentyloxy, neopentyloxy, sec-pentyloxy, tert-amyloxy, n-hexyloxy, isohexyloxy, neohexyloxy, sec-hexyloxy, tert-hexyloxy;
  • the C 3-7 monocyclic cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl;
  • the 5-12-membered monocyclic or fused bicyclic heteroaryl is selected from pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxalyl azolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl; pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl; imidazothiazolyl, imidazoimidazolyl; benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl , indolyl, isoindolyl, in
  • R 1 is selected from fluorine, chlorine, bromine, methoxy, Trifluoromethyl group, cyano group
  • the derivatives are selected from the tricyclic derivatives or their stereoisomers, tautomers and pharmaceutically acceptable salts shown in the following table,
  • the pharmaceutically acceptable salt is selected from inorganic acid or organic acid salt.
  • the present invention further provides a pharmaceutical composition, which is characterized by comprising the aforementioned tricyclic derivatives and one or more pharmaceutically acceptable carriers.
  • the present invention provides a pharmaceutical composition, comprising the tricyclic derivatives of the present invention, and the pharmaceutical composition may further comprise pharmaceutically acceptable carriers, excipients, diluents, and adjuvants and at least one of the vehicles.
  • the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament wherein the medicament is used for the preparation of a disease for the treatment and/or prevention of proteoglycanase 2 inhibition pharmaceutical use.
  • the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament refers to the prevention and/or treatment of inflammatory conditions and/or cartilage degeneration and/or cartilage homeostasis destroy.
  • the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament refers to the prevention and/or treatment of osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, malignant hypercalcemia blood disease or multiple myeloma.
  • pharmaceutically acceptable salts pertain to derivatives of compounds of the present invention wherein the parent compound is modified by salt formation with an acid or salt formation with a base.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • the atoms of the molecules of the compounds of the present invention are isotopes, and the isotope derivatization can usually prolong the half-life, reduce the clearance rate, stabilize the metabolism and improve the activity in vivo. Also, an embodiment is included in which at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (sum of protons and neutrons).
  • isotopes included in the compounds of the present invention include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, chlorine atom, which respectively include 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl.
  • radioisotopes that emit radiation as they decay such as 3 H or 14 C, are useful in the topological examination of pharmaceutical formulations or compounds in vivo. Stable isotopes neither decay or change with their amount nor are they radioactive, so they are safe to use.
  • the isotopes can be converted according to general methods by substituting the reagents used in the synthesis with reagents containing the corresponding isotopes.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that make up the compound.
  • compounds can be labeled with radioisotopes, such as deuterium ( 2 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • one or more hydrogen atoms of the compounds of the present invention are substituted by the isotope deuterium ( 2 H).
  • the compounds of the present invention After deuteration, the compounds of the present invention have the effects of prolonging half-life, reducing clearance rate, stabilizing metabolism and improving in vivo activity.
  • the preparation methods of the isotopic derivatives generally include: a phase transfer catalysis method.
  • a phase transfer catalysis method For example, a preferred method of using deuterated phase transfer catalyst (e.g., tetraalkylammonium salts, NBu 4 HSO 4).
  • deuterated phase transfer catalyst e.g., tetraalkylammonium salts, NBu 4 HSO 4
  • the methylene protons of diphenylmethane compounds are exchanged using a phase transfer catalyst, resulting in higher ratios than with deuterated silanes (eg, triethyldeuterated silane) or with Lewis acids such as trichloro in the presence of an acid (eg, methanesulfonic acid) Aluminium is reduced with sodium deuteroborate to introduce higher deuterium.
  • deuterated silanes e.g, triethyldeuterated silane
  • Lewis acids such as trichloro in the presence of an acid (eg, methan
  • pharmaceutically acceptable carrier refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient
  • representative carriers include water, oil , vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical field.
  • excipient generally refers to the carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect.
  • an "effective amount” of one active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating the target disorder, disease or condition.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible through a low energy barrier.
  • a chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution).
  • protontautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some of the bonding electrons.
  • keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • C 1-6 alkyl means an alkane consisting of 1 to 6 carbons, such examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-amyl, cyclopentyl, n-hexyl, isohexyl, neohexyl , sec-hexyl, tert-hexyl, cyclohexyl;
  • haloC 1-6 alkyl refers to the fact that the hydrogen on the alkyl group may be replaced by one or more halogen atoms, which may be the same or different. wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, trifluoromethyl, 1-chloroethyl, difluoromethyl, dichloroethyl, 2,2-difluoro Ethyl, 3,3,3-trifluoropropyl, 2-fluoro-2-methylpropyl, etc.
  • C 1-6 alkoxy refers to the case where the hydrogen on the alkyl group may be replaced by one or more oxygen atoms. wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like;
  • halo C 1-6 alkoxy denotes a hydrogen on the alkoxy group may be one or more identical or different halogen atoms substituted circumstances. wherein the alkoxy group has the meaning as described herein, such examples include, but are not limited to, chloromethoxy, 1-fluoroethoxy, 1,2-fluoro-chloroethoxy, and the like;
  • nitro means -NO 2
  • halogen means fluorine, chlorine, bromine, iodine.
  • halogenated phenyl refers to the fact that the hydrogen on the phenyl group may be replaced by one or more halogen atoms, which may be the same or different. Such examples include, but are not limited to, dichlorophenyl, 3,4-dichlorophenyl.
  • Cycloalkyl refers to a monocyclic or polycyclic non-aromatic hydrocarbon-based ring structure having the specified number of ring atoms. Cycloalkyl groups may have 3 to 10 carbon atoms, especially 3 to 7 carbon atoms.
  • the cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Heteroaryl means a monocyclic or fused polycyclic aromatic ring structure comprising one or more (preferably 1, 2 or 3) heteroatoms independently selected from O, N and S and a specified number of carbon atoms.
  • the aromatic ring structure may have 5 to 12 ring members, preferably a 5-6 membered monocyclic heteroaryl group.
  • Heteroaryl can be, for example, a five- or six-membered monocyclic ring or a fused dicyclic formed from a fused five- and six-membered ring or two fused six-membered rings or, as another example, two fused five-membered rings.
  • ring structure Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • Heteroaryl rings typically contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, eg, a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogens.
  • the number of basic nitrogen atoms present in a heteroaryl group (including any amino substituents of the ring) will be less than five.
  • Examples of five-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, Thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl.
  • Examples of six-membered monocyclic heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.
  • bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazolyl and imidazoimidazolyl.
  • bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, isobenzoxyl oxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolazinyl, purinyl (e.g.
  • bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, pyridopyridyl, quinoxalinyl, quinazolinyl, cinnolinyl , phthalazinyl, naphthyridinyl and pteridyl.
  • heteroaryl groups are those derived from thienyl, pyrrolyl, benzothienyl, benzofuranyl, indolyl, pyridyl, quinolinyl, imidazolyl, oxazolyl, and pyrazinyl.
  • heteroaryl groups examples include the following:
  • heterocycloalkyl refers to a monocyclic or polycyclic stable non-aromatic ring structure comprising one or more heteroatoms independently selected from O, N and S and a specified number of carbon atoms.
  • the non-aromatic ring structure may have 4 to 10 ring members, especially 4 to 7 ring members.
  • the fused heterocyclic ring system can include carbocycles and need only include one heterocycle.
  • heterocycles include, but are not limited to, morpholine, piperidine (eg, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (eg, 1-pyrrolidine) pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (eg 4-tetrahydropyranyl), imidazoline, imidazolidine ketones, oxazolines, thiazolines, 2-pyrazolines, pyrazolidines, piperazines and N-alkylpiperazines, such as N-methylpiperazine.
  • piperidine eg, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl
  • pyrrolidine eg, 1-pyr
  • thiomorpholines and their S-oxides and S,S-dioxides (especially thiomorpholines).
  • Other examples include azetidines, piperidones, piperazinones, and N-alkylpiperidines, such as N-methylpiperidine.
  • heterocycloalkyl and heterocycloalkyl-fused phenyl groups are shown in the following illustrative examples:
  • nitrogen heterocycle means that one or more carbon atoms in a cycloalkyl group are replaced with nitrogen atoms.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the MS was measured using an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).
  • HPLC High performance liquid chromatography
  • CombiFlash rapid preparation instrument uses CombiFlash Rf+LUMEN (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Yinlong HSGF 254 or GF 254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.17mm ⁇ 0.23mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Rushan Shangbang silica gel 100-200 mesh silica gel as the carrier.
  • Reagents LDA- lithium diisopropylamide, THF- tetrahydrofuran, TEA- triethylamine, Dioxane-1,4- dioxane, BH 3 - borane, EDCl-1- ethyl - (3-dimethylaminopropyl aminopropyl)carbodiimide hydrochloride, HOBT-1-hydroxybenzotriazole, DIPEA-N,N-diisopropylethylamine, DMF-N,N-dimethylformamide, K 2 CO 3 - potassium carbonate, DMSO- dimethylsulphoxide, EtOH- ethanol, NaH- sodium hydride, toluene- toluene, rt- room temperature, PdCl 2 (dppf) - [ 1,1'- bis (diphenylphosphino yl) ferrocene] palladium dichloride, Pd (OAc) 2- diox
  • Step A Synthesis of 4-(2-fluorophenyl)-4-hydroxybut-2-ynoic acid ethyl ester
  • Step B Synthesis of (E)-ethyl 4-(2-fluorophenyl)-4-oxobut-2-enoate
  • Step C Synthesis of 1,2,3,4,5a,6-hexahydro-[1,4]diazaindeno[[1,2-a]quinoline-5,7-dione
  • Step D Synthesis of 1,2,3,4,5,5a,6,7-Octahydro-[1,4]diazaindeno[1,2-a]quinoline
  • Step E Synthesis of (5S)-5-cyclopropyl-5-(3-(2,3,5,5a,6,7-hexahydro-[1,4]diazaindeno[1,2- a]quinolin-4(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione
  • Step A Synthesis of 2,3,4a,5-tetrahydro-1H-pyrazino[1,2-a]quinoline-4,6-dione
  • Step B Synthesis of 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline
  • Step C Synthesis of (5S)-5-cyclopropyl-5-(3-(1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline- 3-yl)-3-oxopropyl)imidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • Step C Synthesis of tert-butyl 3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
  • Step D Synthesis of 1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride
  • 3,4,10,10a-Tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester (1.10 g, 4.0 mmol) was added to methanol (10.0 mL) at room temperature ), a solution of hydrochloric acid in dioxane (5.0 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
  • Step E Synthesis of (5S)-5-(3-(3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl )-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(5-chloro-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(5-chloro-2-formylphenyl)piperazine-1-carboxylate (1.87 g, 5.76 mmol) and 4-methylbenzenesulfonylhydrazide (1.13 g, 6.05 mmol) was added to anhydrous ethanol (20.0 mL), and the reaction was carried out at room temperature for 1 hour under the protection of N 2 .
  • Step C Synthesis of tert-butyl 7-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
  • Step D Synthesis of 7-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • Step E Synthesis of (5S)-5-(3-(7-Chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(3-chloro-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(3-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(3-chloro-2-formylphenyl)piperazine-1-carboxylate (2.00 g, 6.16 mmol) and 4-methylbenzenesulfonylhydrazide (1.13 g, 6.47 mmol) was added to anhydrous ethanol (30.8 mL) and reacted at room temperature for 1 hour under the protection of N 2 .
  • Step C Synthesis of 9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
  • Step D Synthesis of 9-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate 924 mg, 3.00 mmol
  • methanol 15.0 mL
  • a solution of hydrochloric acid in dioxane 3.75 mL, 4.0 mol/L was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
  • Step E Synthesis of (5S)-5-(3-(9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(4-chloro-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(4-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(5-chloro-2-formylphenyl)piperazine-1-carboxylate (1.26 g, 3.88 mmol) and 4-methylbenzenesulfonylhydrazide (758.0 mg, 4.07 mmol) was added to anhydrous ethanol (15.0 mL) and reacted at room temperature for 1 hour under the protection of N 2 .
  • Step C Synthesis of 8-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
  • Step D Synthesis of 8-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • Step E Synthesis of (5S)-5-(3-(8-Chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(5-chloro-3-fluoro-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(5-chloro-3-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(5-chloro-3-fluoro-2-formylphenyl)piperazine-1-carboxylate (2.66 g, 7.76 mmol) and 4-methylbenzenesulfonylhydrazide ( 1.52 g, 8.15 mmol) was added to anhydrous ethanol (30.0 mL) and reacted at room temperature for 1 h under the protection of N 2 .
  • Step C Synthesis of tert-butyl 7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
  • Step D Synthesis of 7-chloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (2.00 g, 6.12 mmol) was added to methanol (8.0 mL), and a solution of hydrochloric acid in dioxane (7.65 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
  • Step E Synthesis of (5S)-5-(3-(7-Chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(3,5-difluoro-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(3,5-difluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(3,5-difluoro-2-formylphenyl)piperazine-1-carboxylate (1.50 g, 4.60 mmol) and 4-methylbenzenesulfonylhydrazide (899 mg, 4.80 mmol) was added to anhydrous ethanol (23.0 mL) and reacted at room temperature for 1 h under the protection of N 2 .
  • Step C Synthesis of 7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
  • Step D Synthesis of 7,9-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (1.13 g, 3.64 mM mol) was added to methanol (18.2 mL), hydrochloric acid in dioxane solution (4.5 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
  • Step E Synthesis of (5S)-5-(3-(7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl )-3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(2-chloro-6-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(2-chloro-6-((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(2-chloro-6-formylphenyl)piperazine-1-carboxylate (1.39 g, 4.28 mmol) and 4-methylbenzenesulfonylhydrazide (836 mg, 4.49 mmol) was added to anhydrous ethanol (21.4 mL) and reacted at room temperature for 1 hour under the protection of N 2 .
  • Step C Synthesis of tert-butyl 6-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
  • Step D Synthesis of 6-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • Step E Synthesis of (5S)-5-(3-(6-Chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(4-trifluoromethyl-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(4-trifluoromethyl-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • Step C Synthesis of 8-trifluoromethyl-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
  • Step D Synthesis of 8-trifluoromethyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • Step E Synthesis of (5S)-5-(3-(8-Trifluoromethyl-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl )-3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(4-cyano-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(4-cyano-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • Step C Synthesis of 8-cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
  • Step D Synthesis of 8-cyano-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • Step E Synthesis of (5S)-5-(3-(8-cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(2-fluoro-6-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(2-fluoro-6-((2-tosylhydrazinomethyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(2-fluoro-6-formylphenyl)piperazine-1-carboxylate 350.0 mg, 1.14 mmol
  • 4-methylbenzenesulfonylhydrazide 222.0 mg, 1.19 mmol
  • Step C Synthesis of tert-butyl 6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
  • Step D Synthesis of 6-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate 110.2 mg, 0.38 mmol
  • methanol 5 mL
  • a solution of hydrochloric acid in dioxane (1 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 1 hour.
  • Step E (5S)-5-Cyclopropyl-5-(3-(6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) -yl)-3-oxopropyl)imidazoline-2,4-dione
  • Step A Synthesis of tert-butyl 4-(5-fluoro-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(5-fluoro-2-(((2-tosylhydrazide)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(5-fluoro-2-formylphenyl)piperazine-1-carboxylate 550.0 mg, 1.78 mmol
  • 4-methylbenzenesulfonylhydrazide 348.8 mg, 1.87 mmol
  • Step C Synthesis of tert-butyl 7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
  • Step D Synthesis of 7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate 340.5 mg, 1.16 mmol
  • methanol 5.0 mL
  • a solution of hydrochloric acid in dioxane (1 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 1 hour.
  • Step E Synthesis of (5S)-5-cyclopropyl-5-(3-(7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H )-yl)-3-oxopropyl)imidazoline-2,4-dione
  • Step A Synthesis of tert-butyl 4-(4-fluoro-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(4-fluoro-2-formylphenyl)piperazine-1-carboxylate 700.0 mg, 2.27 mmol
  • 4-methylbenzenesulfonylhydrazide 443.9 mg, 2.38 mmol
  • Step C Synthesis of 8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
  • Step D Synthesis of 8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (192.0 mg, 0.66 mmol) was added In methanol (2.0 mL), a solution of hydrochloric acid in dioxane (821.0 ⁇ L, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
  • Step E Synthesis of (5S)-5-(3-(8-Fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step B Synthesis of 4,5-dichloro-2-fluorobenzaldehyde
  • Step C Synthesis of tert-butyl 4-(4,5-dichloro-2-formylphenyl)piperazine-1-carboxylate
  • Step D Synthesis of (E)-tert-butyl 4-(4,5-dichloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(4,5-dichloro-2-formylphenyl)piperazine-1-carboxylate (1.16 g, 3.23 mmol) and 4-methylbenzenesulfonylhydrazide (632.0 mg, 3.39 mmol) was added to anhydrous ethanol (12.0 mL) and reacted at room temperature for 1 h under the protection of N 2 .
  • Step E Synthesis of tert-butyl 7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
  • Step F Synthesis of 7,8-dichloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate 568.0 mg, 1.65 mg mol
  • methanol 4.0 mL
  • hydrochloric acid in dioxane 2.1 mL, 4.0 mol per liter
  • Step G Synthesis of (5S)-5-(3-(7,8-Dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl )-3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(3-fluoro-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(3-fluoro-2-((2-tosylhydrazide)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(3-fluoro-2-formylphenyl)piperazine-1-carboxylate (2.50 g, 8.11 mmol) and 4-methylbenzenesulfonylhydrazide (1.59 g, 8.51 mmol) was added to anhydrous ethanol (15.0 mL) and reacted at room temperature for 1 hour under the protection of N 2 .
  • Step C Synthesis of 9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
  • Step D Synthesis of 9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (1.50 g, 5.13 mmol) was added In methanol (10 mL), a solution of hydrochloric acid in dioxane (4 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 1 hour.
  • Step E Synthesis of (5S)-5-cyclopropyl-5-(3-(9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H )-yl)-3-oxopropyl)imidazoline-2,4-dione
  • Step A Synthesis of tert-butyl 4-(5-chloro-4-fluoro-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(5-chloro-4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(5-chloro-4-fluoro-2-formylphenyl)piperazine-1-carboxylate (2.40 g, 7.02 mmol) and 4-methylbenzenesulfonylhydrazide ( 1.37 g, 7.37 mmol) was added to anhydrous ethanol (35.0 mL) and reacted at room temperature for 1 h under the protection of N 2 .
  • Step C Synthesis of tert-butyl 7-chloro-8-fluoro--3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
  • Step D Synthesis of 7-chloro-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate 260 mg, 0.80 mmol
  • methanol 4.0 mL
  • a dioxane solution of hydrochloric acid (0.80 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
  • Step E Synthesis of (5S)-5-(3-(7-Chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(4-chloro-5-fluoro-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(4-chloro-5-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • Step C Synthesis of 8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
  • Step D Synthesis of 8-chloro-7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (369 mg, 1.13 mmol) was added to methanol (5.7 mL), a solution of hydrochloric acid in dioxane (1.4 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
  • Step E Synthesis of (5S)-5-(3-(8-Chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(5-chloro-2-formylphenyl)-1,4-diazepane-1-carboxylate
  • Step B Synthesis of (E)-4-(5-Chloro-2-(((2-Tosylhydrazino)methyl)phenyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester
  • tert-butyl 4-(5-chloro-2-formylphenyl)-1,4-diazepane-1-carboxylate (6.20 g, 18.30 mmol) and 4-methyl benzene sulfonyl hydrazide (3.58 mg, 19.22 mmol) was added absolute ethanol (60.0 ml), under N 2, at room temperature for 1 hour.
  • Step C Synthesis of 8-Chloro-4,5,11,11a-tetrahydro-1H-[1,4]diazaindeno[1,2-a]indole-2(1H)-carboxylic acid tert-butyl ester
  • Step D Synthesis of 8-chloro-1,2,3,4,10,10a-hexahydro-1H-[1,4]diazaindeno[1,2-a]indole hydrochloride
  • Step E Synthesis of (5S)-5-(3-(8-Chloro-3,4,10,10a-tetrahydro-1H-[1,4]diazaindeno[1,2-a]indole -2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of 8-Chloro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazaindeno[1,7-a]indole-3-carboxylic acid tert-butyl ester
  • Step B Synthesis of 8-chloro--2,3,4,5,11,11a-hexahydro-1H-[1,4]diazaindeno[1,7-a]indole hydrochloride
  • Step C Synthesis of (5S)-5-(3-(8-Chloro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazaindeno[1,7- a]Indol-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(4-bromo-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(4-bromo-2-((2-tosylhydrazide)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(4-bromo-2-formylphenyl)piperazine-1-carboxylate (3.76 g, 10.18 mmol) and 4-methylbenzenesulfonylhydrazide (1.90 mg, 10.18 mmol) was added to anhydrous ethanol (20.0 mL), and reacted at room temperature for 2 hours under the protection of N 2 .
  • Step C Synthesis of 8-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
  • Step D Synthesis of 8-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 8-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate 100.0 mg, 0.28 mmol
  • methanol 3.0 mL
  • a solution of hydrochloric acid in dioxane (1 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 12 hours under the protection of N 2 .
  • Step E Synthesis of (5S)-5-(3-(8-Bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazoline-2,4-dione
  • Step A Synthesis of tert-butyl 4-(5-bromo-2-formylphenyl)piperazine-1-carboxylate
  • N-tert-butoxycarbonylpiperazine 10.24 g, 55.0 mmol
  • potassium carbonate 8.97 g, 65.0 mmol
  • Step B Synthesis of (E)-tert-butyl 4-(5-bromo-2-((2-tosylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(5-bromo-2-formylphenyl)piperazine-1-carboxylate 9.68 g, 26.2 mmol
  • 4-methylbenzenesulfonylhydrazide 5.13 g, 27.5 mmol
  • Step C Synthesis of tert-butyl 7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
  • Step D Synthesis of 7-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate 900 mg, 2.55 mmol
  • methanol 12.7 mL
  • hydrochloric acid in dioxane 2.5 mL, 4.0 mol/L
  • Step E Synthesis of (5S)-5-(3-(7-Bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(4-fluoro-2-formyl-5-methoxyphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(4-fluoro-5-methoxy-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • Step C Synthesis of 8-fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
  • Step D Synthesis of 8-fluoro-7-methoxy-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • Step E Synthesis of (5S)-5-(3-(8-Fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H )-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(4,5-difluoro-2-formylphenyl)piperazine-1-carboxylate
  • Step D Synthesis of (E)-tert-butyl 4-(4,5-difluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(4,5-difluoro-2-formylphenyl)piperazine-1-carboxylate 500 mg, 1.53 mmol
  • 4-methylbenzenesulfonylhydrazide 300 mg, 1.61 mmol
  • Step E Synthesis of tert-butyl 7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
  • Step F Synthesis of 7,8-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (280 mg, 0.90 mol) was added to methanol (4.5 mL), hydrochloric acid in dioxane solution (0.90 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
  • Step G Synthesis of (5S)-5-(3-(7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl )-3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step C (S)-tert-Butyl 3-(2-bromo-4,5-difluorophenyl)-2-((diphenylmethylene)amino)propanoate
  • Step D Synthesis of (S)-tert-butyl 2-amino-3-(2-bromo-4,5-difluorophenyl)propanoate
  • aqueous phase was adjusted to a pH value of about 10 with 50% sodium hydroxide, then extracted with ethyl acetate (1.5 liters ⁇ 3 times), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated to obtain 714 grams of transparent oil (S)- tert-Butyl 2-amino-3-(2-bromo-4,5-difluorophenyl)propanoate (yield: 89.5%).
  • Step E Resolution of (S)-tert-butyl 2-amino-3-(2-bromo-4,5-difluorophenyl)propanoate
  • Step F Synthesis of (S)-tert-butyl 3-(2-bromo-4,5-difluorophenyl)-2-((2-(tert-butoxy)-2-oxoethyl)amino)propanoate ester
  • Step G Synthesis of (S)-tert-butyl 1-(2-(tert-butoxy)-2-oxoethyl)-5,6-difluoroindole-2-carboxylate
  • Step H Synthesis of (S)-2-(5,6-difluoro-2-(hydroxymethyl)indol-1-yl)ethan-1-ol
  • Step I Synthesis of (S)-7,8-difluoro-2-((trifluoromethyl)sulfonyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2- a]Indole
  • Step J Synthesis of (S)-7,8-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole
  • Step K Synthesis of (S)-5-cyclopropyl-5-(3-((S)-7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a ]Indol-2(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(5-bromo-4-fluoro-2-formylphenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(5-bromo-4-fluoro-2-(((2-tosylhydrazino)methyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(5-bromo-4-fluoro-2-formylphenyl)piperazine-1-carboxylate (2.60 g, 6.71 mmol) and 4-methylbenzenesulfonylhydrazide ( 1.31 g, 7.04 mmol) was added to anhydrous ethanol (25.0 mL) and reacted at room temperature for 1 h under the protection of N 2 .
  • Step C Synthesis of 7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
  • Step D Synthesis of 7-bromo-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate 200.0 mg, 0.54 mmol
  • methanol 2.0 mL
  • a solution of hydrochloric acid in dioxane (674 ⁇ L, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
  • Step E Synthesis of (5S)-5-(3-(7-Bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(2-((2-toluenesulfonylhydrazide)methyl)-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate
  • Step C Synthesis of tert-butyl 7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
  • Step D Synthesis of 7-(trifluoromethyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
  • tert-butyl 7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (710.2 mg, 2.07 mmol) was added to methanol (8 mL), a solution of hydrochloric acid in dioxane (2.1 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 1 hour under the protection of N 2 .
  • Step E Synthesis of (5S)-5-cyclopropyl-5-(3-oxo-3-(7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1, 2-a]Indol-2(1H)-yl)propylimidazoline-2,4-dione
  • Step A Synthesis of tert-butyl 4-(3-formylpyridin-2-yl)piperazine-1-carboxylate
  • Step B Synthesis of (E)-tert-butyl 4-(3-((2-toluenesulfonylbenzylidene)methyl)pyridin-2-ylpiperazine-1-carboxylate
  • Step C Synthesis of 5a,6,8,9-tetrahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine-7(5H)-carboxylic acid tert-butyl ester
  • Step D Synthesis of 5,5a,6,7,8,9-hexahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine hydrochloride
  • Step E Synthesis of (5S)-5-cyclopropyl-5-(3-oxo-3-(5a,6,8,9-tetrahydropyrido[3',2',4,5]pyrrolo [1,2-a]pyrazin-7(5H)-yl)propyl)imidazolidine-2,4-dione
  • Step A Synthesis of 6,7-dichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate
  • the reaction was completed, cooled to room temperature, diluted with ethyl acetate, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL ⁇ 3 times), the organic phases were combined, and the organic phase was first washed with saturated brine (20 mL ⁇ 2 times). , then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure.
  • the crude product was purified by preparative high performance liquid chromatography.
  • Step B Synthesis of (5S)-5-(3-(6,7-dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2( 1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of 7,8-dichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate
  • the reaction was completed, cooled to room temperature, diluted with ethyl acetate, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL ⁇ 3 times), the organic phases were combined, and the organic phase was first washed with saturated brine (20 mL ⁇ 2 times). , then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure.
  • the crude product was purified by preparative high performance liquid chromatography.
  • Step B Synthesis of (5S)-5-(3-(7,8-Dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2( 1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of 6,7,8-Trichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate
  • the reaction was completed, cooled to room temperature, diluted with ethyl acetate, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL ⁇ 3 times), the organic phases were combined, and the organic phase was first washed with saturated brine (20 mL ⁇ 2 times). , then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure.
  • the crude product was purified by preparative high performance liquid chromatography.
  • Step B Synthesis of (5S)-5-(3-(6,7,8-Trichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole- 2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
  • Step A Synthesis of (S)-5-cyclopropyl-5-(3-oxo-3-(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole- 2-yl)propyl)imidazolidine-2,4-dione
  • Step A Synthesis of 6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole acetate
  • Step B Synthesis of (S)-5-(3-(6-Chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3- Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione

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Abstract

A fused tricyclic derivative relating to the technical field of chemical drugs, a preparation method therefor, and a pharmaceutical application thereof. The fused tricyclic derivative is an inhibitor of aggrecanase-2 (ADAMTS-5). Also provided are a pharmaceutical composition comprising the compound and a use of the compound in the preparation of a drug for treating diseases such as osteoarthritis.

Description

并三环类衍生物、其制备方法及其在医药上的应用Tricyclic derivatives, their preparation method and their application in medicine 技术领域technical field
本发明属于化学药物技术领域，涉及并三环类衍生物、其制备方法及其在医药上的应用。具体而言，所述衍生物是蛋白聚糖酶2(ADAMTS-5，Aggrecanase-2)的抑制剂。本发明还涉及包含这些化合物的药物组合物以及使用该化合物治疗骨关节炎等疾病的药物中的用途。The invention belongs to the technical field of chemical drugs, and relates to a tricyclic derivative, a preparation method thereof and its application in medicine. In particular, the derivatives are inhibitors of proteoglycanase 2 (ADAMTS-5, Aggrecanase-2). The present invention also relates to pharmaceutical compositions containing these compounds and their use in medicines for treating diseases such as osteoarthritis.
背景技术Background technique
骨关节炎(Osteoarthfitis，OA)也称为退行性关节炎，是一种由于多因素引起关节软骨纤维化、皲裂、溃疡、脱失而导致的关节疼痛为主要症状的退行性疾病，会造成患者的运动能力丧失和疼痛，最终的结果往往是需要全关节置换，它在老年人和肥胖者中是最普遍的疾病。目前OA发病机制尚未研究明确，其主要的病因包括年龄、肥胖和关节损伤，在这些因素的作用下导致关节组织内细胞代谢的紊乱，细胞信号传导失调，分解代谢途径被激活。Osteoarthritis (OA), also known as degenerative arthritis, is a degenerative disease with joint pain as the main symptom caused by multi-factor articular cartilage fibrosis, chapped, ulcers, and loss. Loss of mobility and pain, often resulting in the need for total joint replacement, is the most prevalent disease among the elderly and obese. At present, the pathogenesis of OA has not been clearly studied. Its main causes include age, obesity and joint damage. Under the action of these factors, cell metabolism in joint tissue is disordered, cell signal transduction is disordered, and catabolic pathways are activated.
关节软骨主要由软骨细胞和软骨基质组成，其中关节软骨细胞只占关节软骨总体积的一小部分，绝大部分由细胞外基质构成。细胞外基质由两种大分子结构组成：胶原和蛋白多糖。在骨关节疾病中关节软骨退化的主要原因是关节软骨细胞外基质的胶原和蛋白聚糖的降解。当蛋白降解酶对关节软骨细胞外基质及基底膜成分的降解远远大于合成、软骨组织及软骨下骨的结构发生改变时，将导致关节功能出现功能异常，因此蛋白聚糖酶的是开发OA治疗药物的潜在靶标。Articular cartilage is mainly composed of chondrocytes and cartilage matrix, of which articular cartilage cells only account for a small part of the total volume of articular cartilage, and most of them are composed of extracellular matrix. The extracellular matrix consists of two macromolecular structures: collagen and proteoglycans. The main cause of articular cartilage degeneration in osteoarticular diseases is the degradation of collagen and proteoglycans of the articular cartilage extracellular matrix. When the degradation of articular cartilage extracellular matrix and basement membrane components by proteolytic enzymes is much greater than that of synthesis, cartilage tissue and subchondral bone structure changes, it will lead to abnormal joint function. Therefore, proteoglycanase is the development of OA. Potential targets for therapeutic drugs.
聚集蛋白聚糖酶是ADAMTS家族的成员，其是具有血小板反应蛋白(TS)基序的解整合素和金属蛋白酶，并且由分泌的锌金属蛋白酶组成。聚集蛋白聚糖酶是在软骨重塑的早期负责聚集蛋白聚糖切割的主要蛋白酶，基质金属蛋白酶(MMP)在疾病发展期间开始参与该过程并继续胶原蛋白的降解。因此，聚集蛋白聚糖酶活性被认为是在OA等炎症性关节疾病期间软骨退化的标志。Aggrecanases are members of the ADAMTS family, which are disintegrins and metalloproteases with a thrombospondin (TS) motif, and consist of secreted zinc metalloproteases. Aggrecanase is the major protease responsible for the cleavage of aggrecan during the early stages of cartilage remodeling, and matrix metalloproteinases (MMPs) become involved in this process during disease development and continue the degradation of collagen. Therefore, aggrecanase activity is considered to be a marker of cartilage degeneration during inflammatory joint diseases such as OA.
分泌性锌金属蛋白酶的ADAMTS家族包括十九个已知结合及降解软骨外基质(ECM)组分的成员。已发现ADAMTS家族的数个成员裂解软骨的主要蛋白聚糖组分——聚集蛋白聚糖：ADAMTS-1、-4、-5、-8、-9、-15、-16和-18。由于ADAMTS-1、-8、-9、-15、-16和-18的表达和/或聚集蛋白聚糖酶降解活性相当低，因此确信ADAMTS-4(聚集蛋白聚糖酶-1)和ADAMTS-5(聚集蛋白聚糖酶-2)为两种主要的功能性聚集蛋白聚糖酶。The ADAMTS family of secreted zinc metalloproteinases includes nineteen members known to bind and degrade extrachondral matrix (ECM) components. Several members of the ADAMTS family have been found to cleave the major proteoglycan component of cartilage, aggrecan: ADAMTS-1, -4, -5, -8, -9, -15, -16 and -18. Since ADAMTS-1, -8, -9, -15, -16 and -18 expression and/or aggrecanase degrading activity are rather low, it is believed that ADAMTS-4 (aggrecanase-1) and ADAMTS -5 (Aggrecanase-2) are the two main functional aggrecanases.
软骨聚集蛋白聚糖酶1(ADAMTS-4)和软骨聚集蛋白聚糖酶2(ADAMTS-5)是软骨中先后分离出的两种不同的软骨聚集蛋白聚糖酶。这两种蛋白酶特异性切割聚集蛋白聚糖核心蛋白在IGD区域的聚集蛋白聚糖酶Glu373-Ala374键。因此，这些蛋白酶在关节炎关节病的病理学中受到最多的关注，因为它们是体外最有效的聚集蛋白聚糖酶。这些聚集蛋白多糖酶的活性对聚集蛋白多糖的合成和分解之间的代谢平衡至关重要。在正常人体中，聚集蛋白多糖分解代谢的控制机制可能与内源性抑制剂有关，如聚集蛋白多糖酶的基质金属蛋白酶组织抑制剂(TIM-3)。但是在OA患者中TIMP-3和ADAMTS-4合成之间的平衡被打乱，代谢大于合成。有研究这认为这可能是因为ADAMTS-4的从头合成或者是ADAMTS-4和ADAMTS-5的翻译后被激活。通过抑制ADAMTS-4和ADAMTS-5可以有效的防止OA软骨中局蛋白糖的降解，防止软骨的退行性变。Aggrecanase 1 (ADAMTS-4) and aggrecanase 2 (ADAMTS-5) are two different aggrecanases isolated from cartilage successively. These two proteases specifically cleave the aggrecanase Glu373-Ala374 bond in the IGD region of the aggrecan core protein. Therefore, these proteases have received the most attention in the pathology of arthritic arthropathy as they are the most potent aggrecanases in vitro. The activity of these aggrecanases is critical for the metabolic balance between synthesis and breakdown of aggrecan. In normal humans, the control mechanism of aggrecan catabolism may be related to endogenous inhibitors, such as tissue inhibitor of matrix metalloproteinases (TIM-3) of aggrecanase. But in OA patients, the balance between TIMP-3 and ADAMTS-4 synthesis is disturbed, and metabolism exceeds synthesis. Some studies suggest that this may be due to the de novo synthesis of ADAMTS-4 or the post-translational activation of ADAMTS-4 and ADAMTS-5. Inhibition of ADAMTS-4 and ADAMTS-5 can effectively prevent the degradation of local proteoglycans in OA cartilage and prevent cartilage degeneration.
因此，本发明意在发现新的ADAMTS抑制剂、特别是对ADAMTS-5和ADAMTS-4具有抑制活性且具有良好的生物性能、能够被安全地应用到人体中的新化合物，本发明也提供用于预防和/或治疗涉及软骨退化、特别是骨关节炎和/或类风湿性关节炎的疾病的所需工具。Therefore, the present invention aims to discover new ADAMTS inhibitors, especially new compounds with inhibitory activity to ADAMTS-5 and ADAMTS-4 and good biological properties, which can be safely applied to the human body. A desired tool for the prevention and/or treatment of diseases involving cartilage degeneration, in particular osteoarthritis and/or rheumatoid arthritis.
发明内容SUMMARY OF THE INVENTION
鉴于现有技术存在的问题，本发明提供了一系列的并三环类衍生物、其制备方法及其在医药上的应用。In view of the problems existing in the prior art, the present invention provides a series of tricyclic derivatives, their preparation methods and their applications in medicine.
具体而言，本发明提供式了一系列并三环类衍生物，所述衍生选自式(I)、(II)、(III)、(VI)的并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐：Specifically, the present invention provides a series of natricyclic derivatives of formulae selected from the group consisting of natricyclic derivatives of formula (I), (II), (III), (VI) or stereoisomers thereof Conforms, tautomers, pharmaceutically acceptable salts:
Figure PCTCN2021105088-appb-000001
Figure PCTCN2021105088-appb-000001
其中：in:
X选自碳、氮；X is selected from carbon, nitrogen;
Y选自碳、氮、氧；Y is selected from carbon, nitrogen, oxygen;
Z选自碳、氮、氧；Z is selected from carbon, nitrogen, oxygen;
T 1、T 2、T 3、T 4分别选自碳、氮、硫； T 1 , T 2 , T 3 and T 4 are respectively selected from carbon, nitrogen and sulfur;
Figure PCTCN2021105088-appb-000002
代表单键或者双键；
Figure PCTCN2021105088-appb-000002
Represents a single bond or a double bond;
其中，A环和B环上未有取代基，或者A环和/或B环上一个以上氢独立的被一个或多个卤素、C 1-6的烷基、卤代C 1-6的烷基、C 1-6的烷氧基、卤代C 1-6的烷氧基所取代； Wherein, there is no substituent on ring A and ring B, or one or more hydrogens on ring A and/or ring B are independently replaced by one or more halogens, C 1-6 alkyl, halogenated C 1-6 alkyl substituted by alkoxy group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group;
C环被一个以上R 1所取代，R 1选自： A C ring is substituted by R 1 above, R 1 is selected from:
氢，hydrogen,
卤素，halogen,
氰基，cyano,
C 1-6的烷基， C 1-6 alkyl,
卤代C 1-6的烷基， halogenated C 1-6 alkyl,
C 1-6的烷氧基， C 1-6 alkoxy,
卤代C 1-6的烷氧基， Halogenated C 1-6 alkoxy,
硝基，nitro,
酰胺基，amide group,
苯基，phenyl,
卤代苯基，halophenyl,
包含1、2或3个独立地选自N、O和S的杂原子的5-12元单环或稠合二环杂芳基、或其任选地被一个或多个独立选择的卤素、C 1-6烷基、C 1-6烷氧基取代，或 5-12 membered monocyclic or fused bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or optionally halogen, independently selected by one or more, C 1-6 alkyl, C 1-6 alkoxy substituted, or
-NR 7gR 7h； -NR 7g R 7h ;
R 2选自： R 2 is selected from:
-氢，-hydrogen,
C 1-6烷基或其任选地被一个或多个独立选择的R 3基团取代， Or C 1-6 alkyl optionally substituted with one or more independently selected R 3 groups,
C 3-7单环环烷基或其任选地被一个或多个独立选择的R 3基团取代， C 3-7 monocyclic cycloalkyl or its optionally substituted with one or more independently selected R 3 groups,
包含1至2个独立地选自N、O和S的杂原子的4-7元单环杂环烷基、或该单环杂环烷基任选地被一个或多个独立选择的C 1-6烷基、-C(＝O)C 1-6烷基或-C(＝O)OC 1-6烷基取代， Containing 1 to 2 substituents independently selected from N, 4-7 membered monocyclic heterocycloalkyl group of O and S, or the monocyclic heterocycloalkyl are optionally substituted with one or more independently selected a C 1 -6 alkyl, -C(=O)C 1-6 alkyl or -C(=O)OC 1-6 alkyl substituted,
苯基或其任选地被一个或多个独立选择的R 4基团取代， Or phenyl optionally substituted with one or more independently selected R 4 groups,
稠合至包含1、2或3个独立地选自N、O和S的杂原子的5-6元单环杂环烷基的苯基、或该杂环烷基任选地被一个或多个＝O取代，或phenyl fused to a 5-6 membered monocyclic heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or the heterocycloalkyl is optionally substituted by one or more =O substitution, or
包含1或2个独立地选自N、O和S的杂原子的5-6元单环杂芳基、或该单环杂芳基任选地被一个或多个独立选择的R 4基团取代； Comprising 1 or 2 heteroatoms independently selected from N, 5-6 membered hetero atoms O and S, aryl, monocyclic heteroaryl, or monocyclic heteroaryl which is optionally substituted with one or more independently selected R 4 group replace;
R 3选自： R 3 is selected from:
卤素，halogen,
羟基，hydroxyl,
氰基，cyano,
C 1-6烷基， C 1-6 alkyl,
C 1-6烷氧基或其任选地被C 1-6烷氧基或苯基取代， C 1-6 alkoxy or optionally substituted by C 1-6 alkoxy or phenyl,
C 1-6硫代烷氧基， C 1-6 thioalkoxy,
包含一个或多个独立地选自N、S和O的杂原子的4-7元单环杂环烷基、或该单环杂环烷基任选地被一个或多个卤素或-C(＝O)OC 1-6烷基取代， A 4-7 membered monocyclic heterocycloalkyl containing one or more heteroatoms independently selected from N, S and O, or the monocyclic heterocycloalkyl optionally substituted by one or more halogen or -C( =O)OC 1-6 alkyl substitution,
苯基，phenyl,
-S(＝O) 2C 1-6烷基， -S(=O) 2 C 1-6 alkyl,
-C(＝O)OR 5a， -C(=O)OR 5a ,
-C(＝O)NR 5bR 5c， -C(=O)NR 5b R 5c ,
-NHC(＝O)OR 5d， -NHC(=O)OR 5d ,
-NHC(＝O)R 5e，或 -NHC(=O)R 5e , or
-NR 6aR 6b； -NR 6a R 6b ;
R 4选自： R 4 is selected from:
卤素，halogen,
羟基，hydroxyl,
氰基，cyano,
C 1-6烷基或其任选地被一个或多个独立选择的卤素、-NR 7aR 7b或-C(＝O)NR 7cR 7d取代， C 1-6 alkyl or optionally substituted with one or more independently selected halogen, -NR 7a R 7b or -C(=O)NR 7c R 7d ,
C 1-6烷氧基或其任选地被-NR 7eR 7f取代，或 C 1-6 alkoxy or optionally substituted by -NR 7e R 7f , or
-S(＝O) 2C 1-6烷基； -S(=O) 2 C 1-6 alkyl;
R 5a、R 5b、R 5c、R 5d或R 5e独立地选自： R 5a , R 5b , R 5c , R 5d or R 5e are independently selected from:
-氢，或- hydrogen, or
-C 1-6烷基或其任选地被OH或C 1-6烷氧基取代， -C 1-6 alkyl or optionally substituted by OH or C 1-6 alkoxy,
R 6a或R 6b独立地选自： R 6a or R 6b are independently selected from:
-氢，或- hydrogen, or
-C 1-6烷基或其任选地被OH、C 1-6烷氧基或苯基取代； -C 1-6 alkyl or optionally substituted with OH, C 1-6 alkoxy or phenyl;
R 7a、R 7b、R 7c、R 7d、R 7e、R 7f、R 7g或R 7h独立地选自H或C 1-6烷基； R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g or R 7h are independently selected from H or C 1-6 alkyl;
n＝0～2自然数；n=0～2 natural numbers;
m＝0～4自然数。m=0～4 natural numbers.
作为本发明的一种优选技术方案，所述衍生物选自式(Ia)、(IIa)、(IIIa)、(VIa)的并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐，As a preferred technical solution of the present invention, the derivatives are selected from the tricyclic derivatives of formula (Ia), (IIa), (IIIa), (VIa) or their stereoisomers, tautomers body, a pharmaceutically acceptable salt,
Figure PCTCN2021105088-appb-000003
Figure PCTCN2021105088-appb-000003
其中，Y、Z、T 1、T 2、T 3、T 4、R 1、m、n如上定义。 Wherein, Y, Z, T 1 , T 2 , T 3 , T 4 , R 1 , m, and n are as defined above.
作为本发明的一种优选技术方案，所述衍生物选自式(Ib)、(IIb)、(IIIb)、(VIb)的并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐，As a preferred technical solution of the present invention, the derivatives are selected from the tricyclic derivatives of formula (Ib), (IIb), (IIIb), (VIb) or their stereoisomers, tautomers body, a pharmaceutically acceptable salt,
Figure PCTCN2021105088-appb-000004
Figure PCTCN2021105088-appb-000004
其中，Y、Z、T 1、T 2、T 3、T 4、R 1、m、n如上定义。 Wherein, Y, Z, T 1 , T 2 , T 3 , T 4 , R 1 , m, and n are as defined above.
作为本发明的一种优选技术方案，所述衍生物选自式(Ic)、(Id)、(Ie)、(If)、(Ig)、(Ih)、(Ii)、(IIc)、(IId)、(IIIc)的并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐，As a preferred technical solution of the present invention, the derivative is selected from the group consisting of formula (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (IIc), ( IId), (IIIc) and tricyclic derivatives or stereoisomers, tautomers, pharmaceutically acceptable salts thereof,
Figure PCTCN2021105088-appb-000005
Figure PCTCN2021105088-appb-000005
其中，R 1、m如上定义，R 8独立地选自H或C 1-6烷基。 wherein, R 1 and m are as defined above, and R 8 is independently selected from H or C 1-6 alkyl.
作为本发明的一种优选技术方案，所述衍生物选自式(Ij)、(Ik)的并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐，As a preferred technical solution of the present invention, the derivatives are selected from the tricyclic derivatives of formula (Ij), (Ik) or their stereoisomers, tautomers and pharmaceutically acceptable salts ,
Figure PCTCN2021105088-appb-000006
Figure PCTCN2021105088-appb-000006
R 1、m如上定义。 R 1 , m are as defined above.
作为本发明的一种优选技术方案，所述卤素为氟、氯、溴、碘；As a preferred technical solution of the present invention, the halogen is fluorine, chlorine, bromine and iodine;
所述C 1-6的烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、仲戊基、叔戊基、正己基、异己基、新己基、仲己基、叔己基； The C 1-6 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, new Amyl, sec-amyl, tert-amyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl;
所述C 1-6的烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基、新戊氧基、仲戊氧基、叔戊氧基、正己氧基、异己氧基、新己氧基、仲己氧基、叔己氧基； The C 1-6 alkoxy is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-butoxy pentyloxy, isopentyloxy, neopentyloxy, sec-pentyloxy, tert-amyloxy, n-hexyloxy, isohexyloxy, neohexyloxy, sec-hexyloxy, tert-hexyloxy;
所述C 3-7单环环烷基选自环丙基、环丁基、环戊基、环己基、环庚基； The C 3-7 monocyclic cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl;
所述5-12元单环或稠合二环杂芳基选自吡咯基、呋喃基、噻吩基、咪唑基、呋咱基、噁唑基、噁二唑基、噁三唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、三唑基、四唑基；吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基；咪唑并噻唑基、咪唑并咪唑基；苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、异苯并噁唑基、苯并异唑基、苯并噻唑基、苯并异噻唑基、异苯并呋喃基、吲哚基、异吲哚基、吲哚嗪基、嘌呤基、吲唑基、吡唑并嘧啶基、三唑并嘧啶基和吡唑并吡啶基；喹啉基、异喹啉基、吡啶并吡啶基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基、萘啶基和喋啶基；以及基、吡咯基、苯并噻吩基、苯并呋喃基、吲哚基、吡啶基、喹啉基、咪唑基、噁唑基和吡嗪基。The 5-12-membered monocyclic or fused bicyclic heteroaryl is selected from pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxalyl azolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl; pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl; imidazothiazolyl, imidazoimidazolyl; benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl , indolyl, isoindolyl, indolazinyl, purinyl, indazolyl, pyrazolopyrimidinyl, triazolopyrimidyl and pyrazolopyridyl; quinolinyl, isoquinolinyl, pyridine pyridyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridyl; and radicals, pyrrolyl, benzothienyl, benzofuranyl, indolyl, Pyridyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.
作为本发明的一种优选技术方案，R 1选自氟、氯、溴，甲氧基、
Figure PCTCN2021105088-appb-000007
三氟甲基、氰基；R 2选自环丙基，n＝0～2自然数；m＝0～4自然数。其中，
Figure PCTCN2021105088-appb-000008
表示连接位点。 As a preferred technical solution of the present invention, R 1 is selected from fluorine, chlorine, bromine, methoxy,
Figure PCTCN2021105088-appb-000007
Trifluoromethyl group, cyano group; R 2 is selected from cyclopropyl group, n=0～2 natural number; m=0～4 natural number. in,
Figure PCTCN2021105088-appb-000008
Indicates the attachment site.
作为本发明的一种优选技术方案，所述衍生物选自式(Ia)、(IIa)、(IIIa)、(VIa)、(Ib)、(IIb)、(IIIb)、(VIb)的并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐，其中Y选自碳；Z选自碳、氮、氧；T 1、T 2、T 3、T 4分别选自碳、硫；
Figure PCTCN2021105088-appb-000009
代表单键或者双键；R 1选自氢、氟、氯、溴，甲氧基、
Figure PCTCN2021105088-appb-000010
三氟甲基、氰基；n＝0～2自然数；m＝0～4自然数 As a preferred technical solution of the present invention, the derivative is selected from the compound of formula (Ia), (IIa), (IIIa), (VIa), (Ib), (IIb), (IIIb), (VIb) Tricyclic derivatives or stereoisomers, tautomers, pharmaceutically acceptable salts thereof, wherein Y is selected from carbon; Z is selected from carbon, nitrogen, oxygen; T 1 , T 2 , T 3 , T 4 are respectively selected from carbon and sulfur;
Figure PCTCN2021105088-appb-000009
Represents a single bond or a double bond; R 1 is selected from hydrogen, fluorine, chlorine, bromine, methoxy,
Figure PCTCN2021105088-appb-000010
Trifluoromethyl, cyano group; n=0～2 natural number; m=0～4 natural number
作为本发明的一种优选技术方案，所述衍生物选自式(Ic)、(Id)、(Ie)、(If)、(Ig)、(Ih)、(Ii)、(IIc)、(IId)、(IIIc)的并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐，其中R 1选自氢、氟、氯、溴，甲氧基、
Figure PCTCN2021105088-appb-000011
三氟甲基、氰基；m＝0～4自然数；R8选自H、甲基。 As a preferred technical solution of the present invention, the derivative is selected from the group consisting of formula (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (IIc), ( IId), (IIIc) and tricyclic derivatives or stereoisomers, tautomers, pharmaceutically acceptable salts thereof, wherein R 1 is selected from hydrogen, fluorine, chlorine, bromine, methoxy,
Figure PCTCN2021105088-appb-000011
Trifluoromethyl group, cyano group; m=0～4 natural number; R8 is selected from H, methyl group.
作为本发明的一种优选技术方案，所述衍生物选自式(Ij)、(Ik)的并三环类衍生物或其立体异构 体、互变异构体、药学上可接受的盐，其中R 1选自氢、氟、氯、溴，甲氧基、
Figure PCTCN2021105088-appb-000012
三氟甲基、氰基；m＝04自然数。 As a preferred technical solution of the present invention, the derivatives are selected from the tricyclic derivatives of formula (Ij), (Ik) or their stereoisomers, tautomers and pharmaceutically acceptable salts , wherein R 1 is selected from hydrogen, fluorine, chlorine, bromine, methoxy,
Figure PCTCN2021105088-appb-000012
Trifluoromethyl, cyano; m=04 natural number.
作为本发明的一种优选技术方案，所述衍生物选自下表中所示并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐，As a preferred technical solution of the present invention, the derivatives are selected from the tricyclic derivatives or their stereoisomers, tautomers and pharmaceutically acceptable salts shown in the following table,
Figure PCTCN2021105088-appb-000013
Figure PCTCN2021105088-appb-000013
Figure PCTCN2021105088-appb-000014
Figure PCTCN2021105088-appb-000014
Figure PCTCN2021105088-appb-000015
Figure PCTCN2021105088-appb-000015
Figure PCTCN2021105088-appb-000016
Figure PCTCN2021105088-appb-000016
Figure PCTCN2021105088-appb-000017
Figure PCTCN2021105088-appb-000017
作为本发明的一种优选技术方案，所述药学上可接受的盐选自无机酸或有机酸成盐。As a preferred technical solution of the present invention, the pharmaceutically acceptable salt is selected from inorganic acid or organic acid salt.
本发明进一步提供了一种药物组合物，其特征在于，包括前述并三环类衍生物和一种以上药学上可接受的载体。The present invention further provides a pharmaceutical composition, which is characterized by comprising the aforementioned tricyclic derivatives and one or more pharmaceutically acceptable carriers.
一方面，本发明提供一种药物组合物，包含本发明所述的并三环类衍生物，所述的药物组合物可进一步包含药学上可接受的载体，赋形剂，稀释剂，辅剂和媒介物中的至少一种。On the one hand, the present invention provides a pharmaceutical composition, comprising the tricyclic derivatives of the present invention, and the pharmaceutical composition may further comprise pharmaceutically acceptable carriers, excipients, diluents, and adjuvants and at least one of the vehicles.
一些实施例中，本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途，其中，所述药物用于制备用于治疗和/或预防蛋白聚糖酶2抑制相关疾病的药物方面的用途。In some embodiments, the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament is used for the preparation of a disease for the treatment and/or prevention of proteoglycanase 2 inhibition pharmaceutical use.
进一步地，本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途，其中，所述药物是指预防和/或治疗炎症状况和/或软骨退化和/或软骨稳态破坏。Further, the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament refers to the prevention and/or treatment of inflammatory conditions and/or cartilage degeneration and/or cartilage homeostasis destroy.
进一步地，本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途，其中，所述 药物是指预防和/或治疗骨质疏松、糖皮质激素诱导的骨质疏松、佩吉特氏病、骨更新异常增加、牙周疾病、牙损失、骨折、类风湿性关节炎、骨关节炎、假体周围骨质溶解、骨生成不完全、转移性骨疾病、恶性高钙血症或多发性骨髓瘤等疾病。Further, the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament refers to the prevention and/or treatment of osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, malignant hypercalcemia blood disease or multiple myeloma.
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。As used herein, "pharmaceutically acceptable salts" pertain to derivatives of compounds of the present invention wherein the parent compound is modified by salt formation with an acid or salt formation with a base.
本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the present invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated and unsolvated forms are equivalent and are intended to be included within the scope of the present invention.
本发明化合物分子的原子是同位素，通过同位素衍生化通常可以延长半衰期、降低清除率、代谢稳定和提高体内活性等效果。并且，包括一个实施方案，其中至少一个原子被具有相同原子数(质子数)和不同质量数(质子和中子和)的原子取代。本发明化合物中包括的同位素的实例包括氢原子、碳原子、氮原子、氧原子、磷原子、硫原子、氟原子、氯原子，其分别包括 2H、 3H、 13C、 14C、 15N、 17O、 18O、 31P、 32P、 35S、 18F、 36Cl。特别的是，随其衰退而发射辐射的放射性同位素例如 3H或 14C可用于药物制剂或者体内化合物的局部解剖学检验。稳定的同位素既不随其量衰减或变化，也不具有放射性，因此其可以安全使用。当构成本发明化合物分子的原子是同位素时，通过用包含相应同位素的试剂替代合成中所用的试剂，可以根据通用方法转化同位素。 The atoms of the molecules of the compounds of the present invention are isotopes, and the isotope derivatization can usually prolong the half-life, reduce the clearance rate, stabilize the metabolism and improve the activity in vivo. Also, an embodiment is included in which at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (sum of protons and neutrons). Examples of isotopes included in the compounds of the present invention include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, chlorine atom, which respectively include 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl. In particular, radioisotopes that emit radiation as they decay, such as 3 H or 14 C, are useful in the topological examination of pharmaceutical formulations or compounds in vivo. Stable isotopes neither decay or change with their amount nor are they radioactive, so they are safe to use. When the atoms making up the molecules of the compounds of the present invention are isotopes, the isotopes can be converted according to general methods by substituting the reagents used in the synthesis with reagents containing the corresponding isotopes.
例如，本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘( 2H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 For example, the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that make up the compound. For example, compounds can be labeled with radioisotopes, such as deuterium ( 2 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
进一步地，本发明的化合物一个或多个氢原子上被同位素氘( 2H)取代，本发明化合物氘代后，具有延长半衰期、降低清除率、代谢稳定和提高体内活性等效果。 Further, one or more hydrogen atoms of the compounds of the present invention are substituted by the isotope deuterium ( 2 H). After deuteration, the compounds of the present invention have the effects of prolonging half-life, reducing clearance rate, stabilizing metabolism and improving in vivo activity.
所述同位素衍生物的制备方法通常包括：相转移催化方法。例如，优选的氘化方法采用相转移催化剂(例如，四烷基铵盐，NBu 4HSO 4)。使用相转移催化剂交换二苯基甲烷化合物的亚甲基质子，导致比在酸(例如，甲磺酸)存在下用氘化硅烷(例如三乙基氘化甲硅烷)或用路易斯酸如三氯化铝采用氘化硼酸钠还原而引入较高的氘。 The preparation methods of the isotopic derivatives generally include: a phase transfer catalysis method. For example, a preferred method of using deuterated phase transfer catalyst (e.g., tetraalkylammonium salts, NBu 4 HSO 4). The methylene protons of diphenylmethane compounds are exchanged using a phase transfer catalyst, resulting in higher ratios than with deuterated silanes (eg, triethyldeuterated silane) or with Lewis acids such as trichloro in the presence of an acid (eg, methanesulfonic acid) Aluminium is reduced with sodium deuteroborate to introduce higher deuterium.
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂载体或介质，代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient, and representative carriers include water, oil , vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical field.
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。The term "excipient" generally refers to the carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of one active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating the target disorder, disease or condition.
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution). For example, protontautomers (also known as prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体，以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art The diastereoisomers were resolved and the pure enantiomers recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
术语“C 1-6的烷基”表示由1至6个碳组成的烷烃，这样的实例包括，但并不限于甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基，正戊基、异戊基、新戊基、仲戊基、叔戊基、环戊基、正己基、异己基、新己基、仲己基、叔己基、环已基； The term "C 1-6 alkyl" means an alkane consisting of 1 to 6 carbons, such examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-amyl, cyclopentyl, n-hexyl, isohexyl, neohexyl , sec-hexyl, tert-hexyl, cyclohexyl;
术语“卤代C 1-6烷基”表示烷基上的氢可以被一个或多个相同或不同卤素原子所取代的情况。其中烷基基团具有如本发明所述的含义，这样的实例包括，但并不限于三氟甲基，1-氯乙基，二氟甲基，二氯乙基，2,2-二氟乙基，3,3,3-三氟丙基，2-氟-2-甲基丙基等。 The term "haloC 1-6 alkyl" refers to the fact that the hydrogen on the alkyl group may be replaced by one or more halogen atoms, which may be the same or different. wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, trifluoromethyl, 1-chloroethyl, difluoromethyl, dichloroethyl, 2,2-difluoro Ethyl, 3,3,3-trifluoropropyl, 2-fluoro-2-methylpropyl, etc.
术语“C 1-6烷氧基”表示烷基上的氢可以被一个或多个氧原子所取代的情况。其中烷基基团具有如本发明所述的含义，这样的实例包括，但并不限于甲氧基，乙氧基，异丙氧基，等； The term "C 1-6 alkoxy" refers to the case where the hydrogen on the alkyl group may be replaced by one or more oxygen atoms. wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like;
术语“卤代C 1-6烷氧基”表示烷氧基上的氢可以被一个或多个相同或不同卤素原子所取代的情况。其中烷氧基基团具有如本发明所述的含义，这样的实例包括，但并不限于氯甲氧基，1-氟乙氧基，1,2-氟-氯乙氧基等； The term "halo C 1-6 alkoxy" denotes a hydrogen on the alkoxy group may be one or more identical or different halogen atoms substituted circumstances. wherein the alkoxy group has the meaning as described herein, such examples include, but are not limited to, chloromethoxy, 1-fluoroethoxy, 1,2-fluoro-chloroethoxy, and the like;
术语“硝基”是指-NO 2； The term "nitro" means -NO 2;
术语“酰胺基”表示-CO-NH-；The term "amido" means -CO-NH-;
术语“卤素”表示氟、氯、溴、碘。The term "halogen" means fluorine, chlorine, bromine, iodine.
术语“卤代的苯基”表示苯基上的氢可以被一个或多个相同或不同卤素原子所取代的情况。这样的实例包括，但并不限于二氯苯基，3，4-二氯苯基。The term "halogenated phenyl" refers to the fact that the hydrogen on the phenyl group may be replaced by one or more halogen atoms, which may be the same or different. Such examples include, but are not limited to, dichlorophenyl, 3,4-dichlorophenyl.
“环烷基”是指具有规定环原子数的单环或多环非芳族烃基环结构。环烷基可具有3至10个碳原子，特别是3至7个碳原子。所述环烷基包括例如单环结构，诸如环丙基、环丁基、环戊基、环己基及环庚基。"Cycloalkyl" refers to a monocyclic or polycyclic non-aromatic hydrocarbon-based ring structure having the specified number of ring atoms. Cycloalkyl groups may have 3 to 10 carbon atoms, especially 3 to 7 carbon atoms. The cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
“杂芳基”表示包含一个或多个(优选1、2或3个)独立地选自O、N和S的杂原子及规定碳原子数的单环或稠合多环芳环结构。具体的讲，芳环结构可具有5至12个环成员，优选5-6元单环杂芳基。杂芳基可为例如五元或六元单环或由稠合的五元和六元环或两个稠合六元环或作为另一实例 的两个稠合五元环形成的稠合二环结构。各环可含有至多四个通常选自氮、硫和氧的杂原子。杂芳基环通常含有至多4个杂原子，更通常至多3个杂原子，更通常至多2个，例如单个杂原子。在一个实施方案中，杂芳基环含有至少一个环氮原子。杂芳基环中的氮原子可为碱性的，如咪唑或吡啶的情形中，或基本上非碱性的，如吲哚或吡咯氮的情形中。一般而言，杂芳基中存在的碱性氮原子数(包括环的任何氨基取代基)将小于五。"Heteroaryl" means a monocyclic or fused polycyclic aromatic ring structure comprising one or more (preferably 1, 2 or 3) heteroatoms independently selected from O, N and S and a specified number of carbon atoms. Specifically, the aromatic ring structure may have 5 to 12 ring members, preferably a 5-6 membered monocyclic heteroaryl group. Heteroaryl can be, for example, a five- or six-membered monocyclic ring or a fused dicyclic formed from a fused five- and six-membered ring or two fused six-membered rings or, as another example, two fused five-membered rings. ring structure. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen. Heteroaryl rings typically contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, eg, a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogens. In general, the number of basic nitrogen atoms present in a heteroaryl group (including any amino substituents of the ring) will be less than five.
五元单环杂芳基的实例包括(但不限于)吡咯基、呋喃基、噻吩基、咪唑基、呋咱基、噁唑基、噁二唑基、噁三唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、三唑基及四唑基。六元单环杂芳基的实例包括(但不限于)吡啶基、吡嗪基、哒嗪基、嘧啶基及三嗪基。含有五元环稠合至另一五元环的二环杂芳基的特定实例包括(但不限于)咪唑并噻唑基和咪唑并咪唑基。含有六元环稠合至五元环的二环杂芳基的特定实例包括(但不限于)苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、异苯并噁唑基、苯并异唑基、苯并噻唑基、苯并异噻唑基、异苯并呋喃基、吲哚基、异吲哚基、吲哚嗪基、嘌呤基(例如腺嘌呤、鸟嘌呤)、吲唑基、吡唑并嘧啶基、三唑并嘧啶基和吡唑并吡啶基。含有两个稠合六元环的二环杂芳基的特定实例包括(但不限于)喹啉基、异喹啉基、吡啶并吡啶基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基、萘啶基和喋啶基。特定杂芳基为衍生自噻吩基、吡咯基、苯并噻吩基、苯并呋喃基、吲哚基、吡啶基、喹啉基、咪唑基、噁唑基和吡嗪基的那些杂芳基。Examples of five-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, Thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl. Examples of six-membered monocyclic heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl. Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazolyl and imidazoimidazolyl. Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, isobenzoxyl oxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolazinyl, purinyl (e.g. adenine, guanine) , indazolyl, pyrazolopyrimidinyl, triazolopyrimidyl and pyrazolopyridyl. Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, pyridopyridyl, quinoxalinyl, quinazolinyl, cinnolinyl , phthalazinyl, naphthyridinyl and pteridyl. Particular heteroaryl groups are those derived from thienyl, pyrrolyl, benzothienyl, benzofuranyl, indolyl, pyridyl, quinolinyl, imidazolyl, oxazolyl, and pyrazinyl.
代表性杂芳基的实例包括以下：Examples of representative heteroaryl groups include the following:
Figure PCTCN2021105088-appb-000018
Figure PCTCN2021105088-appb-000018
其中各W选自NH、O、>C(＝O)、>SO 2和S。 Wherein each W is selected from NH, O,> C (= O),> SO 2 , and S.
稠合至包含1、2或3个独立地选自N、O和S的杂原子的5-6元单环杂环烷基的苯基表示杂环烷的两个相邻的碳原子与苯环上两个相邻的碳原子进行稠合。phenyl fused to a 5-6 membered monocyclic heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S represents two adjacent carbon atoms of the heterocycloalkane and benzene Two adjacent carbon atoms on the ring are fused.
如本文所用，术语“杂环烷基”表示包含一个或多个独立地选自O、N和S的杂原子及规定碳原子数的单环或多环稳定非芳族环结构。非芳族环结构可具有4至10个环成员，特别是4至7个环成员。稠合杂环系统可包括碳环且仅需要包括一个杂环。杂环的实例包括(但不限于)吗啉、哌啶(例如1-哌啶基、2-哌啶基、3-哌啶基及4-哌啶基)、吡咯烷(例如1-吡咯烷基、2-吡咯烷基及3-吡咯烷基)、吡咯烷酮、吡喃、四氢呋喃、四氢噻吩、二恶烷、四氢吡喃(例如4-四氢吡喃基)、咪唑啉、咪唑烷酮、噁唑啉、噻唑啉、2-吡唑啉、吡唑烷、哌嗪和N-烷基哌嗪，诸如N-甲基哌嗪。其他实例包括硫代吗啉及其S-氧化物及S,S-二氧化物(特别是硫代吗啉)。其他实例包括氮杂环丁烷、哌啶酮、哌嗪酮和N-烷基哌啶，诸如N-甲基哌啶。杂环烷基及杂环烷基稠合的苯基的特定实例如以下说明性实例所示：As used herein, the term "heterocycloalkyl" refers to a monocyclic or polycyclic stable non-aromatic ring structure comprising one or more heteroatoms independently selected from O, N and S and a specified number of carbon atoms. The non-aromatic ring structure may have 4 to 10 ring members, especially 4 to 7 ring members. The fused heterocyclic ring system can include carbocycles and need only include one heterocycle. Examples of heterocycles include, but are not limited to, morpholine, piperidine (eg, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (eg, 1-pyrrolidine) pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (eg 4-tetrahydropyranyl), imidazoline, imidazolidine ketones, oxazolines, thiazolines, 2-pyrazolines, pyrazolidines, piperazines and N-alkylpiperazines, such as N-methylpiperazine. Other examples include thiomorpholines and their S-oxides and S,S-dioxides (especially thiomorpholines). Other examples include azetidines, piperidones, piperazinones, and N-alkylpiperidines, such as N-methylpiperidine. Specific examples of heterocycloalkyl and heterocycloalkyl-fused phenyl groups are shown in the following illustrative examples:
Figure PCTCN2021105088-appb-000019
Figure PCTCN2021105088-appb-000019
其中各U选自CH 2、NH、O和S；且各W选自NH、O、>C(＝O)、>SO 2和S。 Wherein each U is selected from CH 2, NH, O and S; and each W is selected from NH, O,> C (= O),> SO 2 , and S.
如本文所用，术语“氮杂环”表示个环烷基中的一个以上碳原子被氮原子替换。As used herein, the term "nitrogen heterocycle" means that one or more carbon atoms in a cycloalkyl group are replaced with nitrogen atoms.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
附图说明Description of drawings
图1，(S)-2-氨基-3-(2-溴-4,5-二氟苯基)丙酸叔丁酯酒石酸盐单晶结构示意图。Figure 1, (S)-2-amino-3-(2-bromo-4,5-difluorophenyl)propionic acid tert-butyl ester tartrate single crystal structure schematic diagram.
具体实施方式detailed description
下面结合实施例对本发明作进一步详细的描述，但发明的实施方式不限于此。The present invention will be further described in detail below with reference to the examples, but the embodiments of the invention are not limited thereto.
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-III核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。 The structures of compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<"6> (ppm). The measurement of NMR was performed by Bruker AVANCE-III nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).
MS的测定用ISQ EC质谱仪(生产商:Thermo,型号:ISQ EC)。The MS was measured using an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).
高效液相色谱法(HPLC)分析使用Thermo U3000 HPLC DAD高效液相色谱仪和Agilent 1260高效液相色谱仪。High performance liquid chromatography (HPLC) analysis was performed using a Thermo U3000 HPLC DAD high performance liquid chromatograph and an Agilent 1260 high performance liquid chromatograph.
CombiFlash快速制备仪使用CombiFlash Rf+LUMEN(TELEDYNE ISCO)。CombiFlash rapid preparation instrument uses CombiFlash Rf+LUMEN (TELEDYNE ISCO).
薄层层析硅胶板使用烟台银龙HSGF 254或GF 254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.17mm～0.23mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。 The thin layer chromatography silica gel plate uses Yantai Yinlong HSGF 254 or GF 254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.17mm ~ 0.23mm, and the size of the TLC separation and purification products is 0.4mm～0.5mm.
硅胶柱色谱法一般使用乳山上邦硅胶100～200目硅胶为载体。Silica gel column chromatography generally uses Rushan Shangbang silica gel 100-200 mesh silica gel as the carrier.
试剂：LDA-二异丙基氨基锂，THF-四氢呋喃，TEA-三乙胺，Dioxane-1，4-二氧六环，BH 3-硼烷，EDCl-1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐，HOBT-1-羟基苯并三唑，DIPEA-N,N-二异丙基乙胺，DMF-N,N-二甲基甲酰胺，K 2CO 3-碳酸钾，DMSO-二甲基亚砜，EtOH-乙醇，NaH-氢化钠，toluene-甲苯，r.t.-室温，PdCl 2(dppf)-[1,1'-双(二苯基膦基)二茂铁]二氯化钯，Pd(OAc)2-乙酸钯，PhMe-甲苯，HCl-dioxane-盐酸的二氧六环，NaCO 3-碳酸钠，MeOH-甲醇，DCE-二氯乙烷，NCS-N-氯代丁二酰亚胺，TfOH-三氟甲磺酸，TFA-三氟乙酸，AcOH-乙酸，(CH2O)n多聚甲醛，CDI-N,N'-羰基二咪唑，LAH-氢化铝锂，PPA-多聚磷酸，TsOH-甲苯磺酸，NBS-N-溴代丁二酰亚胺，BPO-过氧苯甲酰。 Reagents: LDA- lithium diisopropylamide, THF- tetrahydrofuran, TEA- triethylamine, Dioxane-1,4- dioxane, BH 3 - borane, EDCl-1- ethyl - (3-dimethylaminopropyl aminopropyl)carbodiimide hydrochloride, HOBT-1-hydroxybenzotriazole, DIPEA-N,N-diisopropylethylamine, DMF-N,N-dimethylformamide, K 2 CO 3 - potassium carbonate, DMSO- dimethylsulphoxide, EtOH- ethanol, NaH- sodium hydride, toluene- toluene, rt- room temperature, PdCl 2 (dppf) - [ 1,1'- bis (diphenylphosphino yl) ferrocene] palladium dichloride, Pd (OAc) 2- dioxane palladium acetate, PhMe- toluene, HCl-dioxane- hydrochloric acid, NaCO 3 - sodium carbonate, MeOH- methanol, DCE- dichloroacetyl Alkane, NCS-N-chlorosuccinimide, TfOH-trifluoromethanesulfonic acid, TFA-trifluoroacetic acid, AcOH-acetic acid, (CH2O)n paraformaldehyde, CDI-N,N'-carbonyldiimidazole , LAH-lithium aluminum hydride, PPA-polyphosphoric acid, TsOH-toluenesulfonic acid, NBS-N-bromosuccinimide, BPO-benzoyl peroxide.
实施例1Example 1
合成(5S)-5-环丙基-5-(3-(2,3,5,5a,6,7-六氢-[1,4]二氮杂茚并[1,2-a]喹啉-4(1H)-基)-3-氧代丙基)咪唑烷-2,4-二酮Synthesis of (5S)-5-cyclopropyl-5-(3-(2,3,5,5a,6,7-hexahydro-[1,4]diazaindeno[1,2-a]quinoline Lin-4(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000020
Figure PCTCN2021105088-appb-000020
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(2-氟苯基)-4-羟基丁-2-炔酸乙酯Step A: Synthesis of 4-(2-fluorophenyl)-4-hydroxybut-2-ynoic acid ethyl ester
Figure PCTCN2021105088-appb-000021
Figure PCTCN2021105088-appb-000021
零下78摄氏度下，向含有2-氟苯甲醛(500.0毫克，5.1毫摩尔)的四氢呋喃(12.0毫升)中，滴加二异丙基氨基锂(2.7毫升),在该温度下继续反应0.5小时，然后加入丙炔酸乙酯(664.0毫克，5.4毫摩尔)，缓慢升至零摄氏度。At minus 78 degrees Celsius, to tetrahydrofuran (12.0 ml) containing 2-fluorobenzaldehyde (500.0 mg, 5.1 mmol), was added dropwise lithium diisopropylamide (2.7 ml), and the reaction was continued for 0.5 hours at this temperature, Ethyl propiolate (664.0 mg, 5.4 mmol) was then added, slowly warming to zero degrees Celsius.
反应结束，加入饱和氯化铵溶液淬灭，乙酸乙酯萃取(30毫升×3次)，合并有机相，饱和食盐水洗涤(2毫升×3次)，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/8)。得到510.0毫克淡黄色固体4-(2-氟苯基)-4-羟基丁-2-炔酸乙酯(收率：45.0％)。LCMS:RT＝1.65min,[M+H] +＝223.14。 After the reaction was completed, saturated ammonium chloride solution was added to quench, extracted with ethyl acetate (30 mL×3 times), the organic phases were combined, washed with saturated brine (2 mL×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/8). 510.0 mg of ethyl 4-(2-fluorophenyl)-4-hydroxybut-2-ynoic acid was obtained as a pale yellow solid (yield: 45.0%). LCMS: RT=1.65 min, [M+H] + =223.14.
步骤B：合成(E)-4-(2-氟苯基)-4-氧代丁-2-烯酸乙酯Step B: Synthesis of (E)-ethyl 4-(2-fluorophenyl)-4-oxobut-2-enoate
Figure PCTCN2021105088-appb-000022
Figure PCTCN2021105088-appb-000022
室温下，将向含有4-(2-氟苯基)-4-羟基丁-2-炔酸乙酯(510.0毫克，2.3毫摩尔)的1，4-二氧六环(15.0毫升)中，加入三乙胺(464.6毫克，4.6毫摩尔),N 2保护下，60摄氏度反应12小时。 To 4-(2-fluorophenyl)-4-hydroxybut-2-ynoic acid ethyl ester (510.0 mg, 2.3 mmol) in 1,4-dioxane (15.0 mL) at room temperature, Triethylamine (464.6 mg, 4.6 mmol) was added, and the reaction was carried out at 60 degrees Celsius for 12 hours under the protection of N 2 .
反应结束，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/20)。得到362.0毫克淡黄色固体(E)-4-(2-氟苯基)-4-氧代丁-2-烯酸乙酯(收率：71.0％)。LCMS:RT＝2.23min。After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/20). 362.0 mg of (E)-ethyl 4-(2-fluorophenyl)-4-oxobut-2-enoate as a pale yellow solid was obtained (yield: 71.0%). LCMS: RT=2.23 min.
步骤C：合成1,2,3,4,5a,6-六氢-[1,4]二氮杂茚并[[1,2-a]喹啉-5,7-二酮Step C: Synthesis of 1,2,3,4,5a,6-hexahydro-[1,4]diazaindeno[[1,2-a]quinoline-5,7-dione
Figure PCTCN2021105088-appb-000023
Figure PCTCN2021105088-appb-000023
室温下，将向含有(E)-4-(2-氟苯基)-4-氧代丁-2-烯酸乙酯(244.0毫克，1.1毫摩尔)的N,N-二甲基甲酰胺(5.0毫升)中，加入丙二胺(85.4毫克，1.2毫摩尔)和三乙胺(85.4毫克，1.2毫摩尔),N 2保护下，60摄氏度反应过夜。 Add (E)-ethyl 4-(2-fluorophenyl)-4-oxobut-2-enoate (244.0 mg, 1.1 mmol) in N,N-dimethylformamide at room temperature (5.0 mL), propylenediamine (85.4 mg, 1.2 mmol) and triethylamine (85.4 mg, 1.2 mmol) were added, and the reaction was carried out at 60 degrees Celsius overnight under the protection of N 2 .
反应结束，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/5)。得到100.0毫克白色固体1,2,3,4,5a,6-六氢-[1,4]二氮杂茚并[[1,2-a]喹啉-5,7-二酮(收率：40.0％)。LCMS:RT＝1.77min,[M+H] +＝231.42。 After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). 100.0 mg of white solid 1,2,3,4,5a,6-hexahydro-[1,4]diazaindeno[[1,2-a]quinoline-5,7-dione was obtained (yield : 40.0%). LCMS: RT=1.77 min, [M+H] + =231.42.
步骤D：合成1,2,3,4,5,5a,6,7-八氢-[1,4]二氮杂茚并[1,2-a]喹啉Step D: Synthesis of 1,2,3,4,5,5a,6,7-Octahydro-[1,4]diazaindeno[1,2-a]quinoline
Figure PCTCN2021105088-appb-000024
Figure PCTCN2021105088-appb-000024
零摄氏度下，向含有1,2,3,4,5a,6-六氢-[1,4]二氮杂茚并[[1,2-a]喹啉-5,7-二酮(100.0毫克，0.5毫摩尔)的四氢呋喃(2.5毫升)中，滴加硼烷四氢呋喃溶液(1.0毫升，1.0摩尔每升)，N 2保护下，升温至60摄氏度搅拌3小时。 At zero degrees Celsius, to a compound containing 1,2,3,4,5a,6-hexahydro-[1,4]diazaindeno[[1,2-a]quinoline-5,7-dione (100.0 mg, 0.5 mmol) in tetrahydrofuran (2.5 ml) was added dropwise a solution of borane in tetrahydrofuran (1.0 ml, 1.0 moles per liter), under N 2, warmed to 60 ° C for 3 hours.
反应结束，零摄氏度下，向反应液中缓慢滴加水至无气泡产生，混合液用乙酸乙酯(30毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(30毫升×2次)洗涤，然后用无水硫酸钠干燥。最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到48.5毫克白色固体1,2,3,4,5,5a,6,7-八氢-[1,4]二氮杂茚并[1,2-a]喹啉(收率：48.0％)。LCMS:RT＝1.45min,[M+H] +＝203.22。 The reaction was completed, and water was slowly added dropwise to the reaction solution at zero degrees Celsius until no bubbles were generated. The mixed solution was extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (30 mL×2 times), and then dried over anhydrous sodium sulfate. Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 48.5 mg of white solid 1,2,3,4,5,5a,6,7-octahydro-[1,4]diazaindeno[1,2-a]quinoline was obtained (yield: 48.0%) . LCMS: RT=1.45 min, [M+H] + =203.22.
步骤E：合成(5S)-5-环丙基-5-(3-(2,3,5,5a,6,7-六氢-[1,4]二氮杂茚并[1,2-a]喹啉-4(1H)-基)-3-氧代丙基)咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-cyclopropyl-5-(3-(2,3,5,5a,6,7-hexahydro-[1,4]diazaindeno[1,2- a]quinolin-4(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000025
Figure PCTCN2021105088-appb-000025
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和1,2,3,4,5,5a,6,7-八氢-[1,4]二氮杂茚并[1,2-a]喹啉(48.5毫克，0.24毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (50.0 mg, 0.24 mmol) and 1,2,3,4, 5,5a,6,7-Octahydro-[1,4]diazaindeno[1,2-a]quinoline (48.5 mg, 0.24 mmol) was added to N,N-dimethylformamide (2.0 ml), N,N-diisopropylethylamine (156.0 μl) was added dropwise, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 μl) mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2 protection, were reacted at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到35.5毫克白色固体(5S)-5-环丙基-5-(3-(2,3,5,5a,6,7-六氢-[1,4]二氮杂茚并[1,2-a]喹啉-4(1H)-基)-3-氧代丙基)咪唑烷-2,4-二酮(收率：37.4％)。LCMS:RT＝1.82min,[M+H] +＝397.15。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 35.5 mg of white solid (5S)-5-cyclopropyl-5-(3-(2,3,5,5a,6,7-hexahydro-[1,4]diazaindeno[1,2] was obtained -a]Quinolin-4(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione (yield: 37.4%). LCMS: RT=1.82 min, [M+H] + =397.15.
实施例2Example 2
合成(5S)-5-环丙基-5-(3-(1,2,4,4a,5,6-六氢-3H-吡嗪并[1,2-a]喹啉-3-基)-3-氧丙基)咪唑烷-2,4-二酮Synthesis of (5S)-5-cyclopropyl-5-(3-(1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinolin-3-yl )-3-Oxypropyl)imidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000026
Figure PCTCN2021105088-appb-000026
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成2,3,4a,5-四氢-1H-吡嗪并[1,2-a]喹啉-4,6-二酮Step A: Synthesis of 2,3,4a,5-tetrahydro-1H-pyrazino[1,2-a]quinoline-4,6-dione
Figure PCTCN2021105088-appb-000027
Figure PCTCN2021105088-appb-000027
室温下，将向含有(E)-4-(2-氟苯基)-4-氧代丁-2-烯酸乙酯(222.0毫克，1.0毫摩尔)的N,N-二甲基甲酰胺(10.0毫升)中，加入乙二胺(146.0毫克，1.1毫摩尔)和三乙胺(22.0毫克，2.2毫摩尔),N 2保护下，60摄氏度反应过夜。 Add (E)-ethyl 4-(2-fluorophenyl)-4-oxobut-2-enoate (222.0 mg, 1.0 mmol) in N,N-dimethylformamide at room temperature (10.0 ml) was added ethylene diamine (146.0 mg, 1.1 mmol) and triethylamine (22.0 mg, 2.2 mmol), under N 2, 60 ° C overnight.
反应结束，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/5)。得到89.0毫克白色固体2,3,4a,5-四氢-1H-吡嗪并[1,2-a]喹啉-4,6-二酮(收率：41.0％)。LCMS:RT＝1.80min,[M+H] +＝217.11。 After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). 89.0 mg of 2,3,4a,5-tetrahydro-1H-pyrazino[1,2-a]quinoline-4,6-dione were obtained as a white solid (yield: 41.0%). LCMS: RT=1.80 min, [M+H] + =217.11.
步骤B：合成2,3,4,4a,5,6-六氢-1H-吡嗪并[1,2-a]喹啉Step B: Synthesis of 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline
Figure PCTCN2021105088-appb-000028
Figure PCTCN2021105088-appb-000028
零摄氏度下，向含有2,3,4a,5-四氢-1H-吡嗪并[1,2-a]喹啉-4,6-二酮(89.0毫克，0.41毫摩尔)的四氢呋喃(2.5毫升)中，滴加硼烷四氢呋喃溶液(0.8毫升，1.0摩尔每升)，N 2保护下，升温至60摄氏度搅拌3小时。 Add 2,3,4a,5-tetrahydro-1H-pyrazino[1,2-a]quinoline-4,6-dione (89.0 mg, 0.41 mmol) in tetrahydrofuran (2.5 ml), borane tetrahydrofuran solution (0.8 ml, 1.0 mol per liter) was added dropwise, and under the protection of N 2 , the temperature was raised to 60 degrees Celsius and stirred for 3 hours.
反应结束，零摄氏度下，向反应液中缓慢滴加水至无气泡产生，混合液用乙酸乙酯(30毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(30毫升×2次)洗涤，然后用无水硫酸钠干燥。最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到45.4毫克白色固体2,3,4,4a,5,6-六氢-1H-吡嗪并[1,2-a]喹啉(收率：58.5％)。LCMS:RT＝1.46min,[M+H] +＝189.21。 The reaction was completed, and water was slowly added dropwise to the reaction solution at zero degrees Celsius until no bubbles were generated. The mixed solution was extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (30 mL×2 times), and then dried over anhydrous sodium sulfate. Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 45.4 mg of 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline were obtained as a white solid (yield: 58.5%). LCMS: RT=1.46 min, [M+H] + =189.21.
步骤C：合成(5S)-5-环丙基-5-(3-(1,2,4,4a,5,6-六氢-3H-吡嗪并[1,2-a]喹啉-3-基)-3-氧丙基)咪唑烷-2,4-二酮Step C: Synthesis of (5S)-5-cyclopropyl-5-(3-(1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline- 3-yl)-3-oxopropyl)imidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000029
Figure PCTCN2021105088-appb-000029
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和2,3,4,4a,5,6-六氢-1H-吡嗪并[1,2-a]喹啉(45.4毫克，0.24毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (50.0 mg, 0.24 mmol) and 2,3,4,4a, 5,6-Hexahydro-1H-pyrazino[1,2-a]quinoline (45.4 mg, 0.24 mmol) was added to N,N-dimethylformamide (2.0 mL) and N,N was added dropwise - Diisopropylethylamine (156.0 μl) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1- hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到25.1毫克白色固体(5S)-5-环丙基-5-(3-(1,2,4,4a,5,6-六氢-3H-吡嗪并[1,2-a]喹啉-3-基)-3-氧丙基)咪唑烷-2,4-二酮(收率：27.3％)。LCMS:RT＝1.84min,[M+H] +＝383.15。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 25.1 mg of white solid (5S)-5-cyclopropyl-5-(3-(1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline was obtained -3-yl)-3-oxopropyl)imidazolidine-2,4-dione (yield: 27.3%). LCMS: RT=1.84 min, [M+H] + =383.15.
实施例3Example 3
合成(5S)-5-(3-(3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5 -Cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000030
Figure PCTCN2021105088-appb-000030
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000031
Figure PCTCN2021105088-appb-000031
室温下，向含有2-氟苯甲醛(1.40克，11.33毫摩尔)的二甲基亚砜(12.0毫升)中加入N-叔丁氧羰基哌嗪(2.53克，13.60毫摩尔)和碳酸钾(2.03克，14.73毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2-fluorobenzaldehyde (1.40 g, 11.33 mmol) in dimethyl sulfoxide (12.0 mL) was added N-tert-butoxycarbonylpiperazine (2.53 g, 13.60 mmol) and potassium carbonate ( under 2.03 g, 14.73 mmol), N 2 protection for 12 h at 95 ° C.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和 食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到1.66克淡黄色固体4-(2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：50.5％)。LCMS:RT＝2.16min,[M+H] +＝291.42。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 1.66 g of tert-butyl 4-(2-formylphenyl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 50.5%). LCMS: RT=2.16 min, [M+H] + =291.42.
步骤B：合成(E)-4-(2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000032
Figure PCTCN2021105088-appb-000032
室温下，将4-(2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(1.66克，5.70毫摩尔)和4-甲基苯磺酰肼(1.11克，5.99毫摩尔)加入无水乙醇(20.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(2-formylphenyl)piperazine-1-carboxylate (1.66 g, 5.70 mmol) and 4-methylbenzenesulfonylhydrazide (1.11 g, 5.99 mmol) were added absolute ethanol (20.0 ml), under N 2, at room temperature for 1 hour.
反应结束，蒸干溶剂得到2.62克类白色固体(E)-4-(2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.20min,[M+H] +＝459.12。 After the reaction was completed, the solvent was evaporated to dryness to obtain 2.62 g of off-white solid (E)-4-(2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate tert-butyl ester. No need Purified and used directly in the next reaction. LCMS: RT=2.20 min, [M+H] + =459.12.
步骤C：合成3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of tert- butyl 3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
Figure PCTCN2021105088-appb-000033
Figure PCTCN2021105088-appb-000033
室温下，向含有(E)-4-(2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(2.62克，5.70毫摩尔)的甲苯(30.0毫升)中，分批加入氢化钠(273.6毫克，6.84毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。To a solution containing (E)-tert-butyl 4-(2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (2.62 g, 5.70 mmol) at room temperature In toluene (30.0 mL), sodium hydride (273.6 mg, 6.84 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)溶解，先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到1.10克淡黄色固体3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：70.2％)。LCMS:RT＝2.27min,[M+H] +＝275.21。 The reaction was completed, cooled to room temperature, dissolved in ethyl acetate (50 mL), washed with saturated brine (50 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 1.10 g of tert- butyl 3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a pale yellow solid (yield: 70.2%). LCMS: RT=2.27 min, [M+H] + =275.21.
步骤D：合成1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000034
Figure PCTCN2021105088-appb-000034
室温下，将3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(1.10克，4.0毫摩尔)加入甲醇(10.0毫升)中，滴加盐酸的二氧六环溶液(5.0毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 3,4,10,10a-Tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester (1.10 g, 4.0 mmol) was added to methanol (10.0 mL) at room temperature ), a solution of hydrochloric acid in dioxane (5.0 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到1.20克类白色固体1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.59min,[M+H] +＝175.18。 After the reaction was completed, the solvent was evaporated to dryness to obtain 1.20 g of off-white solid 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.59 min, [M+H] + =175.18.
步骤E：合成(5S)-5-(3-(3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl )-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000035
Figure PCTCN2021105088-appb-000035
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(45.6毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (50.0 mg, 0.24 mmol) and 1,2,3,4, 10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (45.6 mg, 0.26 mmol) was added to N,N-dimethylformamide (2.0 mL) and N,N was added dropwise - Diisopropylethylamine (156.0 μl) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1- hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到35.0毫克白色固体(5S)-5-(3-(3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：39.5％)。LCMS:RT＝1.90min,[M+H] +＝369.23。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 35.0 mg of white solid (5S)-5-(3-(3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropane was obtained yl)-5-cyclopropylimidazolidine-2,4-dione (yield: 39.5%). LCMS: RT=1.90 min, [M+H] + =369.23.
实施例4Example 4
合成(5S)-5-(3-(7-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(7-Chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropane yl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000036
Figure PCTCN2021105088-appb-000036
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(5-氯-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(5-chloro-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000037
Figure PCTCN2021105088-appb-000037
室温下，向含有2-氟-4-氯苯甲醛(2.00克，12.61毫摩尔)的二甲基亚砜(12.0毫升)中加入N-叔丁氧羰基哌嗪(2.82克，15.13毫摩尔)和碳酸钾(2.26克，16.39毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2-fluoro-4-chlorobenzaldehyde (2.00 g, 12.61 mmol) in dimethyl sulfoxide (12.0 mL) was added N-tert-butoxycarbonylpiperazine (2.82 g, 15.13 mmol) at room temperature and potassium carbonate (2.26 g, 16.39 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到1.87克淡黄色固体4-(5-氯-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：45.7％)。LCMS:RT＝2.16min,[M+H] +＝325.20。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 1.87 g of tert-butyl 4-(5-chloro-2-formylphenyl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 45.7%). LCMS: RT=2.16 min, [M+H] + =325.20.
步骤B：合成(E)-4-(5-氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000038
Figure PCTCN2021105088-appb-000038
室温下，将4-(5-氯-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(1.87克，5.76毫摩尔)和4-甲基苯磺酰肼(1.13克，6.05毫摩尔)加入无水乙醇(20.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(5-chloro-2-formylphenyl)piperazine-1-carboxylate (1.87 g, 5.76 mmol) and 4-methylbenzenesulfonylhydrazide (1.13 g, 6.05 mmol) was added to anhydrous ethanol (20.0 mL), and the reaction was carried out at room temperature for 1 hour under the protection of N 2 .
反应结束，蒸干溶剂得到3.10克类白色固体(E)-4-(5-氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.21min,[M+H] +＝493.22。 The reaction was completed, and the solvent was evaporated to dryness to obtain 3.10 g of off-white solid (E)-4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylic acid tertiary Butyl ester. Without purification, it was directly used in the next reaction. LCMS: RT=2.21 min, [M+H] + =493.22.
步骤C：合成7-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of tert-butyl 7-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
Figure PCTCN2021105088-appb-000039
Figure PCTCN2021105088-appb-000039
室温下，向含有(E)-4-(5-氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(1.55克，3.14毫摩尔)的甲苯(20.0毫升)中，分批加入氢化钠(138.2毫克，3.45毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-tert-butyl 4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (1.55 g, 3.14 g) at room temperature mmol) in toluene (20.0 mL), sodium hydride (138.2 mg, 3.45 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)溶解，先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到500.00毫克淡黄色固体7-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：51.6％)。LCMS:RT＝2.23min,[M+H] +＝309.21。 The reaction was completed, cooled to room temperature, dissolved in ethyl acetate (50 mL), washed with saturated brine (50 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 500.00 mg of tert-butyl 7-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a pale yellow solid (yield: 51.6%) . LCMS: RT=2.23 min, [M+H] + =309.21.
步骤D：合成7-氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 7-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000040
Figure PCTCN2021105088-appb-000040
室温下，将7-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(500.0毫克，1.62毫摩尔)加入甲醇(8.0毫升)中，滴加盐酸的二氧六环溶液(2.02毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 7-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (500.0 mg, 1.62 mmol) was added methanol (8.0 ml) was added dropwise a solution of hydrochloric acid in dioxane (2.02 mL, 4.0 moles per liter), under N 2, at room temperature for 3 hours.
反应结束，蒸干溶剂得到400.00毫克类白色固体7-氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.57min,[M+H] +＝209.15。 After the reaction was completed, the solvent was evaporated to dryness to obtain 400.00 mg of off-white solid 7-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.57 min, [M+H] + =209.15.
步骤E：合成(5S)-5-(3-(7-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(7-Chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000041
Figure PCTCN2021105088-appb-000041
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和7-氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(63.5毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 7-chloro-1,2, 3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (63.5 mg, 0.26 mmol) was added to N,N-dimethylformamide (2.0 mL) dropwise Add N,N-diisopropylethylamine (156.0 μl), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) ) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) under N 2 protection at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到30.0毫克白色固体(5S)-5-(3-(7-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：31.0％)。LCMS:RT＝1.86min,[M+H] +＝403.22。 1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),7.70(s,0.5H),7.69(s,0.5H),7.04(d,J＝7.7Hz,1H),6.67–6.54(m,2H),4.41(dd,J＝36.0,11.7Hz,1H),3.87–3.64(m,2H),3.57–3.34(m,1H),3.18–3.07(m,1H),3.07–2.91(m,1H),2.88–2.70(m,1H),2.69–2.56(m,2H),2.46–2.35(m,1H), 2.35–2.20(m,1H),2.03–1.89(m,2H),1.18–0.99(m,1H),0.54–0.40(m,1H),0.40–0.24(m,2H),0.17–0.05(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 30.0 mg of white solid (5S)-5-(3-(7-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 31.0%). LCMS: RT=1.86 min, [M+H] + =403.22. 1 H NMR (400MHz, DMSO-d6)δ10.60(s,1H),7.70(s,0.5H),7.69(s,0.5H),7.04(d,J=7.7Hz,1H),6.67-6.54 (m, 2H), 4.41 (dd, J=36.0, 11.7 Hz, 1H), 3.87–3.64 (m, 2H), 3.57–3.34 (m, 1H), 3.18–3.07 (m, 1H), 3.07–2.91 (m, 1H), 2.88–2.70 (m, 1H), 2.69–2.56 (m, 2H), 2.46–2.35 (m, 1H), 2.35–2.20 (m, 1H), 2.03–1.89 (m, 2H) , 1.18–0.99 (m, 1H), 0.54–0.40 (m, 1H), 0.40–0.24 (m, 2H), 0.17–0.05 (m, 1H).
实施例5Example 5
合成(5S)-5-(3-(9-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropane yl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000042
Figure PCTCN2021105088-appb-000042
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(3-氯-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(3-chloro-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000043
Figure PCTCN2021105088-appb-000043
室温下，向含有2-氯-6-氟苯甲醛(1.59克，10.0毫摩尔)的二甲基亚砜(10.0毫升)中加入N-叔丁氧羰基哌嗪(2.24克，12.0毫摩尔)和碳酸钾(1.79克，13.0毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2-chloro-6-fluorobenzaldehyde (1.59 g, 10.0 mmol) in dimethyl sulfoxide (10.0 mL) was added N-tert-butoxycarbonylpiperazine (2.24 g, 12.0 mmol) at room temperature and potassium carbonate (1.79 g, 13.0 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到2.0克淡黄色固体4-(3-氯-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：61.7％)。LCMS:RT＝2.13min,[M+H] +＝325.19。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 2.0 g of tert-butyl 4-(3-chloro-2-formylphenyl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 61.7%). LCMS: RT=2.13 min, [M+H] + =325.19.
步骤B：合成(E)-4-(3-氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(3-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000044
Figure PCTCN2021105088-appb-000044
室温下，将4-(3-氯-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(2.00克，6.16毫摩尔)和4-甲基苯磺酰肼(1.13克，6.47毫摩尔)加入无水乙醇(30.8毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(3-chloro-2-formylphenyl)piperazine-1-carboxylate (2.00 g, 6.16 mmol) and 4-methylbenzenesulfonylhydrazide (1.13 g, 6.47 mmol) was added to anhydrous ethanol (30.8 mL) and reacted at room temperature for 1 hour under the protection of N 2 .
反应结束，蒸干溶剂得到3.04克白色固体(E)-4-(3-氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.14min,[M+H] +＝493.25。 The reaction was completed, and the solvent was evaporated to dryness to obtain 3.04 g of white solid (E)-4-(3-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylic acid tert-butyl Ester. No purification, directly used in the next reaction. LCMS: RT=2.14min, [M+H] + =493.25.
步骤C：合成9-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of 9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
Figure PCTCN2021105088-appb-000045
Figure PCTCN2021105088-appb-000045
室温下，向含有(E)-4-(3-氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(3.04克，6.16毫摩尔)的甲苯(25.0毫升)中，分批加入氢化钠(246毫克，6.16毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-tert-butyl 4-(3-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (3.04 g, 6.16 g) at room temperature mmol) in toluene (25.0 ml), sodium hydride (246 mg, 6.16 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(80毫升)溶解，先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到924毫克白色固体9-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：48.7％)。LCMS:RT＝2.25min,[M+H] +＝309.23。 After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (80 mL), washed with saturated brine (50 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 924 mg of tert-butyl 9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a white solid (yield: 48.7%). LCMS: RT=2.25 min, [M+H] + =309.23.
步骤D：合成9-氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 9-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000046
Figure PCTCN2021105088-appb-000046
室温下，将9-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(924毫克，3.00毫摩尔)加入甲醇(15.0毫升)中，滴加盐酸的二氧六环溶液(3.75毫升，4.0摩尔/升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (924 mg, 3.00 mmol) was added In methanol (15.0 mL), a solution of hydrochloric acid in dioxane (3.75 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到740毫克白色固体9-氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.61min,[M+H] +＝209.14。 1H NMR(500MHz,DMSO-d6)δ9.46(s,2H),7.08(t,J＝7.9Hz,1H),6.67(d,J＝8.0Hz,1H),6.57(d,J＝7.8Hz,1H),3.92–3.84(m,1H),3.84–3.77(m,1H),3.32–3.29(m,1H),3.29–3.18(m,2H),3.08(dd,J＝15.9,8.3Hz,1H),2.95–2.81(m,2H),2.67(dd,J＝15.9,7.2Hz,1H)。 After the reaction was completed, the solvent was evaporated to dryness to obtain 740 mg of 9-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride as a white solid. It was directly used in the next reaction without purification. LCMS: RT=1.61 min, [M+H] + =209.14. 1 H NMR (500MHz, DMSO-d6)δ9.46(s, 2H), 7.08(t, J=7.9Hz, 1H), 6.67(d, J=8.0Hz, 1H), 6.57(d, J=7.8 Hz, 1H), 3.92–3.84 (m, 1H), 3.84–3.77 (m, 1H), 3.32–3.29 (m, 1H), 3.29–3.18 (m, 2H), 3.08 (dd, J=15.9, 8.3 Hz, 1H), 2.95–2.81 (m, 2H), 2.67 (dd, J=15.9, 7.2 Hz, 1H).
步骤E：合成(5S)-5-(3-(9-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000047
Figure PCTCN2021105088-appb-000047
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和9-氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(99毫克，0.40毫摩尔)加入无水二氯甲烷(7.0毫升)中，滴加N,N-二异丙基乙胺(233微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(102毫克，0.53毫摩尔)和1-羟基苯并三唑(7.0毫克，0.053毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 9-chloro-1,2, 3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (99 mg, 0.40 mmol) was added to anhydrous dichloromethane (7.0 mL), N,N was added dropwise - Diisopropylethylamine (233 μl) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (102 mg, 0.53 mmol) and 1- hydroxybenzotriazole (7.0 mg, 0.053 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到25毫克白色固体(5S)-5-(3-(9-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：26.4％)。LCMS:RT＝1.87min,[M-H] -＝401.19。 1H NMR(400MHz,DMSO-d6)δ10.66–10.54(m,1H),7.69(s,1H),7.03(t,J＝7.9Hz, 1H),6.60(d,J＝8.0Hz,1H),6.50(d,J＝8.0Hz,1H),4.42(dd,J＝46.5,11.9Hz,1H),3.80(dd,J＝32.7,12.2Hz,1H),3.72–3.49(m,2H),3.19–2.98(m,2H),2.93–2.74(m,1H),2.69–2.52(m,2H),2.45–2.17(m,2H),2.04–1.83(m,2H),1.15–0.98(m,1H),0.44(dd,J＝8.4,4.8Hz,1H),0.40–0.25(m,2H),0.19–0.03(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 25 mg of white solid (5S)-5-(3-(9-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 26.4%). LCMS: RT = 1.87 min, [MH] − = 401.19. 1 H NMR (400MHz, DMSO-d6) δ 10.66-10.54 (m, 1H), 7.69 (s, 1H), 7.03 (t, J=7.9Hz, 1H), 6.60 (d, J=8.0Hz, 1H) ),6.50(d,J＝8.0Hz,1H),4.42(dd,J＝46.5,11.9Hz,1H),3.80(dd,J＝32.7,12.2Hz,1H),3.72–3.49(m,2H) ,3.19–2.98(m,2H),2.93–2.74(m,1H),2.69–2.52(m,2H),2.45–2.17(m,2H),2.04–1.83(m,2H),1.15–0.98( m, 1H), 0.44 (dd, J=8.4, 4.8 Hz, 1H), 0.40–0.25 (m, 2H), 0.19–0.03 (m, 1H).
实施例6Example 6
合成(5S)-5-(3-(8-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(8-Chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropane yl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000048
Figure PCTCN2021105088-appb-000048
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(4-氯-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(4-chloro-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000049
Figure PCTCN2021105088-appb-000049
室温下，向含有2-氟-5-氯苯甲醛(2.00克，12.61毫摩尔)的二甲基亚砜(12.0毫升)中加入N-叔丁氧羰基哌嗪(2.82克，15.13毫摩尔)和碳酸钾(2.26克，16.39毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2-fluoro-5-chlorobenzaldehyde (2.00 g, 12.61 mmol) in dimethyl sulfoxide (12.0 mL) was added N-tert-butoxycarbonylpiperazine (2.82 g, 15.13 mmol) at room temperature and potassium carbonate (2.26 g, 16.39 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到1.26克淡黄色固体4-(4-氯-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：30.8％)。LCMS:RT＝2.16min,[M+H] +＝325.23。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 1.26 g of tert-butyl 4-(4-chloro-2-formylphenyl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 30.8%). LCMS: RT=2.16 min, [M+H] + =325.23.
步骤B：合成(E)-4-(4-氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(4-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000050
Figure PCTCN2021105088-appb-000050
室温下，将4-(5-氯-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(1.26克，3.88毫摩尔)和4-甲基苯磺酰肼(758.0毫克，4.07毫摩尔)加入无水乙醇(15.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(5-chloro-2-formylphenyl)piperazine-1-carboxylate (1.26 g, 3.88 mmol) and 4-methylbenzenesulfonylhydrazide (758.0 mg, 4.07 mmol) was added to anhydrous ethanol (15.0 mL) and reacted at room temperature for 1 hour under the protection of N 2 .
反应结束，蒸干溶剂得到1.90克类白色固体(E)-4-(4-氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.21min,[M+H] +＝493.23。 The reaction was completed, and the solvent was evaporated to dryness to obtain 1.90 g of off-white solid (E)-4-(4-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylic acid tertiary Butyl ester. Without purification, it was directly used in the next reaction. LCMS: RT=2.21 min, [M+H] + =493.23.
步骤C：合成8-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of 8-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
Figure PCTCN2021105088-appb-000051
Figure PCTCN2021105088-appb-000051
室温下，向含有(E)-4-(4-氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(1.90克，3.85毫摩尔)的甲苯(20.0毫升)中，分批加入氢化钠(185.0毫克，4.62毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-tert-butyl 4-(4-chloro-2-(((2-tosylhydrazino)methyl)phenyl)piperazine-1-carboxylate (1.90 g, 3.85 g) at room temperature mmol) in toluene (20.0 mL), sodium hydride (185.0 mg, 4.62 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)溶解，先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到600.0毫克淡黄色固体8-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：51.6％)。LCMS:RT＝2.21min,[M+H] +＝309.22。 The reaction was completed, cooled to room temperature, dissolved in ethyl acetate (50 mL), washed with saturated brine (50 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 600.0 mg of tert-butyl 8-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a pale yellow solid (yield: 51.6%) . LCMS: RT=2.21 min, [M+H] + =309.22.
步骤D：合成8-氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 8-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000052
Figure PCTCN2021105088-appb-000052
室温下，将8-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(600.0毫克，1.94毫摩尔)加入甲醇(8.0毫升)中，滴加盐酸的二氧六环溶液(2.40毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 8-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (600.0 mg, 1.94 mmol) was added methanol (8.0 ml) was added dropwise a solution of hydrochloric acid in dioxane (2.40 mL, 4.0 moles per liter), under N 2, at room temperature for 3 hours.
反应结束，蒸干溶剂得到500.0毫克类白色固体8-氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.58min,[M+H] +＝209.17。 After the reaction was completed, the solvent was evaporated to dryness to obtain 500.0 mg of off-white solid 8-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.58 min, [M+H] + =209.17.
步骤E：合成(5S)-5-(3-(8-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(8-Chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000053
Figure PCTCN2021105088-appb-000053
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和8-氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(63.5毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-chloro-1,2, 3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (63.5 mg, 0.26 mmol) was added to N,N-dimethylformamide (2.0 mL) dropwise Add N,N-diisopropylethylamine (156.0 μl), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) ) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) under N 2 protection at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到27.5毫克白色固体(5S)-5-(3-(8-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：28.4％)。LCMS:RT＝1.86min,[M+H] +＝403.25。 1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),7.70(s,0.5H),7.69(s,0.5H),7.10(s,1H),7.04(dd,J＝8.3,1.5Hz,1H),6.55(dd,J＝8.2,4.4Hz,1H),4.41(dd,J＝34.5,12.1Hz,1H),3.90–3.58(m,2H),3.57–3.37(m,1H),3.23–3.07(m,1H),3.07–2.92(m,1H),2.91–2.70(m,1H),2.67–2.53(m,2H),2.46–2.35(m,1H),2.35–2.19(m,1H),2.06–1.86(m,2H),1.20–1.02(m,1H), 0.54–0.41(m,1H),0.41–0.27(m,2H),0.23–0.03(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 27.5 mg of white solid (5S)-5-(3-(8-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 28.4%). LCMS: RT=1.86 min, [M+H] + =403.25. 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),7.70(s,0.5H),7.69(s,0.5H),7.10(s,1H),7.04(dd,J=8.3, 1.5Hz, 1H), 6.55 (dd, J=8.2, 4.4Hz, 1H), 4.41 (dd, J=34.5, 12.1Hz, 1H), 3.90–3.58 (m, 2H), 3.57–3.37 (m, 1H) ), 3.23–3.07 (m, 1H), 3.07–2.92 (m, 1H), 2.91–2.70 (m, 1H), 2.67–2.53 (m, 2H), 2.46–2.35 (m, 1H), 2.35–2.19 (m, 1H), 2.06–1.86 (m, 2H), 1.20–1.02 (m, 1H), 0.54–0.41 (m, 1H), 0.41–0.27 (m, 2H), 0.23–0.03 (m, 1H) .
实施例7Example 7
合成(5S)-5-(3-(7-氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(7-Chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000054
Figure PCTCN2021105088-appb-000054
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(5-氯-3-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(5-chloro-3-fluoro-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000055
Figure PCTCN2021105088-appb-000055
室温下，向含有4-氯-2,6-二氟苯甲醛(2.00克，11.33毫摩尔)的二甲基亚砜(12.0毫升)中加入N-叔丁氧羰基哌嗪(2.53克，13.60毫摩尔)和碳酸钾(2.03克，14.73毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 4-chloro-2,6-difluorobenzaldehyde (2.00 g, 11.33 mmol) in dimethyl sulfoxide (12.0 mL) was added N-tert-butoxycarbonylpiperazine (2.53 g, 13.60 mL) at room temperature mmol) and potassium carbonate (2.03 g, 14.73 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到2.66克淡黄色固体4-(5-氯-3-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：68.5％)。LCMS:RT＝2.16min,[M+H] +＝343.29。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 2.66 g of tert-butyl 4-(5-chloro-3-fluoro-2-formylphenyl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 68.5%). LCMS: RT=2.16 min, [M+H] + =343.29.
步骤B：合成(E)-4-(5-氯-3-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(5-chloro-3-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000056
Figure PCTCN2021105088-appb-000056
室温下，将4-(5-氯-3-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(2.66克，7.76毫摩尔)和4-甲基苯磺酰肼(1.52克，8.15毫摩尔)加入无水乙醇(30.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(5-chloro-3-fluoro-2-formylphenyl)piperazine-1-carboxylate (2.66 g, 7.76 mmol) and 4-methylbenzenesulfonylhydrazide ( 1.52 g, 8.15 mmol) was added to anhydrous ethanol (30.0 mL) and reacted at room temperature for 1 h under the protection of N 2 .
反应结束，蒸干溶剂得到3.97克类白色固体(E)-4-(5-氯-3-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.20min,[M+H] +＝511.23。 The reaction was completed, and the solvent was evaporated to dryness to obtain 3.97 g of off-white solid (E)-4-(5-chloro-3-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1 - Carboxylic acid tert-butyl ester. No purification, directly used in the next reaction. LCMS: RT=2.20min, [M+H] + =511.23.
步骤C：合成7-氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of tert-butyl 7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
Figure PCTCN2021105088-appb-000057
Figure PCTCN2021105088-appb-000057
室温下，向含有(E)-4-(5-氯-3-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(3.97克，7.77毫摩尔)的甲苯(40.0毫升)中，分批加入氢化钠(373.0毫克，9.32毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。At room temperature, tert-butyl 4-(5-chloro-3-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate ( 3.97 g, 7.77 mmol) in toluene (40.0 ml), sodium hydride (373.0 mg, 9.32 mmol, 60% dispersed in paraffin oil) was added in batches, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)溶解，先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到2.00克淡黄色固体7-氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：78.8％)。LCMS:RT＝2.27min,[M+H] +＝327.21。 The reaction was completed, cooled to room temperature, dissolved in ethyl acetate (50 mL), washed with saturated brine (50 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 2.00 g of tert-butyl 7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a pale yellow solid (yield : 78.8%). LCMS: RT=2.27 min, [M+H] + =327.21.
步骤D：合成7-氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 7-chloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000058
Figure PCTCN2021105088-appb-000058
室温下，将7-氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(2.00克，6.12毫摩尔)加入甲醇(8.0毫升)中，滴加盐酸的二氧六环溶液(7.65毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (2.00 g, 6.12 mmol) was added to methanol (8.0 mL), and a solution of hydrochloric acid in dioxane (7.65 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到1.50克类白色固体7-氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.59min,[M+H] +＝227.18。 After the reaction was completed, the solvent was evaporated to dryness to obtain 1.50 g of off-white solid 7-chloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.59 min, [M+H] + =227.18.
步骤E：合成(5S)-5-(3-(7-氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(7-Chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000059
Figure PCTCN2021105088-appb-000059
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和7-氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(69.17毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (50.0 mg, 0.24 mmol) and 7-chloro-9-fluoro- 1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (69.17 mg, 0.26 mmol) was added to N,N-dimethylformamide (2.0 mL ), N,N-diisopropylethylamine (156.0 μl) was added dropwise, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg , 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2 protection, were reacted at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到31.0毫克白色固体(5S)-5-(3-(7-氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：30.7％)。LCMS:RT＝1.90min,[M+H] +＝421.23。 1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),7.70(s,0.5H),7.69(s,0.5H),6.57–6.49(m,2H),4.41(dd,J＝42.1,13.3Hz,1H),3.79–3.67(m,2H),3.62–3.45(m,1H),3.18–3.07(m, 1H),3.07–2.99(m,1H),2.99–2.76(m,1H),2.72–2.54(m,2H),2.46–2.35(m,1H),2.35–2.19(m,1H),2.04–1.85(m,2H),1.19–1.04(m,1H),0.52–0.39(m,1H),0.39–0.26(m,2H),0.17–0.05(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 31.0 mg of (5S)-5-(3-(7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) was obtained as a white solid -yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 30.7%). LCMS: RT=1.90 min, [M+H] + =421.23. 1 H NMR (400MHz, DMSO-d6) δ 10.60(s, 1H), 7.70(s, 0.5H), 7.69(s, 0.5H), 6.57-6.49(m, 2H), 4.41(dd, J= 42.1, 13.3Hz, 1H), 3.79–3.67 (m, 2H), 3.62–3.45 (m, 1H), 3.18–3.07 (m, 1H), 3.07–2.99 (m, 1H), 2.99–2.76 (m, 1H), 2.72–2.54 (m, 2H), 2.46–2.35 (m, 1H), 2.35–2.19 (m, 1H), 2.04–1.85 (m, 2H), 1.19–1.04 (m, 1H), 0.52– 0.39 (m, 1H), 0.39–0.26 (m, 2H), 0.17–0.05 (m, 1H).
实施例8和实施例9Example 8 and Example 9
合成(S)-5-(3-((S)-7-氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮和(S)-5-(3-((R)-7-氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (S)-5-(3-((S)-7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) -yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (S)-5-(3-((R)-7-chloro-9-fluoro-3, 4,10,10a-Tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000060
Figure PCTCN2021105088-appb-000060
通过手性HPLC拆分(5S)-5-(3-(7-氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(Chiralpak AD-H，正己烷：异丙醇＝80：20，洗脱液浓缩、冻干)，先后得到光学纯化合物8和化合物9。Resolution of (5S)-5-(3-(7-chloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) by chiral HPLC )-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (Chiralpak AD-H, n-hexane:isopropanol=80:20, the eluent was concentrated, lyophilized ), optically pure compound 8 and compound 9 were obtained successively.
化合物8：HPLC:RT＝11.195min。LCMS:RT＝1.90min,[M+H] +＝421.22。 1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),7.69(s,0.5H),7.66(s,0.5H),6.58–6.45(m,2H),4.46–4.44(m,0.5H),4.36–4.34(m,0.5H),3.88–3.47(m,3H),3.16–2.77(m,3H),2.68–2.52(m,2H),2.46–2.16(m,2H),2.05–1.87(m,2H),1.15–1.03(m,1H),0.52–0.40(m,1H),0.40–0.27(m,2H),0.15–0.05(m,1H)。 Compound 8: HPLC: RT=11.195 min. LCMS: RT=1.90 min, [M+H] + =421.22. 1 H NMR (500MHz, DMSO-d6)δ10.59(s,1H), 7.69(s,0.5H), 7.66(s,0.5H), 6.58–6.45(m,2H), 4.46–4.44(m, 0.5H), 4.36–4.34 (m, 0.5H), 3.88–3.47 (m, 3H), 3.16–2.77 (m, 3H), 2.68–2.52 (m, 2H), 2.46–2.16 (m, 2H), 2.05–1.87 (m, 2H), 1.15–1.03 (m, 1H), 0.52–0.40 (m, 1H), 0.40–0.27 (m, 2H), 0.15–0.05 (m, 1H).
化合物9：HPLC:RT＝12.772min。LCMS:RT＝1.90min,[M+H] +＝421.21。 1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),7.69(s,0.5H),7.67(s,0.5H),6.53-6.50(m,2H),4.47–4.44(m,0.5H),4.36–4.33(m,0.5H),3.85–3.46(m,3H),3.16–2.77(m,3H),2.67–2.52(m,2H),2.47–2.20(m,2H),2.03–1.86(m,2H),1.15–1.01(m,1H),0.52–0.40(m,1H),0.40–0.24(m,2H),0.17–0.04(m,1H)。 Compound 9: HPLC: RT=12.772 min. LCMS: RT=1.90 min, [M+H] + =421.21. 1 H NMR(500MHz, DMSO-d6)δ10.59(s,1H),7.69(s,0.5H),7.67(s,0.5H),6.53-6.50(m,2H),4.47-4.44(m, 0.5H), 4.36–4.33 (m, 0.5H), 3.85–3.46 (m, 3H), 3.16–2.77 (m, 3H), 2.67–2.52 (m, 2H), 2.47–2.20 (m, 2H), 2.03–1.86 (m, 2H), 1.15–1.01 (m, 1H), 0.52–0.40 (m, 1H), 0.40–0.24 (m, 2H), 0.17–0.04 (m, 1H).
实施例10Example 10
合成(5S)-5-(3-(7,9-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000061
Figure PCTCN2021105088-appb-000061
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(3,5-二氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(3,5-difluoro-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000062
Figure PCTCN2021105088-appb-000062
室温下，向含有2,4,6-三氟苯甲醛(3.20克，20.0毫摩尔)的二甲基亚砜(20.0毫升)中加入N-叔丁氧羰基哌嗪(4.47克，24.0毫摩尔)和碳酸钾(3.59克，26.0毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2,4,6-trifluorobenzaldehyde (3.20 g, 20.0 mmol) in dimethyl sulfoxide (20.0 mL) was added N-tert-butoxycarbonylpiperazine (4.47 g, 24.0 mmol) at room temperature ) and potassium carbonate (3.59 g, 26.0 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到1.50克淡黄色固体4-(3,5-二氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：23.0％)。LCMS:RT＝2.09min,[M+H] +＝327.20。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 1.50 g of tert-butyl 4-(3,5-difluoro-2-formylphenyl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 23.0%). LCMS: RT=2.09 min, [M+H] + =327.20.
步骤B：合成(E)-4-(3,5-二氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(3,5-difluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000063
Figure PCTCN2021105088-appb-000063
室温下，将4-(3,5-二氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(1.50克，4.60毫摩尔)和4-甲基苯磺酰肼(899毫克，4.80毫摩尔)加入无水乙醇(23.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(3,5-difluoro-2-formylphenyl)piperazine-1-carboxylate (1.50 g, 4.60 mmol) and 4-methylbenzenesulfonylhydrazide (899 mg, 4.80 mmol) was added to anhydrous ethanol (23.0 mL) and reacted at room temperature for 1 h under the protection of N 2 .
反应结束，蒸干溶剂得到2.27克类白色固体(E)-4-(3,5-二氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.14min,[M+H] +＝495.20。 The reaction was completed, and the solvent was evaporated to dryness to obtain 2.27 g of off-white solid (E)-4-(3,5-difluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1- Carboxylic acid tert-butyl ester. No purification, directly used in the next reaction. LCMS: RT=2.14min, [M+H] + =495.20.
步骤C：合成7,9-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of 7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
Figure PCTCN2021105088-appb-000064
Figure PCTCN2021105088-appb-000064
室温下，向含有(E)-4-(3,5-二氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(2.27克，4.60毫摩尔)的甲苯(20.0毫升)中，分批加入氢化钠(184毫克，4.60毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-4-(3,5-difluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate tert-butyl ester (2.27 g, 4.60 mmol) in toluene (20.0 mL), sodium hydride (184 mg, 4.60 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)溶解，先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到1.13克白色固体7,9-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：79.1％)。LCMS:RT＝2.20min,[M+H] +＝311.22。 The reaction was completed, cooled to room temperature, dissolved in ethyl acetate (50 mL), washed with saturated brine (50 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 1.13 g of tert-butyl 7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a white solid (yield: 79.1 %). LCMS: RT=2.20 min, [M+H] + =311.22.
步骤D：合成7,9-二氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 7,9-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000065
Figure PCTCN2021105088-appb-000065
室温下，将7,9-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(1.13克，3.64毫摩尔)加入甲醇(18.2毫升)中，滴加盐酸的二氧六环溶液(4.5毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (1.13 g, 3.64 mM mol) was added to methanol (18.2 mL), hydrochloric acid in dioxane solution (4.5 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到900毫克类白色固体7,9-二氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.57min,[M+H] +＝211.18。 1H NMR(400MHz,DMSO-d6)δ9.50(s,2H),6.43(dd,J＝10.0,2.0Hz,1H),6.41–6.34(m,1H),4.02–3.93(m,1H),3.88–3.81(m,1H),3.32–3.28(m,1H),3.27–3.20(m,2H),3.07(dd,J＝15.5,8.4Hz,1H),2.95–2.81(m,2H),2.64(dd,J＝15.6,6.7Hz,1H)。 After the reaction was completed, the solvent was evaporated to dryness to obtain 900 mg of off-white solid 7,9-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.57 min, [M+H] + =211.18. 1 H NMR (400MHz, DMSO-d6)δ9.50(s,2H),6.43(dd,J=10.0,2.0Hz,1H),6.41-6.34(m,1H),4.02-3.93(m,1H) ,3.88–3.81(m,1H),3.32–3.28(m,1H),3.27–3.20(m,2H),3.07(dd,J=15.5,8.4Hz,1H),2.95–2.81(m,2H) , 2.64 (dd, J=15.6, 6.7 Hz, 1H).
步骤E：合成(5S)-5-(3-(7,9-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基 咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl )-3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000066
Figure PCTCN2021105088-appb-000066
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50毫克，0.24毫摩尔)和7,9-二氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(100毫克，0.35毫摩尔)加入无水二氯甲烷(4.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(68毫克，0.35毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50 mg, 0.24 mmol) and 7,9-difluoro-1 ,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (100 mg, 0.35 mmol) was added to anhydrous dichloromethane (4.0 mL), dropwise added N,N-Diisopropylethylamine (156.0 μl) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (68 mg, 0.35 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) under N 2 protection at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到43.5毫克白色固体(5S)-5-(3-(7,9-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：45.8％)。LCMS:RT＝1.85min,[M-H] -＝403.24。 1H NMR(400MHz,DMSO-d6)δ10.68–10.51(m,1H),7.69(d,J＝4.6Hz,1H),6.35(t,J＝8.3Hz,1H),6.32–6.25(m,1H),4.40(dd,J＝41.1,11.4Hz,1H),3.78(dd,J＝30.0,11.9Hz,1H),3.72–3.45(m,2H),3.16–2.97(m,2H),2.97–2.77(m,1H),2.68–2.53(m,2H),2.46–2.18(m,2H),2.03–1.87(m,2H),1.15–1.04(m,1H),0.50–0.41(m,1H),0.41–0.26(m,2H),0.16–0.04(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 43.5 mg of white solid (5S)-5-(3-(7,9-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 45.8%). LCMS: RT = 1.85 min, [MH] − = 403.24. 1 H NMR (400MHz, DMSO-d6)δ10.68-10.51(m,1H),7.69(d,J=4.6Hz,1H),6.35(t,J=8.3Hz,1H),6.32-6.25(m ,1H),4.40(dd,J＝41.1,11.4Hz,1H),3.78(dd,J＝30.0,11.9Hz,1H),3.72-3.45(m,2H),3.16-2.97(m,2H), 2.97–2.77 (m, 1H), 2.68–2.53 (m, 2H), 2.46–2.18 (m, 2H), 2.03–1.87 (m, 2H), 1.15–1.04 (m, 1H), 0.50–0.41 (m , 1H), 0.41–0.26 (m, 2H), 0.16–0.04 (m, 1H).
实施例11Example 11
合成(5S)-5-(3-(6-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(6-Chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropane yl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000067
Figure PCTCN2021105088-appb-000067
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(2-氯-6-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(2-chloro-6-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000068
Figure PCTCN2021105088-appb-000068
室温下，向含有3-氯-2-氟苯甲醛(3.17克，20.0毫摩尔)的二甲基亚砜(20.0毫升)中加入N-叔丁氧羰基哌嗪(4.47克，24.0毫摩尔)和碳酸钾(3.59克，26.0毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 3-chloro-2-fluorobenzaldehyde (3.17 g, 20.0 mmol) in dimethyl sulfoxide (20.0 mL) was added N-tert-butoxycarbonylpiperazine (4.47 g, 24.0 mmol) at room temperature and potassium carbonate (3.59 g, 26.0 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到1.39克白色固体4-(2-氯-6-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：21.4％)。LCMS:RT＝2.16min,[M+H] +＝325.18。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 1.39 g of tert-butyl 4-(2-chloro-6-formylphenyl)piperazine-1-carboxylate was obtained as a white solid (yield: 21.4%). LCMS: RT=2.16 min, [M+H] + =325.18.
步骤B：合成(E)-4-(2-氯-6-((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(2-chloro-6-((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000069
Figure PCTCN2021105088-appb-000069
室温下，将4-(2-氯-6-甲酰基苯基)哌嗪-1-羧酸叔丁酯(1.39克，4.28毫摩尔)和4-甲基苯磺酰肼(836毫克，4.49毫摩尔)加入无水乙醇(21.4毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(2-chloro-6-formylphenyl)piperazine-1-carboxylate (1.39 g, 4.28 mmol) and 4-methylbenzenesulfonylhydrazide (836 mg, 4.49 mmol) was added to anhydrous ethanol (21.4 mL) and reacted at room temperature for 1 hour under the protection of N 2 .
反应结束，蒸干溶剂得到2.12克类白色固体(E)-4-(2-氯-6-((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.22min,[M+H] +＝493.21。 The reaction was completed, and the solvent was evaporated to dryness to obtain 2.12 g of off-white solid (E)-4-(2-chloro-6-((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester. It was directly used in the next reaction without purification. LCMS: RT=2.22 min, [M+H] + =493.21.
步骤C：合成6-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of tert-butyl 6-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
Figure PCTCN2021105088-appb-000070
Figure PCTCN2021105088-appb-000070
室温下，向含有(E)-4-(2-氯-6-((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(2.12克，4.28毫摩尔)的甲苯(21.4毫升)中，分批加入氢化钠(157毫克，4.28毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-tert-butyl 4-(2-chloro-6-((2-tosylhydrazino)methyl)phenyl)piperazine-1-carboxylate (2.12 g, 4.28 mM) at room temperature mol) in toluene (21.4 mL), sodium hydride (157 mg, 4.28 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)溶解，先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到157毫克淡黄色固体6-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：11.9％)。LCMS:RT＝2.25min,[M+H] +＝309.24。 The reaction was completed, cooled to room temperature, dissolved in ethyl acetate (50 mL), washed with saturated brine (50 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 157 mg of tert-butyl 6-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a pale yellow solid (yield: 11.9%) . LCMS: RT=2.25 min, [M+H] + =309.24.
步骤D：合成6-氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 6-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000071
Figure PCTCN2021105088-appb-000071
室温下，将6-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(157毫克，0.51毫摩尔)加入甲醇(2.6毫升)中，滴加盐酸的二氧六环溶液(0.51毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 6-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (157 mg, 0.51 mmol) was added In methanol (2.6 mL), a solution of hydrochloric acid in dioxane (0.51 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到120毫克类白色固体6-氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.57min,[M+H] +＝209.16。 After the reaction was completed, the solvent was evaporated to dryness to obtain 120 mg of off-white solid 6-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.57 min, [M+H] + =209.16.
步骤E：合成(5S)-5-(3-(6-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(6-Chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000072
Figure PCTCN2021105088-appb-000072
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(90.0毫克，0.42毫摩尔)和6-氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(120毫克，0.49毫摩尔)加入无水二氯甲烷(2.0毫升)中，滴加N,N-二异丙基乙胺(281微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(122毫克，0.64毫摩尔)和1-羟基苯并三唑(9.0毫克，0.064毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (90.0 mg, 0.42 mmol) and 6-chloro-1,2, 3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (120 mg, 0.49 mmol) was added to anhydrous dichloromethane (2.0 mL), N,N was added dropwise - Diisopropylethylamine (281 μl) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg, 0.64 mmol) and 1- hydroxybenzotriazole (9.0 mg, 0.064 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到132.7毫克白色固体(5S)-5-(3-(6-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：77.7％)。LCMS:RT＝1.86min,[M+H] +＝403.29。 1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),7.68(s,1H),7.04(d,J＝6.8Hz,1H),6.99(d,J＝7.7Hz,1H),6.67–6.57(m,1H),4.56–4.32(m,2H),3.95–3.77(m,1H),3.25–2.86(m,4H),2.79–2.53(m,2H),2.42–2.18(m,2H),1.99–1.89(m,2H),1.14–1.04(m,1H),0.51–0.40(m,1H),0.40–0.27(m,2H),0.15–0.04(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 132.7 mg of white solid (5S)-5-(3-(6-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 77.7%). LCMS: RT=1.86 min, [M+H] + =403.29. 1 H NMR(400MHz,DMSO-d6)δ10.59(s,1H),7.68(s,1H),7.04(d,J=6.8Hz,1H),6.99(d,J=7.7Hz,1H), 6.67–6.57 (m, 1H), 4.56–4.32 (m, 2H), 3.95–3.77 (m, 1H), 3.25–2.86 (m, 4H), 2.79–2.53 (m, 2H), 2.42–2.18 (m , 2H), 1.99–1.89 (m, 2H), 1.14–1.04 (m, 1H), 0.51–0.40 (m, 1H), 0.40–0.27 (m, 2H), 0.15–0.04 (m, 1H).
实施例12Example 12
合成(5S)-5-(3-(8-三氟甲基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(8-Trifluoromethyl-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000073
Figure PCTCN2021105088-appb-000073
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(4-三氟甲基-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(4-trifluoromethyl-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000074
Figure PCTCN2021105088-appb-000074
室温下，向含有2-氟-5-三氟甲基-苯甲醛(2.00克，10.42毫摩尔)的二甲基亚砜(12.0毫升)中加入N-叔丁氧羰基哌嗪(2.33克，12.50毫摩尔)和碳酸钾(1.87克，13.55毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2-fluoro-5-trifluoromethyl-benzaldehyde (2.00 g, 10.42 mmol) in dimethyl sulfoxide (12.0 mL) was added N-tert-butoxycarbonylpiperazine (2.33 g, 12.50 mmol) and potassium carbonate (1.87 g, 13.55 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到2.83克淡黄色固体4-(4-三氟甲基-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：75.8％)。LCMS:RT＝2.16min,[M+H] +＝359.22。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 2.83 g of tert-butyl 4-(4-trifluoromethyl-2-formylphenyl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 75.8%). LCMS: RT=2.16 min, [M+H] + =359.22.
步骤B：合成(E)-4-(4-三氟甲基-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(4-trifluoromethyl-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000075
Figure PCTCN2021105088-appb-000075
室温下，将4-(4-三氟甲基-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(2.83克，7.90毫摩尔)和4-甲基苯磺酰肼(1.54克，8.30毫摩尔)加入无水乙醇(25.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, 4-(4-trifluoromethyl-2-formylphenyl)piperazine-1-carboxylate tert-butyl ester (2.83 g, 7.90 mmol) and 4-methylbenzenesulfonylhydrazide (1.54 g g, 8.30 mmol) was added to anhydrous ethanol (25.0 mL) and reacted at room temperature for 1 h under the protection of N 2 .
反应结束，蒸干溶剂得到4.20克类白色固体(E)-4-(4-三氟甲基-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.16min,[M+H] +＝527.22。 The reaction was completed, and the solvent was evaporated to dryness to obtain 4.20 g of off-white solid (E)-4-(4-trifluoromethyl-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1- Carboxylic acid tert-butyl ester. No purification, directly used in the next reaction. LCMS: RT=2.16min, [M+H] + =527.22.
步骤C：合成8-三氟甲基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of 8-trifluoromethyl-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
Figure PCTCN2021105088-appb-000076
Figure PCTCN2021105088-appb-000076
室温下，向含有(E)-4-(4-三氟甲基-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(4.20克，7.98毫摩尔)的甲苯(40.0毫升)中，分批加入氢化钠(383.0毫克，9.58毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-4-(4-trifluoromethyl-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate tert-butyl ester (4.20 g, 7.98 mmol) in toluene (40.0 mL), sodium hydride (383.0 mg, 9.58 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(100毫升)溶解，先用饱和食盐水(100毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到2.70克淡黄色固体8-三氟甲基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：98.8％)。LCMS:RT＝2.23min,[M+H] +＝343.25。 After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (100 mL), washed with saturated brine (100 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 2.70 g of tert-butyl 8-trifluoromethyl-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a pale yellow solid (yield: 98.8%). LCMS: RT=2.23 min, [M+H] + =343.25.
步骤D：合成8-三氟甲基-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 8-trifluoromethyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000077
Figure PCTCN2021105088-appb-000077
室温下，将8-三氟甲基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(2.70克，7.89毫摩尔)加入甲醇(30.0毫升)中，滴加盐酸的二氧六环溶液(9.80毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, 8-trifluoromethyl-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester (2.70 g, 7.89 mM mol) was added to methanol (30.0 mL), and a solution of hydrochloric acid in dioxane (9.80 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到1.50克类白色固体8-三氟甲基-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.61min,[M+H] +＝243.19。 After the reaction was completed, the solvent was evaporated to dryness to obtain 1.50 g of off-white solid 8-trifluoromethyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.61 min, [M+H] + =243.19.
步骤E：合成(5S)-5-(3-(8-三氟甲基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(8-Trifluoromethyl-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl )-3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000078
Figure PCTCN2021105088-appb-000078
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和8-三氟甲基-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(81.6毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-trifluoromethyl-1 ,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (81.6 mg, 0.26 mmol) was added to N,N-dimethylformamide (2.0 mL) , N,N-diisopropylethylamine (156.0 μl) was added dropwise, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到26.0毫克白色固体(5S)-5-(3-(8-三氟甲基-3,4,10,10a-四氢 吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：24.8％)。LCMS:RT＝1.89min,[M+H] +＝437.25。 1H NMR(400MHz,DMSO)δ10.60(s,1H),7.70(s,0.5H),7.69(d,J＝2.5Hz,0.5H),7.35(d,J＝8.0Hz,2H),6.65(dd,J＝8.2,4.5Hz,1H),4.44(dd,J＝34.5,11.7Hz,1H),3.96–3.69(m,2H),3.66–3.45(m,1H),3.20–3.08(m,1H),3.08–2.94(m,1H),2.94–2.81(m,1H),2.80–2.52(m,2H),2.45–2.34(m,1H),2.34–2.19(m,1H),2.10–1.86(m,2H),1.16–1.02(m,1H),0.53–0.40(m,1H),0.40–0.24(m,2H),0.21–0.04(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 26.0 mg of white solid (5S)-5-(3-(8-trifluoromethyl-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 24.8%). LCMS: RT=1.89 min, [M+H] + =437.25. 1 H NMR(400MHz, DMSO)δ10.60(s,1H),7.70(s,0.5H),7.69(d,J=2.5Hz,0.5H),7.35(d,J=8.0Hz,2H), 6.65(dd,J=8.2,4.5Hz,1H),4.44(dd,J=34.5,11.7Hz,1H),3.96-3.69(m,2H),3.66-3.45(m,1H),3.20-3.08( m, 1H), 3.08–2.94 (m, 1H), 2.94–2.81 (m, 1H), 2.80–2.52 (m, 2H), 2.45–2.34 (m, 1H), 2.34–2.19 (m, 1H), 2.10–1.86 (m, 2H), 1.16–1.02 (m, 1H), 0.53–0.40 (m, 1H), 0.40–0.24 (m, 2H), 0.21–0.04 (m, 1H).
实施例13Example 13
合成(5S)-5-(3-(8-氰基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(8-cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxo propyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000079
Figure PCTCN2021105088-appb-000079
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(4-氰基-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(4-cyano-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000080
Figure PCTCN2021105088-appb-000080
室温下，向含有4-氟-3-甲酰基苯甲腈(1.49克，10.0毫摩尔)的二甲基亚砜(10.0毫升)中加入N-叔丁氧羰基哌嗪(2.24克，12.0毫摩尔)和碳酸钾(1.79克，13.0毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 4-fluoro-3-formylbenzonitrile (1.49 g, 10.0 mmol) in dimethyl sulfoxide (10.0 mL) was added N-tert-butoxycarbonylpiperazine (2.24 g, 12.0 mmol) at room temperature mol) and potassium carbonate (1.79 g, 13.0 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/5)。得到2.876克淡黄色固体4-(4-氰基-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：91.3％)。LCMS:RT＝2.02min,[M+H] +＝316.23。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). 2.876 g of tert-butyl 4-(4-cyano-2-formylphenyl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 91.3%). LCMS: RT=2.02 min, [M+H] + =316.23.
步骤B：合成(E)-4-(4-氰基-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(4-cyano-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000081
Figure PCTCN2021105088-appb-000081
室温下，将4-(4-氰基-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(2.876克，9.13毫摩尔)和4-甲基苯磺酰肼(1.79毫克，9.59毫摩尔)加入无水乙醇(46.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(4-cyano-2-formylphenyl)piperazine-1-carboxylate (2.876 g, 9.13 mmol) and 4-methylbenzenesulfonylhydrazide (1.79 mg, 9.59 mmol) was added to anhydrous ethanol (46.0 mL), and the reaction was carried out at room temperature for 1 hour under the protection of N 2 .
反应结束，蒸干溶剂得到4.42克类白色固体(E)-4-(4-氰基-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.09min,[M+H] +＝484.30。 The reaction was completed, and the solvent was evaporated to dryness to obtain 4.42 g of off-white solid (E)-4-(4-cyano-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylic acid Tert-butyl ester. No purification, directly used in the next reaction. LCMS: RT=2.09min, [M+H] + =484.30.
步骤C：合成8-氰基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of 8-cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
Figure PCTCN2021105088-appb-000082
Figure PCTCN2021105088-appb-000082
室温下，向含有(E)-4-(4-氰基-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(4.42克，9.13毫摩尔)的甲苯(36.5毫升)中，分批加入氢化钠(365毫克，9.13毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-tert-butyl 4-(4-cyano-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (4.42 g, 9.13 mmol) in toluene (36.5 ml), sodium hydride (365 mg, 9.13 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)溶解，先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/5)。得到940毫克白色固体8-氰基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：34.4％)。LCMS:RT＝2.04min,[M+H] +＝300.25。 The reaction was completed, cooled to room temperature, dissolved in ethyl acetate (50 mL), washed with saturated brine (50 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). Obtained 940 mg of tert-butyl 8-cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate as a white solid (yield: 34.4%) . LCMS: RT=2.04 min, [M+H] + =300.25.
步骤D：合成8-氰基-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 8-cyano-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000083
Figure PCTCN2021105088-appb-000083
室温下，将8-氰基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(940毫克，3.14毫摩尔)加入(31毫升)中，滴加盐酸的二氧六环溶液(3.1毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 8-Cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester (940 mg, 3.14 mmol) at room temperature was added (31 ml) was added dropwise a solution of hydrochloric acid in dioxane (3.1 mL, 4.0 moles per liter), under N 2, at room temperature for 3 hours.
反应结束，蒸干溶剂得到740毫克类白色固体8-氰基-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.29min,[M+H] +＝200.19。 1H NMR(400MHz,DMSO-d6)δ9.50(s,2H),7.50(dd,J＝8.2,1.6Hz,1H),7.44(d,J＝1.2Hz,1H),6.70(d,J＝8.3Hz,1H),4.05–3.96(m,1H),3.96–3.89(m,1H),3.34–3.23(m,3H),3.12(dd,J＝16.2,8.7Hz,1H),2.97–2.80(m,2H),2.69(dd,J＝16.2,7.1Hz,1H)。 After the reaction was completed, the solvent was evaporated to dryness to obtain 740 mg of off-white solid 8-cyano-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.29 min, [M+H] + =200.19. 1 H NMR(400MHz, DMSO-d6)δ9.50(s,2H),7.50(dd,J=8.2,1.6Hz,1H),7.44(d,J=1.2Hz,1H),6.70(d,J = 8.3Hz, 1H), 4.05–3.96 (m, 1H), 3.96–3.89 (m, 1H), 3.34–3.23 (m, 3H), 3.12 (dd, J=16.2, 8.7Hz, 1H), 2.97– 2.80 (m, 2H), 2.69 (dd, J=16.2, 7.1 Hz, 1H).
步骤E：合成(5S)-5-(3-(8-氰基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(8-cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000084
Figure PCTCN2021105088-appb-000084
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和8-氰基-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(96.0毫克，0.41毫摩尔)加入无水二氯甲烷(2.0毫升)中，滴加N,N-二异丙基乙胺(156微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(68毫克，0.35毫摩尔)和1-羟基苯并三唑(5.0毫克，0.035毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-cyano-1,2 ,3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (96.0 mg, 0.41 mmol) was added to anhydrous dichloromethane (2.0 mL), N, N-diisopropylethylamine (156 μl), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (68 mg, 0.35 mmol) and 1 - hydroxybenzotriazole (5.0 mg, 0.035 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝4/1)。得到55.5毫克白色固体(5S)-5-(3-(8-氰基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：59.8％)。LCMS:RT＝1.74min,[M-H] -＝392.26。 1H NMR(400MHz,DMSO-d6)δ10.63–10.55(m,1H),7.69(s,1H),7.45(d,J＝8.2Hz,1H),7.38(s,1H),6.63(dd,J＝8.1,5.3Hz,1H),4.44(dd,J＝37.8,11.9Hz,1H),3.90–3.51(m,3H), 3.14–2.83(m,3H),2.70–2.57(m,2H),2.46–2.19(m,2H),2.01–1.88(m,2H),1.14–1.05(m,1H),0.50–0.41(m,1H),0.41–0.27(m,2H),0.10(d,J＝5.3Hz,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=4/1). 55.5 mg of white solid (5S)-5-(3-(8-cyano-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl) was obtained -3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 59.8%). LCMS: RT = 1.74 min, [MH] − = 392.26. 1 H NMR (400MHz, DMSO-d6)δ10.63-10.55(m,1H),7.69(s,1H),7.45(d,J=8.2Hz,1H),7.38(s,1H),6.63(dd , J=8.1, 5.3Hz, 1H), 4.44 (dd, J=37.8, 11.9Hz, 1H), 3.90–3.51 (m, 3H), 3.14–2.83 (m, 3H), 2.70–2.57 (m, 2H) ), 2.46–2.19 (m, 2H), 2.01–1.88 (m, 2H), 1.14–1.05 (m, 1H), 0.50–0.41 (m, 1H), 0.41–0.27 (m, 2H), 0.10 (d , J=5.3Hz, 1H).
实施例14Example 14
合成(5S)-5-环丙基-5-(3-(6-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)咪唑啉-2,4-二酮Synthesis of (5S)-5-cyclopropyl-5-(3-(6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl )-3-Oxypropyl)imidazoline-2,4-dione
Figure PCTCN2021105088-appb-000085
Figure PCTCN2021105088-appb-000085
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(2-氟-6-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(2-fluoro-6-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000086
Figure PCTCN2021105088-appb-000086
室温下，向含有2，3-二氟苯甲醛(2.00克，14.07毫摩尔)的二甲基亚砜(12.0毫升)中加入N-叔丁氧羰基哌嗪(2.62克，14.07毫摩尔)和碳酸钾(2.33克，16.89毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2,3-difluorobenzaldehyde (2.00 g, 14.07 mmol) in dimethyl sulfoxide (12.0 mL) was added N-tert-butoxycarbonylpiperazine (2.62 g, 14.07 mmol) and potassium carbonate (2.33 g, 16.89 mmol), N 2 protection for 12 h at 95 ° C.
反应结束，加水50毫升水和50毫升乙酸乙酯稀释，分液，收集有机相，有机相先用饱和食盐水(3毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到350.0毫克米黄色固体4-(2-氟-6-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：8.1％)。LCMS:RT＝2.11min,[M+H] +＝309.22。 After the reaction was completed, 50 mL of water and 50 mL of ethyl acetate were added to dilute, the layers were separated, and the organic phase was collected. The organic phase was washed with saturated brine (3 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 350.0 mg of tert-butyl 4-(2-fluoro-6-formylphenyl)piperazine-1-carboxylate was obtained as a beige solid (yield: 8.1%). LCMS: RT=2.11 min, [M+H] + =309.22.
步骤B：合成(E)-4-(2-氟-6-((2-甲苯磺酰基肼基甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(2-fluoro-6-((2-tosylhydrazinomethyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000087
Figure PCTCN2021105088-appb-000087
室温下，将4-(2-氟-6-甲酰基苯基)哌嗪-1-羧酸叔丁酯(350.0毫克，1.14毫摩尔)和4-甲基苯磺酰肼(222.0毫克，1.19毫摩尔)加入无水乙醇(10.0毫升)中，N 2保护下，室温反应2小时。 At room temperature, tert-butyl 4-(2-fluoro-6-formylphenyl)piperazine-1-carboxylate (350.0 mg, 1.14 mmol) and 4-methylbenzenesulfonylhydrazide (222.0 mg, 1.19 mmol) was added to anhydrous ethanol (10.0 mL), and reacted at room temperature for 2 hours under the protection of N 2 .
反应结束，蒸干溶剂得到540.9毫克米黄色固体(E)-4-(2-氟-6-((2-甲苯磺酰基肼基甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.18min,[M+H] +＝477.28。 After the reaction was completed, the solvent was evaporated to dryness to obtain 540.9 mg of beige solid (E)-4-(2-fluoro-6-((2-toluenesulfonylhydrazinomethyl)phenyl)piperazine-1-carboxylate tert-butyl ester . No purification, directly used in the next reaction. LCMS: RT=2.18min, [M+H] + =477.28.
步骤C：合成6-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of tert-butyl 6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
Figure PCTCN2021105088-appb-000088
Figure PCTCN2021105088-appb-000088
室温下，向含有(E)-4-(2-氟-6-((2-甲苯磺酰基肼基甲基)苯基)哌嗪-1-羧酸叔丁酯(540.9毫克，1.13毫摩尔)的甲苯(10.0毫升)中，分批加入氢化钠(49.0毫克，1.23毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。To the mixture containing (E)-tert-butyl 4-(2-fluoro-6-((2-tosylhydrazinomethyl)phenyl)piperazine-1-carboxylate (540.9 mg, 1.13 mmol) at room temperature ) in toluene (10.0 mL), sodium hydride (49.0 mg, 1.23 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)和水(50毫升)稀释，分液，收集有机相，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到110.2毫克米黄色固体6-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：33.2％)。LCMS:RT＝2.20min,[M+H] +＝293.23。 After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The organic phase was collected and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 110.2 mg of tert-butyl 6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a beige solid (yield: 33.2%) . LCMS: RT=2.20 min, [M+H] + =293.23.
步骤D：合成6-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 6-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000089
Figure PCTCN2021105088-appb-000089
室温下，将6-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(110.2毫克，0.38毫摩尔)加入甲醇(5毫升)中，滴加盐酸的二氧六环溶液(1毫升，4.0摩尔每升)，室温反应1小时。At room temperature, tert-butyl 6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (110.2 mg, 0.38 mmol) was added In methanol (5 mL), a solution of hydrochloric acid in dioxane (1 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 1 hour.
反应结束，蒸干溶剂得到85.0毫克白色固体6-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.50min,[M+H] +＝193.16。 After the reaction was completed, the solvent was evaporated to dryness to obtain 85.0 mg of 6-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride as a white solid. It was directly used in the next reaction without purification. LCMS: RT=1.50 min, [M+H] + =193.16.
步骤E：(5S)-5-环丙基-5-(3-(6-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)咪唑啉-2,4-二酮Step E: (5S)-5-Cyclopropyl-5-(3-(6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) -yl)-3-oxopropyl)imidazoline-2,4-dione
Figure PCTCN2021105088-appb-000090
Figure PCTCN2021105088-appb-000090
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(94.7毫克，0.45毫摩尔)和6-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(85.0毫克，0.37毫摩尔)加入N,N-二甲基甲酰胺(5.0毫升)中，滴加N,N-二异丙基乙胺(144.1毫克)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(85.5毫克，0.45毫摩尔)和1-羟基苯并三唑(7.5毫克，0.06毫摩尔)，室温反应过夜。At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (94.7 mg, 0.45 mmol) and 6-fluoro-1,2, 3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (85.0 mg, 0.37 mmol) was added to N,N-dimethylformamide (5.0 mL) dropwise Add N,N-diisopropylethylamine (144.1 mg) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (85.5 mg, 0.45 mmol) and 1-hydroxybenzotriazole (7.5 mg, 0.06 mmol) at room temperature overnight.
反应结束，加水(50毫升)和乙酸乙酯(50毫升)稀释，分液，收集有机相，饱和食盐水(3毫升×2次)洗涤，无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到55.0毫克米黄色固体(5S)-5-环丙基-5-(3-(6-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)咪唑啉-2,4-二酮(收率：38.3％)。LCMS:RT＝1.81min,[M+H] +＝387.24。 1H NMR(400MHz,DMSO-d 6)δ(ppm):10.59(s,1H),7.68(s,1H),6.92(d,J＝6.8Hz,1H),6.88(dd,J＝12.4,8.4Hz,1H),6.67–6.57(m,1H),4.55–4.34(m,1H),3.95–3.75(m,2H),3.25–2.86(m,3H),2.79–2.57(m,2H),2.45–2.18(m,2H),2.02–1.90(m,2H),1.31–1.21(m,1H),1.15–1.04(m,1H),0.50–0.41(m,1H),0.40–0.28(m,2H),0.17–0.06(m,1H)。 After the reaction was completed, water (50 mL) and ethyl acetate (50 mL) were added to dilute, the layers were separated, the organic phase was collected, washed with saturated brine (3 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 55.0 mg of (5S)-5-cyclopropyl-5-(3-(6-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2 was obtained as a beige solid (1H)-yl)-3-oxopropyl)imidazoline-2,4-dione (yield: 38.3%). LCMS: RT=1.81 min, [M+H] + =387.24. 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 10.59 (s, 1H), 7.68 (s, 1H), 6.92 (d, J=6.8 Hz, 1H), 6.88 (dd, J=12.4, 8.4Hz, 1H), 6.67–6.57 (m, 1H), 4.55–4.34 (m, 1H), 3.95–3.75 (m, 2H), 3.25–2.86 (m, 3H), 2.79–2.57 (m, 2H) ,2.45–2.18(m,2H),2.02–1.90(m,2H),1.31–1.21(m,1H),1.15–1.04(m,1H),0.50–0.41(m,1H),0.40–0.28( m, 2H), 0.17–0.06 (m, 1H).
实施例15Example 15
合成(5S)-5-环丙基-5-(3-(7-氟-3,4,10,10a-四氢吡嗪[1,2-a]吲哚-2(1H)-基)-3-氧丙基)咪唑啉-2,4-二酮Synthesis of (5S)-5-cyclopropyl-5-(3-(7-fluoro-3,4,10,10a-tetrahydropyrazine[1,2-a]indol-2(1H)-yl) -3-Oxypropyl)imidazoline-2,4-dione
Figure PCTCN2021105088-appb-000091
Figure PCTCN2021105088-appb-000091
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(5-氟-2-甲酰苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(5-fluoro-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000092
Figure PCTCN2021105088-appb-000092
室温下，向含有2,4-二氟苯甲醛(2.00克，14.07毫摩尔)的二甲基亚砜(12.0毫升)中加入N-叔丁氧羰基哌嗪(2.62克，14.07毫摩尔)和碳酸钾(2.33克，16.89毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2,4-difluorobenzaldehyde (2.00 g, 14.07 mmol) in dimethyl sulfoxide (12.0 mL) was added N-tert-butoxycarbonylpiperazine (2.62 g, 14.07 mmol) and potassium carbonate (2.33 g, 16.89 mmol), N 2 protection for 12 h at 95 ° C.
反应结束，加水50毫升水和50毫升乙酸乙酯稀释，分液，收集有机相，有机相先用饱和食盐水(3毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到550.0毫克米黄色固体4-(5-氟-2-甲酰苯基)哌嗪-1-羧酸叔丁酯(收率：12.7％)。LCMS:RT＝2.09min,[M+H] +＝309.22。 1H NMR(400MHz,CDCl 3)δ(ppm):10.20(s,1H),7.84(dd,J＝8.4,6.8Hz,1H),6.86–6.79(m,1H),6.75(dd,J＝10.8,2.4Hz,1H),3.69–3.60(m,4H),3.10–3.00(m,4H),1.49(s,9H)。 After the reaction was completed, 50 mL of water and 50 mL of ethyl acetate were added to dilute, the layers were separated, and the organic phase was collected. The organic phase was washed with saturated brine (3 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 550.0 mg of tert-butyl 4-(5-fluoro-2-formylphenyl)piperazine-1-carboxylate was obtained as a beige solid (yield: 12.7%). LCMS: RT=2.09 min, [M+H] + =309.22. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 10.20 (s, 1H), 7.84 (dd, J=8.4, 6.8 Hz, 1H), 6.86-6.79 (m, 1H), 6.75 (dd, J= 10.8, 2.4Hz, 1H), 3.69–3.60 (m, 4H), 3.10–3.00 (m, 4H), 1.49 (s, 9H).
步骤B：合成(E)-4-(5-氟-2-(((2-甲苯磺酰肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(5-fluoro-2-(((2-tosylhydrazide)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000093
Figure PCTCN2021105088-appb-000093
室温下，将4-(5-氟-2-甲酰苯基)哌嗪-1-羧酸叔丁酯(550.0毫克，1.78毫摩尔)和4-甲基苯磺酰肼(348.8毫克，1.87毫摩尔)加入无水乙醇(10.0毫升)中，N 2保护下，室温反应2小时。 At room temperature, tert-butyl 4-(5-fluoro-2-formylphenyl)piperazine-1-carboxylate (550.0 mg, 1.78 mmol) and 4-methylbenzenesulfonylhydrazide (348.8 mg, 1.87 mmol) was added to anhydrous ethanol (10.0 mL), and reacted at room temperature for 2 hours under the protection of N 2 .
反应结束，蒸干溶剂得到850.0毫克米黄色固体(E)-4-(5-氟-2-(((2-甲苯磺酰肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.14min,[M+H] +＝477.25。 After the reaction was completed, the solvent was evaporated to dryness to obtain 850.0 mg of beige solid (E)-4-(5-fluoro-2-(((2-toluenesulfohydrazide)methyl)phenyl)piperazine-1-carboxylic acid tertiary Butyl ester. No purification, directly used in the next reaction. LCMS: RT=2.14min, [M+H] + =477.25.
步骤C：合成7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of tert-butyl 7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
Figure PCTCN2021105088-appb-000094
Figure PCTCN2021105088-appb-000094
室温下，向含有(E)-4-(5-氟-2-(((2-甲苯磺酰肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(850.0毫克，1.78毫摩尔)的甲苯(10.0毫升)中，分批加入氢化钠(77.0毫克，1.93毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-tert-butyl 4-(5-fluoro-2-(((2-tosylhydrazide)methyl)phenyl)piperazine-1-carboxylate (850.0 mg, 1.78 g) at room temperature mmol) in toluene (10.0 mL), sodium hydride (77.0 mg, 1.93 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)和水(50毫升)稀释，分液，收集有机相，减压浓缩。 所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到340.5毫克米黄色固体7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：65.3％)。LCMS:RT＝2.16min,[M+H] +＝293.26。 After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The organic phase was collected and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 340.5 mg of tert-butyl 7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a beige solid (yield: 65.3%) . LCMS: RT=2.16 min, [M+H] + =293.26.
步骤D：合成7-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000095
Figure PCTCN2021105088-appb-000095
室温下，将7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(340.5毫克，1.16毫摩尔)加入甲醇(5.0毫升)中，滴加盐酸的二氧六环溶液(1毫升，4.0摩尔每升)，室温反应1小时。At room temperature, tert-butyl 7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (340.5 mg, 1.16 mmol) was added In methanol (5.0 mL), a solution of hydrochloric acid in dioxane (1 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 1 hour.
反应结束，蒸干溶剂得到260.0毫克白色固体7-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.49min,[M+H] +＝193.18。 After the reaction was completed, the solvent was evaporated to dryness to obtain 260.0 mg of 7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride as a white solid. It was directly used in the next reaction without purification. LCMS: RT=1.49 min, [M+H] + =193.18.
步骤E：合成(5S)-5-环丙基-5-(3-(7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧代丙基)咪唑啉-2,4-二酮Step E: Synthesis of (5S)-5-cyclopropyl-5-(3-(7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H )-yl)-3-oxopropyl)imidazoline-2,4-dione
Figure PCTCN2021105088-appb-000096
Figure PCTCN2021105088-appb-000096
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(289.5毫克，1.36毫摩尔)和7-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(260.0毫克，1.14毫摩尔)加入N,N-二甲基甲酰胺(10毫升)中，滴加N,N-二异丙基乙胺(440.8毫克)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(261.5毫克，1.36毫摩尔)和1-羟基苯并三唑(23.0毫克，0.17毫摩尔)，室温反应过夜。At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (289.5 mg, 1.36 mmol) and 7-fluoro-1,2, 3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (260.0 mg, 1.14 mmol) was added to N,N-dimethylformamide (10 mL) dropwise Add N,N-diisopropylethylamine (440.8 mg) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (261.5 mg, 1.36 mmol) and 1-hydroxybenzotriazole (23.0 mg, 0.17 mmol) at room temperature overnight.
反应结束，加水(50毫升)和乙酸乙酯(50毫升)稀释，分液，收集有机相，饱和食盐水(3毫升×2次)洗涤，无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到90.0毫克米黄色固体(5S)-5-环丙基-5-(3-(7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧代丙基)咪唑啉-2,4-二酮(收率：20.5％)。LCMS:RT＝1.81min,[M+H] +＝387.27。 1H NMR(400MHz,DMSO-d 6)δ(ppm):10.59(s,1H),7.68(d,J＝4.8Hz,1H),7.01(s,1H),6.46–6.38(m,1H),6.35–6.27(m,1H),4.49–4.32(m,1H),3.85–3.71(m,1H),3.70–3.60(m,1H),3.21–2.81(m,4H),2.78–2.61(m,1H),2.41–2.17(m,2H),2.01–1.89(m,2H),1.35–1.25(m,1H),1.13–1.05(m,1H),0.51–0.40(m,1H),0.40–0.27(m,2H),0.15–0.05(m,1H)。 After the reaction was completed, water (50 mL) and ethyl acetate (50 mL) were added to dilute, the layers were separated, the organic phase was collected, washed with saturated brine (3 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 90.0 mg of (5S)-5-cyclopropyl-5-(3-(7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2 was obtained as a beige solid (1H)-yl)-3-oxopropyl)imidazoline-2,4-dione (yield: 20.5%). LCMS: RT=1.81 min, [M+H] + =387.27. 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 10.59 (s, 1H), 7.68 (d, J=4.8 Hz, 1H), 7.01 (s, 1H), 6.46-6.38 (m, 1H) ,6.35–6.27(m,1H),4.49–4.32(m,1H),3.85–3.71(m,1H),3.70–3.60(m,1H),3.21–2.81(m,4H),2.78–2.61( m, 1H), 2.41–2.17 (m, 2H), 2.01–1.89 (m, 2H), 1.35–1.25 (m, 1H), 1.13–1.05 (m, 1H), 0.51–0.40 (m, 1H), 0.40–0.27 (m, 2H), 0.15–0.05 (m, 1H).
实施例16Example 16
合成(5S)-5-(3-(8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(8-Fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropane yl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000097
Figure PCTCN2021105088-appb-000097
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(4-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(4-fluoro-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000098
Figure PCTCN2021105088-appb-000098
室温下，向含有2,5-二氟苯甲醛(2.00克，14.08毫摩尔)的二甲基亚砜(12.0毫升)中加入N-叔丁氧羰基哌嗪(3.15克，16.90毫摩尔)和碳酸钾(2.53克，18.30毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2,5-difluorobenzaldehyde (2.00 g, 14.08 mmol) in dimethyl sulfoxide (12.0 mL) was added N-tert-butoxycarbonylpiperazine (3.15 g, 16.90 mmol) and potassium carbonate (2.53 g, 18.30 mmol), N 2 protection for 12 h at 95 ° C.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到700.0毫克淡黄色固体4-(4-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：16.1％)。LCMS:RT＝2.16min,[M+H] +＝309.27。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 700.0 mg of tert-butyl 4-(4-fluoro-2-formylphenyl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 16.1%). LCMS: RT=2.16 min, [M+H] + =309.27.
步骤B：合成(E)-4-(4-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000099
Figure PCTCN2021105088-appb-000099
室温下，将4-(4-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(700.0毫克，2.27毫摩尔)和4-甲基苯磺酰肼(443.9毫克，2.38毫摩尔)加入无水乙醇(10.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(4-fluoro-2-formylphenyl)piperazine-1-carboxylate (700.0 mg, 2.27 mmol) and 4-methylbenzenesulfonylhydrazide (443.9 mg, 2.38 mmol) was added to anhydrous ethanol (10.0 mL) and reacted at room temperature for 1 hour under the protection of N 2 .
反应结束，蒸干溶剂得到1.08克类白色固体(E)-4-(4-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.16min,[M+H] +＝477.30。 The reaction was completed, and the solvent was evaporated to dryness to obtain 1.08 g of off-white solid (E)-4-(4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylic acid tertiary Butyl ester. No purification, directly used in the next reaction. LCMS: RT=2.16min, [M+H] + =477.30.
步骤C：合成8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of 8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
Figure PCTCN2021105088-appb-000100
Figure PCTCN2021105088-appb-000100
室温下，向含有(E)-4-(4-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(1.08克，2.27毫摩尔)的甲苯(10.0毫升)中，分批加入氢化钠(109.0毫克，2.72毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-tert-butyl 4-(4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (1.08 g, 2.27 g) at room temperature mmol) in toluene (10.0 mL), sodium hydride (109.0 mg, 2.72 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)溶解，先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到192.0毫克淡黄色固体8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：28.93％)。LCMS:RT＝2.05min,[M+H] +＝293.27。 The reaction was completed, cooled to room temperature, dissolved in ethyl acetate (50 mL), washed with saturated brine (50 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 192.0 mg of tert-butyl 8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a pale yellow solid (yield: 28.93%) . LCMS: RT=2.05 min, [M+H] + =293.27.
步骤D：合成8-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000101
Figure PCTCN2021105088-appb-000101
室温下，将8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(192.0毫克，0.66毫摩尔)加入甲醇(2.0毫升)中，滴加盐酸的二氧六环溶液(821.0微升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (192.0 mg, 0.66 mmol) was added In methanol (2.0 mL), a solution of hydrochloric acid in dioxane (821.0 μL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到59.0毫克类白色固体8-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.43min,[M+H] +＝193.17。 After the reaction was completed, the solvent was evaporated to dryness to obtain 59.0 mg of off-white solid 8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.43 min, [M+H] + =193.17.
步骤E：合成(5S)-5-(3-(8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(8-Fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000102
Figure PCTCN2021105088-appb-000102
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和8-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(59.0毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-fluoro-1,2, 3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (59.0 mg, 0.26 mmol) was added to N,N-dimethylformamide (2.0 mL) dropwise Add N,N-diisopropylethylamine (156.0 μl), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) ) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) under N 2 protection at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到22.0毫克白色固体(5S)-5-(3-(8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：23.7％)。LCMS:RT＝1.79min,[M+H] +＝387.28。 1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),7.70(s,1H),6.96(d,J＝8.9Hz,1H),6.83(td,J＝9.6,1.8Hz,1H),6.57–6.45(m,1H),4.42(dd,J＝38.9,11.8Hz,1H),3.80(dd,J＝27.3,11.3Hz,1H),3.67–3.53(m,1H),3.49–3.36(m,1H),3.20–2.90(m,2H),2.90–2.73(m,1H),2.72–2.63(m,1H),2.63–2.53(m,1H),2.42(ddd,J＝36.3,12.6,10.1Hz,1H),2.33–2.16(m,1H),2.07–1.85(m,2H),1.17–1.00(m,1H),0.57–0.41(m,1H),0.41–0.20(m,2H),0.19–0.02(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 22.0 mg of white solid (5S)-5-(3-(8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 23.7%). LCMS: RT=1.79 min, [M+H] + =387.28. 1 H NMR(400MHz, DMSO-d6)δ10.60(s,1H),7.70(s,1H),6.96(d,J=8.9Hz,1H),6.83(td,J=9.6,1.8Hz,1H) ), 6.57–6.45 (m, 1H), 4.42 (dd, J=38.9, 11.8Hz, 1H), 3.80 (dd, J=27.3, 11.3Hz, 1H), 3.67–3.53 (m, 1H), 3.49– 3.36 (m, 1H), 3.20–2.90 (m, 2H), 2.90–2.73 (m, 1H), 2.72–2.63 (m, 1H), 2.63–2.53 (m, 1H), 2.42 (ddd, J=36.3 ,12.6,10.1Hz,1H),2.33–2.16(m,1H),2.07–1.85(m,2H),1.17–1.00(m,1H),0.57–0.41(m,1H),0.41–0.20(m , 2H), 0.19–0.02 (m, 1H).
实施例17Example 17
合成(5S)-5-(3-(7,8-二氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(7,8-Dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000103
Figure PCTCN2021105088-appb-000103
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(4,5-二氯-2-氟苯基)甲醇Step A: Synthesis of (4,5-dichloro-2-fluorophenyl)methanol
Figure PCTCN2021105088-appb-000104
Figure PCTCN2021105088-appb-000104
零摄氏度下，向含有4,5-二氯-2-氟苯甲酸(4.0克，19.14毫摩尔)的四氢呋喃(20.0毫升)中，滴加硼烷四氢呋喃溶液(38.0毫升，1.0摩尔每升)，N 2保护下，升温至65摄氏度搅拌1小时。 To a solution of 4,5-dichloro-2-fluorobenzoic acid (4.0 g, 19.14 mmol) in tetrahydrofuran (20.0 mL) was added dropwise a solution of borane in tetrahydrofuran (38.0 mL, 1.0 mol/L) at zero degrees Celsius, under N 2, warmed to 65 ° C for 1 hour.
反应结束，零摄氏度下，向反应液中缓慢滴加水至无气泡产生，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(30毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。得到3.46克白色固体(4,5-二氯-2-氟苯基)甲醇(收率：92.7％)。LCMS:RT＝1.91min。The reaction was completed, and at zero degrees Celsius, water was slowly added dropwise to the reaction solution until no bubbles were generated, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, and the organic phase was first washed with saturated brine (30 mL × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. 3.46 g of white solid (4,5-dichloro-2-fluorophenyl)methanol was obtained (yield: 92.7%). LCMS: RT=1.91 min.
步骤B：合成4,5-二氯-2-氟苯甲醛Step B: Synthesis of 4,5-dichloro-2-fluorobenzaldehyde
Figure PCTCN2021105088-appb-000105
Figure PCTCN2021105088-appb-000105
零摄氏度下，向含有(4,5-二氯-2-氟苯基)甲醇(3.46克，17.74毫摩尔)的二氯甲烷(177.0毫升)中，加入碳酸氢钠(7.53克，88.70毫摩尔)和戴斯-马丁氧化剂(11.29克，26.61毫摩尔)，N 2保护下，室温反应1小时。 To dichloromethane (177.0 mL) containing (4,5-dichloro-2-fluorophenyl)methanol (3.46 g, 17.74 mmol) at zero degrees Celsius was added sodium bicarbonate (7.53 g, 88.70 mmol) ) and Dess-Martin oxidant (11.29 g, 26.61 mmol) under N 2 protection at room temperature for 1 hour.
反应结束，加水淬灭，再加入亚硫酸钠至反应液分层、澄清，然后用二氯甲烷(50.0毫升×3次)萃取水相，合并有机相，有机相先用饱和食盐水(30毫升×2次)洗涤，再用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到1.80克白色固体4,5-二氯-2-氟苯甲醛(收率：52.6％)。LCMS:RT＝2.04min。The reaction was completed, quenched by adding water, and then adding sodium sulfite until the reaction solution was layered and clarified, and then the aqueous phase was extracted with dichloromethane (50.0 ml × 3 times), the organic phases were combined, and the organic phase was first washed with saturated brine (30 ml × 2 times), washed with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 1.80 g of white solid 4,5-dichloro-2-fluorobenzaldehyde were obtained (yield: 52.6%). LCMS: RT=2.04 min.
步骤C：合成4-(4,5-二氯-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step C: Synthesis of tert-butyl 4-(4,5-dichloro-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000106
Figure PCTCN2021105088-appb-000106
室温下，向含有4,5-二氯-2-氟苯甲醛(1.80克，9.33毫摩尔)的二甲基亚砜(11.0毫升)中加入N-叔丁氧羰基哌嗪(2.08克，11.20毫摩尔)和碳酸钾(1.67克，12.13毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 4,5-dichloro-2-fluorobenzaldehyde (1.80 g, 9.33 mmol) in dimethyl sulfoxide (11.0 mL) was added N-tert-butoxycarbonylpiperazine (2.08 g, 11.20 mL) at room temperature mmol) and potassium carbonate (1.67 g, 12.13 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到1.16克淡黄色固体4-(4,5-二氯-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：34.7％)。LCMS:RT＝2.25min,[M+H] +＝359.17。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 1.16 g of tert-butyl 4-(4,5-dichloro-2-formylphenyl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 34.7%). LCMS: RT=2.25 min, [M+H] + =359.17.
步骤D：合成(E)-4-(4,5-二氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step D: Synthesis of (E)-tert-butyl 4-(4,5-dichloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000107
Figure PCTCN2021105088-appb-000107
室温下，将4-(4,5-二氯-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(1.16克，3.23毫摩尔)和4-甲基苯磺酰肼(632.0毫克，3.39毫摩尔)加入无水乙醇(12.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(4,5-dichloro-2-formylphenyl)piperazine-1-carboxylate (1.16 g, 3.23 mmol) and 4-methylbenzenesulfonylhydrazide (632.0 mg, 3.39 mmol) was added to anhydrous ethanol (12.0 mL) and reacted at room temperature for 1 h under the protection of N 2 .
反应结束，蒸干溶剂得到1.10克类白色固体(E)-4-(4,5-二氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.16min,[M+H] +＝527.22。 The reaction was completed, and the solvent was evaporated to dryness to obtain 1.10 g of off-white solid (E)-4-(4,5-dichloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1- Carboxylic acid tert-butyl ester. No purification, directly used in the next reaction. LCMS: RT=2.16min, [M+H] + =527.22.
步骤E：合成7,8-二氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step E: Synthesis of tert-butyl 7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
Figure PCTCN2021105088-appb-000108
Figure PCTCN2021105088-appb-000108
室温下，向含有(E)-4-(4,5-二氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(1.10克，2.09毫摩尔)的甲苯(10.0毫升)中，分批加入氢化钠(100.3毫克，2.51毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-4-(4,5-dichloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate tert-butyl ester (1.10 g, 2.09 mmol) in toluene (10.0 mL), sodium hydride (100.3 mg, 2.51 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)溶解，先用饱和食盐水(100毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到568.0毫克淡黄色固体7,8-二氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：79.2％)。LCMS:RT＝2.30min,[M+H] +＝343.15。 After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (50 mL), washed with saturated brine (100 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 568.0 mg of tert-butyl 7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a pale yellow solid (yield: 79.2%). LCMS: RT=2.30 min, [M+H] + =343.15.
步骤F：合成7,8-二氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step F: Synthesis of 7,8-dichloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000109
Figure PCTCN2021105088-appb-000109
室温下，将7,8-二氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(568.0毫克，1.65毫摩尔)加入甲醇(4.0毫升)中，滴加盐酸的二氧六环溶液(2.1毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (568.0 mg, 1.65 mg mol) was added to methanol (4.0 mL), a solution of hydrochloric acid in dioxane (2.1 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到450.0毫克类白色固体7,8-二氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.67min,[M+H] +＝243.12。 After the reaction was completed, the solvent was evaporated to dryness to obtain 450.0 mg of off-white solid 7,8-dichloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.67 min, [M+H] + =243.12.
步骤G：合成(5S)-5-(3-(7,8-二氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step G: Synthesis of (5S)-5-(3-(7,8-Dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl )-3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000110
Figure PCTCN2021105088-appb-000110
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和7,8-二氯-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(98.0毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 7,8-dichloro-1 ,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (98.0 mg, 0.26 mmol) was added to N,N-dimethylformamide (2.0 mL) , N,N-diisopropylethylamine (156.0 μl) was added dropwise, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到35.0毫克白色固体(5S)-5-(3-(7,8-二氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：33.4％)。LCMS:RT＝1.93min,[M+H] +＝437.15。 1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),7.70(s,0.5H),7.68(s,0.5H),7.25(s,0.5H),7.25(s,0.5H),6.81(s,0.5H),6.79(s,0.5H),4.40(dd,J＝37.0,12.7Hz,1H),3.87–3.74(m,1H), 3.73–3.65(m,1H),3.64–3.45(m,1H),3.26–3.08(m,1H),3.05–2.93(m,1H),2.92–2.74(m,1H),2.73–2.53(m,2H),2.48–2.33(m,1H),2.35–2.19(m,1H),2.10–1.87(m,2H),1.16–1.00(m,1H),0.56–0.41(m,1H),0.41–0.26(m,2H),0.23–0.04(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 35.0 mg of white solid (5S)-5-(3-(7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 33.4%). LCMS: RT=1.93 min, [M+H] + =437.15. 1 H NMR(400MHz, DMSO-d6)δ10.59(s,1H),7.70(s,0.5H),7.68(s,0.5H),7.25(s,0.5H),7.25(s,0.5H) ,6.81(s,0.5H),6.79(s,0.5H),4.40(dd,J=37.0,12.7Hz,1H),3.87–3.74(m,1H), 3.73–3.65(m,1H),3.64 –3.45 (m, 1H), 3.26–3.08 (m, 1H), 3.05–2.93 (m, 1H), 2.92–2.74 (m, 1H), 2.73–2.53 (m, 2H), 2.48–2.33 (m, 1H), 2.35–2.19 (m, 1H), 2.10–1.87 (m, 2H), 1.16–1.00 (m, 1H), 0.56–0.41 (m, 1H), 0.41–0.26 (m, 2H), 0.23– 0.04 (m, 1H).
实施例18和实施例19Example 18 and Example 19
合成(S)-5-(3-((S)-7,8-二氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮和(S)-5-(3-((R)-7,8-二氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (S)-5-(3-((S)-7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (S)-5-(3-((R)-7,8-dichloro-3,4, 10,10a-Tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000111
Figure PCTCN2021105088-appb-000111
通过手性HPLC拆分(5S)-5-(3-(7,8-二氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(Chiralpak AD-H，正己烷：异丙醇＝80：20，洗脱液浓缩、冻干)，先后得到光学纯化合物18和化合物19。Resolution of (5S)-5-(3-(7,8-dichloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) by chiral HPLC -yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (Chiralpak AD-H, n-hexane:isopropanol=80:20, eluent concentrated, lyophilized) , optically pure compound 18 and compound 19 were obtained successively.
化合物18：HPLC:RT＝18.225min。LCMS:RT＝1.93min,[M+H] +＝437.15。 1H NMR(400MHz,CDCl 3)δ7.64(s,1H),7.12(s,0.5H),7.11(s,0.5H),6.50(s,0.5H),6.48(s,0.5H),5.90(s,0.5H),5.79(s,0.5H),4.68–4.58(m,1H),3.77(d,J＝13.3Hz,1H),3.57–3.19(m,3H),3.15–2.72(m,3H),2.69–2.18(m,5H),1.23–1.12(m,1H),0.64–0.53(m,1H),0.53–0.36(m,2H),0.36–0.25(m,1H)。 Compound 18: HPLC: RT=18.225 min. LCMS: RT=1.93 min, [M+H] + =437.15. 1 H NMR (400MHz, CDCl 3 ) δ 7.64(s, 1H), 7.12(s, 0.5H), 7.11(s, 0.5H), 6.50(s, 0.5H), 6.48(s, 0.5H), 5.90(s, 0.5H), 5.79(s, 0.5H), 4.68–4.58(m, 1H), 3.77(d, J=13.3Hz, 1H), 3.57–3.19(m, 3H), 3.15–2.72( m, 3H), 2.69–2.18 (m, 5H), 1.23–1.12 (m, 1H), 0.64–0.53 (m, 1H), 0.53–0.36 (m, 2H), 0.36–0.25 (m, 1H).
化合物19：HPLC:RT＝22.461min。LCMS:RT＝1.93min,[M+H] +＝437.18。 1H NMR(400MHz,CDCl 3)δ7.57(s,1H),7.12(s,1H),6.50(s,0.5H),6.47(s,0.5H),5.84(s,0.5H),5.75(s,0.5H),4.69–4.56(m,1H),3.77(d,J＝13.5Hz,1H),3.55–3.43(m,2H),3.28–2.72(m,4H),2.67–2.46(m,2H),2.46–2.17(m,3H),1.23–1.14(m,1H),0.65–0.54(m,1H),0.52–0.36(m,2H),0.36–0.25(m,1H)。 Compound 19: HPLC: RT=22.461 min. LCMS: RT=1.93 min, [M+H] + =437.18. 1 H NMR (400MHz, CDCl 3 ) δ 7.57(s, 1H), 7.12(s, 1H), 6.50(s, 0.5H), 6.47(s, 0.5H), 5.84(s, 0.5H), 5.75 (s, 0.5H), 4.69–4.56 (m, 1H), 3.77 (d, J=13.5Hz, 1H), 3.55–3.43 (m, 2H), 3.28–2.72 (m, 4H), 2.67–2.46 ( m, 2H), 2.46–2.17 (m, 3H), 1.23–1.14 (m, 1H), 0.65–0.54 (m, 1H), 0.52–0.36 (m, 2H), 0.36–0.25 (m, 1H).
实施例20Example 20
合成(5S)-5-环丙基-5-(3-(9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧代丙基)咪唑啉-2,4-二酮Synthesis of (5S)-5-cyclopropyl-5-(3-(9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl )-3-oxopropyl)imidazoline-2,4-dione
Figure PCTCN2021105088-appb-000112
Figure PCTCN2021105088-appb-000112
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(3-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(3-fluoro-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000113
Figure PCTCN2021105088-appb-000113
室温下，向含有2,6-二氟苯甲醛(2.00克，14.07毫摩尔)的二甲基亚砜(12.0毫升)中加入N-叔丁氧羰基哌嗪(2.62克，14.07毫摩尔)和碳酸钾(2.33克，16.89毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2,6-difluorobenzaldehyde (2.00 g, 14.07 mmol) in dimethyl sulfoxide (12.0 mL) was added N-tert-butoxycarbonylpiperazine (2.62 g, 14.07 mmol) and potassium carbonate (2.33 g, 16.89 mmol), N 2 protection for 12 h at 95 ° C.
反应结束，加水50毫升水和50毫升乙酸乙酯稀释，分液，收集有机相，有机相先用饱和食盐水(3毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到2.5克米黄色固体4-(3-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：57.6％)。LCMS:RT＝2.07min,[M+H] +＝309.20。 After the reaction was completed, 50 mL of water and 50 mL of ethyl acetate were added to dilute, the layers were separated, and the organic phase was collected. The organic phase was washed with saturated brine (3 mL×2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 2.5 g of tert-butyl 4-(3-fluoro-2-formylphenyl)piperazine-1-carboxylate were obtained as a beige solid (yield: 57.6%). LCMS: RT=2.07 min, [M+H] + =309.20.
步骤B：合成(E)-4-(3-氟-2-((2-甲苯磺酰肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(3-fluoro-2-((2-tosylhydrazide)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000114
Figure PCTCN2021105088-appb-000114
室温下，将4-(3-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(2.50克，8.11毫摩尔)和4-甲基苯磺酰肼(1.59克，8.51毫摩尔)加入无水乙醇(15.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(3-fluoro-2-formylphenyl)piperazine-1-carboxylate (2.50 g, 8.11 mmol) and 4-methylbenzenesulfonylhydrazide (1.59 g, 8.51 mmol) was added to anhydrous ethanol (15.0 mL) and reacted at room temperature for 1 hour under the protection of N 2 .
反应结束，蒸干溶剂得到3.80克米黄色固体(E)-4-(3-氟-2-((2-甲苯磺酰肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.13min,[M+H] +＝477.22。 The reaction was completed, and the solvent was evaporated to dryness to obtain 3.80 g of beige solid (E)-4-(3-fluoro-2-((2-toluenesulfonylhydrazide)methyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester. It was directly used in the next reaction without purification. LCMS: RT=2.13 min, [M+H] + =477.22.
步骤C：合成9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of 9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
Figure PCTCN2021105088-appb-000115
Figure PCTCN2021105088-appb-000115
室温下，向含有4-(3-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(3.8克，7.97毫摩尔)的甲苯(12毫升)中，分批加入氢化钠(344.4毫克，8.61毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。To 4-(3-fluoro-2-formylphenyl)piperazine-1-carboxylate tert-butyl ester (3.8 g, 7.97 mmol) in toluene (12 mL) was added portionwise sodium hydride at room temperature (344.4 mg, 8.61 mmol, 60% dispersed in paraffin oil), replaced with nitrogen for 20 minutes, and reacted at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(100毫升)和水(100毫升)稀释，分液，收集有机相，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到1.50克米黄色固体9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：64.4％)。LCMS:RT＝2.18min,[M+H] +＝293.23。 After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (100 mL), and the layers were separated. The organic phase was collected and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 1.50 g of tert-butyl 9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a beige solid (yield: 64.4%) . LCMS: RT=2.18 min, [M+H] + =293.23.
步骤D：合成9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000116
Figure PCTCN2021105088-appb-000116
室温下，将9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(1.50克，5.13毫摩尔)加入甲醇(10毫升)中，滴加盐酸的二氧六环溶液(4毫升，4.0摩尔每升)，室温反应1小时。At room temperature, tert-butyl 9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (1.50 g, 5.13 mmol) was added In methanol (10 mL), a solution of hydrochloric acid in dioxane (4 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 1 hour.
反应结束，蒸干溶剂得到1.1克米黄色固体9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝147min,[M+H] +＝193.18。 1H NMR(400MHz,DMSO)δ(ppm):9.90–9.61(m,2H),7.13–7.03(m,1H),6.49–6.41(m,2H),3.97–3.86(m,1H),3.84–3.76(m,1H),3.34–3.18(m,3H),3.12–3.03(m,1H),2.93–2.76(m,2H),2.69–2.60(m,1H)。 After the reaction was completed, the solvent was evaporated to dryness to obtain 1.1 g of beige solid 9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=147 min, [M+H] + =193.18. 1 H NMR (400MHz, DMSO) δ(ppm): 9.90–9.61 (m, 2H), 7.13–7.03 (m, 1H), 6.49–6.41 (m, 2H), 3.97–3.86 (m, 1H), 3.84 – 3.76 (m, 1H), 3.34 – 3.18 (m, 3H), 3.12 – 3.03 (m, 1H), 2.93 – 2.76 (m, 2H), 2.69 – 2.60 (m, 1H).
步骤E：合成(5S)-5-环丙基-5-(3-(9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧代丙基)咪唑啉-2,4-二酮Step E: Synthesis of (5S)-5-cyclopropyl-5-(3-(9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H )-yl)-3-oxopropyl)imidazoline-2,4-dione
Figure PCTCN2021105088-appb-000117
Figure PCTCN2021105088-appb-000117
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(55.7毫克，0.26毫摩尔)和9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(60.0毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(5.0毫升)中，滴加N,N-二异丙基乙胺(101.7毫克)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(60.4毫克，0.31毫摩尔)和1-羟基苯并三唑(5.3毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (55.7 mg, 0.26 mmol) and 9-fluoro-1,2, 3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (60.0 mg, 0.26 mmol) was added to N,N-dimethylformamide (5.0 mL) dropwise Add N,N-diisopropylethylamine (101.7 mg) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (60.4 mg, 0.31 mmol) and 1-hydroxybenzotriazole (5.3 mg, 0.04 mmol) under N 2 protection at room temperature overnight.
反应结束，加水(50毫升)和乙酸乙酯(50毫升)稀释，分液，收集有机相，饱和食盐水(3毫升×2次)洗涤，无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到30.2毫克米黄色固体(5S)-5-环丙基-5-(3-(9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧代丙基)咪唑啉-2,4-二酮(收率：29.8％)。LCMS:RT＝1.81min,[M+H] +＝387.21。 1H NMR(400MHz,DMSO-d 6)δ(ppm):10.59(s,1H),7.69(s,1H),7.09–7.00(m,1H),6.43–6.35(m,2H),4.51–4.32(m,1H),3.86–3.71(m,2H),3.70–3.62(m,1H),3.60–3.35(m,1H),3.06–2.99(m,1H),2.94–2.73(m,1H),2.68–2.52(m,2H),2.45–2.17(m,2H),2.01–1.87(m,2H),1.14–1.04(m,1H),0.49–0.40(m,1H),0.39–0.27(m,2H),0.15–0.04(m,1H)。 After the reaction was completed, water (50 mL) and ethyl acetate (50 mL) were added to dilute, the layers were separated, the organic phase was collected, washed with saturated brine (3 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 30.2 mg of beige solid (5S)-5-cyclopropyl-5-(3-(9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2 was obtained (1H)-yl)-3-oxopropyl)imidazoline-2,4-dione (yield: 29.8%). LCMS: RT=1.81 min, [M+H] + =387.21. 1 H NMR (400MHz, DMSO-d 6 )δ(ppm): 10.59(s,1H), 7.69(s,1H), 7.09-7.00(m,1H), 6.43-6.35(m,2H), 4.51- 4.32 (m, 1H), 3.86–3.71 (m, 2H), 3.70–3.62 (m, 1H), 3.60–3.35 (m, 1H), 3.06–2.99 (m, 1H), 2.94–2.73 (m, 1H) ), 2.68–2.52 (m, 2H), 2.45–2.17 (m, 2H), 2.01–1.87 (m, 2H), 1.14–1.04 (m, 1H), 0.49–0.40 (m, 1H), 0.39–0.27 (m, 2H), 0.15–0.04 (m, 1H).
实施例21Example 21
合成(5S)-5-(3-(7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(7-Chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000118
Figure PCTCN2021105088-appb-000118
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(5-氯-4-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(5-chloro-4-fluoro-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000119
Figure PCTCN2021105088-appb-000119
室温下，向含有4-氯-2,5-二氟苯甲醛(5.30克，30.0毫摩尔)的二甲基亚砜(30.0毫升)中加入N-叔丁氧羰基哌嗪(6.15克，33.0毫摩尔)和碳酸钾(5.17克，37.5毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 4-chloro-2,5-difluorobenzaldehyde (5.30 g, 30.0 mmol) in dimethyl sulfoxide (30.0 mL) was added N-tert-butoxycarbonylpiperazine (6.15 g, 33.0 mL) at room temperature mmol) and potassium carbonate (5.17 g, 37.5 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(80毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到2.40克白色固体4-(5-氯-4-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：23.4％)。LCMS:RT＝2.18min,[M+H] +＝343.18。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (80 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (50 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 2.40 g of tert-butyl 4-(5-chloro-4-fluoro-2-formylphenyl)piperazine-1-carboxylate was obtained as a white solid (yield: 23.4%). LCMS: RT=2.18 min, [M+H] + =343.18.
步骤B：合成(E)-4-(5-氯-4-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(5-chloro-4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000120
Figure PCTCN2021105088-appb-000120
室温下，将4-(5-氯-4-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(2.40克，7.02毫摩尔)和4-甲基苯磺酰肼(1.37克，7.37毫摩尔)加入无水乙醇(35.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(5-chloro-4-fluoro-2-formylphenyl)piperazine-1-carboxylate (2.40 g, 7.02 mmol) and 4-methylbenzenesulfonylhydrazide ( 1.37 g, 7.37 mmol) was added to anhydrous ethanol (35.0 mL) and reacted at room temperature for 1 h under the protection of N 2 .
反应结束，蒸干溶剂得到3.59克类白色固体(E)-4-(5-氯-4-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.23min,[M+H] +＝511.25。 The reaction was completed, and the solvent was evaporated to dryness to obtain 3.59 g of off-white solid (E)-4-(5-chloro-4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1 - Carboxylic acid tert-butyl ester. No purification, directly used in the next reaction. LCMS: RT=2.23min, [M+H] + =511.25.
步骤C：合成7-氯-8-氟--3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of tert-butyl 7-chloro-8-fluoro--3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
Figure PCTCN2021105088-appb-000121
Figure PCTCN2021105088-appb-000121
室温下，向含有(E)-4-(5-氯-4-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(3.59克，7.02毫摩尔)的甲苯(28.0毫升)中，分批加入氢化钠(281毫克，7.02毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。At room temperature, tert-butyl 4-(5-chloro-4-fluoro-2-(((2-tosylhydrazino)methyl)phenyl)piperazine-1-carboxylate ( 3.59 g, 7.02 mmol) in toluene (28.0 ml), sodium hydride (281 mg, 7.02 mmol, 60% dispersed in paraffin oil) was added in batches, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(100毫升)溶解，先用饱和食盐水(100毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到260毫克淡黄色固体7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：11.4％)。LCMS:RT＝2.23min,[M+H] +＝327.21。 After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (100 mL), washed with saturated brine (100 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 260 mg of tert-butyl 7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a pale yellow solid (yield : 11.4%). LCMS: RT=2.23 min, [M+H] + =327.21.
步骤D：合成7-氯-8-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 7-chloro-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000122
Figure PCTCN2021105088-appb-000122
室温下，将7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(260毫克，0.80毫摩尔)加入甲醇(4.0毫升)中，滴加盐酸的二氧六环溶液(0.80毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (260 mg, 0.80 mmol) was added to methanol (4.0 mL), and a dioxane solution of hydrochloric acid (0.80 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到210毫克类白色固体7-氯-8-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.57min,[M+H] +＝227.13。 1H NMR(400MHz,DMSO-d6)δ9.24(s,2H),7.19(dd,J＝9.0Hz,1H),6.81(d,J＝6.1Hz,1H),3.86–3.74(m,2H),3.29–3.11(m,3H),3.03(dd,J＝16.0,8.0Hz,1H),2.98–2.80(m,2H),2.62(dd,J＝16.0,7.2Hz,1H)。 After the reaction was completed, the solvent was evaporated to dryness to obtain 210 mg of off-white solid 7-chloro-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.57 min, [M+H] + =227.13. 1 H NMR (400MHz, DMSO-d6) δ 9.24(s, 2H), 7.19(dd, J=9.0Hz, 1H), 6.81(d, J=6.1Hz, 1H), 3.86-3.74(m, 2H) ), 3.29–3.11 (m, 3H), 3.03 (dd, J=16.0, 8.0 Hz, 1H), 2.98–2.80 (m, 2H), 2.62 (dd, J=16.0, 7.2 Hz, 1H).
步骤E：合成(5S)-5-(3-(7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(7-Chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000123
Figure PCTCN2021105088-appb-000123
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(60.0毫克，0.28毫摩尔)和7-氯-8-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(89毫克，0.34毫摩尔)加入无水二氯甲烷(4.0毫升)中，滴加N,N-二异丙基乙胺(187微升，1.13毫摩尔)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(81毫克，0.42毫摩尔)和1-羟基苯并三唑(6.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (60.0 mg, 0.28 mmol) and 7-chloro-8-fluoro- 1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (89 mg, 0.34 mmol) was added to anhydrous dichloromethane (4.0 mL) dropwise Add N,N-diisopropylethylamine (187 μl, 1.13 mmol) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg , 0.42 mmol) and 1-hydroxybenzotriazole (6.0 mg, 0.04 mmol), under N 2 protection, were reacted at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到33.5毫克白色固体(5S)-5-(3-(7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：28.1％)。LCMS:RT＝1.88min,[M+H] +＝421.15。 1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),7.68(d,J＝6.9Hz,1H),7.14(d,J＝8.7Hz,1H),6.71(t,J＝6.9Hz,1H),4.39(dd,J＝38.9,11.0Hz,1H),3.77(dd,J＝28.4,12.3Hz,1H),3.66(t,J＝11.5Hz,1H),3.54–3.34(m,1H),3.18–2.92(m,2H),2.90–2.69(m,1H),2.69–2.52(m,2H),2.46–2.17(m,2H),2.02–1.86(m,2H),1.14–1.04(m,1H),0.50–0.40(m,1H),0.40–0.26(m,2H),0.16–0.05(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 33.5 mg of (5S)-5-(3-(7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) was obtained as a white solid -yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 28.1%). LCMS: RT=1.88 min, [M+H] + =421.15. 1 H NMR (400MHz, DMSO-d6)δ10.59(s,1H),7.68(d,J=6.9Hz,1H),7.14(d,J=8.7Hz,1H),6.71(t,J=6.9 Hz, 1H), 4.39 (dd, J=38.9, 11.0Hz, 1H), 3.77 (dd, J=28.4, 12.3Hz, 1H), 3.66 (t, J=11.5Hz, 1H), 3.54–3.34 (m ,1H),3.18–2.92(m,2H),2.90–2.69(m,1H),2.69–2.52(m,2H),2.46–2.17(m,2H),2.02–1.86(m,2H),1.14 -1.04 (m, 1H), 0.50 - 0.40 (m, 1H), 0.40 - 0.26 (m, 2H), 0.16 - 0.05 (m, 1H).
实施例22和实施例23Example 22 and Example 23
合成(5S)-5-(3-((S)-7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮和(5S)-5-(3-((R)-7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-((S)-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) -yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (5S)-5-(3-((R)-7-chloro-8-fluoro-3, 4,10,10a-Tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000124
Figure PCTCN2021105088-appb-000124
通过手性HPLC拆分((5S)-5-(3-(7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(Chiralpak AD-H，正己烷：异丙醇＝80：20，洗脱液浓缩、冻干)，先后得到光学纯化合物22和化合物23。((5S)-5-(3-(7-Chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2() was resolved by chiral HPLC 1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (Chiralpak AD-H, n-hexane:isopropanol=80:20, the eluent was concentrated, frozen dry), optically pure compound 22 and compound 23 were obtained successively.
化合物22:HPLC:RT＝17.479min。LCMS:RT＝1.88min,[M+H] +＝421.15。 1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),7.70(s,0.5H),7.68(s,0.5H),7.16(d,J＝4.4Hz,0.5H),7.14(d,J＝4.4Hz,0.5H),6.73(d,J＝6.1Hz,0.5H),6.71(d,J＝6.1Hz,0.5H),4.46–4.44(m,0.5H),4.37–4.34(m,0.5H),3.83–3.81(m,0.5H),3.76–3.73(m,0.5H),3.66(t,J＝12.2Hz,1H),3.53–3.34(m,1H),3.16–2.93(m,2H),2.88–2.69(m,1H),2.68–2.52(m,2H),2.48–2.17(m,2H),2.01–1.88(m,2H),1.14–1.05(m,1H),0.49–0.41(m,1H),0.39–0.27(m,2H),0.14–0.05(m,1H)。 Compound 22: HPLC: RT=17.479 min. LCMS: RT=1.88 min, [M+H] + =421.15. 1 H NMR(500MHz,DMSO-d6)δ10.59(s,1H),7.70(s,0.5H),7.68(s,0.5H),7.16(d,J=4.4Hz,0.5H),7.14( d, J=4.4Hz, 0.5H), 6.73 (d, J=6.1Hz, 0.5H), 6.71 (d, J=6.1Hz, 0.5H), 4.46–4.44 (m, 0.5H), 4.37–4.34 (m, 0.5H), 3.83–3.81 (m, 0.5H), 3.76–3.73 (m, 0.5H), 3.66 (t, J=12.2Hz, 1H), 3.53–3.34 (m, 1H), 3.16– 2.93 (m, 2H), 2.88–2.69 (m, 1H), 2.68–2.52 (m, 2H), 2.48–2.17 (m, 2H), 2.01–1.88 (m, 2H), 1.14–1.05 (m, 1H) ), 0.49–0.41 (m, 1H), 0.39–0.27 (m, 2H), 0.14–0.05 (m, 1H).
化合物23:HPLC:RT＝20.353min。LCMS:RT＝1.88min,[M+H] +＝421.15。 1H NMR(500MHz,DMSO-d6)δ10.61(s,0.5H),10.60(s,0.5H),7.70(s,0.5H),7.68(s,0.5H),7.16(d,J＝4.0Hz,0.5H), 7.15(d,J＝4.0Hz,0.5H),6.73(d,J＝6.1Hz,0.5H),6.71(d,J＝6.1Hz,0.5H),4.46–4.44(m,0.5H),4.37-4.34(m,0.5H),3.83–3.81(m,0.5H),3.76–3.74(m,0.5H),3.66(t,J＝13.7Hz,1H),3.54–3.34(m,1H),3.17–2.93(m,2H),2.87–2.69(m,1H),2.68–2.52(m,2H),2.48–2.20(m,2H),2.01–1.88(m,2H),1.14–1.05(m,1H),0.49–0.41(m,1H),0.40–0.28(m,2H),0.10(dt,J＝9.7,4.7Hz,1H)。 Compound 23: HPLC: RT=20.353 min. LCMS: RT=1.88 min, [M+H] + =421.15. 1 H NMR (500MHz, DMSO-d6) δ10.61(s, 0.5H), 10.60(s, 0.5H), 7.70(s, 0.5H), 7.68(s, 0.5H), 7.16(d, J= 4.0Hz, 0.5H), 7.15(d, J＝4.0Hz, 0.5H), 6.73(d, J＝6.1Hz, 0.5H), 6.71(d, J＝6.1Hz, 0.5H), 4.46–4.44( m, 0.5H), 4.37-4.34 (m, 0.5H), 3.83–3.81 (m, 0.5H), 3.76–3.74 (m, 0.5H), 3.66 (t, J=13.7Hz, 1H), 3.54– 3.34 (m, 1H), 3.17–2.93 (m, 2H), 2.87–2.69 (m, 1H), 2.68–2.52 (m, 2H), 2.48–2.20 (m, 2H), 2.01–1.88 (m, 2H) ), 1.14–1.05 (m, 1H), 0.49–0.41 (m, 1H), 0.40–0.28 (m, 2H), 0.10 (dt, J=9.7, 4.7Hz, 1H).
实施例24Example 24
合成(5S)-5-(3-(8-氯-7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(8-Chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000125
Figure PCTCN2021105088-appb-000125
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(4-氯-5-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(4-chloro-5-fluoro-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000126
Figure PCTCN2021105088-appb-000126
室温下，向含有5-氯-2,4-二氟苯甲醛(3.53克，20.0毫摩尔)的二甲基亚砜(20.0毫升)中加入N-叔丁氧羰基哌嗪(3.91克，21.0毫摩尔)和碳酸钾(3.31克，24.0毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 5-chloro-2,4-difluorobenzaldehyde (3.53 g, 20.0 mmol) in dimethyl sulfoxide (20.0 mL) was added N-tert-butoxycarbonylpiperazine (3.91 g, 21.0 mL) at room temperature mmol) and potassium carbonate (3.31 g, 24.0 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(80毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到4.27克白色固体4-(4-氯-5-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：62.5％)。LCMS:RT＝2.18min,[M+H] +＝343.19。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (80 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (50 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 4.27 g of tert-butyl 4-(4-chloro-5-fluoro-2-formylphenyl)piperazine-1-carboxylate was obtained as a white solid (yield: 62.5%). LCMS: RT=2.18 min, [M+H] + =343.19.
步骤B：合成(E)-4-(4-氯-5-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(4-chloro-5-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000127
Figure PCTCN2021105088-appb-000127
室温下，将4-(4-氯-5-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(4.27克，12.5毫摩尔)和4-甲基苯磺酰肼(2.44克，13.1毫摩尔)加入无水乙醇(62.5毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(4-chloro-5-fluoro-2-formylphenyl)piperazine-1-carboxylate (4.27 g, 12.5 mmol) and 4-methylbenzenesulfonylhydrazide ( 2.44 g, 13.1 mmol) was added absolute ethanol (62.5 ml), under N 2, at room temperature for 1 hour.
反应结束，蒸干溶剂得到6.39克类白色固体(E)-4-(4-氯-5-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.21min,[M+H] +＝511.23。 The reaction was completed, and the solvent was evaporated to dryness to obtain 6.39 g of off-white solid (E)-4-(4-chloro-5-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1 - Carboxylic acid tert-butyl ester. No purification, directly used in the next reaction. LCMS: RT=2.21min, [M+H] + =511.23.
步骤C：合成8-氯-7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of 8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
Figure PCTCN2021105088-appb-000128
Figure PCTCN2021105088-appb-000128
室温下，向含有(E)-4-(4-氯-5-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(6.39克，12.5毫摩尔)的甲苯(28.0毫升)中，分批加入氢化钠(500毫克，12.5毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。At room temperature, tert-butyl 4-(4-chloro-5-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate ( 6.39 g, 12.5 mmol) in toluene (28.0 ml), sodium hydride (500 mg, 12.5 mmol, 60% dispersed in paraffin oil) was added in batches, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(100毫升)溶解，先用饱和食盐水(100毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到369毫克淡黄色固体8-氯-7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：9.0％)。LCMS:RT＝2.23min,[M+H] +＝327.22。 After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (100 mL), washed with saturated brine (100 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 369 mg of tert-butyl 8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a pale yellow solid (yield : 9.0%). LCMS: RT=2.23 min, [M+H] + =327.22.
步骤D：合成8-氯-7-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 8-chloro-7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000129
Figure PCTCN2021105088-appb-000129
室温下，将8-氯-7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(369毫克，1.13毫摩尔)加入甲醇(5.7毫升)中，滴加盐酸的二氧六环溶液(1.4毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (369 mg, 1.13 mmol) was added to methanol (5.7 mL), a solution of hydrochloric acid in dioxane (1.4 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到300毫克类白色固体8-氯-7-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.59min,[M+H] +＝227.12。 1H NMR(500MHz,DMSO-d6)δ9.32(s,2H),7.19(d,J＝8.9Hz,1H),6.81(d,J＝6.1Hz,1H),3.86–3.76(m,2H),3.28–3.18(m,3H),3.03(dd,J＝16.0,7.9Hz,1H),2.97–2.80(m,2H),2.62(dd,J＝16.0,7.2Hz,1H)。 After the reaction was completed, the solvent was evaporated to dryness to obtain 300 mg of off-white solid 8-chloro-7-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.59 min, [M+H] + =227.12. 1 H NMR (500MHz, DMSO-d6)δ9.32(s,2H),7.19(d,J=8.9Hz,1H),6.81(d,J=6.1Hz,1H),3.86-3.76(m,2H) ), 3.28–3.18 (m, 3H), 3.03 (dd, J=16.0, 7.9Hz, 1H), 2.97–2.80 (m, 2H), 2.62 (dd, J=16.0, 7.2Hz, 1H).
步骤E：合成(5S)-5-(3-(8-氯-7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(8-Chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000130
Figure PCTCN2021105088-appb-000130
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(60.0毫克，0.28毫摩尔)和8-氯-7-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(89毫克，0.34毫摩尔)加入无水二氯甲烷(4.0毫升)中，滴加N,N-二异丙基乙胺(187微升，1.13毫摩尔)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(81毫克，0.42毫摩尔)和1-羟基苯并三唑(6.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (60.0 mg, 0.28 mmol) and 8-chloro-7-fluoro- 1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (89 mg, 0.34 mmol) was added to anhydrous dichloromethane (4.0 mL) dropwise Add N,N-diisopropylethylamine (187 μl, 1.13 mmol) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg , 0.42 mmol) and 1-hydroxybenzotriazole (6.0 mg, 0.04 mmol), under N 2 protection, were reacted at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到41.4毫克白色固体(5S)-5-(3-(8-氯-7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：34.7％)。LCMS:RT＝1.89min,[M-H] -＝419.20。 1H NMR(400MHz,DMSO-d6)δ10.67–10.52(m,1H),7.68(d,J＝5.1Hz,1H),7.16(d, J＝7.7Hz,1H),6.71–6.58(m,1H),4.39(dd,J＝33.3,12.9Hz,1H),3.87–3.73(m,2H),3.44(s,1H),3.17–2.54(m,5H),2.45–2.17(m,2H),2.03–1.86(m,2H),1.15–1.03(m,1H),0.50–0.40(m,1H),0.40–0.24(m,2H),0.15–0.04(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 41.4 mg of (5S)-5-(3-(8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) was obtained as a white solid -yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 34.7%). LCMS: RT = 1.89 min, [MH] − = 419.20. 1 H NMR (400MHz, DMSO-d6) δ 10.67-10.52 (m, 1H), 7.68 (d, J=5.1Hz, 1H), 7.16 (d, J=7.7Hz, 1H), 6.71-6.58 (m ,1H),4.39(dd,J=33.3,12.9Hz,1H),3.87–3.73(m,2H),3.44(s,1H),3.17–2.54(m,5H),2.45–2.17(m,2H ), 2.03–1.86 (m, 2H), 1.15–1.03 (m, 1H), 0.50–0.40 (m, 1H), 0.40–0.24 (m, 2H), 0.15–0.04 (m, 1H).
实施例25和实施例26Example 25 and Example 26
合成(5S)-5-(3-((S)-8-氯-7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮和(5S)-5-(3-((R)-8-氯-7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-((S)-8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) -yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (5S)-5-(3-((R)-8-chloro-7-fluoro-3, 4,10,10a-Tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000131
Figure PCTCN2021105088-appb-000131
通过手性HPLC拆分(5S)-5-(3-(8-氯-7-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(Chiralpak AD-H，正己烷：异丙醇＝80：20，洗脱液浓缩、冻干)，先后得到光学纯化合物25和化合物26。Resolution of (5S)-5-(3-(8-chloro-7-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) by chiral HPLC )-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (Chiralpak AD-H, n-hexane:isopropanol=80:20, the eluent was concentrated, lyophilized ), optically pure compound 25 and compound 26 were obtained successively.
化合物25:HPLC:RT＝18.760min。LCMS:RT＝1.89min,[M-H] -＝419.20。 1H NMR(400MHz,CDCl 3)δ7.65(s,1H),7.11–7.01(m,1H),6.25(d,J＝3.8Hz,0.5H),6.23(d,J＝3.8Hz,0.5H),5.90(s,0.5H),5.80(s,0.5H),4.68–4.65(m,0.5H),4.62–4.58(m,0.5H),3.80–3.74(m,1H),3.55–3.40(m,2H),3.30–3.07(m,1H),3.06–2.86(m,2H),2.83–2.18(m,6H),1.24–1.13(m,1H),0.59(d,J＝5.0Hz,1H),0.51–0.36(m,2H),0.36–0.25(m,1H)。 Compound 25: HPLC: RT=18.760 min. LCMS: RT = 1.89 min, [MH] − = 419.20. 1 H NMR (400MHz, CDCl 3 ) δ 7.65 (s, 1H), 7.11-7.01 (m, 1H), 6.25 (d, J=3.8Hz, 0.5H), 6.23 (d, J=3.8Hz, 0.5 H), 5.90(s, 0.5H), 5.80(s, 0.5H), 4.68–4.65(m, 0.5H), 4.62–4.58(m, 0.5H), 3.80–3.74(m, 1H), 3.55– 3.40 (m, 2H), 3.30–3.07 (m, 1H), 3.06–2.86 (m, 2H), 2.83–2.18 (m, 6H), 1.24–1.13 (m, 1H), 0.59 (d, J=5.0 Hz, 1H), 0.51–0.36 (m, 2H), 0.36–0.25 (m, 1H).
化合物26:HPLC:RT＝22.109min。LCMS:RT＝1.89min,[M-H] -＝419.20。 1H NMR(400MHz,CDCl 3)δ7.67–7.54(m,1H),7.06(s,0.5H),7.04(s,0.5H),6.25(d,J＝9.5Hz,0.5H),6.22(d,J＝9.5Hz,0.5H),5.86(s,0.5H),5.78(s,0.5H),4.71–4.56(m,1H),3.80–3.74(m,1H),3.51–3.45(m,2H),3.30–3.08(m,1H),3.05–2.85(m,2H),2.83–2.18(m,6H),1.23–1.13(m,1H),0.65–0.52(m,1H),0.52–0.36(m,2H),0.36–0.24(m,1H)。 Compound 26: HPLC: RT=22.109 min. LCMS: RT = 1.89 min, [MH] − = 419.20. 1 H NMR (400 MHz, CDCl 3 ) δ 7.67-7.54 (m, 1H), 7.06 (s, 0.5H), 7.04 (s, 0.5H), 6.25 (d, J=9.5Hz, 0.5H), 6.22 (d, J=9.5Hz, 0.5H), 5.86(s, 0.5H), 5.78(s, 0.5H), 4.71–4.56(m, 1H), 3.80–3.74(m, 1H), 3.51–3.45( m, 2H), 3.30–3.08 (m, 1H), 3.05–2.85 (m, 2H), 2.83–2.18 (m, 6H), 1.23–1.13 (m, 1H), 0.65–0.52 (m, 1H), 0.52–0.36 (m, 2H), 0.36–0.24 (m, 1H).
实施例27Example 27
合成(5S)-5-(3-(8-氯-3,4,10,10a-四氢-1H-[1,4]二氮杂茚并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(8-Chloro-3,4,10,10a-tetrahydro-1H-[1,4]diazaindeno[1,2-a]indole-2( 1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000132
Figure PCTCN2021105088-appb-000132
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(5-氯-2-甲酰基苯基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(5-chloro-2-formylphenyl)-1,4-diazepane-1-carboxylate
Figure PCTCN2021105088-appb-000133
Figure PCTCN2021105088-appb-000133
室温下，向含有2-氟-4-氯苯甲醛(4.00克，25.23毫摩尔)的二甲基亚砜(24.0毫升)中加入1,4-二氮杂环庚烷-1-羧酸叔丁酯(6.06克，30.28毫摩尔)和碳酸钾(4.53克，32.80毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2-fluoro-4-chlorobenzaldehyde (4.00 g, 25.23 mmol) in dimethylsulfoxide (24.0 mL) was added tert-1,4-diazepane-1-carboxylic acid at room temperature under butyl ester (6.06 g, 30.28 mmol) and potassium carbonate (4.53 g, 32.80 mmol), N 2 protection for 12 h at 95 ° C.
反应结束，加水淬灭，混合液用乙酸乙酯(100毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到6.20克淡黄色固体4-(5-氯-2-甲酰基苯基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯(收率：72.5％)。LCMS:RT＝2.16min,[M+H] +＝339.19。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (100 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 6.20 g of tert-butyl 4-(5-chloro-2-formylphenyl)-1,4-diazepan-1-carboxylate was obtained as a pale yellow solid (yield: 72.5%). LCMS: RT=2.16 min, [M+H] + =339.19.
步骤B：合成(E)-4-(5-氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯Step B: Synthesis of (E)-4-(5-Chloro-2-(((2-Tosylhydrazino)methyl)phenyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester
Figure PCTCN2021105088-appb-000134
Figure PCTCN2021105088-appb-000134
室温下，将4-(5-氯-2-甲酰基苯基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯(6.20克，18.30毫摩尔)和4-甲基苯磺酰肼(3.58毫克，19.22毫摩尔)加入无水乙醇(60.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(5-chloro-2-formylphenyl)-1,4-diazepane-1-carboxylate (6.20 g, 18.30 mmol) and 4-methyl benzene sulfonyl hydrazide (3.58 mg, 19.22 mmol) was added absolute ethanol (60.0 ml), under N 2, at room temperature for 1 hour.
反应结束，蒸干溶剂得到9.28克类白色固体(E)-4-(5-氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.25min,[M+H] +＝507.23。 The reaction was completed, and the solvent was evaporated to dryness to obtain 9.28 g of off-white solid (E)-4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)-1,4-diazepine Cycloheptane-1-carboxylate tert-butyl ester. It was used in the next step without purification. LCMS: RT=2.25min, [M+H] + =507.23.
步骤C：合成8-氯-4,5,11,11a-四氢-1H-[1,4]二氮杂茚并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of 8-Chloro-4,5,11,11a-tetrahydro-1H-[1,4]diazaindeno[1,2-a]indole-2(1H)-carboxylic acid tert-butyl ester
Figure PCTCN2021105088-appb-000135
Figure PCTCN2021105088-appb-000135
室温下，向含有(E)-4-(5-氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯(9.28克，18.30毫摩尔)的甲苯(100.0毫升)中，分批加入氢化钠(878.0毫克，21.96毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)-1,4-diazepan-1-carboxylate at room temperature tert-butyl acid (9.28 g, 18.30 mmol) in toluene (100.0 mL), add sodium hydride (878.0 mg, 21.96 mmol, 60% dispersed in paraffin oil) in batches, replace nitrogen for 20 minutes, and react at 135 degrees Celsius for 2 Hour.
反应结束，冷却至室温，乙酸乙酯(100毫升)溶解，先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到2.12克淡黄色固体8-氯-4,5,11,11a-四氢-1H-[1,4]二氮杂茚并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：35.9％)。LCMS:RT＝2.27min,[M+H] +＝323.26。 The reaction was completed, cooled to room temperature, dissolved in ethyl acetate (100 mL), washed with saturated brine (50 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 2.12 g of 8-chloro-4,5,11,11a-tetrahydro-1H-[1,4]diazaindeno[1,2-a]indole-2(1H)-carboxylic acid were obtained as a pale yellow solid tert-Butyl ester (yield: 35.9%). LCMS: RT=2.27 min, [M+H] + =323.26.
步骤D：合成8-氯-1,2,3,4,10,10a-六氢-1H-[1,4]二氮杂茚并[1,2-a]吲哚盐酸盐Step D: Synthesis of 8-chloro-1,2,3,4,10,10a-hexahydro-1H-[1,4]diazaindeno[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000136
Figure PCTCN2021105088-appb-000136
室温下，将8-氯-4,5,11,11a-四氢-1H-[1,4]二氮杂茚并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(2.12克，6.57毫摩尔)加入甲醇(20.0毫升)中，滴加盐酸的二氧六环溶液(8.2毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 8-Chloro-4,5,11,11a-tetrahydro-1H-[1,4]diazaindeno[1,2-a]indole-2(1H)-carboxylate tert-butyl at room temperature ester (2.12 g, 6.57 mmol) was added methanol (20.0 ml) was added dropwise a solution of hydrochloric acid in dioxane (8.2 ml, 4.0 moles per liter), under N 2, at room temperature for 3 hours.
反应结束，蒸干溶剂得到1.35克类白色固体8-氯-1,2,3,4,10,10a-六氢-1H-[1,4]二氮杂茚并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.59min,[M+H] +＝223.18。 1H NMR(400MHz,DMSO-d6)δ9.57(s,2H),6.97(d,J＝7.7Hz,1H),6.57(dd,J＝7.7,1.7Hz,1H),6.45(d,J＝1.5Hz,1H),4.32–4.18(m,1H),3.52–3.43(m,1H),3.41–3.29(m,2H),3.26–3.15(m,1H),3.11–2.96(m,3H),2.66(dd,J＝16.6,7.9Hz,1H),2.24–1.98(m,2H)。 After the reaction was completed, the solvent was evaporated to dryness to obtain 1.35 g of off-white solid 8-chloro-1,2,3,4,10,10a-hexahydro-1H-[1,4]diazaindeno[1,2-a] Indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.59 min, [M+H] + =223.18. 1 H NMR (400MHz, DMSO-d6) δ9.57(s, 2H), 6.97(d, J=7.7Hz, 1H), 6.57(dd, J=7.7, 1.7Hz, 1H), 6.45(d, J = 1.5Hz, 1H), 4.32–4.18 (m, 1H), 3.52–3.43 (m, 1H), 3.41–3.29 (m, 2H), 3.26–3.15 (m, 1H), 3.11–2.96 (m, 3H) ), 2.66 (dd, J=16.6, 7.9 Hz, 1H), 2.24–1.98 (m, 2H).
步骤E：合成(5S)-5-(3-(8-氯-3,4,10,10a-四氢-1H-[1,4]二氮杂茚并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(8-Chloro-3,4,10,10a-tetrahydro-1H-[1,4]diazaindeno[1,2-a]indole -2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000137
Figure PCTCN2021105088-appb-000137
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和8-氯-1,2,3,4,10,10a-六氢-1H-[1,4]二氮杂茚并[1,2-a]吲哚盐酸盐(67.1毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-chloro-1,2, 3,4,10,10a-Hexahydro-1H-[1,4]diazaindeno[1,2-a]indole hydrochloride (67.1 mg, 0.26 mmol) was added to N,N-dimethyl N,N-diisopropylethylamine (156.0 μl) was added dropwise to ethylformamide (2.0 ml), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到35.5毫克白色固体(5S)-5-(3-(8-氯-3,4,10,10a-四氢-1H-[1,4]二氮杂茚并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：35.6)。LCMS:RT＝1.84min,[M+H] +＝416.91。 1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),7.77–7.65(m,1H),6.96(dd,J＝13.6,7.5Hz,1H),6.55–6.47(m,2H),4.15–3.86(m,1H),3.85–3.59(m,3H),3.23–3.01(m,2H),3.00–2.77(m,2H),2.66–2.53(m,1H),2.46–2.17(m,2H),2.02–1.76(m,4H),1.14–1.02(m,1H),0.50–0.40(m,1H),0.40–0.25(m,2H),0.15–0.02(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 35.5 mg of white solid (5S)-5-(3-(8-chloro-3,4,10,10a-tetrahydro-1H-[1,4]diazaindeno[1,2-a]indone was obtained Indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 35.6). LCMS: RT=1.84 min, [M+H] + =416.91. 1 H NMR (400MHz, DMSO-d6) δ 10.59 (s, 1H), 7.77–7.65 (m, 1H), 6.96 (dd, J=13.6, 7.5Hz, 1H), 6.55–6.47 (m, 2H) ,4.15–3.86(m,1H),3.85–3.59(m,3H),3.23–3.01(m,2H),3.00–2.77(m,2H),2.66–2.53(m,1H),2.46–2.17( m, 2H), 2.02–1.76 (m, 4H), 1.14–1.02 (m, 1H), 0.50–0.40 (m, 1H), 0.40–0.25 (m, 2H), 0.15–0.02 (m, 1H).
实施例28Example 28
合成(5S)-5-(3-(8-氯-1,2,4,5,11,11a-六氢-3H-[1,4]二氮杂茚并[1,7-a]吲哚-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(8-Chloro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazaindeno[1,7-a]indoline dol-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000138
Figure PCTCN2021105088-appb-000138
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成8-氯--1,2,4,5,11,11a-六氢-3H-[1,4]二氮杂茚并[1,7-a]吲哚-3-羧酸叔丁酯Step A: Synthesis of 8-Chloro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazaindeno[1,7-a]indole-3-carboxylic acid tert-butyl ester
Figure PCTCN2021105088-appb-000139
Figure PCTCN2021105088-appb-000139
室温下，向含有(E)-4-(5-氯-2-(((2-甲苯磺酰基肼基)甲基)苯基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯(9.28克，18.30毫摩尔)的甲苯(100.0毫升)中，分批加入氢化钠(878.0毫克，21.96毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-4-(5-chloro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)-1,4-diazepan-1-carboxylate at room temperature tert-butyl acid (9.28 g, 18.30 mmol) in toluene (100.0 mL), add sodium hydride (878.0 mg, 21.96 mmol, 60% dispersed in paraffin oil) in batches, replace nitrogen for 20 minutes, and react at 135 degrees Celsius for 2 Hour.
反应结束，冷却至室温，乙酸乙酯(100毫升)溶解，先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到1.28克淡黄色固体8-氯--1,2,4,5,11,11a-六氢-3H-[1,4]二氮杂茚并[1,7-a]吲哚-3-羧酸叔丁酯(收率：21.7％)。LCMS:RT＝2.25min,[M+H] +＝323.37。 The reaction was completed, cooled to room temperature, dissolved in ethyl acetate (100 mL), washed with saturated brine (50 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 1.28 g of pale yellow solid 8-chloro--1,2,4,5,11,11a-hexahydro-3H-[1,4]diazaindeno[1,7-a]indole-3- tert-Butyl carboxylate (yield: 21.7%). LCMS: RT=2.25 min, [M+H] + =323.37.
步骤B：合成8-氯--2,3,4,5,11,11a-六氢-1H-[1,4]二氮杂茚并[1,7-a]吲哚盐酸盐Step B: Synthesis of 8-chloro--2,3,4,5,11,11a-hexahydro-1H-[1,4]diazaindeno[1,7-a]indole hydrochloride
Figure PCTCN2021105088-appb-000140
Figure PCTCN2021105088-appb-000140
室温下，将8-氯--1,2,4,5,11,11a-六氢-3H-[1,4]二氮杂茚并[1,7-a]吲哚-3-羧酸叔丁酯(1.28克，4.00毫摩尔)加入甲醇(20.0毫升)中，滴加盐酸的二氧六环溶液(5.0毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 8-Chloro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazaindeno[1,7-a]indole-3-carboxylic acid at room temperature tert-butyl ester (1.28 g, 4.00 mmol) was added methanol (20.0 ml) was added dropwise a solution of hydrochloric acid in dioxane (5.0 mL, 4.0 moles per liter), under N 2, at room temperature for 3 hours.
反应结束，蒸干溶剂得到750.0毫克类白色固体8-氯--2,3,4,5,11,11a-六氢-1H-[1,4]二氮杂茚并[1,7-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.59min,[M+H] +＝223.18。 1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),9.07(s,1H),6.99(d,J＝7.7Hz,1H),6.57(dd,J＝7.7,1.6Hz,1H),6.52(d,J＝1.5Hz,1H),4.04–3.89(m,1H),3.84–3.63(m,1H),3.37–3.29(m,1H),3.29–3.23(m,2H),3.23–3.08(m,3H),2.61(dd,J＝16.4,8.0Hz,1H),2.15–2.04(m,1H),2.00–1.81(m,1H)。 After the reaction was completed, the solvent was evaporated to dryness to obtain 750.0 mg of off-white solid 8-chloro--2,3,4,5,11,11a-hexahydro-1H-[1,4]diazaindeno[1,7-a ] Indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.59 min, [M+H] + =223.18. 1 H NMR (400MHz, DMSO-d6) δ 9.51(s, 1H), 9.07(s, 1H), 6.99(d, J=7.7Hz, 1H), 6.57(dd, J=7.7, 1.6Hz, 1H) ),6.52(d,J＝1.5Hz,1H),4.04-3.89(m,1H),3.84-3.63(m,1H),3.37-3.29(m,1H),3.29-3.23(m,2H), 3.23–3.08 (m, 3H), 2.61 (dd, J=16.4, 8.0 Hz, 1H), 2.15–2.04 (m, 1H), 2.00–1.81 (m, 1H).
步骤C：合成(5S)-5-(3-(8-氯-1,2,4,5,11,11a-六氢-3H-[1,4]二氮杂茚并[1,7-a]吲哚-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step C: Synthesis of (5S)-5-(3-(8-Chloro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazaindeno[1,7- a]Indol-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000141
Figure PCTCN2021105088-appb-000141
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和8-氯--2,3,4,5,11,11a-六氢-1H-[1,4]二氮杂茚并[1,7-a]吲哚盐酸盐(67.1毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-chloro-2,3 ,4,5,11,11a-Hexahydro-1H-[1,4]diazaindeno[1,7-a]indole hydrochloride (67.1 mg, 0.26 mmol) was added to N,N-bis N,N-diisopropylethylamine (156.0 μl) was added dropwise to methylformamide (2.0 ml), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide amine hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到31.5毫克白色固体(5S)-5-(3-(8-氯-1,2,4,5,11,11a-六氢-3H-[1,4]二氮杂茚并[1,7-a]吲哚-3-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：31.5％)。LCMS:RT ＝1.88min,[M+H] +＝416.23。 1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),7.69(dd,J＝10.6,6.8Hz,1H),7.00–6.88(m,1H),6.58–6.38(m,2H),3.93–3.79(m,1H),3.79–3.49(m,4H),3.42–3.08(m,2H),3.04–2.76(m,1H),2.61–2.52(m,1H),2.46–2.14(m,2H),2.05–1.85(m,3H),1.84–1.57(m,1H),1.14–1.02(m,1H),0.49–0.39(m,1H),0.39–0.25(m,2H),0.14–0.04(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 31.5 mg of white solid (5S)-5-(3-(8-chloro-1,2,4,5,11,11a-hexahydro-3H-[1,4]diazaindeno[1,7] was obtained -a]Indol-3-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 31.5%). LCMS: RT = 1.88 min, [M+H] + =416.23. 1 H NMR (400MHz, DMSO-d6)δ10.58(s,1H),7.69(dd,J=10.6,6.8Hz,1H),7.00-6.88(m,1H),6.58-6.38(m,2H) ,3.93–3.79(m,1H),3.79–3.49(m,4H),3.42–3.08(m,2H),3.04–2.76(m,1H),2.61–2.52(m,1H),2.46–2.14( m, 2H), 2.05–1.85 (m, 3H), 1.84–1.57 (m, 1H), 1.14–1.02 (m, 1H), 0.49–0.39 (m, 1H), 0.39–0.25 (m, 2H), 0.14–0.04 (m, 1H).
实施例29Example 29
合成(5S)-5-(3-(8-溴-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑啉-2,4-二酮Synthesis of (5S)-5-(3-(8-Bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropane yl)-5-cyclopropylimidazoline-2,4-dione
Figure PCTCN2021105088-appb-000142
Figure PCTCN2021105088-appb-000142
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(4-溴-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(4-bromo-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000143
Figure PCTCN2021105088-appb-000143
室温下，向含有5-溴-2-氟苯甲醛(10.00克，49.26毫摩尔)的二甲基亚砜(35.0毫升)中加入N-叔丁氧羰基哌嗪(9.17克，49.26毫摩尔)和碳酸钾(8.17克，59.11毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 5-bromo-2-fluorobenzaldehyde (10.00 g, 49.26 mmol) in dimethyl sulfoxide (35.0 mL) was added N-tert-butoxycarbonylpiperazine (9.17 g, 49.26 mmol) at room temperature and potassium carbonate (8.17 g, 59.11 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加乙酸乙酯(200毫升)和水(200毫升)稀释，分液，收集有机相，有机相先用饱和食盐水(10毫升×3次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到3.76克米黄色固体4-(4-溴-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：20.7％)。LCMS:RT＝2.20min,[M+H] +＝369.13。 After the reaction was completed, ethyl acetate (200 ml) and water (200 ml) were added to dilute, the layers were separated, and the organic phase was collected. The organic phase was washed with saturated brine (10 ml × 3 times), dried over anhydrous sodium sulfate, and reduced under reduced pressure. concentrate. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 3.76 g of tert-butyl 4-(4-bromo-2-formylphenyl)piperazine-1-carboxylate were obtained as a beige solid (yield: 20.7%). LCMS: RT=2.20 min, [M+H] + =369.13.
步骤B：合成(E)-4-(4-溴-2-((2-甲苯磺酰肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(4-bromo-2-((2-tosylhydrazide)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000144
Figure PCTCN2021105088-appb-000144
室温下，将4-(4-溴-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(3.76克，10.18毫摩尔)和4-甲基苯磺酰肼(1.90毫克，10.18毫摩尔)加入无水乙醇(20.0毫升)中，N 2保护下，室温反应2小时。 At room temperature, tert-butyl 4-(4-bromo-2-formylphenyl)piperazine-1-carboxylate (3.76 g, 10.18 mmol) and 4-methylbenzenesulfonylhydrazide (1.90 mg, 10.18 mmol) was added to anhydrous ethanol (20.0 mL), and reacted at room temperature for 2 hours under the protection of N 2 .
反应结束，蒸干溶剂得到5.47克米黄色固体(E)-4-(4-溴-2-((2-甲苯磺酰肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.21min,[M+H] +＝539.19。 The reaction was completed, and the solvent was evaporated to dryness to obtain 5.47 g of beige solid (E)-4-(4-bromo-2-((2-toluenesulfonylhydrazide)methyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester. It was directly used in the next reaction without purification. LCMS: RT=2.21 min, [M+H] + =539.19.
步骤C：合成8-溴-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of 8-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
Figure PCTCN2021105088-appb-000145
Figure PCTCN2021105088-appb-000145
室温下，向含有(E)-4-(4-溴-2-((2-甲苯磺酰肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(5.47克，10.18毫摩尔)的甲苯(25.0毫升)中，分批加入氢化钠(439.6毫克，10.99毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-tert-butyl 4-(4-bromo-2-((2-tosylhydrazide)methyl)phenyl)piperazine-1-carboxylate (5.47 g, 10.18 mM) at room temperature mol) in toluene (25.0 mL), sodium hydride (439.6 mg, 10.99 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(100毫升)和水(100毫升)稀释，分液，收集有机相，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到1.5克米黄色固体8-溴-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：41.7％)。LCMS:RT＝2.25min,[M+H] +＝353.16。 After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (100 mL), and the layers were separated. The organic phase was collected and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 1.5 g of tert-butyl 8-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a beige solid (yield: 41.7%) . LCMS: RT=2.25min, [M+H] + =353.16.
步骤D：合成8-溴-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 8-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000146
Figure PCTCN2021105088-appb-000146
室温下，将8-溴-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(100.0毫克，0.28毫摩尔)加入甲醇(3.0毫升)中，滴加盐酸的二氧六环溶液(1毫升，4.0摩尔每升)，N 2保护下，室温反应12小时。 At room temperature, tert-butyl 8-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (100.0 mg, 0.28 mmol) was added In methanol (3.0 mL), a solution of hydrochloric acid in dioxane (1 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 12 hours under the protection of N 2 .
反应结束，蒸干溶剂得到75.0毫克米黄色固体8-溴-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.59min,[M+H] +＝253.09。 1H NMR(400MHz,DMSO)δ(ppm):9.72–9.52(m,2H),7.25(s,1H),7.19(dd,J＝8.4,1.6Hz,1H),6.57(d,J＝8.4Hz,1H),3.86–3.73(m,2H),3.33–3.17(m,3H),3.09–2.98(m,1H),2.98–2.76(m,2H),2.67–2.57(m,1H)。 After the reaction was completed, the solvent was evaporated to dryness to obtain 75.0 mg of beige solid 8-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.59 min, [M+H] + =253.09. 1 H NMR (400MHz, DMSO) δ (ppm): 9.72-9.52 (m, 2H), 7.25 (s, 1H), 7.19 (dd, J=8.4, 1.6Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 3.86–3.73 (m, 2H), 3.33–3.17 (m, 3H), 3.09–2.98 (m, 1H), 2.98–2.76 (m, 2H), 2.67–2.57 (m, 1H).
步骤E：合成(5S)-5-(3-(8-溴-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑啉-2,4-二酮Step E: Synthesis of (5S)-5-(3-(8-Bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazoline-2,4-dione
Figure PCTCN2021105088-appb-000147
Figure PCTCN2021105088-appb-000147
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(66.0毫克，0.31毫摩尔)和8-溴-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(75.0毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(5毫升)中，滴加N,N-二异丙基乙胺(100.4毫克)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(59.6毫克，0.31毫摩尔)和1-羟基苯并三唑(5.3毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (66.0 mg, 0.31 mmol) and 8-bromo-1,2, 3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (75.0 mg, 0.26 mmol) was added to N,N-dimethylformamide (5 mL) dropwise Add N,N-diisopropylethylamine (100.4 mg) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (59.6 mg, 0.31 mmol) and 1-hydroxybenzotriazole (5.3 mg, 0.04 mmol) under N 2 protection at room temperature overnight.
反应结束，加水(50毫升)和乙酸乙酯(50毫升)稀释，分液，收集有机相，饱和食盐水(3毫升×2次)洗涤，无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到60.0毫克米黄色固体(5S)-5-(3-(8-溴-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑啉-2,4-二酮(收率：51.8％)。LCMS:RT＝1.88min,[M+H] +＝447.20。 1H NMR(400MHz,DMSO-d 6)δ(ppm):10.60(s,1H),7.69(d,J＝3.6Hz,1H),7.21(s,1H),7.15(dd,J＝8.4,1.6Hz,1H),6.51(dd,J＝8.4,4.4Hz,1H),4.49–4.31(m,1H),3.86–3.71(m,1H),3.68–3.58(m,1H),3.54–3.42(m,1H),3.19–2.93(m,2H),2.91–2.69(m,1H),2.68–2.52(m,2H),2.47–2.15(m,2H),1.98–1.87(m,2H), 1.14–1.05(m,1H),0.50–0.40(m,1H),0.40–0.27(m,2H),0.15–0.05(m,1H)。 After the reaction was completed, water (50 mL) and ethyl acetate (50 mL) were added to dilute, the layers were separated, the organic phase was collected, washed with saturated brine (3 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 60.0 mg of beige solid (5S)-5-(3-(8-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl) was obtained -3-Oxypropyl)-5-cyclopropylimidazoline-2,4-dione (yield: 51.8%). LCMS: RT=1.88 min, [M+H] + =447.20. 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 10.60 (s, 1H), 7.69 (d, J=3.6 Hz, 1H), 7.21 (s, 1H), 7.15 (dd, J=8.4, 1.6Hz, 1H), 6.51 (dd, J=8.4, 4.4Hz, 1H), 4.49–4.31 (m, 1H), 3.86–3.71 (m, 1H), 3.68–3.58 (m, 1H), 3.54–3.42 (m, 1H), 3.19–2.93 (m, 2H), 2.91–2.69 (m, 1H), 2.68–2.52 (m, 2H), 2.47–2.15 (m, 2H), 1.98–1.87 (m, 2H) , 1.14–1.05 (m, 1H), 0.50–0.40 (m, 1H), 0.40–0.27 (m, 2H), 0.15–0.05 (m, 1H).
实施例30Example 30
合成(5S)-5-(3-(7-溴-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(7-Bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropane yl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000148
Figure PCTCN2021105088-appb-000148
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(5-溴-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(5-bromo-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000149
Figure PCTCN2021105088-appb-000149
室温下，向含有4-溴-2-氟苯甲醛(10.15克，50.0毫摩尔)的二甲基亚砜(50.0毫升)中加入N-叔丁氧羰基哌嗪(10.24克，55.0毫摩尔)和碳酸钾(8.97克，65.0毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 4-bromo-2-fluorobenzaldehyde (10.15 g, 50.0 mmol) in dimethyl sulfoxide (50.0 mL) was added N-tert-butoxycarbonylpiperazine (10.24 g, 55.0 mmol) at room temperature and potassium carbonate (8.97 g, 65.0 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(200毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(100毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到9.68克白色固体4-(5-溴-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：52.4％)。LCMS:RT＝2.19min,[M+H] +＝369.15。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (200 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (100 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 9.68 g of tert-butyl 4-(5-bromo-2-formylphenyl)piperazine-1-carboxylate was obtained as a white solid (yield: 52.4%). LCMS: RT=2.19 min, [M+H] + =369.15.
步骤B：合成(E)-4-(5-溴-2-((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(5-bromo-2-((2-tosylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000150
Figure PCTCN2021105088-appb-000150
室温下，将4-(5-溴-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(9.68克，26.2毫摩尔)和4-甲基苯磺酰肼(5.13克，27.5毫摩尔)加入无水乙醇(131毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(5-bromo-2-formylphenyl)piperazine-1-carboxylate (9.68 g, 26.2 mmol) and 4-methylbenzenesulfonylhydrazide (5.13 g, 27.5 mmol) was added to anhydrous ethanol (131 mL) and reacted at room temperature for 1 h under the protection of N 2 .
反应结束，蒸干溶剂得到14.2克类白色固体(E)-4-(5-溴-2-((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.23min,[M+H] +＝539.17。 The reaction was completed, and the solvent was evaporated to dryness to obtain 14.2 g of off-white solid (E)-4-(5-bromo-2-((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester. It was directly used in the next reaction without purification. LCMS: RT=2.23 min, [M+H] + =539.17.
步骤C：合成7-溴-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of tert-butyl 7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
Figure PCTCN2021105088-appb-000151
Figure PCTCN2021105088-appb-000151
室温下，向含有(E)-4-(5-溴-2-((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(14.2克，26.2毫摩尔)的甲苯(144毫升)中，分批加入氢化钠(1.15克，26.2毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-tert-butyl 4-(5-bromo-2-((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate (14.2 g, 26.2 mM) at room temperature mol) in toluene (144 ml), sodium hydride (1.15 g, 26.2 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(500毫升)溶解，先用饱和食盐水(150毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到5.40克淡黄色固体7-溴-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：58.4％)。LCMS:RT＝2.27min,[M+H] +＝353.10。 The reaction was completed, cooled to room temperature, dissolved in ethyl acetate (500 mL), washed with saturated brine (150 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 5.40 g of tert-butyl 7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a pale yellow solid (yield: 58.4%) . LCMS: RT=2.27 min, [M+H] + =353.10.
步骤D：合成7-溴-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 7-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000152
Figure PCTCN2021105088-appb-000152
室温下，将7-溴-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(900毫克，2.55毫摩尔)加入甲醇(12.7毫升)中，滴加盐酸的二氧六环溶液(2.5毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (900 mg, 2.55 mmol) was added In methanol (12.7 mL), a solution of hydrochloric acid in dioxane (2.5 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到740毫克类白色固体7-溴-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.59min,[M+H] +＝253.13。 After the reaction was completed, the solvent was evaporated to dryness to obtain 740 mg of off-white solid 7-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.59 min, [M+H] + =253.13.
步骤E：合成(5S)-5-(3-(7-溴-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(7-Bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000153
Figure PCTCN2021105088-appb-000153
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(300毫克，1.41毫摩尔)和7-溴-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(492毫克，1.70毫摩尔)加入无水二氯甲烷(14.0毫升)中，滴加N,N-二异丙基乙胺(934微升，5.65毫摩尔)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(406毫克，2.12毫摩尔)和1-羟基苯并三唑(29毫克，0.21毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (300 mg, 1.41 mmol) and 7-bromo-1,2, 3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (492 mg, 1.70 mmol) was added to anhydrous dichloromethane (14.0 mL), N,N was added dropwise - Diisopropylethylamine (934 μl, 5.65 mmol) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (406 mg, 2.12 mmol) ) and 1-hydroxybenzotriazole (29 mg, 0.21 mmol) under N 2 protection at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(40毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(30毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到495毫克白色固体(5S)-5-(3-(7-溴-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：77.4％)。LCMS:RT＝1.89min,[M-H] -＝445.17。 1H NMR(500MHz,DMSO-d6)δ10.58(s,1H),7.68(d,J＝8.5Hz,1H),6.98(d,J＝7.6Hz,1H),6.78–6.66(m,2H),4.40(dd,J＝45.3,12.8Hz,1H),3.86–3.64(m,2H),3.54–3.35(m,1H),3.17–2.80(m,4H),2.80–2.60(m,1H),2.46–2.18(m,2H),2.05–1.85(m,2H),1.14–1.04(m,1H),0.52–0.40(m,1H),0.40–0.24(m,2H),0.16–0.04(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (40 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (30 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 495 mg of white solid (5S)-5-(3-(7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 77.4%). LCMS: RT = 1.89 min, [MH] − = 445.17. 1 H NMR (500MHz, DMSO-d6)δ10.58(s,1H),7.68(d,J=8.5Hz,1H),6.98(d,J=7.6Hz,1H),6.78-6.66(m,2H) ), 4.40 (dd, J=45.3, 12.8Hz, 1H), 3.86–3.64 (m, 2H), 3.54–3.35 (m, 1H), 3.17–2.80 (m, 4H), 2.80–2.60 (m, 1H ), 2.46–2.18 (m, 2H), 2.05–1.85 (m, 2H), 1.14–1.04 (m, 1H), 0.52–0.40 (m, 1H), 0.40–0.24 (m, 2H), 0.16–0.04 (m, 1H).
实施例31Example 31
合成(5S)-5-(3-(8-氟-7-甲氧基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(8-Fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl )-3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000154
Figure PCTCN2021105088-appb-000154
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(4-氟-2-甲酰基-5-甲氧基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(4-fluoro-2-formyl-5-methoxyphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000155
Figure PCTCN2021105088-appb-000155
室温下，向含有2,5-二氟-4-甲氧基苯甲醛(2.0克，11.62毫摩尔)的二甲基亚砜(12.0毫升)中加入N-叔丁氧羰基哌嗪(2.60克，13.94毫摩尔)和碳酸钾(2.09克，15.11毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2,5-difluoro-4-methoxybenzaldehyde (2.0 g, 11.62 mmol) in dimethyl sulfoxide (12.0 mL) was added N-tert-butoxycarbonylpiperazine (2.60 g) at room temperature , 13.94 mmol) and potassium carbonate (2.09 g, 15.11 mmol) were reacted under N 2 protection at 95 degrees Celsius for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到2.03克淡黄色固体4-(4-氟-2-甲酰基-5-甲氧基苯基)哌嗪-1-羧酸叔丁酯(收率：51.6％)。LCMS:RT＝2.09min,[M+H] +＝339.24。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 2.03 g of tert-butyl 4-(4-fluoro-2-formyl-5-methoxyphenyl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 51.6%). LCMS: RT=2.09 min, [M+H] + =339.24.
步骤B：合成(E)-4-(4-氟-5-甲氧基-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(4-fluoro-5-methoxy-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000156
Figure PCTCN2021105088-appb-000156
室温下，将4-(4-氟-2-甲酰基-5-甲氧基苯基)哌嗪-1-羧酸叔丁酯(2.03克，6.00毫摩尔)和4-甲基苯磺酰肼(1.17克，6.30毫摩尔)加入无水乙醇(20.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(4-fluoro-2-formyl-5-methoxyphenyl)piperazine-1-carboxylate (2.03 g, 6.00 mmol) and 4-methylbenzenesulfonyl hydrazine (1.17 g, 6.30 mmol) was added absolute ethanol (20.0 ml), under N 2, at room temperature for 1 hour.
反应结束，蒸干溶剂得到3.04克类白色固体(E)-4-(4-氟-5-甲氧基-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.13min,[M+H] +＝507.28。 The reaction was completed, and the solvent was evaporated to dryness to obtain 3.04 g of off-white solid (E)-4-(4-fluoro-5-methoxy-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine -1-Carboxylic acid tert-butyl ester. Without purification, it was directly used in the next reaction. LCMS: RT=2.13 min, [M+H] + =507.28.
步骤C：合成8-氟-7-甲氧基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of 8-fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
Figure PCTCN2021105088-appb-000157
Figure PCTCN2021105088-appb-000157
室温下，向含有(E)-4-(4-氟-5-甲氧基-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(3.04克，6.00毫摩尔)的甲苯(30.0毫升)中，分批加入氢化钠(288.0毫克，7.20毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。at room temperature, to tert-butyl containing (E)-4-(4-fluoro-5-methoxy-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate To the ester (3.04 g, 6.00 mmol) in toluene (30.0 mL), sodium hydride (288.0 mg, 7.20 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(100毫升)溶解，先用饱和食盐水(100毫升×2次)洗涤，然 后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到1.01克淡黄色固体8-氟-7-甲氧基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：52.17％)。LCMS:RT＝2.13min,[M+H] +＝323.24。 After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (100 mL), washed with saturated brine (100 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 1.01 g of 8-fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester ( Yield: 52.17%). LCMS: RT=2.13 min, [M+H] + =323.24.
步骤D：合成8-氟-7-甲氧基-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 8-fluoro-7-methoxy-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000158
Figure PCTCN2021105088-appb-000158
室温下，将8-氟-7-甲氧基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(1.01克，3.13毫摩尔)加入甲醇(10.0毫升)中，滴加盐酸的二氧六环溶液(3.9毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 8-Fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester (1.01 g , 3.13 mmol) was added to methanol (10.0 mL), hydrochloric acid in dioxane solution (3.9 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到809.1毫克类白色固体8-氟-7-甲氧基-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.47min,[M+H] +＝223.22。 After the reaction was completed, the solvent was evaporated to dryness to obtain 809.1 mg of off-white solid 8-fluoro-7-methoxy-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloric acid Salt. It was directly used in the next reaction without purification. LCMS: RT=1.47 min, [M+H] + =223.22.
步骤E：合成(5S)-5-(3-(8-氟-7-甲氧基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(8-Fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H )-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000159
Figure PCTCN2021105088-appb-000159
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和8-氟-7-甲氧基-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(67.0毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 8-fluoro-7-methoxy Base-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (67.0 mg, 0.26 mmol) was added to N,N-dimethylformamide ( 2.0 ml), N,N-diisopropylethylamine (156.0 μl) was added dropwise, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol) under N 2 protection at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到29.0毫克白色固体(5S)-5-(3-(8-氟-7-甲氧基-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：29.0％)。LCMS:RT＝1.79min,[M+H] +＝417.25。 1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),7.69(d,J＝6.1Hz,1H),6.94(d,J＝10.9Hz,1H),6.45(d,J＝7.2Hz,1H),4.40(dd,J＝25.8,11.4Hz,1H),3.89–3.61(m,5H),3.46–3.20(m,1H),3.08(dt,J＝44.0,11.9Hz,1H),2.97–2.54(m,3H),2.57–2.16(m,3H),2.01–1.85(m,2H),1.14–1.02(m,1H),0.50–0.40(m,1H),0.40–0.25(m,2H),0.16–0.04(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 29.0 mg of (5S)-5-(3-(8-fluoro-7-methoxy-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2() was obtained as a white solid 1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 29.0%). LCMS: RT=1.79 min, [M+H] + =417.25. 1 H NMR(400MHz, DMSO-d6)δ10.59(s,1H),7.69(d,J=6.1Hz,1H),6.94(d,J=10.9Hz,1H),6.45(d,J=7.2 Hz, 1H), 4.40 (dd, J=25.8, 11.4Hz, 1H), 3.89–3.61 (m, 5H), 3.46–3.20 (m, 1H), 3.08 (dt, J=44.0, 11.9Hz, 1H) ,2.97–2.54(m,3H),2.57–2.16(m,3H),2.01–1.85(m,2H),1.14–1.02(m,1H),0.50–0.40(m,1H),0.40–0.25( m, 2H), 0.16–0.04 (m, 1H).
实施例32Example 32
合成(5S)-5-(3-(7-(1H-吡唑-4-基)-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(7-(1H-pyrazol-4-yl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H )-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000160
Figure PCTCN2021105088-appb-000160
具体合成路线如下：The specific synthetic route is as follows:
Figure PCTCN2021105088-appb-000161
室温下，向含有(5S)-5-(3-(7-溴-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(50.0毫克，0.11毫摩尔)的乙二醇二甲醚/乙醇/水(1.6毫升/0.2毫升/0.2毫升)溶液中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)-1H-吡唑(43毫克，0.22毫摩尔)、碳酸钠(24毫克，0.22毫摩尔)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(8.0毫克，0.011毫摩尔)，N 2保护下，110摄氏度反应4小时。
Figure PCTCN2021105088-appb-000161
at room temperature, to a compound containing (5S)-5-(3-(7-bromo-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione (50.0 mg, 0.11 mmol) in ethylene glycol dimethyl ether/ethanol/water (1.6 mL/0.2 mL/0.2 mL) To the solution was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroboran-2-yl)-1H-pyrazole (43 mg, 0.22 mmol), carbonic acid sodium (24 mg, 0.22 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (8.0 mg, 0.011 mmol) dichloride, N 2 protection, 110 C reaction 4 Hour.
反应结束，冷却至室温，用乙酸乙酯(50毫升)稀释，依次用水(20毫升)，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)。得到4毫克白色固体(5S)-5-(3-(7-(1H-吡唑-4-基)-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：8.4％)。LCMS:RT＝1.68min,[M+H] +＝435.30。 After the reaction was completed, cooled to room temperature, diluted with ethyl acetate (50 mL), followed by water (20 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1). 4 mg of white solid (5S)-5-(3-(7-(1H-pyrazol-4-yl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole was obtained -2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 8.4%). LCMS: RT=1.68 min, [M+H] + =435.30.
实施例33Example 33
合成(5S)-5-(3-(7,8-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(7,8-Difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000162
Figure PCTCN2021105088-appb-000162
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(4,5-二氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(4,5-difluoro-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000163
Figure PCTCN2021105088-appb-000163
室温下，向含有4,5-二氟-2-氟苯甲醛(3.0克，13.6毫摩尔)的甲苯(54.0毫升)中加入N-叔丁氧羰基哌嗪(3.03克，16.3毫摩尔)、碳酸铯(6.20克，19.04毫摩尔)、乙酸钯(61毫克，0.27毫摩尔)和1,1'-联萘-2,2'-双二苯膦BINAP(423毫克，0.68毫摩尔)，N 2保护下，110摄氏度反应4小时。 To a solution of 4,5-difluoro-2-fluorobenzaldehyde (3.0 g, 13.6 mmol) in toluene (54.0 mL) at room temperature was added N-tert-butoxycarbonylpiperazine (3.03 g, 16.3 mmol), Cesium carbonate (6.20 g, 19.04 mmol), palladium acetate (61 mg, 0.27 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine BINAP (423 mg, 0.68 mmol), N 2 under the protection of 110 degrees Celsius for 4 hours.
反应结束，冷却至室温，用乙酸乙酯(200毫升)稀释，依次用水(100毫升)，有机相先用饱和食盐水(100毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到500毫克淡黄色固体4-(4,5-二氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：11.3％)。LCMS:RT＝2.13min,[M+H] +＝327.20。 After the reaction was completed, cooled to room temperature, diluted with ethyl acetate (200 mL), followed by water (100 mL), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 500 mg of tert-butyl 4-(4,5-difluoro-2-formylphenyl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 11.3%). LCMS: RT=2.13 min, [M+H] + =327.20.
步骤D：合成(E)-4-(4,5-二氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step D: Synthesis of (E)-tert-butyl 4-(4,5-difluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000164
Figure PCTCN2021105088-appb-000164
室温下，将4-(4,5-二氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(500毫克，1.53毫摩尔)和4-甲基苯磺酰肼(300毫克，1.61毫摩尔)加入无水乙醇(7.6毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(4,5-difluoro-2-formylphenyl)piperazine-1-carboxylate (500 mg, 1.53 mmol) and 4-methylbenzenesulfonylhydrazide (300 mg, 1.61 mmol) was added to anhydrous ethanol (7.6 mL) and reacted at room temperature for 1 h under the protection of N 2 .
反应结束，蒸干溶剂得到760毫克类白色固体(E)-4-(4,5-二氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.19min,[M+H] +＝495.21。 After the reaction was completed, the solvent was evaporated to dryness to obtain 760 mg of off-white solid (E)-4-(4,5-difluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1- Carboxylic acid tert-butyl ester. No purification, directly used in the next reaction. LCMS: RT=2.19min, [M+H] + =495.21.
步骤E：合成7,8-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step E: Synthesis of tert-butyl 7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
Figure PCTCN2021105088-appb-000165
Figure PCTCN2021105088-appb-000165
室温下，向含有(E)-4-(4,5-二氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(760毫克，1.53毫摩尔)的甲苯(7.6毫升)中，分批加入氢化钠(61毫克，1.53毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-4-(4,5-difluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1-carboxylate tert-butyl ester (760 mg, 1.53 mmol) in toluene (7.6 mL), sodium hydride (61 mg, 1.53 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)溶解，先用饱和食盐水(100毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到280毫克淡黄色固体7,8-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：59.0％)。LCMS:RT＝2.18min,[M+H] +＝311.25。 After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (50 mL), washed with saturated brine (100 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 280 mg of tert-butyl 7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a pale yellow solid (yield: 59.0%). LCMS: RT=2.18 min, [M+H] + =311.25.
步骤F：合成7,8-二氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step F: Synthesis of 7,8-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000166
Figure PCTCN2021105088-appb-000166
室温下，将7,8-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(280毫克，0.90毫摩尔)加入甲醇(4.5毫升)中，滴加盐酸的二氧六环溶液(0.90毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (280 mg, 0.90 mol) was added to methanol (4.5 mL), hydrochloric acid in dioxane solution (0.90 mL, 4.0 mol per liter) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到250毫克类白色固体7,8-二氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.56min,[M+H] +＝211.16。 After the reaction was completed, the solvent was evaporated to dryness to obtain 250 mg of off-white solid 7,8-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.56 min, [M+H] + =211.16.
步骤G：合成(5S)-5-(3-(7,8-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step G: Synthesis of (5S)-5-(3-(7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl )-3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000167
Figure PCTCN2021105088-appb-000167
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和7,8-二氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(72毫克，0.26毫摩尔)加入无水二氯甲烷(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升，0.94毫摩尔)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 7,8-difluoro-1 ,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (72 mg, 0.26 mmol) was added to anhydrous dichloromethane (2.0 mL), dropwise added N,N-Diisopropylethylamine (156.0 μL, 0.94 mmol) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到27.2毫克白色固体(5S)-5-(3-(7,8-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：28.6％)。LCMS:RT＝1.82min,[M+H] +＝405.29。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 27.2 mg of white solid (5S)-5-(3-(7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 28.6%). LCMS: RT=1.82 min, [M+H] + =405.29.
实施例34和实施例35Example 34 and Example 35
合成(5S)-5-(3-((S)-7,8-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮和(5S)-5-(3-((R)-7,8-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-((S)-7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- base)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (5S)-5-(3-((R)-7,8-difluoro-3,4, 10,10a-Tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000168
Figure PCTCN2021105088-appb-000168
通过手性HPLC拆分(5S)-5-(3-(7,8-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(Chiralpak AD-H，正己烷：异丙醇＝80：20，洗脱液浓缩、冻干)，先后得到光学纯化合物34和化合物35。Resolution of (5S)-5-(3-(7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) by chiral HPLC -yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (Chiralpak AD-H, n-hexane:isopropanol=80:20, eluent concentrated, lyophilized) , optically pure compound 34 and compound 35 were obtained successively.
化合物34：HPLC:RT＝16.898min。LCMS:RT＝1.82min,[M+H] +＝405.29。 1H NMR(400MHz,CDCl 3)δ7.69(s,1H),6.95–6.89(m,1H),6.28(d,J＝6.4Hz,0.5H),6.25(d,J＝6.4Hz,0.5H),5.94(m,0.5H),5.83(m,0.5H),4.69–4.63(m,0.5H),4.62–4.57(m,0.5H),3.81–3.74(m,1H),3.52–3.34(m,2H),3.32–3.09(m,1H),3.04–2.84(m,2H),2.84–2.64(m,1H),2.64–2.46(m,2H),2.46–2.17(m,3H),1.24–1.13(m,1H),0.65–0.53(m,1H),0.53–0.35(m,2H),0.35–0.28(m,1H)。 Compound 34: HPLC: RT=16.898 min. LCMS: RT=1.82 min, [M+H] + =405.29. 1 H NMR (400MHz, CDCl 3 ) δ 7.69 (s, 1H), 6.95-6.89 (m, 1H), 6.28 (d, J=6.4Hz, 0.5H), 6.25 (d, J=6.4Hz, 0.5 H), 5.94 (m, 0.5H), 5.83 (m, 0.5H), 4.69–4.63 (m, 0.5H), 4.62–4.57 (m, 0.5H), 3.81–3.74 (m, 1H), 3.52– 3.34 (m, 2H), 3.32–3.09 (m, 1H), 3.04–2.84 (m, 2H), 2.84–2.64 (m, 1H), 2.64–2.46 (m, 2H), 2.46–2.17 (m, 3H) ), 1.24–1.13 (m, 1H), 0.65–0.53 (m, 1H), 0.53–0.35 (m, 2H), 0.35–0.28 (m, 1H).
化合物35：HPLC:RT＝19.139min。LCMS:RT＝1.82min,[M+H] +＝405.29。 1H NMR(400MHz,CDCl 3)δ7.74(s,0.5H),7.70(s,0.5H),6.96–6.89(m,1H),6.31–6.21(m,1H),5.92(s,0.5H),5.85(s,0.5H),4.66–4.63(m,0.5H),4.61–4.58(m,0.5H),3.79(d,J＝12.7Hz,1H),3.48–3.41(m,2H),3.31–3.09(m,1H),3.03–2.62(m,3H),2.63–2.47(m,2H),2.46–2.17(m,3H),1.24–1.13(m,1H),0.64–0.53(m,1H),0.52–0.36(m,2H),0.34–0.28(m,1H)。 Compound 35: HPLC: RT=19.139 min. LCMS: RT=1.82 min, [M+H] + =405.29. 1 H NMR (400MHz, CDCl 3 ) δ 7.74(s, 0.5H), 7.70(s, 0.5H), 6.96-6.89(m, 1H), 6.31-6.21(m, 1H), 5.92(s, 0.5 H), 5.85 (s, 0.5H), 4.66–4.63 (m, 0.5H), 4.61–4.58 (m, 0.5H), 3.79 (d, J=12.7Hz, 1H), 3.48–3.41 (m, 2H) ), 3.31–3.09 (m, 1H), 3.03–2.62 (m, 3H), 2.63–2.47 (m, 2H), 2.46–2.17 (m, 3H), 1.24–1.13 (m, 1H), 0.64–0.53 (m, 1H), 0.52–0.36 (m, 2H), 0.34–0.28 (m, 1H).
化合物34另一种合成路线Another synthetic route to compound 34
合成(S)-5-环丙基-5-(3-((S)-7,8-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)咪唑烷-2,4-二酮Synthesis of (S)-5-cyclopropyl-5-(3-((S)-7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole -2(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000169
Figure PCTCN2021105088-appb-000169
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(2-溴-4,5-二氟苯基)甲醇Step A: Synthesis of (2-bromo-4,5-difluorophenyl)methanol
Figure PCTCN2021105088-appb-000170
Figure PCTCN2021105088-appb-000170
零摄氏度下，向含有2-溴-4,5-二氟苯甲酸(600克，2.53摩尔)的四氢呋喃(4升)中，滴加硼烷四氢呋喃溶液(3.8升，1.0摩尔每升)，反应放热，滴加速度维持内温在50到80摄氏度之间，加完后继续搅拌反应1小时。To a solution of 2-bromo-4,5-difluorobenzoic acid (600 g, 2.53 mol) in tetrahydrofuran (4 liters) at zero degrees Celsius, borane tetrahydrofuran solution (3.8 liters, 1.0 mol per liter) was added dropwise to react Exothermic, the drop rate maintained the internal temperature between 50 and 80 degrees Celsius, and the stirring was continued for 1 hour after the addition.
反应结束，反应液缓慢倒入冰水中搅拌至无气泡产生，混合液减压浓缩掉大部分溶剂四氢呋喃，残留物过滤，所得滤液用乙酸乙酯(1.2升×3次)萃取，合并有机相先用饱和食盐水(1.5升×2次)洗涤，然后用无水硫酸钠干燥，浓缩得585克白色固体(2-溴-4,5-二氟苯基)甲醇(收率：98.4％)。LCMS:RT＝1.88min。After the reaction was completed, the reaction solution was slowly poured into ice water and stirred until no bubbles were generated. The mixed solution was concentrated under reduced pressure to remove most of the solvent, tetrahydrofuran, and the residue was filtered. Washed with saturated brine (1.5 L×2 times), dried over anhydrous sodium sulfate, and concentrated to obtain 585 g of white solid (2-bromo-4,5-difluorophenyl)methanol (yield: 98.4%). LCMS:RT=1.88min.
步骤B：合成1-溴-2-(溴甲基)-4,5-二氟苯Step B: Synthesis of 1-bromo-2-(bromomethyl)-4,5-difluorobenzene
Figure PCTCN2021105088-appb-000171
Figure PCTCN2021105088-appb-000171
零摄氏度下，向含有(2-溴-4,5-二氟苯基)甲醇(545克，2.44摩尔)的二氯甲烷(4升)中，分批慢慢滴入三溴化磷(397克/137毫升，1.46摩尔)，加完后于室温下继续搅拌反应2小时。To dichloromethane (4 L) containing (2-bromo-4,5-difluorophenyl)methanol (545 g, 2.44 mol) at zero degrees Celsius, phosphorus tribromide (397 g/137 mL, 1.46 mol), after the addition, the reaction was continued to stir at room temperature for 2 hours.
反应结束，反应液缓慢倒入冰水中，混合液用二氯甲烷(1.5升×2次)萃取，合并有机相，用碳酸氢钠溶液洗涤2次，有机相无水硫酸钠干燥，浓缩。所得粗品用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/50)，得到596克无色透明液体1-溴-2-(溴甲基)-4,5-二氟苯(收率：85.4％)。LCMS:RT＝2.13min。After the reaction was completed, the reaction solution was slowly poured into ice water, the mixture was extracted with dichloromethane (1.5L×2 times), the organic phases were combined, washed twice with sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/50) to obtain 596 g of colorless transparent liquid 1-bromo-2-(bromomethyl)-4,5-difluoro Benzene (yield: 85.4%). LCMS: RT=2.13 min.
步骤C：(S)-3-(2-溴-4,5-二氟苯基)-2-((二苯基亚甲基)氨基)丙酸叔丁酯Step C: (S)-tert-Butyl 3-(2-bromo-4,5-difluorophenyl)-2-((diphenylmethylene)amino)propanoate
Figure PCTCN2021105088-appb-000172
Figure PCTCN2021105088-appb-000172
零摄氏度下，向溶有1-溴-2-(溴甲基)-4,5-二氟苯(720克，2.51摩尔)和2-((二苯基亚甲基)氨基)乙酸叔丁酯(705克，2.39摩尔)的二氯甲烷(2升)中，先后加入(1S，2R，4S，5R)-2-((S)-(烯丙氧基)(喹啉-5-基)甲基)-1-(蒽-9-基甲基)-5-乙烯基奎尼丁-1-溴化铵(76克，126毫摩尔)和50％的氢氧化钾水溶液(3.4千克，50.4摩尔)，于室温下继续搅拌反应4小时。At zero degrees Celsius, dissolve 1-bromo-2-(bromomethyl)-4,5-difluorobenzene (720 g, 2.51 mol) and tert-butyl 2-((diphenylmethylene)amino)acetic acid ester (705 g, 2.39 mol) in dichloromethane (2 L), followed by (1S,2R,4S,5R)-2-((S)-(allyloxy)(quinolin-5-yl )methyl)-1-(anthracene-9-ylmethyl)-5-vinylquinidine-1-ammonium bromide (76 g, 126 mmol) and 50% aqueous potassium hydroxide (3.4 kg, 50.4 moles), and the reaction was continued to stir at room temperature for 4 hours.
反应结束，反应液静置分液，有机相用水洗涤2次，分液干燥，浓缩。所得残留物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到1198克淡黄色油状(S)-3-(2-溴-4,5-二氟苯基)-2-((二苯基亚甲基)氨基)丙酸叔丁酯(收率：95.5％，ee＝84％)。LCMS:RT＝2.45min,[M+H] +＝500.17。 After the reaction was completed, the reaction solution was allowed to stand for separation, and the organic phase was washed twice with water, separated, dried, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 1198 g of (S)-tert-butyl 3-(2-bromo-4,5-difluorophenyl)-2-((diphenylmethylene)amino)propanoate were obtained as pale yellow oil (yield: 95.5 %, ee=84%). LCMS: RT=2.45 min, [M+H] + =500.17.
步骤D：合成(S)-2-氨基-3-(2-溴-4,5-二氟苯基)丙酸叔丁酯Step D: Synthesis of (S)-tert-butyl 2-amino-3-(2-bromo-4,5-difluorophenyl)propanoate
Figure PCTCN2021105088-appb-000173
Figure PCTCN2021105088-appb-000173
室温下，将(S)-3-(2-溴-4,5-二氟苯基)-2-((二苯基亚甲基)氨基)丙酸叔丁酯(1190克，2.38摩尔)溶解于四氢呋喃(3升)中，加入柠檬酸(1143克,5.95摩尔)的3升水溶液于室温下反应16小时。(S)-tert-butyl 3-(2-bromo-4,5-difluorophenyl)-2-((diphenylmethylene)amino)propanoate (1190 g, 2.38 mol) at room temperature It was dissolved in tetrahydrofuran (3 L), and a 3 L aqueous solution of citric acid (1143 g, 5.95 mol) was added to react at room temperature for 16 hours.
反应结束，反应液减压浓缩掉大部分溶剂四氢呋喃所得残留物用5摩尔每升的盐酸调节pH值为2左右。用(1升萃取液：乙酸乙酯/正己烷＝1/10)萃取6次至水相无上点。所得水相用50％氢氧化钠调节pH值为10左右，然后用乙酸乙酯(1.5升×3次)萃取，合并有机相用无水硫酸钠干燥，浓缩得714克透明油状(S)-2-氨基-3-(2-溴-4,5-二氟苯基)丙酸叔丁酯(收率：89.5％)。LCMS:RT＝1.65min,[M- tBu+H] +＝280.07。 After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove most of the solvent tetrahydrofuran, and the pH value of the residue was adjusted to about 2 with 5 moles of hydrochloric acid per liter. It was extracted 6 times with (1 liter of extract: ethyl acetate/n-hexane=1/10) until the aqueous phase had no upper point. The obtained aqueous phase was adjusted to a pH value of about 10 with 50% sodium hydroxide, then extracted with ethyl acetate (1.5 liters × 3 times), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated to obtain 714 grams of transparent oil (S)- tert-Butyl 2-amino-3-(2-bromo-4,5-difluorophenyl)propanoate (yield: 89.5%). LCMS: RT = 1.65min, [M- t Bu + H] + = 280.07.
步骤E：拆分(S)-2-氨基-3-(2-溴-4,5-二氟苯基)丙酸叔丁酯Step E: Resolution of (S)-tert-butyl 2-amino-3-(2-bromo-4,5-difluorophenyl)propanoate
Figure PCTCN2021105088-appb-000174
Figure PCTCN2021105088-appb-000174
室温下，向含有2-氨基-3-(2-溴-4,5-二氟苯基)丙酸叔丁酯(324.0克，964.3毫摩尔，ee＝84％)的甲醇(3.24升)中加入L-酒石酸(347.0克，2.31摩尔),室温下搅拌12小时。In methanol (3.24 L) at room temperature L-tartaric acid (347.0 g, 2.31 mol) was added, and the mixture was stirred at room temperature for 12 hours.
反应结束，抽滤，滤饼用少量冷的甲醇洗涤，干燥后得282.3克白色固体(S)-2-氨基-3-(2-溴-4,5-二氟苯基)丙酸叔丁酯酒石酸盐(收率：60.2％,ee＝100％)。 1H NMR(400MHz,DMSO)δ7.86(dd,J＝10.3,7.8Hz,1H),7.54(dd,J＝11.7,8.6Hz,1H),3.78–3.73(m,1H),3.06(dd,J＝13.8,7.4Hz,1H),2.91(dd,J＝13.9,7.9Hz,1H),1.32(s,9H)。 After the reaction was completed, suction filtration, the filter cake was washed with a small amount of cold methanol, and dried to obtain 282.3 g of white solid (S)-2-amino-3-(2-bromo-4,5-difluorophenyl) tert-butyl propanoate Ester tartrate (yield: 60.2%, ee=100%). 1 H NMR (400MHz, DMSO) δ 7.86 (dd, J=10.3, 7.8Hz, 1H), 7.54 (dd, J=11.7, 8.6Hz, 1H), 3.78-3.73 (m, 1H), 3.06 (dd , J=13.8, 7.4Hz, 1H), 2.91 (dd, J=13.9, 7.9Hz, 1H), 1.32 (s, 9H).
其中，(S)-2-氨基-3-(2-溴-4,5-二氟苯基)丙酸叔丁酯酒石酸盐的单晶结构示意图如图1所示，具体晶体参数如下：Wherein, the single crystal structure schematic diagram of (S)-2-amino-3-(2-bromo-4,5-difluorophenyl) propionic acid tert-butyl ester tartrate is shown in Figure 1, and the specific crystal parameters are as follows:
Figure PCTCN2021105088-appb-000175
Figure PCTCN2021105088-appb-000175
步骤F：合成(S)-3-(2-溴-4,5-二氟苯基)-2-((2-(叔丁氧基)-2-氧乙基)氨基)丙酸叔丁酯Step F: Synthesis of (S)-tert-butyl 3-(2-bromo-4,5-difluorophenyl)-2-((2-(tert-butoxy)-2-oxoethyl)amino)propanoate ester
Figure PCTCN2021105088-appb-000176
Figure PCTCN2021105088-appb-000176
向(S)-2-氨基-3-(2-溴-4,5-二氟苯基)丙酸叔丁酯酒石酸盐(282.3克，582.1摩尔)中加入水，在冰浴下，用饱和氢氧化钠调pH至12，乙酸乙酯(500毫升×3次)萃取,先用饱和食盐水(200毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩得到无色油状物(S)-2-氨基-3-(2-溴-4,5-二氟苯基)丙酸叔丁酯粗品溶解于乙腈(2.0升)中，依次加入碳酸钾(120.1克，870.6毫摩尔)和溴乙酸叔丁酯(118.9克，609.4摩尔)，置换氮气,70摄氏度反应过夜。To (S)-tert-butyl 2-amino-3-(2-bromo-4,5-difluorophenyl)propanoate tartrate (282.3 g, 582.1 mol) was added water and saturated with water under an ice bath The pH was adjusted to 12 with sodium hydroxide, extracted with ethyl acetate (500 ml × 3 times), washed with saturated brine (200 ml × 2 times), then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain a colorless oil The crude product (S)-tert-butyl 2-amino-3-(2-bromo-4,5-difluorophenyl)propanoate was dissolved in acetonitrile (2.0 L), followed by potassium carbonate (120.1 g, 870.6 mL) mol) and tert-butyl bromoacetate (118.9 g, 609.4 mol), replaced with nitrogen, and reacted at 70 degrees Celsius overnight.
反应结束，冷却至室温，抽滤，滤饼用乙酸乙酯洗涤，滤液减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到233.8克淡黄色油状物(S)-3-(2-溴-4,5-二氟苯 基)-2-((2-(叔丁氧基)-2-氧乙基)氨基)丙酸叔丁酯(收率：89.5％)。LCMS:RT＝2.24min,[M+H] +＝450.19。 After the reaction was completed, it was cooled to room temperature, filtered with suction, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 233.8 g of pale yellow oil (S)-3-(2-bromo-4,5-difluorophenyl)-2-((2-(tert-butoxy)-2-oxoethyl)amino)propane were obtained tert-butyl acid (yield: 89.5%). LCMS: RT=2.24 min, [M+H] + =450.19.
步骤G：合成(S)-1-(2-(叔丁氧基)-2-氧乙基)-5,6-二氟吲哚-2-羧酸叔丁酯Step G: Synthesis of (S)-tert-butyl 1-(2-(tert-butoxy)-2-oxoethyl)-5,6-difluoroindole-2-carboxylate
Figure PCTCN2021105088-appb-000177
Figure PCTCN2021105088-appb-000177
室温下，向含有(S)-3-(2-溴-4,5-二氟苯基)-2-((2-(叔丁氧基)-2-氧乙基)氨基)丙酸叔丁酯(233.8克，519.5毫摩尔)的1,4-二氧六环(1.5升)中，依次加入碳酸铯(220.0克，675.4毫摩尔)、1,1'-联萘-2,2'-双二苯膦(32.4克，52.0毫摩尔)和醋酸钯(5.8克，26.0毫摩尔)，置换氮气，110摄氏度反应过夜。at room temperature, to a compound containing tert- To butyl ester (233.8 g, 519.5 mmol) in 1,4-dioxane (1.5 L), add cesium carbonate (220.0 g, 675.4 mmol), 1,1'-binaphthyl-2,2' -Bisdiphenylphosphine (32.4 g, 52.0 mmol) and palladium acetate (5.8 g, 26.0 mmol), replaced with nitrogen, and reacted at 110 degrees Celsius overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(300毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(300毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到175.6克淡黄色固体(S)-1-(2-(叔丁氧基)-2-氧乙基)-5,6-二氟吲哚-2-羧酸叔丁酯(收率：91.5％)。LCMS:RT＝2.23min。 1H NMR(500MHz,CDCl 3)δ6.87–6.79(m,1H),6.14(dd,J＝11.1,6.4Hz,1H),4.47(dd,J＝10.6,8.7Hz,1H),3.90(q,J＝18.1Hz,2H),3.32(dd,J＝16.0,10.6Hz,1H),3.10(dd,J＝16.0,8.7Hz,1H),1.49(s,9H),1.42(s,9H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (300 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (300 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 175.6 g of pale yellow solid (S)-tert-butyl 1-(2-(tert-butoxy)-2-oxoethyl)-5,6-difluoroindole-2-carboxylate was obtained (yield: 91.5 %). LCMS: RT=2.23 min. 1 H NMR (500 MHz, CDCl 3 ) δ 6.87-6.79 (m, 1H), 6.14 (dd, J=11.1, 6.4 Hz, 1H), 4.47 (dd, J=10.6, 8.7 Hz, 1H), 3.90 ( q,J＝18.1Hz,2H),3.32(dd,J＝16.0,10.6Hz,1H),3.10(dd,J＝16.0,8.7Hz,1H),1.49(s,9H),1.42(s,9H) ).
步骤H：合成(S)-2-(5,6-二氟-2-(羟甲基)吲哚-1-基)乙-1-醇Step H: Synthesis of (S)-2-(5,6-difluoro-2-(hydroxymethyl)indol-1-yl)ethan-1-ol
Figure PCTCN2021105088-appb-000178
Figure PCTCN2021105088-appb-000178
N 2保护以及冰水浴下，向含有(S)-1-(2-(叔丁氧基)-2-氧乙基)-5,6-二氟吲哚-2-羧酸叔丁酯(44.9克，121.5毫摩尔)的甲苯(100毫升)中慢慢滴加二异丁基氢化铝的甲苯溶液(365.6毫升，1.5摩尔/升)，加毕，撤去冰水浴，加热至80℃反应0.5小时。 N 2 protection and an ice water bath, the indole-5,6-difluoro-containing (S) -1- (2- (tert-butoxy) -2-oxoethyl) -2-carboxylate ( 44.9 g, 121.5 mmol) in toluene (100 mL) was slowly added dropwise a solution of diisobutylaluminum hydride in toluene (365.6 mL, 1.5 mol/L), after the addition was completed, the ice-water bath was removed, and the reaction was heated to 80 °C for 0.5 Hour.
反应结束，将反应液缓慢倒入冰中，待反应淬灭后加入30％NaOH溶液(300毫升)破环乳化，混合液用乙酸乙酯(200毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(300毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物直接用于下一步反应。LCMS:RT＝1.74min,[M+H] +＝230.15。 1H NMR(500MHz,CDCl 3)δ6.90–6.83(m,1H),6.29–6.17(m,1H),3.93–3.85(m,2H),3.85–3.75(m,2H),3.67(dd,J＝12.0,4.2Hz,1H),3.34–3.25(m,2H),3.07–2.96(m,1H),2.95–2.85(m,1H)。 After the reaction was completed, the reaction solution was slowly poured into ice. After the reaction was quenched, 30% NaOH solution (300 mL) was added to break the ring for emulsification. The mixed solution was extracted with ethyl acetate (200 mL×3 times), and the organic phases were combined. The phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was directly used in the next reaction. LCMS: RT=1.74 min, [M+H] + =230.15. 1 H NMR (500 MHz, CDCl 3 ) δ 6.90-6.83 (m, 1H), 6.29-6.17 (m, 1H), 3.93-3.85 (m, 2H), 3.85-3.75 (m, 2H), 3.67 (dd , J=12.0, 4.2Hz, 1H), 3.34–3.25 (m, 2H), 3.07–2.96 (m, 1H), 2.95–2.85 (m, 1H).
步骤I：合成(S)-7,8-二氟-2-((三氟甲基)磺酰基)-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚Step I: Synthesis of (S)-7,8-difluoro-2-((trifluoromethyl)sulfonyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2- a]Indole
Figure PCTCN2021105088-appb-000179
Figure PCTCN2021105088-appb-000179
将上述粗产物溶于四氢呋喃(486毫升)，依次加入三苯基膦(95.6克，364.5毫摩尔)和三氟甲磺酰胺(19.0克，127.6毫摩尔)，冰水浴冷却，缓慢加入偶氮二甲酸二异丙酯(73.7克，364.5毫摩尔)，加毕，撤去冷浴，室温反应1小时。The above crude product was dissolved in tetrahydrofuran (486 mL), triphenylphosphine (95.6 g, 364.5 mmol) and trifluoromethanesulfonamide (19.0 g, 127.6 mmol) were added successively, cooled in an ice-water bath, and azodicarbonate was added slowly Diisopropyl formate (73.7 g, 364.5 mmol) was added, the cooling bath was removed, and the reaction was carried out at room temperature for 1 hour.
反应结束，蒸干溶剂，将所得粘稠混合物溶于乙酸乙酯(200毫升)，加入2升正己烷，抽滤，滤渣用正己烷/乙酸乙酯混合溶剂(10/1)洗涤直至无产物，减压蒸干滤液，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/20-1/10)，得到13.5克淡黄色固体(S)-7,8-二氟-2-((三氟甲基) 磺酰基)-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚(收率：32.5％)。LCMS:RT＝2.13min。 1H NMR(500MHz,CDCl 3)δ6.92–6.85(m,1H),6.21(dd,J＝11.0,6.4Hz,1H),3.84(dd,J＝11.2,3.4Hz,2H),3.70–3.60(m,1H),3.57(td,J＝11.6,2.8Hz,1H),3.45(t,J＝10.8Hz,1H),3.31(dd,J＝12.9,2.6Hz,1H),3.13(ddd,J＝12.8,11.8,3.5Hz,1H),2.90(dd,J＝15.1,7.9Hz,1H),2.45(dd,J＝15.1,7.9Hz,1H)。 After the reaction was completed, the solvent was evaporated to dryness, the resulting viscous mixture was dissolved in ethyl acetate (200 ml), 2 liters of n-hexane was added, suction filtration, and the filter residue was washed with n-hexane/ethyl acetate mixed solvent (10/1) until there was no product , the filtrate was evaporated to dryness under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/20-1/10) to obtain 13.5 g of pale yellow solid (S)-7,8 -Difluoro-2-((trifluoromethyl)sulfonyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole (yield: 32.5%) . LCMS: RT=2.13 min. 1 H NMR (500 MHz, CDCl 3 ) δ 6.92–6.85 (m, 1H), 6.21 (dd, J=11.0, 6.4 Hz, 1H), 3.84 (dd, J=11.2, 3.4 Hz, 2H), 3.70– 3.60(m,1H),3.57(td,J=11.6,2.8Hz,1H),3.45(t,J=10.8Hz,1H),3.31(dd,J=12.9,2.6Hz,1H),3.13(ddd , J=12.8, 11.8, 3.5Hz, 1H), 2.90 (dd, J=15.1, 7.9Hz, 1H), 2.45 (dd, J=15.1, 7.9Hz, 1H).
步骤J：合成(S)-7,8-二氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚Step J: Synthesis of (S)-7,8-difluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole
Figure PCTCN2021105088-appb-000180
Figure PCTCN2021105088-appb-000180
冰水浴冷却下，向含有((S)-7,8-二氟-2-((三氟甲基)磺酰基)-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚(7.7克，22.5毫摩尔)的甲苯(64.3毫升)中，缓慢加入双(2-甲氧基乙氧基)铝二氢化钠(25.7毫升，90.1毫摩尔，70％的甲苯溶液)，加毕，撤去冰水浴，室温反应过夜。Under ice-water bath cooling, add ((S)-7,8-difluoro-2-((trifluoromethyl)sulfonyl)-1,2,3,4,10,10a-hexahydropyrazino[ 1,2-a]Indole (7.7 g, 22.5 mmol) in toluene (64.3 mL) was slowly added sodium bis(2-methoxyethoxy)aluminum dihydride (25.7 mL, 90.1 mmol, 70 % toluene solution), the addition was completed, the ice-water bath was removed, and the reaction was carried out at room temperature overnight.
反应结束，将反应液缓慢倒入冰中，待充分淬灭后加入30％NaOH溶液(100毫升)，混合液用乙酸乙酯(150毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(200毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物直接用于下一步反应。LCMS:RT＝1.56min,[M+H] +＝211.16。 After the reaction was completed, the reaction solution was slowly poured into ice. After being fully quenched, 30% NaOH solution (100 mL) was added. The mixture was extracted with ethyl acetate (150 mL × 3 times), and the organic phases were combined. It was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was directly used in the next reaction. LCMS: RT=1.56 min, [M+H] + =211.16.
步骤K：合成(S)-5-环丙基-5-(3-((S)-7,8-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)咪唑烷-2,4-二酮Step K: Synthesis of (S)-5-cyclopropyl-5-(3-((S)-7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2-a ]Indol-2(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000181
Figure PCTCN2021105088-appb-000181
室温下，将上述粗产物溶于无水二氯甲烷(75毫升)中，加入(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(4.78克，22.5毫摩尔)，滴加N,N-二异丙基乙胺(5.6毫升，33.8毫摩尔)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(6.47克，33.8毫摩尔)和1-羟基苯并三唑(304毫克，2.254毫摩尔)，N 2保护下，室温反应过夜。 The above crude product was dissolved in anhydrous dichloromethane (75 mL) at room temperature, and (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid was added (4.78 g, 22.5 mmol), N,N-diisopropylethylamine (5.6 mL, 33.8 mmol) was added dropwise, followed by 1-ethyl-(3-dimethylaminopropyl)carbonyl carbodiimide hydrochloride (6.47 g, 33.8 mmol) and 1-hydroxybenzotriazole (304 mg, 2.254 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(100毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(100毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到6.4克白色固体(S)-5-环丙基-5-(3-((S)-7,8-二氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)咪唑烷-2,4-二酮(收率：70.3％)。LCMS:RT＝1.82min,[M+H] +＝405.29。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (100 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (100 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 6.4 g of white solid (S)-5-cyclopropyl-5-(3-((S)-7,8-difluoro-3,4,10,10a-tetrahydropyrazino[1,2- a] Indol-2(1H)-yl)-3-oxopropyl)imidazolidine-2,4-dione (yield: 70.3%). LCMS: RT=1.82 min, [M+H] + =405.29.
实施例36Example 36
合成(5S)-5-(3-(7-溴-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(7-Bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000182
Figure PCTCN2021105088-appb-000182
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(5-溴-4-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(5-bromo-4-fluoro-2-formylphenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000183
Figure PCTCN2021105088-appb-000183
室温下，向含有4-溴-2,5-二氟苯甲醛(6.00克，27.15毫摩尔)的二甲基亚砜(36.0毫升)中加入N-叔丁氧羰基哌嗪(2.60克，32.58毫摩尔)和碳酸钾(4.87克，35.30毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 4-bromo-2,5-difluorobenzaldehyde (6.00 g, 27.15 mmol) in dimethyl sulfoxide (36.0 mL) was added N-tert-butoxycarbonylpiperazine (2.60 g, 32.58 g) at room temperature mmol) and potassium carbonate (4.87 g, 35.30 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(100毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(100毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到2.60克淡黄色固体4-(5-溴-4-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(收率：17.2％)。LCMS:RT＝2.20min,[M+H] +＝387.12。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (100 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (100 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 2.60 g of tert-butyl 4-(5-bromo-4-fluoro-2-formylphenyl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 17.2%). LCMS: RT=2.20 min, [M+H] + =387.12.
步骤B：合成(E)-4-(5-溴-4-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(5-bromo-4-fluoro-2-(((2-tosylhydrazino)methyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000184
Figure PCTCN2021105088-appb-000184
室温下，将4-(5-溴-4-氟-2-甲酰基苯基)哌嗪-1-羧酸叔丁酯(2.60克，6.71毫摩尔)和4-甲基苯磺酰肼(1.31克，7.04毫摩尔)加入无水乙醇(25.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(5-bromo-4-fluoro-2-formylphenyl)piperazine-1-carboxylate (2.60 g, 6.71 mmol) and 4-methylbenzenesulfonylhydrazide ( 1.31 g, 7.04 mmol) was added to anhydrous ethanol (25.0 mL) and reacted at room temperature for 1 h under the protection of N 2 .
反应结束，蒸干溶剂得到3.73克类白色固体(E)-4-(5-溴-4-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.25min,[M+H] +＝555.19。 The reaction was completed, and the solvent was evaporated to dryness to obtain 3.73 g of off-white solid (E)-4-(5-bromo-4-fluoro-2-(((2-toluenesulfonylhydrazino)methyl)phenyl)piperazine-1 - Carboxylic acid tert-butyl ester. No purification, directly used in the next reaction. LCMS: RT=2.25min, [M+H] + =555.19.
步骤C：合成7-溴-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of 7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
Figure PCTCN2021105088-appb-000185
Figure PCTCN2021105088-appb-000185
室温下，向含有(E)-4-(5-溴-4-氟-2-(((2-甲苯磺酰基肼基)甲基)苯基)哌嗪-1-羧酸叔丁酯(3.73克，6.72毫摩尔)的甲苯(40.0毫升)中，分批加入氢化钠(322.0毫克，7.20毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。At room temperature, tert-butyl 4-(5-bromo-4-fluoro-2-(((2-tosylhydrazino)methyl)phenyl)piperazine-1-carboxylate ( 3.73 g, 6.72 mmol) in toluene (40.0 ml), sodium hydride (322.0 mg, 7.20 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(100毫升)溶解，先用饱和食盐水(100毫升×2次)洗涤，然 后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到1.77克淡黄色固体7-溴-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：71.1％)。LCMS:RT＝2.25min,[M+H] +＝371.21。 After the reaction was completed, it was cooled to room temperature, dissolved in ethyl acetate (100 mL), washed with saturated brine (100 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 1.77 g of tert-butyl 7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a pale yellow solid (yield : 71.1%). LCMS: RT=2.25 min, [M+H] + =371.21.
步骤D：合成7-溴-8-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 7-bromo-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000186
Figure PCTCN2021105088-appb-000186
室温下，将7-溴-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(200.0毫克，0.54毫摩尔)加入甲醇(2.0毫升)中，滴加盐酸的二氧六环溶液(674微升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (200.0 mg, 0.54 mmol) was added to methanol (2.0 mL), and a solution of hydrochloric acid in dioxane (674 μL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到150.0毫克类白色固体7-溴-8-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.59min,[M+H] +＝271.08。 After the reaction was completed, the solvent was evaporated to dryness to obtain 150.0 mg of off-white solid 7-bromo-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.59 min, [M+H] + =271.08.
步骤E：合成(5S)-5-(3-(7-溴-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(7-Bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000187
Figure PCTCN2021105088-appb-000187
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和7-溴-8-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(79.7毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (50.0 mg, 0.24 mmol) and 7-bromo-8-fluoro- 1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (79.7 mg, 0.26 mmol) was added to N,N-dimethylformamide (2.0 mL) ), N,N-diisopropylethylamine (156.0 μl) was added dropwise, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg , 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2 protection, were reacted at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到25.3毫克白色固体(5S)-5-(3-(7-溴-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：22.6％)。LCMS:RT＝1.88min,[M+H] +＝465.18。 1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),7.68(d,J＝9.3Hz,1H),7.12(dd,J＝8.4,3.1Hz,1H),6.81(dd,J＝9.4,5.6Hz,1H),4.39(dd,J＝49.1,11.5Hz,1H),3.77(dd,J＝37.1,12.2Hz,1H),3.66(t,J＝13.1Hz,1H),3.54–3.33(m,1H),3.18–2.89(m,2H),2.86–2.51(m,3H),2.47–2.16(m,2H),2.03–1.85(m,2H),1.16–1.03(m,1H),0.52–0.39(m,1H),0.39–0.24(m,2H),0.17–0.03(m,1H). The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 25.3 mg of (5S)-5-(3-(7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) was obtained as a white solid -yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 22.6%). LCMS: RT=1.88 min, [M+H] + =465.18. 1 H NMR (500MHz, DMSO-d6) δ 10.59 (s, 1H), 7.68 (d, J=9.3Hz, 1H), 7.12 (dd, J=8.4, 3.1Hz, 1H), 6.81 (dd, J ＝9.4,5.6Hz,1H),4.39(dd,J＝49.1,11.5Hz,1H),3.77(dd,J＝37.1,12.2Hz,1H),3.66(t,J＝13.1Hz,1H),3.54 –3.33 (m, 1H), 3.18–2.89 (m, 2H), 2.86–2.51 (m, 3H), 2.47–2.16 (m, 2H), 2.03–1.85 (m, 2H), 1.16–1.03 (m, 1H), 0.52–0.39 (m, 1H), 0.39–0.24 (m, 2H), 0.17–0.03 (m, 1H).
实施例37和实施例38Example 37 and Example 38
合成(S)-5-(3-((S)-7-溴-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮和(S)-5-(3-((R)-7-溴-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (S)-5-(3-((S)-7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) -yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione and (S)-5-(3-((R)-7-bromo-8-fluoro-3, 4,10,10a-Tetrahydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000188
Figure PCTCN2021105088-appb-000188
通过手性HPLC拆分(5S)-5-(3-(7-溴-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(Chiralpak AD-H，正己烷：异丙醇＝80：20，洗脱液浓缩、冻干)，先后得到光学纯化合物37和化合物38。Resolution of (5S)-5-(3-(7-bromo-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) by chiral HPLC )-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (Chiralpak AD-H, n-hexane:isopropanol=80:20, the eluent was concentrated, lyophilized ), optically pure compound 37 and compound 38 were obtained successively.
化合物37：HPLC:RT＝17.451min。LCMS:RT＝1.88min,[M+H] +＝465.19。 1H NMR(400MHz,CDCl 3)δ7.65(s,1H),6.94–6.85(m,1H),6.57(d,J＝2.7Hz,0.5H),6.56(d,J＝2.7Hz,0.5H),5.92(s,0.5H),5.81(s,0.5H),4.69–4.64(m,0.5H),4.62–4.56(m,0.5H),3.81–3.74(m,1H),3.54–3.43(m,1H),3.43–3.20(m,1H),3.17–2.63(m,4H),2.63–2.18(m,5H),1.24–1.12(m,1H),0.64–0.54(m,1H),0.52–0.36(m,2H),0.36–0.25(m,1H)。 Compound 37: HPLC: RT=17.451 min. LCMS: RT=1.88 min, [M+H] + =465.19. 1 H NMR (400MHz, CDCl 3 ) δ 7.65 (s, 1H), 6.94-6.85 (m, 1H), 6.57 (d, J=2.7Hz, 0.5H), 6.56 (d, J=2.7Hz, 0.5 H), 5.92 (s, 0.5H), 5.81 (s, 0.5H), 4.69–4.64 (m, 0.5H), 4.62–4.56 (m, 0.5H), 3.81–3.74 (m, 1H), 3.54– 3.43 (m, 1H), 3.43–3.20 (m, 1H), 3.17–2.63 (m, 4H), 2.63–2.18 (m, 5H), 1.24–1.12 (m, 1H), 0.64–0.54 (m, 1H) ), 0.52–0.36 (m, 2H), 0.36–0.25 (m, 1H).
化合物38：HPLC:RT＝21.053min。LCMS:RT＝1.88min,[M+H] +＝465.18。 1H NMR(400MHz,CDCl 3)δ7.82(s,0.5H),7.80(s,0.5H),6.91(s,0.5H),6.89(s,0.5H),6.57(d,J＝5.4Hz,0.5H),6.55(d,J＝5.4Hz,0.5H),5.96(s,0.5H),5.88(s,0.5H),4.68–4.63(m,0.5H),4.62–4.57(m,0.5H),3.81–3.74(m,1H),3.50–3.39(m,2H),3.19–2.61(m,4H),2.62–2.17(m,5H),1.24–1.13(m,1H),0.65–0.53(m,1H),0.53–0.35(m,2H),0.35–0.25(m,1H)。 Compound 38: HPLC: RT=21.053 min. LCMS: RT=1.88 min, [M+H] + =465.18. 1 H NMR (400MHz, CDCl 3 ) δ 7.82(s, 0.5H), 7.80(s, 0.5H), 6.91(s, 0.5H), 6.89(s, 0.5H), 6.57(d, J=5.4 Hz, 0.5H), 6.55(d, J＝5.4Hz, 0.5H), 5.96(s, 0.5H), 5.88(s, 0.5H), 4.68–4.63(m, 0.5H), 4.62–4.57(m ,0.5H),3.81–3.74(m,1H),3.50–3.39(m,2H),3.19–2.61(m,4H),2.62–2.17(m,5H),1.24–1.13(m,1H), 0.65–0.53 (m, 1H), 0.53–0.35 (m, 2H), 0.35–0.25 (m, 1H).
实施例39Example 39
合成(5S)-5-环丙基-5-(3-氧代-3-(7-(三氟甲基)-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)丙基咪唑啉-2,4-二酮Synthesis of (5S)-5-cyclopropyl-5-(3-oxo-3-(7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a] ]Indol-2(1H)-yl)propylimidazoline-2,4-dione
Figure PCTCN2021105088-appb-000189
Figure PCTCN2021105088-appb-000189
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(2-甲酰基-5-(三氟甲基)苯基)哌嗪-1-羧酸叔丁酯Step A: Synthesis of tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000190
Figure PCTCN2021105088-appb-000190
室温下，向含有2-氟-4-三氟甲基-苯甲醛(2.00克，10.41毫摩尔)的二甲基亚砜(10.0毫升)中加入N-叔丁氧羰基哌嗪(1.94克，10.41毫摩尔)和碳酸钾(1.73克，12.49毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2-fluoro-4-trifluoromethyl-benzaldehyde (2.00 g, 10.41 mmol) in dimethyl sulfoxide (10.0 mL) was added N-tert-butoxycarbonylpiperazine (1.94 g, 10.41 mmol) and potassium carbonate (1.73 g, 12.49 mmol), under N 2, at 95 ° C for 12 hours.
反应结束，加乙酸乙酯(50毫升)和水(50毫升)稀释，分液，收集有机相，有机相先用饱和食盐水(3毫升×2次)洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到1.30克米黄色固体4-(2-甲酰基-5-(三氟甲基)苯基)哌嗪-1-羧酸叔丁酯(收率：34.9％)。LCMS:RT＝2.18min,[M+H] +＝359.24。 After the reaction was completed, ethyl acetate (50 mL) and water (50 mL) were added to dilute, the layers were separated, and the organic phase was collected. The organic phase was washed with saturated brine (3 mL × 2 times), dried over anhydrous sodium sulfate, and reduced under reduced pressure. concentrate. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 1.30 g of tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate was obtained as a beige solid (yield: 34.9%). LCMS: RT=2.18 min, [M+H] + =359.24.
步骤B：合成(E)-4-(2-((2-甲苯磺酰肼基)甲基)-5-(三氟甲基)苯基)哌嗪-1-甲酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(2-((2-toluenesulfonylhydrazide)methyl)-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000191
Figure PCTCN2021105088-appb-000191
室温下，将4-(2-甲酰基-5-(三氟甲基)苯基)哌嗪-1-羧酸叔丁酯(1.30克，3.63毫摩尔)和4-甲基苯磺酰肼(709.4毫克，3.81毫摩尔)加入无水乙醇(12毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate (1.30 g, 3.63 mmol) and 4-methylbenzenesulfonylhydrazide were combined (709.4 mg, 3.81 mmol) was added dry ethanol (12 ml), under N 2, at room temperature for 1 hour.
反应结束，蒸干溶剂得到1.91克米黄色固体(E)-4-(2-((2-甲苯磺酰肼基)甲基)-5-(三氟甲基)苯基)哌嗪-1-甲酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.21min,[M+H] +＝527.25。 After the reaction was completed, the solvent was evaporated to dryness to obtain 1.91 g of beige solid (E)-4-(2-((2-toluenesulfonylhydrazide)methyl)-5-(trifluoromethyl)phenyl)piperazine-1 - tert-butyl formate. It was directly used in the next reaction without purification. LCMS: RT=2.21 min, [M+H] + =527.25.
步骤C：合成7-(三氟甲基)-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step C: Synthesis of tert-butyl 7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate
Figure PCTCN2021105088-appb-000192
Figure PCTCN2021105088-appb-000192
室温下，向含有(E)-4-(2-((2-甲苯磺酰肼基)甲基)-5-(三氟甲基)苯基)哌嗪-1-甲酸叔丁酯(1.91克，3.63毫摩尔)的甲苯(15毫升)中，分批加入氢化钠(145.1毫克，3.63毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。Add (E)-4-(2-((2-toluenesulfonylhydrazide)methyl)-5-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (1.91 g, 3.63 mmol) in toluene (15 mL), sodium hydride (145.1 mg, 3.63 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)和水(50毫升)稀释，分液，收集有机相，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到710.2毫克米黄色固体7-(三氟甲基)-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：57.2％)。LCMS:RT＝2.25min,[M+H] +＝343.19。 After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The organic phase was collected and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 710.2 mg of tert-butyl 7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a beige solid (received rate: 57.2%). LCMS: RT=2.25 min, [M+H] + =343.19.
步骤D：合成7-(三氟甲基)-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 7-(trifluoromethyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000193
Figure PCTCN2021105088-appb-000193
室温下，将7-(三氟甲基)-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(710.2毫克，2.07毫摩尔)加入甲醇(8毫升)中，滴加盐酸的二氧六环溶液(2.1毫升，4.0摩尔每升)，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate (710.2 mg, 2.07 mmol) was added to methanol (8 mL), a solution of hydrochloric acid in dioxane (2.1 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 1 hour under the protection of N 2 .
反应结束，蒸干溶剂得到410.0毫克米黄色固体7-(三氟甲基)-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.59min,[M+H] +＝243.17。 After the reaction was completed, the solvent was evaporated to dryness to obtain 410.0 mg of beige solid 7-(trifluoromethyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride . It was directly used in the next reaction without purification. LCMS: RT=1.59 min, [M+H] + =243.17.
步骤E：合成(5S)-5-环丙基-5-(3-氧代-3-(7-(三氟甲基)-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)丙基咪唑啉-2,4-二酮Step E: Synthesis of (5S)-5-cyclopropyl-5-(3-oxo-3-(7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1, 2-a]Indol-2(1H)-yl)propylimidazoline-2,4-dione
Figure PCTCN2021105088-appb-000194
Figure PCTCN2021105088-appb-000194
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(167.5毫克，0.79毫摩尔)和7-(三氟甲基)-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(200.0毫克，0.72毫摩尔)加入N,N-二甲基甲酰胺(10毫升)中，滴加N,N-二异丙基乙胺(278.3毫克)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(165.1毫克，0.86毫摩尔)和1-羟基苯并三唑(14.6毫克，0.11毫摩尔)，N 2保护下，室温反应过夜。 (S)-3-(4-Cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (167.5 mg, 0.79 mmol) and 7-(trifluoromethyl) -1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indole hydrochloride (200.0 mg, 0.72 mmol) was added to N,N-dimethylformamide (10 ml), N,N-diisopropylethylamine (278.3 mg) was added dropwise, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (165.1 mg) , 0.86 mmol) and 1-hydroxybenzotriazole (14.6 mg, 0.11 mmol), under N 2 protection, were reacted at room temperature overnight.
反应结束，加水(50毫升)和乙酸乙酯(50毫升)稀释，分液，收集有机相，饱和食盐水(3毫升×2次)洗涤，无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到150.0毫克白色固体(5S)-5-环丙基-5-(3-氧代-3-(7-(三氟甲基)-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)丙基咪唑啉-2,4-二酮(收率：47.9％)。LCMS:RT＝1.89min,[M+H] +＝437.23。 1H NMR(500MHz,DMSO-d 6)δ(ppm):10.60(s,1H),7.70(d,J＝8.0Hz,1H),7.23(dd,J＝7.0,4.0Hz,1H),6.89(d,J＝7.5Hz,1H),6.80(d,J＝7.0Hz,1H),4.52–4.34(m,1H),3.92–3.85(m,1H),3.76–3.72(m,1H),3.65–3.52(m,1H),3.49–3.36(m,1H),3.18–3.00(m,2H),2.95–2.75(m,1H),2.71–2.59(m,2H),2.48–2.20(m,2H),2.03–1.88(m,2H),1.14–1.06(m,1H),0.49–0.41(m,1H),0.40–0.28(m,2H),0.15–0.06(m,1H)。 After the reaction was completed, water (50 mL) and ethyl acetate (50 mL) were added to dilute, the layers were separated, the organic phase was collected, washed with saturated brine (3 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 150.0 mg of white solid (5S)-5-cyclopropyl-5-(3-oxo-3-(7-(trifluoromethyl)-3,4,10,10a-tetrahydropyrazino[1] was obtained ,2-a]Indol-2(1H)-yl)propylimidazoline-2,4-dione (yield: 47.9%). LCMS: RT=1.89 min, [M+H] + =437.23. 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm): 10.60 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.23 (dd, J=7.0, 4.0 Hz, 1H), 6.89 (d, J=7.5Hz, 1H), 6.80 (d, J=7.0Hz, 1H), 4.52–4.34 (m, 1H), 3.92–3.85 (m, 1H), 3.76–3.72 (m, 1H), 3.65–3.52 (m, 1H), 3.49–3.36 (m, 1H), 3.18–3.00 (m, 2H), 2.95–2.75 (m, 1H), 2.71–2.59 (m, 2H), 2.48–2.20 (m , 2H), 2.03–1.88 (m, 2H), 1.14–1.06 (m, 1H), 0.49–0.41 (m, 1H), 0.40–0.28 (m, 2H), 0.15–0.06 (m, 1H).
实施例40Example 40
合成(5S)-5-环丙基-5-(3-氧代-3-(5a,6,8,9-四氢吡啶并[3',2',4,5]吡咯并[1,2-a]吡嗪-7(5H)-基)丙基)咪唑烷-2,4-二酮Synthesis of (5S)-5-cyclopropyl-5-(3-oxo-3-(5a,6,8,9-tetrahydropyrido[3',2',4,5]pyrrolo[1, 2-a]pyrazin-7(5H)-yl)propyl)imidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000195
Figure PCTCN2021105088-appb-000195
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(3-甲酰基吡啶-2-基)哌嗪-1-甲酸叔丁酯Step A: Synthesis of tert-butyl 4-(3-formylpyridin-2-yl)piperazine-1-carboxylate
Figure PCTCN2021105088-appb-000196
Figure PCTCN2021105088-appb-000196
室温下，向含有2-氟烟碱(3.00克，24.0毫摩尔)的二甲基亚砜(30毫升)中加入N-叔丁氧羰基哌嗪(4.34克，24.0毫摩尔)和碳酸钾(4.96克，36.0毫摩尔)，N 2保护下，95摄氏度反应12小时。 To 2-fluoronicotine (3.00 g, 24.0 mmol) in dimethyl sulfoxide (30 mL) was added N-tert-butoxycarbonylpiperazine (4.34 g, 24.0 mmol) and potassium carbonate ( under 4.96 g, 36.0 mmol), N 2 protection for 12 h at 95 ° C.
反应结束，加水淬灭，混合液用乙酸乙酯(50毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/3)。得到5.50克淡黄色固体4-(3-甲酰基吡啶-2-基)哌嗪-1-甲酸叔丁酯(收率：78.8％)。LCMS:RT＝2.16min,[M+H] +＝292.27。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). 5.50 g of tert-butyl 4-(3-formylpyridin-2-yl)piperazine-1-carboxylate was obtained as a pale yellow solid (yield: 78.8%). LCMS: RT=2.16 min, [M+H] + =292.27.
步骤B：合成(E)-4-(3-((2-甲苯磺酰基亚苄基)甲基)吡啶-2-基哌嗪-1-甲酸叔丁酯Step B: Synthesis of (E)-tert-butyl 4-(3-((2-toluenesulfonylbenzylidene)methyl)pyridin-2-ylpiperazine-1-carboxylate
Figure PCTCN2021105088-appb-000197
Figure PCTCN2021105088-appb-000197
室温下，将4-(3-甲酰基吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.00克，3.43毫摩尔)和4-甲基苯磺酰肼(706毫克，3.78毫摩尔)加入无水乙醇(20.0毫升)中，N 2保护下，室温反应1小时。 At room temperature, tert-butyl 4-(3-formylpyridin-2-yl)piperazine-1-carboxylate (1.00 g, 3.43 mmol) and 4-methylbenzenesulfonylhydrazide (706 mg, 3.78 mmol) were combined ) was added to absolute ethanol (20.0 mL), and the reaction was carried out at room temperature for 1 hour under the protection of N 2 .
反应结束，蒸干溶剂得到1.36克类白色固体(E)-4-(3-((2-甲苯磺酰基亚苄基)甲基)吡啶-2-基哌嗪-1-甲酸叔丁酯。无需纯化，直接用于下一步反应。LCMS:RT＝2.21min,[M+H] +＝460.23。、 After the reaction was completed, the solvent was evaporated to dryness to obtain 1.36 g of off-white solid (E)-4-(3-((2-toluenesulfonylbenzylidene)methyl)pyridin-2-ylpiperazine-1-carboxylic acid tert-butyl ester. Without purification, it was directly used in the next reaction. LCMS: RT=2.21min, [M+H] + =460.23.,
步骤C：合成5a,6,8,9-四氢吡啶并[3',2',4,5]吡咯并[1,2-a]吡嗪-7(5H)-甲酸叔丁酯Step C: Synthesis of 5a,6,8,9-tetrahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine-7(5H)-carboxylic acid tert-butyl ester
Figure PCTCN2021105088-appb-000198
Figure PCTCN2021105088-appb-000198
室温下，向含有(E)-4-(3-((2-甲苯磺酰基亚苄基)甲基)吡啶-2-基哌嗪-1-甲酸叔丁酯(1.36克，2.96毫摩尔)的甲苯(15.0毫升)中，分批加入氢化钠(142.1毫克，3.45毫摩尔，60％分散于石蜡油)，置换氮气20分钟，135摄氏度反应2小时。To the mixture containing (E)-tert-butyl 4-(3-((2-toluenesulfonylbenzylidene)methyl)pyridin-2-ylpiperazine-1-carboxylate (1.36 g, 2.96 mmol) at room temperature In the toluene (15.0 mL) of 100%, sodium hydride (142.1 mg, 3.45 mmol, 60% dispersed in paraffin oil) was added in portions, nitrogen was replaced for 20 minutes, and the reaction was performed at 135 degrees Celsius for 2 hours.
反应结束，冷却至室温，乙酸乙酯(50毫升)溶解，先用饱和食盐水(50毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到600.0毫克淡黄色固体5a,6,8,9-四氢吡啶并[3',2',4,5]吡咯并[1,2-a]吡嗪-7(5H)-甲酸叔丁酯(收率：73.2％)。LCMS:RT＝2.23min,[M+H] +＝276.35。 The reaction was completed, cooled to room temperature, dissolved in ethyl acetate (50 mL), washed with saturated brine (50 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 600.0 mg of 5a,6,8,9-tetrahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine-7(5H)-carboxylic acid tert-butyl ester was obtained as a pale yellow solid (Yield: 73.2%). LCMS: RT=2.23 min, [M+H] + =276.35.
步骤D：合成5,5a,6,7,8,9-六氢吡啶并[3',2',4,5]吡咯并[1,2-a]吡嗪盐酸盐Step D: Synthesis of 5,5a,6,7,8,9-hexahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine hydrochloride
Figure PCTCN2021105088-appb-000199
Figure PCTCN2021105088-appb-000199
室温下，将5a,6,8,9-四氢吡啶并[3',2',4,5]吡咯并[1,2-a]吡嗪-7(5H)-甲酸叔丁酯(600.0毫克，2.17毫摩尔)加入甲醇(6.0毫升)中，滴加盐酸的二氧六环溶液(2.71毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, 5a,6,8,9-tetrahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine-7(5H)-carboxylic acid tert-butyl ester (600.0 mg, 2.17 mmol) was added to methanol (6.0 mL), a solution of hydrochloric acid in dioxane (2.71 mL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到430.0毫克类白色固体5,5a,6,7,8,9-六氢吡啶并[3',2',4,5]吡咯并[1,2-a]吡嗪盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.49min,[M+H] +＝176.23。 After the reaction was completed, the solvent was evaporated to dryness to obtain 430.0 mg of off-white solid 5,5a,6,7,8,9-hexahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine Hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.49 min, [M+H] + =176.23.
步骤E：合成(5S)-5-环丙基-5-(3-氧代-3-(5a,6,8,9-四氢吡啶并[3',2',4,5]吡咯并[1,2-a]吡嗪-7(5H)-基)丙基)咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-cyclopropyl-5-(3-oxo-3-(5a,6,8,9-tetrahydropyrido[3',2',4,5]pyrrolo [1,2-a]pyrazin-7(5H)-yl)propyl)imidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000200
Figure PCTCN2021105088-appb-000200
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和5,5a,6,7,8,9-六氢吡啶并[3',2',4,5]吡咯并[1,2-a]吡嗪盐酸盐(45.7毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (50.0 mg, 0.24 mmol) and 5,5a,6,7, 8,9-Hexahydropyrido[3',2',4,5]pyrrolo[1,2-a]pyrazine hydrochloride (45.7 mg, 0.26 mmol) was added to N,N-dimethylmethane amide (2.0 ml), N,N-diisopropylethylamine (156.0 μl) was added dropwise, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到28.0毫克白色固体(5S)-5-环丙基-5-(3-氧代-3-(5a,6,8,9-四氢吡啶并[3',2',4,5]吡咯并[1,2-a]吡嗪-7(5H)-基)丙基)咪唑烷-2,4-二酮(收率：31.5％)。LCMS:RT＝1.83min,[M+H] +＝370.10。 1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),7.77(d,J＝4.8Hz,1H),7.68(s,1H),7.29(d,J＝6.8Hz,1H),6.47(dd,J＝6.9,5.3Hz,1H),4.50–4.33(m,1H),4.01–3.92(m,1H),3.86–3.74(m,1H),3.74–3.50(m,1H),3.09–2.77(m,3H),2.66–2.20(m,4H),1.98–1.88(m,2H), 1.14–1.06(m,1H),0.49–0.41(m,1H),0.40–0.28(m,2H),0.14–0.06(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 28.0 mg of white solid (5S)-5-cyclopropyl-5-(3-oxo-3-(5a,6,8,9-tetrahydropyrido[3',2',4,5]pyrrole was obtained [1,2-a]pyrazin-7(5H)-yl)propyl)imidazolidine-2,4-dione (yield: 31.5%). LCMS: RT=1.83 min, [M+H] + =370.10. 1 H NMR (500MHz, DMSO-d6)δ10.59(s,1H),7.77(d,J=4.8Hz,1H),7.68(s,1H),7.29(d,J=6.8Hz,1H), 6.47(dd,J=6.9,5.3Hz,1H), 4.50-4.33(m,1H), 4.01-3.92(m,1H), 3.86-3.74(m,1H), 3.74-3.50(m,1H), 3.09–2.77(m,3H), 2.66–2.20(m,4H), 1.98–1.88(m,2H), 1.14–1.06(m,1H), 0.49–0.41(m,1H), 0.40–0.28(m , 2H), 0.14–0.06 (m, 1H).
实施例41Example 41
合成(5S)-5-(3-(6,7-二氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(6,7-dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000201
Figure PCTCN2021105088-appb-000201
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成6,7-二氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚三氟乙酸盐Step A: Synthesis of 6,7-dichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate
Figure PCTCN2021105088-appb-000202
Figure PCTCN2021105088-appb-000202
室温下，将7-氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(241.7毫克，0.92毫摩尔)和N-氯代丁二酰亚胺(122.85毫克，0.92毫摩尔)加入二氯乙烷(3.0毫升)中，滴加三氟甲磺酸(161.7微升)，N 2保护下，75摄氏度反应过夜。 7-Chloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (241.7 mg, 0.92 mmol) and N- chlorosuccinimide (122.85 mg, 0.92 mmol) was added dichloroethane (3.0 ml) was added dropwise trifluoromethanesulfonic acid (161.7 [mu] l), under N 2, overnight at 75 ° C the reaction .
反应结束，冷却至室温，乙酸乙酯稀释，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的三氟乙酸)和乙腈；流速：20毫升/分钟；梯度：由30％乙腈在14.50分钟洗脱出来；检测波长：254nm。纯化后，冻干得40.0毫克白色固体6,7-二氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚三氟乙酸盐(收率：11.6％)。LCMS:RT＝1.66min,[M+H] +＝261.11。 1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.83(s,1H),6.96(d,J＝8.0Hz,1H),4.82(dd,J＝14.1,3.6Hz,1H),3.88(qd,J＝8.8,2.9Hz,1H),3.34–3.22(m,3H),3.13(ddd,J＝15.0,11.9,4.7Hz,2H),3.03(ddd,J＝15.9,8.0,4.7Hz,1H),2.66(dd,J＝15.8,8.7Hz,1H)。 The reaction was completed, cooled to room temperature, diluted with ethyl acetate, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, and the organic phase was first washed with saturated brine (20 mL × 2 times). , then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. Separation conditions were as follows, column: Agilent 5 Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: wash with 30% acetonitrile at 14.50 minutes come out; detection wavelength: 254nm. After purification, lyophilization gave 40.0 mg of 6,7-dichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoletrifluoroethyl as a white solid acid salt (yield: 11.6%). LCMS: RT=1.66 min, [M+H] + =261.11. 1 H NMR(400MHz, DMSO-d6)δ9.01(s,1H),8.83(s,1H),6.96(d,J=8.0Hz,1H),4.82(dd,J=14.1,3.6Hz,1H) ), 3.88 (qd, J=8.8, 2.9Hz, 1H), 3.34–3.22 (m, 3H), 3.13 (ddd, J=15.0, 11.9, 4.7Hz, 2H), 3.03 (ddd, J=15.9, 8.0 , 4.7Hz, 1H), 2.66 (dd, J=15.8, 8.7Hz, 1H).
步骤B：合成(5S)-5-(3-(6,7-二氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step B: Synthesis of (5S)-5-(3-(6,7-dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2( 1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000203
Figure PCTCN2021105088-appb-000203
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(22.6毫克，0.11毫摩尔)和6,7-氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚三氟乙酸盐(40.0毫克，0.11毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(72.7微升)，然后依次加入1-乙基-(3-二甲基氨基丙基) 碳酰二亚胺盐酸盐(23.0毫克，0.12毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (22.6 mg, 0.11 mmol) and 6,7-chloro-9- Fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate (40.0 mg, 0.11 mmol) was added with N,N-dimethylmethane amide (2.0 ml), N,N-diisopropylethylamine (72.7 μl) was added dropwise, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (23.0 mg, 0.12 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到10.5毫克白色固体(5S)-5-(3-(6,7-二氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：21.0％)。LCMS:RT＝1.97min,[M+H] +＝455.21。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 10.5 mg of white solid (5S)-5-(3-(6,7-dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2 was obtained) (1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 21.0%). LCMS: RT=1.97 min, [M+H] + =455.21.
实施例42Example 42
合成(5S)-5-(3-(7,8-二氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(7,8-Dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)- yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000204
Figure PCTCN2021105088-appb-000204
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成7,8-二氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚三氟乙酸盐Step A: Synthesis of 7,8-dichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate
Figure PCTCN2021105088-appb-000205
Figure PCTCN2021105088-appb-000205
室温下，将7-氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(241.7毫克，0.92毫摩尔)和N-氯代丁二酰亚胺(122.85毫克，0.92毫摩尔)加入二氯乙烷(3.0毫升)中，滴加三氟甲磺酸(161.7微升)，N 2保护下，75摄氏度反应过夜。 7-Chloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (241.7 mg, 0.92 mmol) and N- chlorosuccinimide (122.85 mg, 0.92 mmol) was added dichloroethane (3.0 ml) was added dropwise trifluoromethanesulfonic acid (161.7 [mu] l), under N 2, overnight at 75 ° C the reaction .
反应结束，冷却至室温，乙酸乙酯稀释，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的三氟乙酸)和乙腈；流速：20毫升/分钟；梯度：由30％乙腈在15.50分钟洗脱出来；检测波长：254nm。纯化后，冻干得40.0毫克白色固体7,8-二氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚三氟乙酸盐(收率：11.6％)。LCMS:RT＝1.66min,[M+H] +＝261.12。 1H NMR(400MHz,DMSO-d6)δ8.98(s,2H),6.83(s,1H),3.93(ddd,J＝16.6,9.9,3.3Hz,1H),3.30–3.20(m,2H),3.20–3.12(m,2H),2.93(dt,J＝17.5,8.0Hz,2H),2.75(dd,J＝16.0,6.0Hz,1H)。 The reaction was completed, cooled to room temperature, diluted with ethyl acetate, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, and the organic phase was first washed with saturated brine (20 mL × 2 times). , then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. Separation conditions were as follows, column: Agilent 5 Prep-C18 100mm×30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: wash with 30% acetonitrile at 15.50 min come out; detection wavelength: 254nm. After purification, lyophilization gave 40.0 mg of 7,8-dichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoletrifluoroethyl as a white solid acid salt (yield: 11.6%). LCMS: RT=1.66 min, [M+H] + =261.12. 1 H NMR (400MHz, DMSO-d6)δ8.98(s,2H),6.83(s,1H),3.93(ddd,J=16.6,9.9,3.3Hz,1H),3.30-3.20(m,2H) , 3.20–3.12 (m, 2H), 2.93 (dt, J=17.5, 8.0 Hz, 2H), 2.75 (dd, J=16.0, 6.0 Hz, 1H).
步骤B：合成(5S)-5-(3-(7,8-二氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step B: Synthesis of (5S)-5-(3-(7,8-Dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2( 1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000206
Figure PCTCN2021105088-appb-000206
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(22.6毫克，0.11毫摩尔)和6,7-氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚三氟乙酸盐(40.0毫克，0.11毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(72.7微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(23.0毫克，0.12毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (22.6 mg, 0.11 mmol) and 6,7-chloro-9- Fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate (40.0 mg, 0.11 mmol) was added with N,N-dimethylmethane amide (2.0 mL), N,N-diisopropylethylamine (72.7 μL) was added dropwise, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (23.0 mg, 0.12 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到8.5毫克白色固体(5S)-5-(3-(7,8-二氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：17.0％)。LCMS:RT＝1.97min,[M+H] +＝455.21。 1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),7.68(d,J＝5.5Hz,1H),6.75(d,J＝7.0Hz,1H),4.39(dd,J＝43.6,11.3Hz,1H),3.87–3.51(m,3H),3.16–2.77(m,3H),2.74–2.54(m,2H),2.48–2.15(m,2H),2.04–1.81(m,2H),1.17–1.03(m,1H),0.53–0.41(m,1H),0.41–0.26(m,2H),0.19–0.05(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 8.5 mg of white solid (5S)-5-(3-(7,8-dichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2 was obtained) (1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 17.0%). LCMS: RT=1.97 min, [M+H] + =455.21. 1 H NMR (400MHz, DMSO-d6) δ 10.59 (s, 1H), 7.68 (d, J=5.5Hz, 1H), 6.75 (d, J=7.0Hz, 1H), 4.39 (dd, J=43.6 ,11.3Hz,1H),3.87–3.51(m,3H),3.16–2.77(m,3H),2.74–2.54(m,2H),2.48–2.15(m,2H),2.04–1.81(m,2H ), 1.17–1.03 (m, 1H), 0.53–0.41 (m, 1H), 0.41–0.26 (m, 2H), 0.19–0.05 (m, 1H).
实施例43Example 43
合成(5S)-5-(3-(6,7,8-三氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(6,7,8-Trichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H )-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000207
Figure PCTCN2021105088-appb-000207
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成6,7,8-三氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚三氟乙酸盐Step A: Synthesis of 6,7,8-Trichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate
Figure PCTCN2021105088-appb-000208
Figure PCTCN2021105088-appb-000208
室温下，将7-氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(241.7毫克，0.92毫摩尔)和N-氯代丁二酰亚胺(122.85毫克，0.92毫摩尔)加入二氯乙烷(3.0毫升)中，滴加三氟甲磺酸(161.7微升)，N 2保护下，75摄氏度反应过夜。 7-Chloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (241.7 mg, 0.92 mmol) and N- chlorosuccinimide (122.85 mg, 0.92 mmol) was added dichloroethane (3.0 ml) was added dropwise trifluoromethanesulfonic acid (161.7 [mu] l), under N 2, overnight at 75 ° C the reaction .
反应结束，冷却至室温，乙酸乙酯稀释，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。粗产品用制备型高效液相色谱纯化。分离条件如下，色谱柱：Agilent 5 Prep-C18 100mm×30mm 5μM；流动相：水(含有0.1％的三氟乙酸)和乙腈；流速：20毫升/分钟；梯度：由30％乙腈在17.50分钟洗脱出来；检测波长：254nm。纯化后，冻干得40.0毫克白色固体6,7,8-三氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚三氟乙酸盐(收率：14.7％)。LCMS:RT＝1.66min,[M+H] +＝295.09。 The reaction was completed, cooled to room temperature, diluted with ethyl acetate, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, and the organic phase was first washed with saturated brine (20 mL × 2 times). , then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. Separation conditions are as follows, column: Agilent 5 Prep-C18 100mm x 30mm 5μM; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 20 ml/min; gradient: wash with 30% acetonitrile at 17.50 minutes come out; detection wavelength: 254nm. After purification, lyophilization gave 40.0 mg of 6,7,8-trichloro-9-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole tris as a white solid Fluoroacetate (yield: 14.7%). LCMS: RT=1.66 min, [M+H] + =295.09.
步骤B：合成(5S)-5-(3-(6,7,8-三氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step B: Synthesis of (5S)-5-(3-(6,7,8-Trichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole- 2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000209
Figure PCTCN2021105088-appb-000209
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(20.8毫克，0.10毫摩尔)和6,7,8-三氯-9-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚三氟乙酸盐(40.0毫克，0.10毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(65.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(21.1毫克，0.11毫摩尔)和1-羟基苯并三唑(3.0毫克，0.02毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (20.8 mg, 0.10 mmol) and 6,7,8-trichloro -9-Fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole trifluoroacetate (40.0 mg, 0.10 mmol) was added to N,N-difluoroacetate N,N-diisopropylethylamine (65.0 μl) was added dropwise to methylformamide (2.0 ml), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide amine hydrochloride (21.1 mg, 0.11 mmol) and 1-hydroxybenzotriazole (3.0 mg, 0.02 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到5.6毫克白色固体(5S)-5-(3-(6,7,8-三氯-9-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：11.4％)。LCMS:RT＝2.02min,[M+H] +＝489.13。 1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),7.68(s,1H),4.61(d,J＝12.1Hz,1H),4.41(dd,J＝62.5,12.1Hz,1H),3.96–3.55(m,2H),3.23–2.62(m,5H),2.47–2.17(m,2H),2.03–1.86(m,2H),1.14–1.04(m,1H),0.52–0.41(m,1H),0.41–0.25(m,2H),0.18–0.04(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 5.6 mg of (5S)-5-(3-(6,7,8-trichloro-9-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole) were obtained as a white solid -2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 11.4%). LCMS: RT=2.02 min, [M+H] + =489.13. 1 H NMR (400MHz, DMSO-d6)δ10.60(s,1H),7.68(s,1H),4.61(d,J=12.1Hz,1H),4.41(dd,J=62.5,12.1Hz,1H) ), 3.96–3.55 (m, 2H), 3.23–2.62 (m, 5H), 2.47–2.17 (m, 2H), 2.03–1.86 (m, 2H), 1.14–1.04 (m, 1H), 0.52–0.41 (m, 1H), 0.41–0.25 (m, 2H), 0.18–0.04 (m, 1H).
实施例44Example 44
合成(S)-5-环丙基-5-(3-氧代-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙基)咪唑烷-2,4-二酮Synthesis of (S)-5-cyclopropyl-5-(3-oxo-3-(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl )propyl)imidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000210
Figure PCTCN2021105088-appb-000210
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成(S)-5-环丙基-5-(3-氧代-3-(1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)丙基)咪唑烷-2,4-二酮Step A: Synthesis of (S)-5-cyclopropyl-5-(3-oxo-3-(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole- 2-yl)propyl)imidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000211
Figure PCTCN2021105088-appb-000211
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚(45.0毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(111.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 2,3,4,9- Tetrahydro-1H-pyrido[3,4-b]indole (45.0 mg, 0.26 mmol) was added to N,N-dimethylformamide (2.0 mL) and N,N-diisopropyl was added dropwise Ethylamine (111.0 μl) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) followed by 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到40.0毫克白色固体(S)-5-环丙基-5-(3-氧代-3-(1,3,4,9-四氢 -2H-吡啶并[3,4-b]吲哚-2-基)丙基)咪唑烷-2,4-二酮(收率：45.5％)。LCMS:RT＝1.77min,[M+H] +＝367.23。 1H NMR(500MHz,DMSO-d6)δ10.83(s,1H),10.61(s,1H),7.72(d,J＝19.3Hz,1H),7.39(d,J＝7.7Hz,1H),7.29(d,J＝8.0Hz,1H),7.07–6.99(m,1H),6.99–6.91(m,1H),4.66(d,J＝8.9Hz,2H),3.85–3.67(m,2H),2.79–2.60(m,2H),2.57–2.30(m,2H),2.04–1.91(m,2H),1.17–1.04(m,1H),0.50–0.41(m,1H),0.41–0.26(m,2H),0.14–0.05(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 40.0 mg of white solid (S)-5-cyclopropyl-5-(3-oxo-3-(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole was obtained) -2-yl)propyl)imidazolidine-2,4-dione (yield: 45.5%). LCMS: RT=1.77 min, [M+H] + =367.23. 1 H NMR(500MHz,DMSO-d6)δ10.83(s,1H),10.61(s,1H),7.72(d,J=19.3Hz,1H),7.39(d,J=7.7Hz,1H), 7.29(d,J＝8.0Hz,1H),7.07-6.99(m,1H),6.99-6.91(m,1H),4.66(d,J＝8.9Hz,2H),3.85-3.67(m,2H) ,2.79–2.60(m,2H),2.57–2.30(m,2H),2.04–1.91(m,2H),1.17–1.04(m,1H),0.50–0.41(m,1H),0.41–0.26( m, 2H), 0.14–0.05 (m, 1H).
实施例45Example 45
合成(S)-5-(3-(6-氯-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (S)-5-(3-(6-Chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3-oxopropyl )-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000212
Figure PCTCN2021105088-appb-000212
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成6-氯-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚乙酸盐Step A: Synthesis of 6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole acetate
Figure PCTCN2021105088-appb-000213
Figure PCTCN2021105088-appb-000213
室温下，向含有2-(5-氯-1H-吲哚-3-基)乙-1-胺(1.00克，4.33毫摩尔)的醋酸(10.0毫升)和甲醇(1.0毫升)的混合溶液中，加入多聚甲醛(156.0毫克，5.20毫摩尔)，N 2保护下，80摄氏度反应3.5小时。 To a mixed solution of 2-(5-chloro-1H-indol-3-yl)ethan-1-amine (1.00 g, 4.33 mmol) in acetic acid (10.0 mL) and methanol (1.0 mL) at room temperature , adding paraformaldehyde (156.0 mg, 5.20 mmol), under the protection of N 2 , the reaction was carried out at 80 degrees Celsius for 3.5 hours.
反应结束，冷却至室温，抽滤，滤饼用少量醋酸洗涤，干燥得500.0毫克白色固体6-氯-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚乙酸盐(收率：43.3％)。LCMS:RT＝1.58min,[M+H] +＝207.13。 The reaction was completed, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of acetic acid, and dried to obtain 500.0 mg of white solid 6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indone doxyacetate (yield: 43.3%). LCMS: RT=1.58 min, [M+H] + =207.13.
步骤B：合成(S)-5-(3-(6-氯-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step B: Synthesis of (S)-5-(3-(6-Chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3- Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000214
Figure PCTCN2021105088-appb-000214
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和6-氯-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚乙酸盐(69.1毫克，0.26毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(50.0毫克，0.26毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 6-chloro-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indole acetate (69.1 mg, 0.26 mmol) was added to N,N-dimethylformamide (2.0 mL) and N , N-diisopropylethylamine (156.0 μl), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到53.4毫克白色固体(S)-5-(3-(6-氯-1,3,4,9-四氢-2H-吡啶并 [3,4-b]吲哚-2-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：55.5％)。LCMS:RT＝1.86min,[M+H] +＝401.17。 1H NMR(500MHz,DMSO-d6)δ11.11–11.03(m,1H),10.62(s,1H),7.72(d,J＝23.0Hz,1H),7.47–7.40(m,1H),7.32(dd,J＝8.5,3.0Hz,1H),7.07–7.00(m,1H),4.66(d,J＝7.1Hz,2H),3.76(dt,J＝39.6,5.6Hz,2H),2.70(d,J＝51.9Hz,2H),2.57–2.46(m,1H),2.43–2.31(m,1H),2.04–1.91(m,2H),1.15–1.06(m,1H),0.50–0.41(m,1H),0.41–0.27(m,2H),0.15–0.07(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 53.4 mg of white solid (S)-5-(3-(6-chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3 was obtained -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 55.5%). LCMS: RT=1.86 min, [M+H] + =401.17. 1 H NMR (500MHz, DMSO-d6)δ11.11-11.03(m,1H),10.62(s,1H),7.72(d,J=23.0Hz,1H),7.47-7.40(m,1H),7.32 (dd, J=8.5, 3.0Hz, 1H), 7.07–7.00 (m, 1H), 4.66 (d, J=7.1Hz, 2H), 3.76 (dt, J=39.6, 5.6Hz, 2H), 2.70 ( d, J=51.9Hz, 2H), 2.57–2.46 (m, 1H), 2.43–2.31 (m, 1H), 2.04–1.91 (m, 2H), 1.15–1.06 (m, 1H), 0.50–0.41 ( m, 1H), 0.41–0.27 (m, 2H), 0.15–0.07 (m, 1H).
实施例46Example 46
合成(S)-5-(3-(7-氯-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (S)-5-(3-(7-Chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3-oxopropyl )-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000215
Figure PCTCN2021105088-appb-000215
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成2-(6-氯-1H-吲哚-3-基)乙酰胺Step A: Synthesis of 2-(6-Chloro-1H-indol-3-yl)acetamide
Figure PCTCN2021105088-appb-000216
Figure PCTCN2021105088-appb-000216
室温下，向含有2-(6-氯-1H-吲哚-3-基)乙酸(500.0毫克，2.39毫摩尔)的四氢呋喃(7.0毫升)中，加入N,N'-羰基二咪唑(426.5毫克，2.63毫摩尔)，N 2保护下，搅拌1.5小时后，加入氨水(10.0毫升)，室温反应过夜。 To 2-(6-chloro-1H-indol-3-yl)acetic acid (500.0 mg, 2.39 mmol) in tetrahydrofuran (7.0 mL) was added N,N'-carbonyldiimidazole (426.5 mg) at room temperature , 2.63 mmol), under N 2, after stirring for 1.5 hours, was added aqueous ammonia (10.0 ml) at room temperature overnight.
反应结束，冷却至室温，加水淬灭，混合液用乙酸乙酯(30毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(30毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到400.0毫克黄色固体2-(6-氯-1H-吲哚-3-基)乙酰胺(收率：80.2％)。LCMS:RT＝1.70min,[M+H] +＝209.15。 The reaction was completed, cooled to room temperature, quenched by adding water, the mixture was extracted with ethyl acetate (30 ml × 3 times), the organic phases were combined, the organic phase was washed with saturated brine (30 ml × 2 times), and then with anhydrous It was dried over sodium sulfate and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 400.0 mg of 2-(6-chloro-1H-indol-3-yl)acetamide were obtained as a yellow solid (yield: 80.2%). LCMS: RT=1.70 min, [M+H] + =209.15.
步骤B：合成2-(6-氯-1H-吲哚-3-基)乙-1-胺盐酸盐Step B: Synthesis of 2-(6-Chloro-1H-indol-3-yl)ethan-1-amine hydrochloride
Figure PCTCN2021105088-appb-000217
Figure PCTCN2021105088-appb-000217
室温下，向含有2-(6-氯-1H-吲哚-3-基)乙酰胺(400.0毫克，1.92毫摩尔)的四氢呋喃(2.0毫升)中，滴加氢化铝锂四氢呋喃溶液(7.7毫升，1.0摩尔每升)，N 2保护下，40摄氏度反应1小时。 To a solution of 2-(6-chloro-1H-indol-3-yl)acetamide (400.0 mg, 1.92 mmol) in tetrahydrofuran (2.0 mL) was added dropwise a solution of lithium aluminum hydride in tetrahydrofuran (7.7 mL) at room temperature , 1.0 mol per liter), under the protection of N 2 , react at 40 degrees Celsius for 1 hour.
反应结束，冷却至室温，缓慢加入饱和氢氧化钠溶液淬灭，乙酸乙酯稀释，抽滤，滤液用水(30毫升×2次)洗涤，饱和食盐水(30毫升×2次)洗涤，然后用无水硫酸钠干燥，减压浓缩得到粗品。所得残余物用乙酸乙酯(10毫升)溶解，再用盐酸乙酸乙酯溶液(1.0摩尔每升)调节pH到3，抽滤，滤饼用乙酸乙酯洗涤，干燥得到150.0毫克黄色固体2-(6-氯-1H-吲哚-3-基)乙-1-胺盐酸盐(收率：33.7％)。LCMS:RT＝1.56min,[M+H] +＝195.15。 The reaction was completed, cooled to room temperature, quenched by slowly adding saturated sodium hydroxide solution, diluted with ethyl acetate, suction filtered, the filtrate was washed with water (30 mL×2 times), washed with saturated brine (30 mL×2 times), and then washed with Dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain crude product. The obtained residue was dissolved in ethyl acetate (10 mL), adjusted to pH 3 with ethyl acetate solution of hydrochloric acid (1.0 mol/L), filtered with suction, and the filter cake was washed with ethyl acetate and dried to obtain 150.0 mg of yellow solid 2- (6-Chloro-1H-indol-3-yl)ethan-1-amine hydrochloride (yield: 33.7%). LCMS: RT=1.56 min, [M+H] + =195.15.
步骤C：合成7-氯-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚乙酸盐Step C: Synthesis of 7-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole acetate
Figure PCTCN2021105088-appb-000218
Figure PCTCN2021105088-appb-000218
室温下，向含有2-(6-氯-1H-吲哚-3-基)乙-1-胺盐酸盐(150.0毫克，0.65毫摩尔)的醋酸(1.0毫升)和甲醇(0.1毫升)的混合溶液中，加入多聚甲醛(23.3毫克，0.78毫摩尔)，N 2保护下，80摄氏度反应3.5小时。 To a solution of 2-(6-chloro-1H-indol-3-yl)ethan-1-amine hydrochloride (150.0 mg, 0.65 mmol) in acetic acid (1.0 mL) and methanol (0.1 mL) at room temperature To the mixed solution, paraformaldehyde (23.3 mg, 0.78 mmol) was added, and the reaction was carried out at 80 degrees Celsius for 3.5 hours under the protection of N 2 .
反应结束，冷却至室温，抽滤，滤饼用少量醋酸洗涤，干燥得35.0毫克白色固体7-氯-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚乙酸盐(收率：20.2％)。LCMS:RT＝1.58min,[M+H] +＝207.20。 After the reaction was completed, it was cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of acetic acid, and dried to obtain 35.0 mg of white solid 7-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Doxyacetic acid salt (yield: 20.2%). LCMS: RT=1.58 min, [M+H] + =207.20.
步骤D：合成(S)-5-(3-(7-氯-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step D: Synthesis of (S)-5-(3-(7-Chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3- Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000219
Figure PCTCN2021105088-appb-000219
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(25.3毫克，0.12毫摩尔)和7-氯-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚乙酸盐(35.0毫克，0.13毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(78.8微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(25.2毫克，0.13毫摩尔)和1-羟基苯并三唑(2.5毫克，0.01毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (25.3 mg, 0.12 mmol) and 7-chloro-2,3, 4,9-Tetrahydro-1H-pyrido[3,4-b]indole acetate (35.0 mg, 0.13 mmol) was added to N,N-dimethylformamide (2.0 mL) and N , N-diisopropylethylamine (78.8 μl), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (25.2 mg, 0.13 mmol) and 1-hydroxybenzotriazole (2.5 mg, 0.01 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到23.0毫克白色固体(S)-5-(3-(7-氯-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：47.8％)。LCMS:RT＝1.86min,[M+H] +＝401.20。 1H NMR(500MHz,DMSO)δ11.03(s,1H),10.62(s,1H),7.72(d,J＝19.2Hz,1H),7.40(d,J＝8.4Hz,1H),7.38–7.33(m,1H),6.98(dd,J＝8.4,1.9Hz,1H),4.65(d,J＝7.7Hz,2H),3.77(dt,J＝40.4,5.6Hz,2H),2.80–2.61(m,2H),2.58–2.43(m,1H),2.43–2.30(m,1H),2.03–1.91(m,2H),1.17–1.05(m,1H),0.50–0.41(m,1H),0.41–0.25(m,2H),0.16–0.05(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 23.0 mg of white solid (S)-5-(3-(7-chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3 was obtained -Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 47.8%). LCMS: RT=1.86 min, [M+H] + =401.20. 1 H NMR (500MHz, DMSO) δ 11.03(s, 1H), 10.62(s, 1H), 7.72(d, J=19.2Hz, 1H), 7.40(d, J=8.4Hz, 1H), 7.38– 7.33(m, 1H), 6.98(dd, J=8.4, 1.9Hz, 1H), 4.65(d, J=7.7Hz, 2H), 3.77(dt, J=40.4, 5.6Hz, 2H), 2.80–2.61 (m, 2H), 2.58–2.43 (m, 1H), 2.43–2.30 (m, 1H), 2.03–1.91 (m, 2H), 1.17–1.05 (m, 1H), 0.50–0.41 (m, 1H) , 0.41–0.25 (m, 2H), 0.16–0.05 (m, 1H).
实施例47Example 47
合成(S)-5-(3-(7-氯-3,4-二氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑啉-2,4-二酮Synthesis of (S)-5-(3-(7-Chloro-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl)-5 -Cyclopropylimidazoline-2,4-dione
Figure PCTCN2021105088-appb-000220
Figure PCTCN2021105088-appb-000220
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(2-(((叔丁氧基羰基)氨基)乙基)-6-氯-1H-吲哚-2-羧酸乙酯Step A: Synthesis of 1-(2-(((tert-butoxycarbonyl)amino)ethyl)-6-chloro-1H-indole-2-carboxylic acid ethyl ester
Figure PCTCN2021105088-appb-000221
Figure PCTCN2021105088-appb-000221
零摄氏度下，向含有6-氯-1H-吲哚-2-羧酸乙酯(2.00克，8.94毫摩尔)的DMF(15.0毫升)中，分批加入氢化钠(536.5毫克，13.41毫摩尔，60％分散于石蜡油),升温至室温搅拌反应0.5小时。加入(2-溴乙基)氨基甲酸叔丁酯(2.61克，11.62毫摩尔)，升温至70摄氏度搅拌12小时。To ethyl 6-chloro-1H-indole-2-carboxylate (2.00 g, 8.94 mmol) in DMF (15.0 mL) at zero degrees C was added portionwise sodium hydride (536.5 mg, 13.41 mmol, 60% dispersed in paraffin oil), warmed to room temperature and stirred for 0.5 hours. tert-butyl (2-bromoethyl)carbamate (2.61 g, 11.62 mmol) was added, and the temperature was raised to 70 degrees Celsius and stirred for 12 hours.
反应结束，冷却至室温，加入乙酸乙酯(50毫升)和水(50毫升)稀释，分液，收集有机相，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到1.60克米黄色固体1-(2-(((叔丁氧基羰基)氨基)乙基)-6-氯-1H-吲哚-2-羧酸乙酯(收率：57.2％)。LCMS:RT＝2.21min,[M-Boc+H] +＝267.19。 After the reaction was completed, it was cooled to room temperature, ethyl acetate (50 mL) and water (50 mL) were added to dilute, the layers were separated, the organic phase was collected, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 1.60 g of ethyl 1-(2-(((tert-butoxycarbonyl)amino)ethyl)-6-chloro-1H-indole-2-carboxylate was obtained as a beige solid (yield: 57.2%). LCMS : RT=2.21 min, [M-Boc+H] + =267.19.
步骤B：合成1-(2-氨基乙基)-6-氯-1H-吲哚-2-羧酸乙酯三氟乙酸盐Step B: Synthesis of 1-(2-aminoethyl)-6-chloro-1H-indole-2-carboxylate ethyl ester trifluoroacetate
Figure PCTCN2021105088-appb-000222
Figure PCTCN2021105088-appb-000222
室温下，将1-(2-(((叔丁氧基羰基)氨基)乙基)-6-氯-1H-吲哚-2-羧酸乙酯(1.60克，4.36毫摩尔)加入二氯甲烷(15毫升)中，滴加三氟乙酸(3毫升，40.39毫摩尔)，室温反应1小时。At room temperature, ethyl 1-(2-(((tert-butoxycarbonyl)amino)ethyl)-6-chloro-1H-indole-2-carboxylate (1.60 g, 4.36 mmol) was added to dichloro Trifluoroacetic acid (3 mL, 40.39 mmol) was added dropwise to methane (15 mL), and the mixture was reacted at room temperature for 1 hour.
反应结束，蒸干溶剂得到2.00克米黄色固体1-(2-氨基乙基)-6-氯-1H-吲哚-2-羧酸乙酯三氟乙酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.66min,[M+H] +＝267.18。 After the reaction was completed, the solvent was evaporated to dryness to obtain 2.00 g of beige solid 1-(2-aminoethyl)-6-chloro-1H-indole-2-carboxylic acid ethyl ester trifluoroacetate. It was directly used in the next reaction without purification. LCMS: RT=1.66 min, [M+H] + =267.18.
步骤C：合成7-氯-3,4-二氢吡嗪[1,2-a]吲哚-1(2H)-酮Step C: Synthesis of 7-chloro-3,4-dihydropyrazin[1,2-a]indol-1(2H)-one
Figure PCTCN2021105088-appb-000223
Figure PCTCN2021105088-appb-000223
室温下，向含有1-(2-氨基乙基)-6-氯-1H-吲哚-2-羧酸乙酯三氟乙酸盐(2.00克，4.16毫摩尔)的四氢呋喃(30毫升)中加入水(15毫升)和碳酸氢钠(3.49克，41.59毫摩尔)，N 2保护下，60摄氏度反应12小时。 To 1-(2-aminoethyl)-6-chloro-1H-indole-2-carboxylate ethyl ester trifluoroacetate (2.00 g, 4.16 mmol) in tetrahydrofuran (30 mL) at room temperature was added water (15 mL) and sodium bicarbonate (3.49 g, 41.59 mmol), under N 2, 60 ° C for 12 hours.
反应结束，冷却至室温，加入乙酸乙酯(50毫升)和水(50毫升)稀释，分液，收集有机相，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到900毫克黄色固体7-氯-3,4-二氢吡嗪[1,2-a]吲哚-1(2H)-酮(收率：77.7％)。LCMS:RT＝1.81min,[M+H] +＝221.15。 After the reaction was completed, it was cooled to room temperature, ethyl acetate (50 mL) and water (50 mL) were added to dilute, the layers were separated, the organic phase was collected, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 900 mg of 7-chloro-3,4-dihydropyrazin[1,2-a]indol-1(2H)-one was obtained as a yellow solid (yield: 77.7%). LCMS: RT=1.81 min, [M+H] + =221.15.
步骤D：合成7-氯-1,2,3,4-四氢吡嗪[1,2-a]吲哚Step D: Synthesis of 7-chloro-1,2,3,4-tetrahydropyrazine[1,2-a]indole
Figure PCTCN2021105088-appb-000224
Figure PCTCN2021105088-appb-000224
0摄氏度下，向7-氯-3,4-二氢吡嗪[1,2-a]吲哚-1(2H)-酮(900.0毫克，4.08毫摩尔)的四氢呋喃(23毫升)溶液中分批加入氢化铝锂(464.4毫克，12.24毫摩尔)，加完后升温至60摄氏度，N 2保护下，搅拌反应3h。 To a solution of 7-chloro-3,4-dihydropyrazin[1,2-a]indol-1(2H)-one (900.0 mg, 4.08 mmol) in tetrahydrofuran (23 mL) at 0 degrees Celsius Lithium aluminum hydride (464.4 mg, 12.24 mmol) was added in batches, and the temperature was raised to 60 degrees Celsius after the addition, and the reaction was stirred for 3 h under the protection of N 2 .
反应结束，将反应体系降温至0摄氏度，加入水(0.9毫升)，15％NaOH(aq)(2.7mL)，水(0.9mL),搅拌0.5h，硅藻土过滤，蒸干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到800.0毫克黄色固体7-氯-1,2,3,4-四氢吡嗪[1,2-a]吲哚(收率：94.9％)。LCMS:RT＝1.59min, [M+H] +＝207.15。 1H NMR(400MHz,DMSO-d 6)δ(ppm):7.47–7.43(m,2H),7.00(dd,J＝8.4,2.0Hz,1H),6.17–6.13(m,1H),5.75(s,1H),4.02(d,J＝0.4Hz,2H),3.94(t,J＝5.6Hz,2H),3.15(t,J＝5.6Hz,2H)。 After the reaction was completed, the reaction system was cooled to 0 degrees Celsius, water (0.9 mL), 15% NaOH (aq) (2.7 mL), and water (0.9 mL) were added, stirred for 0.5 h, filtered through celite, evaporated to dryness, and the residue obtained The product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 800.0 mg of 7-chloro-1,2,3,4-tetrahydropyrazine[1,2-a]indole was obtained as a yellow solid (yield: 94.9%). LCMS: RT=1.59 min, [M+H] + =207.15. 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 7.47-7.43 (m, 2H), 7.00 (dd, J=8.4, 2.0 Hz, 1H), 6.17-6.13 (m, 1H), 5.75 ( s, 1H), 4.02 (d, J=0.4Hz, 2H), 3.94 (t, J=5.6Hz, 2H), 3.15 (t, J=5.6Hz, 2H).
步骤E：合成(S)-5-(3-(7-氯-3,4-二氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑啉-2,4-二酮Step E: Synthesis of (S)-5-(3-(7-Chloro-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropyl )-5-cyclopropylimidazoline-2,4-dione
Figure PCTCN2021105088-appb-000225
Figure PCTCN2021105088-appb-000225
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(102.7毫克，0.48毫摩尔)和7-氯-1,2,3,4-四氢吡嗪[1,2-a]吲哚(100.0毫克，0.48毫摩尔)加入二氯甲烷(12.0毫升)中，滴加N,N-二异丙基乙胺(93.8毫克)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(111.3毫克，0.58毫摩尔)和1-羟基苯并三唑(9.8毫克，0.07毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (102.7 mg, 0.48 mmol) and 7-chloro-1,2, 3,4-Tetrahydropyrazine[1,2-a]indole (100.0 mg, 0.48 mmol) was added to dichloromethane (12.0 mL), and N,N-diisopropylethylamine (93.8 mg) was added dropwise. ), then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (111.3 mg, 0.58 mmol) and 1-hydroxybenzotriazole (9.8 mg, 0.07 mmol) were added in sequence mol), under N 2, at room temperature overnight.
反应结束，加水(50毫升)和二氯甲烷(50毫升)稀释，分液，收集有机相，饱和食盐水(3毫升×2次)洗涤，无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到45.0毫克白色固体(S)-5-(3-(7-氯-3,4-二氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑啉-2,4-二酮(收率：23.2％)。LCMS:RT＝1.88min,[M+H] +＝401.22。 1H NMR(500MHz,DMSO-d 6)δ(ppm):10.60(s,1H),7.71(s,1H),7.53(d,J＝7.5Hz,1H),7.49(d,J＝8.0Hz,1H),7.04(d,J＝8.5Hz,1H),6.35(d,J＝10.5Hz,1H),4.88(s,1H),4.83(s,1H),4.21–4.15(m,1H),4.11–4.06(m,1H),3.99–3.91(m,2H),3.00–2.86(m,1H),2.44–2.31(m,1H),2.05–1.92(m,2H),1.15–1.05(m,1H),0.48–0.40(m,1H),0.40–0.27(m,2H),0.14–0.06(m,1H)。 After the reaction was completed, water (50 mL) and dichloromethane (50 mL) were added to dilute, the layers were separated, the organic phase was collected, washed with saturated brine (3 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 45.0 mg of white solid (S)-5-(3-(7-chloro-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropane was obtained yl)-5-cyclopropylimidazoline-2,4-dione (yield: 23.2%). LCMS: RT=1.88 min, [M+H] + =401.22. 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm): 10.60 (s, 1H), 7.71 (s, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.49 (d, J=8.0 Hz) ,1H),7.04(d,J＝8.5Hz,1H),6.35(d,J＝10.5Hz,1H),4.88(s,1H),4.83(s,1H),4.21–4.15(m,1H) ,4.11–4.06(m,1H),3.99–3.91(m,2H),3.00–2.86(m,1H),2.44–2.31(m,1H),2.05–1.92(m,2H),1.15–1.05( m, 1H), 0.48–0.40 (m, 1H), 0.40–0.27 (m, 2H), 0.14–0.06 (m, 1H).
实施例48Example 48
合成(S)-5-环丙基-5-(3-(9-甲基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-3-氧丙基)咪唑烷-2,4-二酮Synthesis of (S)-5-cyclopropyl-5-(3-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl )-3-Oxypropyl)imidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000226
Figure PCTCN2021105088-appb-000226
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-羧酸叔丁酯Step A: Synthesis of tert- butyl 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate
Figure PCTCN2021105088-appb-000227
Figure PCTCN2021105088-appb-000227
零摄氏度下，向含有2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚(200.0毫克，1.16毫摩尔)的二氯甲烷中，氮气保护下，依次滴加三乙胺(323.0微升)和二碳酸二叔丁酯(294.0微升)，室温反应2小时。At zero degrees Celsius, add 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200.0 mg, 1.16 mmol) in dichloromethane, under nitrogen protection, dropwise in sequence Triethylamine (323.0 μl) and di-tert-butyl dicarbonate (294.0 μl) were added, and the mixture was reacted at room temperature for 2 hours.
反应结束，加水淬灭，混合液用二氯甲烷(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到240.0毫克白色固体1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-羧酸叔丁酯(收率：75.97％)。LCMS:RT＝2.11min,[M+H] +＝273.20。 The reaction was completed, quenched by adding water, the mixture was extracted with dichloromethane (20 ml × 3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 ml × 2 times), and then dried with anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 240.0 mg of tert- butyl 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate was obtained as a white solid (yield: 75.97%). LCMS: RT=2.11 min, [M+H] + =273.20.
步骤B：合成9-甲基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-羧酸叔丁酯Step B: Synthesis of tert-butyl 9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate
Figure PCTCN2021105088-appb-000228
Figure PCTCN2021105088-appb-000228
零摄氏度下，向含有1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-羧酸叔丁酯(240.0毫克，2.32毫摩尔)的四氢呋喃中，加入三乙胺加入氢化钠(44.0毫克，1.84毫摩尔，60％分散于石蜡油)，氮气保护下，室温搅拌30分钟后，加入碘甲烷(109.8微升)，摄氏度反应2小时。In tetrahydrofuran containing tert- butyl 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate (240.0 mg, 2.32 mmol) at zero degrees Celsius, Triethylamine was added, sodium hydride (44.0 mg, 1.84 mmol, 60% dispersed in paraffin oil) was added, and under nitrogen protection, after stirring at room temperature for 30 minutes, methyl iodide (109.8 microliters) was added, and the reaction was performed at degrees Celsius for 2 hours.
反应结束，加饱和氯化铵溶液淬灭，混合液用乙酸乙酯(40毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(30毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/30)。得到140.0毫克白色固体9-甲基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-羧酸叔丁酯(收率：21.1％)。LCMS:RT＝2.21min,[M+H] +＝287.22。 The reaction was completed, quenched by adding saturated ammonium chloride solution, the mixture was extracted with ethyl acetate (40 ml × 3 times), the organic phases were combined, the organic phase was washed with saturated brine (30 ml × 2 times), and then It was dried over sodium sulfate and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30). 140.0 mg of tert-butyl 9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate was obtained as a white solid (yield: 21.1%). LCMS: RT=2.21 min, [M+H] + =287.22.
步骤C：合成9-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚盐酸盐Step C: Synthesis of 9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole hydrochloride
Figure PCTCN2021105088-appb-000229
Figure PCTCN2021105088-appb-000229
室温下，将9-甲基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-羧酸叔丁酯(140.0毫克，0.49毫摩尔)加入甲醇(2.0毫升)中，滴加盐酸的二氧六环溶液(610微升，4.0摩尔每升)，N 2保护下，室温反应3小时。 At room temperature, tert-butyl 9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate (140.0 mg, 0.49 mmol) was added In methanol (2.0 mL), a solution of hydrochloric acid in dioxane (610 μL, 4.0 mol/L) was added dropwise, and the reaction was carried out at room temperature for 3 hours under the protection of N 2 .
反应结束，蒸干溶剂得到110.0毫克类白色固体9-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.52min,[M+H] +＝187.21。 After the reaction was completed, the solvent was evaporated to dryness to obtain 110.0 mg of off-white solid 9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.52 min, [M+H] + =187.21.
步骤D：合成(S)-5-环丙基-5-(3-(9-甲基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-3-氧丙基)咪唑烷-2,4-二酮Step D: Synthesis of (S)-5-cyclopropyl-5-(3-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole- 2-yl)-3-oxopropyl)imidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000230
Figure PCTCN2021105088-appb-000230
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(104.0毫克，0.49毫摩尔)和9-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚盐酸盐盐酸盐(110.0毫克，0.49毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中，滴加N,N-二异丙基乙胺(328.0微升)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(105.0毫克，0.54毫摩尔)和1-羟基苯并三唑(10.0毫克，0.07毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (104.0 mg, 0.49 mmol) and 9-methyl-2,3 ,4,9-Tetrahydro-1H-pyrido[3,4-b]indole hydrochloride hydrochloride (110.0 mg, 0.49 mmol) was added to N,N-dimethylformamide (2.0 mL) , N,N-diisopropylethylamine (328.0 μl) was added dropwise, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (105.0 mg, 0.54 mmol) and 1-hydroxybenzotriazole (10.0 mg, 0.07 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到39.5毫克白色固体(S)-5-环丙基-5-(3-(9-甲基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)-3-氧丙基)咪唑烷-2,4-二酮(收率：21.2％)。LCMS:RT＝1.84min,[M+H] +＝381.24。 1H NMR(500MHz,DMSO)δ10.62(s,1H),7.73(d,J＝22.5Hz,1H),7.51–7.34(m,2H),7.17–7.06(m,1H),7.01(t,J＝7.4Hz,1H),4.73(s,2H),3.88–3.75(m,1H),3.72(t,J＝5.6Hz,1H),3.66(d,J＝10.9Hz,3H),2.72(d,J＝54.0Hz,2H),2.60–2.49(m,1H),2.45–2.33(m,1H),2.11–1.90(m,2H),1.17–1.05(m,1H),0.51–0.40(m,1H),0.40–0.27(m,2H),0.17–0.06(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 39.5 mg of white solid (S)-5-cyclopropyl-5-(3-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole was obtained) -2-yl)-3-oxopropyl)imidazolidine-2,4-dione (yield: 21.2%). LCMS: RT=1.84 min, [M+H] + =381.24. 1 H NMR(500MHz, DMSO)δ10.62(s,1H),7.73(d,J=22.5Hz,1H),7.51-7.34(m,2H),7.17-7.06(m,1H),7.01(t , J＝7.4Hz, 1H), 4.73(s, 2H), 3.88–3.75(m, 1H), 3.72(t, J＝5.6Hz, 1H), 3.66(d, J＝10.9Hz, 3H), 2.72 (d, J=54.0Hz, 2H), 2.60–2.49 (m, 1H), 2.45–2.33 (m, 1H), 2.11–1.90 (m, 2H), 1.17–1.05 (m, 1H), 0.51–0.40 (m, 1H), 0.40–0.27 (m, 2H), 0.17–0.06 (m, 1H).
实施例49Example 49
合成(5S)-5-(3-(3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-氧代丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(3,4-Dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)-3-oxopropyl)-5-cyclopropyl Imidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000231
Figure PCTCN2021105088-appb-000231
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成N-(2-(苯并呋喃-3-基)乙基)甲酰胺Step A: Synthesis of N-(2-(benzofuran-3-yl)ethyl)carboxamide
Figure PCTCN2021105088-appb-000232
Figure PCTCN2021105088-appb-000232
室温下，含有2-(苯并呋喃-3-基)乙胺(1.00克，6.20毫摩尔)的甲酸乙酯(3.0毫升)溶液加热60摄氏度反应3小时。At room temperature, a solution of 2-(benzofuran-3-yl)ethanamine (1.00 g, 6.20 mmol) in ethyl formate (3.0 mL) was heated at 60 degrees Celsius for 3 hours.
反应结束，用乙酸乙酯(100)稀释，有机相依次用饱和氯化铵，饱和食盐水(50毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。得到1.22克淡黄色固体N-(2-(苯并呋喃-3-基)乙基)甲酰胺，粗产物直接用于下一步反应。LCMS:RT＝1.75min,[M+H] +＝190.19。 After the reaction was completed, it was diluted with ethyl acetate (100), and the organic phase was washed with saturated ammonium chloride and saturated brine (50 mL) successively, then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. 1.22 g of N-(2-(benzofuran-3-yl)ethyl)carboxamide were obtained as a pale yellow solid, and the crude product was directly used in the next reaction. LCMS: RT=1.75 min, [M+H] + =190.19.
步骤B：合成3,4-二氢苯并呋喃[2,3-c]吡啶Step B: Synthesis of 3,4-dihydrobenzofuro[2,3-c]pyridine
Figure PCTCN2021105088-appb-000233
Figure PCTCN2021105088-appb-000233
室温下，向N-(2-(苯并呋喃-3-基)乙基)甲酰胺(1.22克，6.45毫摩尔)的甲磺酸(6.2毫升)溶液中加入多聚磷酸(750毫克)，加热至90摄氏度反应3小时。To a solution of N-(2-(benzofuran-3-yl)ethyl)formamide (1.22 g, 6.45 mmol) in methanesulfonic acid (6.2 mL) at room temperature was added polyphosphoric acid (750 mg), Heated to 90 degrees Celsius and reacted for 3 hours.
反应结束，将反应液缓慢滴加至冰水中，用乙酸乙酯(30毫升×3次)萃取，合并有机相，有机相依次用水(50毫升)和饱和食盐水(50毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩，得到1.01克淡黄色固体3,4-二氢苯并呋喃[2,3-c]吡啶，粗产物无需纯化，直接用于下一步反应。LCMS:RT＝1.40min,[M+H] +＝172.12。 After the reaction was completed, the reaction solution was slowly added dropwise to ice water, extracted with ethyl acetate (30 mL×3 times), the organic phases were combined, and the organic phases were washed with water (50 mL) and saturated brine (50 mL) in turn, and then with Dry over anhydrous sodium sulfate, and finally concentrate under reduced pressure to obtain 1.01 g of pale yellow solid 3,4-dihydrobenzofuro[2,3-c]pyridine. The crude product is directly used in the next reaction without purification. LCMS: RT=1.40 min, [M+H] + =172.12.
步骤C：合成1,2,3,4-四氢苯并呋喃[2,3-c]吡啶Step C: Synthesis of 1,2,3,4-Tetrahydrobenzofuro[2,3-c]pyridine
Figure PCTCN2021105088-appb-000234
Figure PCTCN2021105088-appb-000234
室温下，向含有3,4-二氢苯并呋喃[2,3-c]吡啶(1.01克，5.91毫摩尔)的甲醇(58.8毫升)溶液中，依次加入甲酸铵溶液(1.86克，29.6毫摩尔，溶于14.5毫升水)，10％钯碳(59毫克)，置换氮气，70摄氏度反应3小时。To a solution of 3,4-dihydrobenzofuro[2,3-c]pyridine (1.01 g, 5.91 mmol) in methanol (58.8 mL) at room temperature was successively added ammonium formate solution (1.86 g, 29.6 mmol) mol, dissolved in 14.5 ml of water), 10% palladium on carbon (59 mg), replaced with nitrogen, and reacted at 70 degrees Celsius for 3 hours.
反应结束，冷却至室温，用乙酸乙酯(30毫升×3次)萃取，合并有机相，有机相依次用水(50毫升)和饱和食盐水(50毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩，得到900毫克淡黄色固体1,2,3,4-四氢苯并呋喃[2,3-c]吡啶，粗产物无需纯化，直接用于下一步反应。LCMS:RT＝1.49min,[M+H] +＝174.17。 After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate (30 mL×3 times), the organic phases were combined, the organic phases were washed with water (50 mL) and saturated brine (50 mL) in turn, and then dried over anhydrous sodium sulfate, Finally, it was concentrated under reduced pressure to obtain 900 mg of pale yellow solid 1,2,3,4-tetrahydrobenzofuran[2,3-c]pyridine. The crude product was directly used in the next reaction without purification. LCMS: RT=1.49 min, [M+H] + =174.17.
步骤D：合成(5S)-5-(3-(3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-氧代丙基)-5-环丙基咪唑烷-2,4-二酮Step D: Synthesis of (5S)-5-(3-(3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)-3-oxopropyl)-5- Cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000235
Figure PCTCN2021105088-appb-000235
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和1,2,3,4-四氢苯并呋喃[2,3-c](49毫克，0.28毫摩尔)加入无水二氯甲烷(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升，0.94毫摩尔)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(68毫克，0.35毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 1,2,3,4- Tetrahydrobenzofuran[2,3-c] (49 mg, 0.28 mmol) was added to anhydrous dichloromethane (2.0 mL), and N,N-diisopropylethylamine (156.0 μL, 0.94 mL) was added dropwise. mmol), then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (68 mg, 0.35 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到19.2毫克白色固体(5S)-5-(3-(8-氯-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：22.1％)。LCMS:RT＝1.83min,[M-H] -＝366.23。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 19.2 mg of white solid (5S)-5-(3-(8-chloro-3,4,10,10a-tetrahydropyrazino[1,2-a]indol-2(1H)-yl)- 3-Oxypropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 22.1%). LCMS: RT = 1.83 min, [MH] − = 366.23.
实施例50Example 50
合成(5S)-5-(3-(5,6-二氢噻吩并[2'，3'：4,5]吡咯并[1,2-a]吡嗪-7(8H)-基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(5,6-dihydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazin-7(8H)-yl)- 5-Cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000236
Figure PCTCN2021105088-appb-000236
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成4-(2-(((叔丁氧基羰基)氨基)乙基)-4H-噻吩并[3,2-b]吡咯-5-羧酸乙酯Step A: Synthesis of 4-(2-(((tert-butoxycarbonyl)amino)ethyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate ethyl ester
Figure PCTCN2021105088-appb-000237
Figure PCTCN2021105088-appb-000237
冰浴下，向含有4H-噻吩并[3,2-b]吡咯-5-羧酸乙酯(2.00克，10.2毫摩尔)的N,N-二甲基甲酰胺(10.2毫升)中分批加入氢化钠(451毫克，11.3毫摩尔，60％分散于石蜡油)，室温搅拌15分钟。然后加入1,2,3-氧杂噻唑烷-3-羧酸叔丁酯2,2-二氧化物(2.62克，11.7毫摩尔)，室温反应12小时。4H-thieno[3,2-b]pyrrole-5-carboxylate ethyl ester (2.00 g, 10.2 mmol) in N,N-dimethylformamide (10.2 mL) was batched under ice bath Sodium hydride (451 mg, 11.3 mmol, 60% dispersed in paraffin oil) was added and stirred at room temperature for 15 minutes. Then, 1,2,3-oxathiazolidine-3-carboxylate tert-butyl ester 2,2-dioxide (2.62 g, 11.7 mmol) was added, and the mixture was reacted at room temperature for 12 hours.
反应结束，加水淬灭，混合液用乙酸乙酯(80毫升×3次)萃取，合并有机相，有机相依次用饱和碳酸氢钠(80毫升)、食盐水(80毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩，得到4.00克棕色固体4-(2-(((叔丁氧基羰基)氨基)乙基)-4H-噻吩并[3,2-b]吡咯-5-羧酸乙酯，直接用于下一步反应。LCMS:RT＝1.73min,[M-Boc+H] +＝239.17。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (80 mL×3 times), the organic phases were combined, and the organic phases were washed with saturated sodium bicarbonate (80 mL) and brine (80 mL×2 times) in turn, It was then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 4.00 g of brown solid 4-(2-(((tert-butoxycarbonyl)amino)ethyl)-4H-thieno[3,2-b]pyrrole -5-Carboxylic acid ethyl ester, directly used in the next reaction. LCMS: RT=1.73 min, [M-Boc+H] + =239.17.
步骤B：合成6,7-二氢噻吩并[2'，3'：4,5]吡咯并[1,2-a]吡嗪-8(5H)-酮Step B: Synthesis of 6,7-dihydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazin-8(5H)-one
Figure PCTCN2021105088-appb-000238
Figure PCTCN2021105088-appb-000238
室温下，向4-(2-(((叔丁氧基羰基)氨基)乙基)-4H-噻吩并[3,2-b]吡咯-5-羧酸乙酯(4.00克，11.82毫摩尔)的二氯甲烷(35.0毫升)溶液中，加入三氟乙酸(10.0毫升),室温反应两小时。减压蒸干溶剂，所得粗产物直接用于下一步反应。LCMS:RT＝1.58min,[M+H] +＝239.19。 To ethyl 4-(2-(((tert-butoxycarbonyl)amino)ethyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate (4.00 g, 11.82 mmol) at room temperature ) in dichloromethane (35.0 ml) solution, trifluoroacetic acid (10.0 ml) was added, and the reaction was carried out at room temperature for two hours. The solvent was evaporated to dryness under reduced pressure, and the obtained crude product was directly used in the next step reaction. LCMS: RT=1.58 min, [ M+H] + =239.19.
上述粗产物溶于四氢呋喃(51.0毫升)和甲醇(51.0毫升)的混合溶剂，加入碳酸钾(8.4克，61.2毫摩尔)，反应12小时。反应完毕，反应液用乙酸乙酯(80毫升×3次)萃取，合并有机相，依次用水(100毫升)、饱和食盐水(100毫升)洗涤，无水硫酸钠干燥，减压浓缩，得到1.90克黄色固体，所得粗产物无需纯化，直接用于下一步反应。LCMS:RT＝1.65min,[M+H] +＝193.11。 The above crude product was dissolved in a mixed solvent of tetrahydrofuran (51.0 mL) and methanol (51.0 mL), potassium carbonate (8.4 g, 61.2 mmol) was added, and the reaction was carried out for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (80 mL×3 times), the organic phases were combined, washed with water (100 mL) and saturated brine (100 mL) in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.90 g yellow solid, the obtained crude product was directly used in the next reaction without purification. LCMS: RT=1.65 min, [M+H] + =193.11.
步骤C：合成5,6,7,8-四氢噻吩并[2'，3'：4,5]吡咯并[1,2-a]吡嗪Step C: Synthesis of 5,6,7,8-Tetrahydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazine
Figure PCTCN2021105088-appb-000239
Figure PCTCN2021105088-appb-000239
室温下，向6,7-二氢噻吩并[2'，3'：4,5]吡咯并[1,2-a]吡嗪-8(5H)-酮(1.90克，9.90毫摩尔)加入硼烷四氢呋喃溶液(51.0毫升，51.0毫摩尔，1摩尔/升)，加热至60摄氏度反应3小时。To 6,7-dihydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazin-8(5H)-one (1.90 g, 9.90 mmol) was added at room temperature Borane tetrahydrofuran solution (51.0 mL, 51.0 mmol, 1 mol/L) was heated to 60 degrees Celsius and reacted for 3 hours.
反应结束，冷却至室温，反应液慢慢加入到冰水中，用乙酸乙酯(80毫升×2次)萃取，合并有机相，依次用饱和碳酸氢钠(100毫升)、饱和食盐水(100毫升)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)。得到165毫克白色固体5,6,7,8-四氢噻吩并[2'，3'：4,5]吡咯并[1,2-a]吡嗪(收率：9.4％)。LCMS:RT＝1.72min,[M+H] +＝179.02。 The reaction was completed, cooled to room temperature, the reaction solution was slowly added to ice water, extracted with ethyl acetate (80 mL × 2 times), the organic phases were combined, and saturated sodium bicarbonate (100 mL) and saturated brine (100 mL) were used successively. ), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1). 165 mg of 5,6,7,8-tetrahydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazine were obtained as a white solid (yield: 9.4%). LCMS: RT=1.72 min, [M+H] + =179.02.
步骤D：合成(5S)-5-(3-(5,6-二氢噻吩并[2'，3'：4,5]吡咯并[1,2-a]吡嗪-7(8H)-基)-5-环丙基咪唑烷-2,4-二酮Step D: Synthesis of (5S)-5-(3-(5,6-dihydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazine-7(8H)- yl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000240
Figure PCTCN2021105088-appb-000240
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50.0毫克，0.24毫摩尔)和5,6,7,8-四氢噻吩并[2'，3'：4,5]吡咯并[1,2-a]吡嗪(50.3毫克，0.28毫摩尔)加入无水二氯甲烷(2.0毫升)中，滴加N,N-二异丙基乙胺(156.0微升，0.94毫摩尔)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(68.0毫克，0.35毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (50.0 mg, 0.24 mmol) and 5,6,7,8- Tetrahydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazine (50.3 mg, 0.28 mmol) was added to anhydrous dichloromethane (2.0 mL), and N, N-diisopropylethylamine (156.0 μl, 0.94 mmol) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (68.0 mg, 0.35 mmol) mol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到8.0毫克白色固体(5S)-5-(3-(5,6-二氢噻吩并[2'，3'：4,5]吡咯并[1,2-a]吡嗪-7(8H)-基)-5-环丙基咪唑烷-2,4-二酮(收率：9.1％)。LCMS:RT＝1.78min,[M-H] -＝371.23。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 8.0 mg of white solid (5S)-5-(3-(5,6-dihydrothieno[2',3':4,5]pyrrolo[1,2-a]pyrazine-7(8H) was obtained -yl)-5-cyclopropylimidazolidine-2,4-dione (yield: 9.1%). LCMS: RT=1.78 min, [MH] − =371.23.
实施例51Example 51
合成(S)-5-(3-(7-氯-8-氟-3,4-二氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑啉-2,4-二酮Synthesis of (S)-5-(3-(7-Chloro-8-fluoro-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-3-oxopropane yl)-5-cyclopropylimidazoline-2,4-dione
Figure PCTCN2021105088-appb-000241
Figure PCTCN2021105088-appb-000241
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成6-氯-5-氟-1H-吲哚-2-羧酸乙酯Step A: Synthesis of ethyl 6-chloro-5-fluoro-1H-indole-2-carboxylate
Figure PCTCN2021105088-appb-000242
Figure PCTCN2021105088-appb-000242
室温下，向含有(3-氯-4-氟苯基)肼盐酸盐(2.00克，10.15毫摩尔)的乙醇(15毫升)中加入2-氧代丙酸乙酯(1.41克，12.18毫摩尔)升温至78摄氏度，搅拌反应1小试。旋干溶剂，加入甲苯(25mL)溶解，加入对甲苯磺酸(5.24g)，N 2保护下，110摄氏度反应12小时。 To (3-chloro-4-fluorophenyl)hydrazine hydrochloride (2.00 g, 10.15 mmol) in ethanol (15 mL) was added ethyl 2-oxopropionate (1.41 g, 12.18 mmol) at room temperature mol) was heated to 78 degrees Celsius, and the reaction was stirred for a small test. The solvent was spin-dried, toluene (25 mL) was added to dissolve, p-toluenesulfonic acid (5.24 g) was added, and the reaction was carried out at 110 degrees Celsius for 12 hours under the protection of N 2 .
反应结束，加水(100mL)稀释，乙酸乙酯(30毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(5毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到260.0毫克米黄色固体6-氯-5-氟-1H-吲哚-2-羧酸乙酯(收率：10.6％)。LCMS:RT＝2.05min,[M+MeCN+H] +＝283.11。 The reaction was completed, diluted with water (100 mL), extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (5 mL × 2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 260.0 mg of ethyl 6-chloro-5-fluoro-1H-indole-2-carboxylate were obtained as a beige solid (yield: 10.6%). LCMS: RT=2.05 min, [M+MeCN+H] + =283.11.
步骤B：合成1-(2-(((叔丁氧基羰基)氨基)乙基)-6-氯-5-氟-1H-吲哚-2-羧酸乙酯Step B: Synthesis of ethyl 1-(2-(((tert-butoxycarbonyl)amino)ethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylate
Figure PCTCN2021105088-appb-000243
Figure PCTCN2021105088-appb-000243
零摄氏度下，向含有6-氯-5-氟-1H-吲哚-2-羧酸乙酯(260.0毫克，1.08毫摩尔)的DMF(13.0毫升)中，分批加入氢化钠(64.5毫克，1.61毫摩尔，60％分散于石蜡油),升温至室温搅拌反应0.5小时。加入(2-溴乙基)氨基甲酸叔丁酯(313.5毫克，1.40毫摩尔)，升温至70摄氏度搅拌12小时。To ethyl 6-chloro-5-fluoro-1H-indole-2-carboxylate (260.0 mg, 1.08 mmol) in DMF (13.0 mL) at zero degrees Celsius was added sodium hydride (64.5 mg, 1.61 mmol, 60% dispersed in paraffin oil), warmed to room temperature and stirred for 0.5 hours. tert-Butyl (2-bromoethyl)carbamate (313.5 mg, 1.40 mmol) was added, and the temperature was raised to 70° C. and stirred for 12 hours.
反应结束，冷却至室温，加入水(50毫升)稀释，乙酸乙酯萃取(30毫升×3次)，合并有机相，饱和食盐水洗涤(5毫升×2次)洗涤，然后用无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/10)。得到240.0毫克米黄色固体1-(2-(((叔丁氧基羰基)氨基)乙基)-6-氯-5-氟-1H-吲哚-2-羧酸乙酯(收率：58.0％)。LCMS:RT＝2.23min,[M-Boc+H] +＝285.16。 The reaction was completed, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (30 mL×3 times), combined with the organic phases, washed with saturated brine (5 mL×2 times), and then washed with anhydrous sodium sulfate Dry and concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). 240.0 mg of ethyl 1-(2-(((tert-butoxycarbonyl)amino)ethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylate was obtained as a beige solid (yield: 58.0 %). LCMS: RT=2.23 min, [M-Boc+H] + =285.16.
步骤B：合成1-(2-氨基乙基)-6-氯-5-氟-1H-吲哚-2-羧酸乙酯三氟乙酸盐Step B: Synthesis of 1-(2-aminoethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylate ethyl ester trifluoroacetate
Figure PCTCN2021105088-appb-000244
Figure PCTCN2021105088-appb-000244
室温下，将1-(2-(((叔丁氧基羰基)氨基)乙基)-6-氯-5-氟-1H-吲哚-2-羧酸乙酯(240.0毫克，0.62毫摩尔)加入二氯甲烷(5毫升)中，滴加三氟乙酸(1毫升，13.46毫摩尔)，室温反应1小时。At room temperature, ethyl 1-(2-(((tert-butoxycarbonyl)amino)ethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylate (240.0 mg, 0.62 mmol ) was added to dichloromethane (5 mL), trifluoroacetic acid (1 mL, 13.46 mmol) was added dropwise, and the mixture was reacted at room temperature for 1 hour.
反应结束，蒸干溶剂得到248.6毫克黄色固体1-(2-氨基乙基)-6-氯-5-氟-1H-吲哚-2-羧酸乙酯三氟乙酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.70min,[M+H] +＝285.16。 After the reaction was completed, the solvent was evaporated to dryness to obtain 248.6 mg of ethyl 1-(2-aminoethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylate trifluoroacetate as a yellow solid. It was directly used in the next reaction without purification. LCMS: RT=1.70 min, [M+H] + =285.16.
步骤C：合成7-氯-8-氟-3,4-二氢吡嗪[1,2-a]吲哚-1(2H)-酮Step C: Synthesis of 7-chloro-8-fluoro-3,4-dihydropyrazin[1,2-a]indol-1(2H)-one
Figure PCTCN2021105088-appb-000245
Figure PCTCN2021105088-appb-000245
室温下，向含有1-(2-氨基乙基)-6-氯-5-氟-1H-吲哚-2-羧酸乙酯三氟乙酸盐(248.6毫克，0.62毫摩尔)的四氢呋喃(6毫升)中加入水(3毫升)和碳酸氢钠(523.8毫克，6.23毫摩尔)，N 2保护下，80摄氏度反应3小时。 Add 1-(2-aminoethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylate ethyl ester trifluoroacetate (248.6 mg, 0.62 mmol) in tetrahydrofuran ( 6 mL) was added with water (3 mL) and sodium bicarbonate (523.8 mg, 6.23 mmol), and the reaction was carried out at 80 degrees Celsius for 3 hours under the protection of N 2 .
反应结束，冷却至室温，加入乙酸乙酯(50毫升)和水(50毫升)稀释，分液，收集有机相，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到145.0毫克黄色固体7-氯-8-氟-3,4-二氢吡嗪[1,2-a]吲哚-1(2H)-酮(收率：97.5％)。LCMS:RT＝1.81min,[M+H] +＝239.10。 After the reaction was completed, it was cooled to room temperature, ethyl acetate (50 mL) and water (50 mL) were added to dilute, the layers were separated, the organic phase was collected, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 145.0 mg of 7-chloro-8-fluoro-3,4-dihydropyrazin[1,2-a]indol-1(2H)-one was obtained as a yellow solid (yield: 97.5%). LCMS: RT=1.81 min, [M+H] + =239.10.
步骤D：合成7-氯-8-氟-1,2,3,4-四氢吡嗪并[1,2-a]吲哚Step D: Synthesis of 7-chloro-8-fluoro-1,2,3,4-tetrahydropyrazino[1,2-a]indole
Figure PCTCN2021105088-appb-000246
Figure PCTCN2021105088-appb-000246
0摄氏度下，向7-氯-8-氟-3,4-二氢吡嗪[1,2-a]吲哚-1(2H)-酮(145毫克，0.61毫摩尔)的四氢呋喃(10毫升)溶液中分批加入氢化铝锂(76.3毫克，2.01毫摩尔)，加完后升温至60摄氏度，N 2保护下，搅拌反应3h。 To 7-chloro-8-fluoro-3,4-dihydropyrazin[1,2-a]indol-1(2H)-one (145 mg, 0.61 mmol) in tetrahydrofuran (10 mL) at 0 degrees Celsius ) solution was added in batches of lithium aluminum hydride (76.3 mg, 2.01 mmol), and the temperature was raised to 60 degrees Celsius after the addition, and the reaction was stirred for 3 h under the protection of N 2 .
反应结束，将反应体系降温至0摄氏度，加入Na 2SO 4·10H 2O,搅拌0.5h，硅藻土过滤，蒸干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到102.0毫克黄色固体7-氯-8-氟-1,2,3,4-四氢吡嗪并[1,2-a]吲哚(收率：74.7％)。LCMS:RT＝1.59min,[M+H] +＝225.12。 After the reaction was completed, the reaction system was cooled to 0 degrees Celsius, Na 2 SO 4 ·10H 2 O was added, stirred for 0.5 h, filtered through celite, evaporated to dryness, and the obtained residue was purified by silica gel column chromatography (eluent: methanol/ Dichloromethane = 1/20). 102.0 mg of 7-chloro-8-fluoro-1,2,3,4-tetrahydropyrazino[1,2-a]indole was obtained as a yellow solid (yield: 74.7%). LCMS: RT=1.59 min, [M+H] + =225.12.
步骤E：合成(S)-5-(3-(7-氯-8-氟-3,4-二氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑啉-2,4-二酮Step E: Synthesis of (S)-5-(3-(7-Chloro-8-fluoro-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-3 -Oxypropyl)-5-cyclopropylimidazoline-2,4-dione
Figure PCTCN2021105088-appb-000247
Figure PCTCN2021105088-appb-000247
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(106.0毫克，0.50毫摩尔)和7-氯-8-氟-3,4-二氢吡嗪[1,2-a]吲哚-1(2H)-酮(102.0毫克，0.45毫摩尔)加入DMF(10毫升)中，滴加N,N-二异丙基乙胺(176.0毫克,1.36毫摩尔)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(104.4毫克，0.54毫摩尔)和1-羟基苯并三唑(9.2毫克，0.07毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (106.0 mg, 0.50 mmol) and 7-chloro-8-fluoro- 3,4-Dihydropyrazin[1,2-a]indol-1(2H)-one (102.0 mg, 0.45 mmol) was added to DMF (10 mL) and N,N-diisopropyl was added dropwise Ethylamine (176.0 mg, 1.36 mmol) followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (104.4 mg, 0.54 mmol) followed by 1-hydroxybenzene benzotriazole (9.2 mg, 0.07 mmol), under N 2, at room temperature overnight.
反应结束，加水(50毫升)和乙酸乙酯(50毫升)稀释，分液，收集有机相，饱和食盐水(3毫升×2次)洗涤，无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到103.1毫克米黄色固体合成(S)-5-(3-(7-氯-8-氟-3,4-二氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑啉-2,4-二酮(收率：54.2％)。LCMS:RT＝1.88min,[M+H] +＝419.22。 1H NMR(500MHz,DMSO-d 6)δ(ppm):10.60(s,1H),7.71(s,1H),7.47–7.40(m,1H),7.13(dd,J＝10.0,9.0Hz,1H), 6.42(d,J＝4.0Hz,1H),4.92(s,1H),4.87(s,1H),4.22(t,J＝5.0Hz,1H),4.12(t,J＝5.0Hz,1H),4.01–3.92(m,2H),3.17(s,1H),2.44–2.31(m,1H),2.06–1.93(m,2H),1.16–1.06(m,1H),0.49–0.41(m,1H),0.40–0.28(m,2H),0.14–0.07(m,1H)。 After the reaction was completed, water (50 mL) and ethyl acetate (50 mL) were added to dilute, the layers were separated, the organic phase was collected, washed with saturated brine (3 mL×2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 103.1 mg of beige solid were obtained. Synthesis of (S)-5-(3-(7-chloro-8-fluoro-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl )-3-oxopropyl)-5-cyclopropylimidazoline-2,4-dione (yield: 54.2%). LCMS: RT=1.88 min, [M+H] + =419.22. 1 H NMR (500 MHz, DMSO-d 6 ) δ (ppm): 10.60 (s, 1H), 7.71 (s, 1H), 7.47-7.40 (m, 1H), 7.13 (dd, J=10.0, 9.0 Hz, 1H), 6.42(d, J＝4.0Hz, 1H), 4.92(s, 1H), 4.87(s, 1H), 4.22(t, J＝5.0Hz, 1H), 4.12(t, J＝5.0Hz, 1H), 4.01–3.92 (m, 2H), 3.17 (s, 1H), 2.44–2.31 (m, 1H), 2.06–1.93 (m, 2H), 1.16–1.06 (m, 1H), 0.49–0.41 ( m, 1H), 0.40–0.28 (m, 2H), 0.14–0.07 (m, 1H).
实施例52Example 52
合成(5S)-5-(3-(6-溴-7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Synthesis of (5S)-5-(3-(6-bromo-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H) -yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000248
Figure PCTCN2021105088-appb-000248
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成6-溴-7-氯-8-氟--3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯Step A: Synthesis of 6-bromo-7-chloro-8-fluoro--3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester
Figure PCTCN2021105088-appb-000249
Figure PCTCN2021105088-appb-000249
室温下，向含有7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(500毫克，1.54毫摩尔)的四氯化碳(15.0毫升)中加入N-溴代丁二酰亚胺(301毫克，1.69毫摩尔)和过氧苯甲酰(4.0毫克，0.015毫摩尔)，N 2保护下，80摄氏度反应1小时。 Add 7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester (500 mg, 1.54 mmol) was added carbon tetrachloride (15.0 ml) and N- bromosuccinimide (301 mg, 1.69 mmol) and benzoyl peroxide (4.0 mg, 0.015 mmol), N 2 protection at 80 degrees Celsius for 1 hour.
反应结束，反应液用二氯甲烷(80毫升)稀释，有机相依次用饱和碳酸氢钠(50毫升)、饱和食盐水(50毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/20)。得到420毫克黄色固体6-溴-7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(收率：67.2％)。LCMS:RT＝2.34min,[M+H] +＝407.15。 After the reaction was completed, the reaction solution was diluted with dichloromethane (80 mL), and the organic phase was washed with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL) successively, then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/20). 420 mg of tert-butyl 6-bromo-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate was obtained as a yellow solid (Yield: 67.2%). LCMS: RT=2.34 min, [M+H] + =407.15.
步骤D：合成6-溴-7-氯-8-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐Step D: Synthesis of 6-bromo-7-chloro-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride
Figure PCTCN2021105088-appb-000250
Figure PCTCN2021105088-appb-000250
室温下，将6-溴-7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-羧酸叔丁酯(92毫克，0.23毫摩尔)加入甲醇(2.0毫升)中，滴加盐酸的二氧六环溶液(0.28毫升，4.0摩尔每升)，N 2保护下，室温反应3小时。 6-Bromo-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate tert-butyl ester ( 92 mg, 0.23 mmol) was added methanol (2.0 ml) was added dropwise a solution of hydrochloric acid in dioxane (0.28 mL, 4.0 moles per liter), under N 2, at room temperature for 3 hours.
反应结束，蒸干溶剂得到78毫克类白色固体6-溴-7-氯-8-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝1.65min,[M+H] +＝307.04。 After the reaction was completed, the solvent was evaporated to dryness to obtain 78 mg of off-white solid 6-bromo-7-chloro-8-fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole Hydrochloride. It was directly used in the next reaction without purification. LCMS: RT=1.65 min, [M+H] + =307.04.
步骤E：合成(5S)-5-(3-(6-溴-7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮Step E: Synthesis of (5S)-5-(3-(6-bromo-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2 (1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione
Figure PCTCN2021105088-appb-000251
Figure PCTCN2021105088-appb-000251
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(50毫克，0.24毫摩尔)和6-溴-7-氯-8-氟-1,2,3,4,10,10a-六氢吡嗪并[1,2-a]吲哚盐酸盐(78毫克，0.23毫摩尔)加入无水二氯甲烷(4.0毫升)中，滴加N,N-二异丙基乙胺(156微升，0.94毫摩尔)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(68毫克，0.35毫摩尔)和1-羟基苯并三唑(5.0毫克，0.04毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propionic acid (50 mg, 0.24 mmol) and 6-bromo-7-chloro- 8-Fluoro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole hydrochloride (78 mg, 0.23 mmol) was added to anhydrous dichloromethane (4.0 mL ), N,N-diisopropylethylamine (156 μl, 0.94 mmol) was added dropwise, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (68 mg, 0.35 mmol) and 1-hydroxybenzotriazole (5.0 mg, 0.04 mmol), under N 2, at room temperature overnight.
反应结束，加水淬灭，混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升×2次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1)。得到38.5毫克白色固体(5S)-5-(3-(6-溴-7-氯-8-氟-3,4,10,10a-四氢吡嗪并[1,2-a]吲哚-2(1H)-基)-3-氧丙基)-5-环丙基咪唑烷-2,4-二酮(收率：33.9％)。LCMS:RT＝1.95min,[M+H] +＝499.12。 1H NMR(500MHz,DMSO-d6)δ10.62–10.56(m,1H),7.68(s,1H),7.27–7.22(m,1H),4.72–4.65(m,1H),4.37(dd,J＝68.9,12.3Hz,1H),3.86(dd,J＝45.5,12.6Hz,1H),3.60–3.50(m,1H),3.26–3.11(m,1H),3.10–2.75(m,3H),2.75–2.57(m,1H),2.47–2.17(m,2H),2.00–1.90(m,2H),1.10(d,J＝7.7Hz,1H),0.49–0.40(m,1H),0.40–0.28(m,2H),0.14–0.06(m,1H)。 The reaction was completed, quenched by adding water, the mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL×2 times), and then dried over anhydrous sodium sulfate, Finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). 38.5 mg of white solid (5S)-5-(3-(6-bromo-7-chloro-8-fluoro-3,4,10,10a-tetrahydropyrazino[1,2-a]indole- 2(1H)-yl)-3-oxopropyl)-5-cyclopropylimidazolidine-2,4-dione (yield: 33.9%). LCMS: RT=1.95 min, [M+H] + =499.12. 1 H NMR (500MHz, DMSO-d6)δ10.62-10.56(m,1H), 7.68(s,1H), 7.27-7.22(m,1H), 4.72-4.65(m,1H), 4.37(dd, J=68.9, 12.3Hz, 1H), 3.86 (dd, J=45.5, 12.6Hz, 1H), 3.60–3.50 (m, 1H), 3.26–3.11 (m, 1H), 3.10–2.75 (m, 3H) ,2.75–2.57(m,1H),2.47–2.17(m,2H),2.00–1.90(m,2H),1.10(d,J=7.7Hz,1H),0.49–0.40(m,1H),0.40 –0.28(m,2H),0.14–0.06(m,1H).
实施例53Example 53
合成(S)-5-环丙基-5-(3-(3,4-二氢苯并[4,5]咪唑并[1,2-a]吡嗪-2(1H)-基)-3-氧丙基)咪唑啉-2,4-二酮Synthesis of (S)-5-cyclopropyl-5-(3-(3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)- 3-Oxypropyl)imidazoline-2,4-dione
Figure PCTCN2021105088-appb-000252
Figure PCTCN2021105088-appb-000252
具体合成路线如下：The specific synthetic route is as follows:
步骤A：合成1-(2-((叔丁氧羰基)氨基)乙基)-1H苯并[d]咪唑-2-羧酸乙酯Step A: Synthesis of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H benzo[d]imidazole-2-carboxylate
Figure PCTCN2021105088-appb-000253
Figure PCTCN2021105088-appb-000253
零摄氏度下，向含有1H苯并[d]咪唑-2-羧酸乙酯(1.00克，5.68毫摩尔)的DMF(12毫升)中，分批加入氢化钠(340.5毫克，8.51毫摩尔，60％分散于石蜡油),升温至室温搅拌反应0.5小时。加入(2-溴乙基)氨基甲酸叔丁酯(1.65克，7.38毫摩尔)，升温至70摄氏度搅拌12小时。To ethyl 1H benzo[d]imidazole-2-carboxylate (1.00 g, 5.68 mmol) in DMF (12 mL) at zero degrees C was added portionwise sodium hydride (340.5 mg, 8.51 mmol, 60 % dispersed in paraffin oil), warmed to room temperature and stirred for 0.5 hours. tert-butyl (2-bromoethyl)carbamate (1.65 g, 7.38 mmol) was added, and the temperature was raised to 70°C and stirred for 12 hours.
反应结束，冷却至室温，加入水(50毫升)稀释，乙酸乙酯萃取(30毫升×3次)，合并有机相，饱和食盐水洗涤(2毫升×3次)，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/20)。得到1.20克米黄色固体1-(2-((叔丁氧羰基)氨基)乙基)-1H苯并[d]咪唑-2- 羧酸乙酯(收率：68.3％)。LCMS:RT＝2.21min,[M+H] +＝320.28。 The reaction was completed, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (30 mL × 3 times), combined with the organic phases, washed with saturated brine (2 mL × 3 times), dried over anhydrous sodium sulfate, reduced pressure concentrate. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/20). 1.20 g of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H benzo[d]imidazole-2-carboxylate was obtained as a beige solid (yield: 68.3%). LCMS: RT=2.21 min, [M+H] + =320.28.
步骤B：合成1-(2-氨基乙基)-1H苯并[d]咪唑-2-羧酸乙酯盐酸盐Step B: Synthesis of 1-(2-aminoethyl)-1H benzo[d]imidazole-2-carboxylate ethyl ester hydrochloride
Figure PCTCN2021105088-appb-000254
Figure PCTCN2021105088-appb-000254
室温下，将1-(2-((叔丁氧羰基)氨基)乙基)-1H苯并[d]咪唑-2-羧酸乙酯(1.00克，3.13毫摩尔)加入二氯甲烷(15毫升)中，滴加盐酸/二氧六环(2毫升，8毫摩尔)，室温反应1小时。At room temperature, ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H benzo[d]imidazole-2-carboxylate (1.00 g, 3.13 mmol) was added to dichloromethane (15 ml), hydrochloric acid/dioxane (2 ml, 8 mmol) was added dropwise, and the reaction was carried out at room temperature for 1 hour.
反应结束，蒸干溶剂得到800.7毫克黄色固体1-(2-氨基乙基)-1H苯并[d]咪唑-2-羧酸乙酯盐酸盐。无需纯化，直接用于下一步反应。LCMS:RT＝0.86min,[M+H] +＝220.20。 After the reaction was completed, the solvent was evaporated to dryness to obtain 800.7 mg of ethyl 1-(2-aminoethyl)-1H benzo[d]imidazole-2-carboxylate hydrochloride as a yellow solid. It was directly used in the next reaction without purification. LCMS: RT=0.86 min, [M+H] + =220.20.
步骤C：合成3,4-二氢苯并[4,5]咪唑并[1,2-a]吡嗪-1(2H)-酮Step C: Synthesis of 3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-1(2H)-one
Figure PCTCN2021105088-appb-000255
Figure PCTCN2021105088-appb-000255
室温下，向含有1-(2-氨基乙基)-1H苯并[d]咪唑-2-羧酸乙酯盐酸盐(800.7毫克，3.13毫摩尔)的四氢呋喃(20毫升)中加入水(10毫升)和碳酸氢钠(2.63克，31.31毫摩尔)，N 2保护下，60摄氏度反应12小时。 To ethyl 1-(2-aminoethyl)-1H benzo[d]imidazole-2-carboxylate hydrochloride (800.7 mg, 3.13 mmol) in tetrahydrofuran (20 mL) was added water (20 mL) at room temperature. 10 ml) and sodium bicarbonate (2.63 g, 31.31 mmol), under N 2, 60 ° C for 12 hours.
反应结束，冷却至室温，加入乙酸乙酯(100毫升)和水(100毫升)稀释，分液，收集有机相，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到112.4毫克黄色油状物3,4-二氢苯并[4,5]咪唑并[1,2-a]吡嗪-1(2H)-酮(收率：19.2％)。LCMS:RT＝1.29min,[M+H] +＝188.16。 After the reaction was completed, it was cooled to room temperature, ethyl acetate (100 mL) and water (100 mL) were added to dilute, the layers were separated, the organic phase was collected, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 112.4 mg of 3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-1(2H)-one was obtained as a yellow oil (yield: 19.2%). LCMS: RT=1.29 min, [M+H] + =188.16.
步骤D：合成1,2,3,4-四氢苯并[4,5]咪唑并[1,2-a]吡嗪Step D: Synthesis of 1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine
Figure PCTCN2021105088-appb-000256
Figure PCTCN2021105088-appb-000256
0摄氏度下，向3,4-二氢苯并[4,5]咪唑并[1,2-a]吡嗪-1(2H)-酮(112.4毫克，0.60毫摩尔)的四氢呋喃(10毫升)溶液中分批加入氢化铝锂(68.4毫克，1.80毫摩尔)，加完后升温至66摄氏度，N 2保护下，搅拌反应3h。 To 3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-1(2H)-one (112.4 mg, 0.60 mmol) in tetrahydrofuran (10 mL) at 0 degrees Celsius Lithium aluminum hydride (68.4 mg, 1.80 mmol) was added to the solution in batches, and the temperature was raised to 66 degrees Celsius after the addition, and the reaction was stirred for 3 h under the protection of N 2 .
反应结束，将反应体系降温至0摄氏度，加入Na 2SO 4·10H 2O,搅拌0.5h，硅藻土过滤，蒸干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到75.2毫克黄色油状物1,2,3,4-四氢苯并[4,5]咪唑并[1,2-a]吡嗪(收率：72.3％)。LCMS:RT＝0.28min,[M+H] +＝174.20。 After the reaction was completed, the reaction system was cooled to 0 degrees Celsius, Na 2 SO 4 ·10H 2 O was added, stirred for 0.5 h, filtered through celite, evaporated to dryness, and the obtained residue was purified by silica gel column chromatography (eluent: methanol/ Dichloromethane = 1/20). 75.2 mg of 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine was obtained as a yellow oil (yield: 72.3%). LCMS: RT=0.28 min, [M+H] + =174.20.
步骤E：合成(S)-5-环丙基-5-(3-(3,4-二氢苯并[4,5]咪唑并[1,2-a]吡嗪-2(1H)-基)-3-氧丙基)咪唑啉-2,4-二酮Step E: Synthesis of (S)-5-cyclopropyl-5-(3-(3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)- yl)-3-oxopropyl)imidazoline-2,4-dione
Figure PCTCN2021105088-appb-000257
Figure PCTCN2021105088-appb-000257
室温下，将(S)-3-(4-环丙基-2,5-二氧杂咪唑啉-4-基)丙酸(101.3毫克，0.48毫摩尔)和1,2,3,4-四氢苯并[4,5]咪唑并[1,2-a]吡嗪(75.2毫克，0.43毫摩尔)加入DMF(5毫升)中，滴加N,N-二异丙基乙胺 (168.3毫克,1.30毫摩尔)，然后依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(108.2毫克，0.56毫摩尔)和1-羟基苯并三唑(11.7毫克，0.09毫摩尔)，N 2保护下，室温反应过夜。 At room temperature, (S)-3-(4-cyclopropyl-2,5-dioximidazolin-4-yl)propanoic acid (101.3 mg, 0.48 mmol) and 1,2,3,4- Tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (75.2 mg, 0.43 mmol) was added to DMF (5 mL) and N,N-diisopropylethylamine (168.3 mmol) was added dropwise mg, 1.30 mmol), then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (108.2 mg, 0.56 mmol) and 1-hydroxybenzotriazole ( 11.7 mg, 0.09 mmol), under N 2, at room temperature overnight.
反应结束，加水(100毫升)稀释，用MeOH:DCM＝1:10的混合溶剂萃取(30毫升×3次)，合并有机相，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得到61.1毫克黄色固体(S)-5-环丙基-5-(3-(3,4-二氢苯并[4,5]咪唑并[1,2-a]吡嗪-2(1H)-基)-3-氧丙基)咪唑啉-2,4-二酮(收率：38.3％)。LCMS:RT＝1.47min,[M+H] +＝368.26。 1H NMR(500MHz,DMSO-d 6)δ(ppm):10.62(s,1H),7.86–7.75(m,2H),7.72(s,1H),7.54–7.46(m,2H),5.09(s,1H),5.06(d,J＝7.5Hz,1H),4.41–4.38(m,1H),4.27–4.24(m,1H),4.08–4.06(m,2H),2.86–2.71(m,1H),2.46–2.34(m,1H),2.03–1.96(m,2H),1.16–1.08(m,1H),0.50–0.42(m,1H),0.40–0.26(m,2H),0.15–0.07(m,1H)。 After the reaction was completed, water (100 mL) was added to dilute, and the mixture was extracted with a mixed solvent of MeOH:DCM=1:10 (30 mL×3 times), the organic phases were combined, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20). 61.1 mg of yellow solid (S)-5-cyclopropyl-5-(3-(3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H) was obtained -yl)-3-oxopropyl)imidazoline-2,4-dione (yield: 38.3%). LCMS: RT=1.47 min, [M+H] + =368.26. 1 H NMR (500MHz, DMSO-d 6 )δ(ppm): 10.62(s, 1H), 7.86-7.75(m, 2H), 7.72(s, 1H), 7.54-7.46(m, 2H), 5.09( s, 1H), 5.06 (d, J=7.5Hz, 1H), 4.41–4.38 (m, 1H), 4.27–4.24 (m, 1H), 4.08–4.06 (m, 2H), 2.86–2.71 (m, 1H), 2.46–2.34 (m, 1H), 2.03–1.96 (m, 2H), 1.16–1.08 (m, 1H), 0.50–0.42 (m, 1H), 0.40–0.26 (m, 2H), 0.15– 0.07(m, 1H).
实施例54Example 54
54.1化合物对人ADAMTS5抑制活性54.1 Inhibitory activity of compounds on human ADAMTS5
(1)主要实验材料(1) Main experimental materials
酶：人ADAMTS5(R&D systems，货号：2198-AD)；Enzyme: human ADAMTS5 (R&D systems, product number: 2198-AD);
底物：WAAG-3R(Anaspec，货号：60431-1)；Substrate: WAAG-3R (Anaspec, Cat. No. 60431-1);
检测缓冲液：50mM Tris,100mM NaCl,5mM CaCl2,0.05％Brij35,pH 7.5Assay buffer: 50mM Tris, 100mM NaCl, 5mM CaCl2, 0.05% Brij35, pH 7.5
(2)实验步骤(2) Experimental steps
将化合物溶于DMSO配制为30或100mM储备液。检测时设置8个浓度梯度，首先采用DMSO将储备液浓度调整至3或3.33mM，即可得最高浓度，采用DMSO从最高浓度以1/3梯度稀释得到其余7个浓度。然后从一系列DMSO稀释液中分别取2μl加入198μl缓冲液，得到最高浓度30或33.3μM的化合物连续稀释液。Compounds were dissolved in DMSO to make 30 or 100 mM stock solutions. 8 concentration gradients were set during the detection. First, the concentration of the stock solution was adjusted to 3 or 3.33 mM with DMSO to obtain the highest concentration, and the remaining 7 concentrations were obtained by 1/3 gradient dilution from the highest concentration with DMSO. 2 μl of each of the series of DMSO dilutions were then added to 198 μl of buffer, resulting in serial dilutions of compound at the highest concentration of 30 or 33.3 μM.
将5μl人ADAMTS5酶溶液(30μg/ml)和5μl化合物的连续稀释液加入到384孔板(CISBIO，货号：6008280)中，并在37℃下孵育30min，然后加入5μl缓冲液稀释的底物(75μM)引发反应，在37℃条件下，采用FLUOstar Omega(BMG LABTECH)读取荧光30min(激发波长355nm，发射波长460nm)。5 μl of human ADAMTS5 enzyme solution (30 μg/ml) and 5 μl of serial dilutions of compounds were added to a 384-well plate (CISBIO, Cat. No. 6008280) and incubated at 37°C for 30 min, followed by addition of 5 μl of buffer-diluted substrate ( 75μM) to initiate the reaction, and at 37°C, the fluorescence was read by FLUOstar Omega (BMG LABTECH) for 30min (excitation wavelength 355nm, emission wavelength 460nm).
(3)数据处理(3) Data processing
以化合物浓度的对数值为横坐标，抑制率为纵坐标，采用GraphPad 6拟合后计算IC 50值。 Logarithmic value of compound concentration as abscissa, ordinate inhibition rate, calculated using IC 50 values GraphPad 6 after fitting.
表1本发明化合物对人ADAMTS5的效力Table 1 Efficacy of compounds of the present invention on human ADAMTS5
Figure PCTCN2021105088-appb-000258
Figure PCTCN2021105088-appb-000258
54.2化合物对人MMP-9抑制活性54.2 Inhibitory activity of compounds on human MMP-9
(1)实验材料(1) Experimental materials
酶：人MMP-9(R&D systems，货号：911-MP)；Enzyme: human MMP-9 (R&D systems, catalog number: 911-MP);
底物：MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH2(R&D systems，货号：ES001)；Substrate: MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH2 (R&D systems, Cat. No. ES001);
检测缓冲液：50mM Tris,10mM CaCl2,150mM NaCl,0.05％(w/v)Brij-35,pH 7.5(TCNB)。Assay buffer: 50 mM Tris, 10 mM CaCl2, 150 mM NaCl, 0.05% (w/v) Brij-35, pH 7.5 (TCNB).
(2)实验步骤(2) Experimental steps
将化合物溶于DMSO配制为30或100mM储备液，检测时设置8个浓度梯度，首先采用DMSO将储备液浓度调整至30或33.3mM，即可得最高浓度，采用DMSO从最高浓度以1/3梯度稀释得到其余7个浓度。然后从一系列DMSO稀释液中分别取2μl加入198μl缓冲液，得得到最高浓度300或333.3μM的化合物连续稀释液。The compound was dissolved in DMSO to prepare a 30 or 100 mM stock solution, and 8 concentration gradients were set during the detection. First, the concentration of the stock solution was adjusted to 30 or 33.3 mM with DMSO, and the highest concentration was obtained. Use DMSO from the highest concentration to 1/3 The remaining 7 concentrations were obtained by serial dilution. 2 μl of each of the series of DMSO dilutions were then added to 198 μl of buffer to obtain serial dilutions of the compound at the highest concentration of 300 or 333.3 μM.
将5μl人MMP-9酶溶液(0.2μg/ml，提前采用1mM APMA37℃孵育24h激活)和5μl化合物的连续稀释液加入到384孔板(CISBIO，货号：6008280)中，并在37℃下孵育20min，然后加入5μl缓冲液稀释的底物(30μM)引发反应，在37℃条件下，采用FLUOstar Omega(BMG LABTECH)读取荧光20min(激发波长340nm，发射波长420nm)。Add 5 μl of human MMP-9 enzyme solution (0.2 μg/ml, activated with 1 mM APMA at 37°C for 24h in advance) and 5 μl of compound serial dilutions into a 384-well plate (CISBIO, Cat. No. 6008280) and incubate at 37°C After 20 min, 5 μl of buffer diluted substrate (30 μM) was added to initiate the reaction, and at 37°C, the fluorescence was read by FLUOstar Omega (BMG LABTECH) for 20 min (excitation wavelength 340 nm, emission wavelength 420 nm).
(3)数据处理(3) Data processing
以化合物浓度的对数值为横坐标，抑制率为纵坐标，采用GraphPad 6拟合后计算IC50值。Taking the logarithmic value of the compound concentration as the abscissa and the inhibition rate as the ordinate, the IC50 value was calculated after fitting with GraphPad 6.
表8本发明化合物对人MMP-9的效力Table 8 Efficacy of compounds of the present invention on human MMP-9
Figure PCTCN2021105088-appb-000259
Figure PCTCN2021105088-appb-000259
从上述结果可见，本发明化合物表现优异的ADAMTS5抑制活性，同时，相对于MMP-9具有更好的选择性。From the above results, it can be seen that the compounds of the present invention exhibit excellent ADAMTS5 inhibitory activity, and at the same time, have better selectivity relative to MMP-9.
实施例55：本发明化合物的大鼠药代动力学特征考察Example 55: Investigation of the rat pharmacokinetic characteristics of the compounds of the present invention
(1).实验材料(1). Experimental materials
SD大鼠：雄性，180-250g，购于广东省医学实验动物中心。SD rats: male, 180-250 g, purchased from Guangdong Medical Laboratory Animal Center.
试剂：DMSO(二甲亚砜)，PEG-400(聚乙二醇400)，生理盐水，肝素，乙腈，甲酸，普萘洛尔(内标)均为市售可得。Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, and propranolol (internal standard) are commercially available.
仪器：赛默飞LC-MS(U300 UPLC，TSQ QUANTUMN ULTRA三重四级杆质谱)。Instrument: Thermo Fisher Scientific LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometry).
(2).实验方法(2). Experimental method
称取化合物溶于DMSO-PEG-400-生理盐水(5：60：35，v/v/v)体系中，大鼠静脉或灌胃给药后，于5min、15min、30min、1h、2h、5h、7h、24h采集静脉血200μL于肝素化EP管中，12000rpm离心2min，取血浆-80℃冻存待测。精密称取一定量供试品用DMSO溶解至1mg/mL，作为储备液。准确吸取适量的化合物储备液，加入乙腈稀释制成标准系列溶液。准确吸取上述标准系列溶液各20μL，加入空白血浆180μL，涡旋混匀，配制成相当于血浆浓度为0.3、1、3、10、30、100、300、1000、3000ng/mL的血浆样品，每一浓度进行双样本分析，建立标准曲线。取20μL血浆(静脉给药5min、15min、30min、1h血浆稀释10倍)，加入内标普萘洛尔(5ng/mL)的乙腈溶液200μL，涡旋混匀后4000rpm离心5min，取上清LC-MS分析。LC-MS检测条件如下：The compound was weighed and dissolved in DMSO-PEG-400-physiological saline (5:60:35, v/v/v) system. After intravenous or intragastric administration to rats, 5min, 15min, 30min, 1h, 2h, 5min, 15min, 30min, 1h, 2h, 200 μL of venous blood was collected at 5 h, 7 h, and 24 h into heparinized EP tubes, centrifuged at 12,000 rpm for 2 min, and the plasma was frozen at -80°C for testing. Precisely weigh a certain amount of the test sample and dissolve it in DMSO to 1 mg/mL as a stock solution. Accurately draw an appropriate amount of compound stock solution, add acetonitrile and dilute to make standard series solutions. Accurately aspirate 20 μL of each of the above standard series solutions, add 180 μL of blank plasma, vortex and mix to prepare plasma samples with plasma concentrations of 0.3, 1, 3, 10, 30, 100, 300, 1000, and 3000 ng/mL. A two-sample analysis was performed at one concentration, and a standard curve was established. Take 20 μL of plasma (intravenous administration of 5min, 15min, 30min, 1h plasma dilution 10 times), add 200μL of acetonitrile solution of internal standard propranolol (5ng/mL), vortex and mix, centrifuge at 4000rpm for 5min, take the supernatant LC - MS analysis. LC-MS detection conditions are as follows:
色谱柱：赛默飞HYPERSIL GOLD C-18 UPLC柱，100*2.1mm，1.9μm。Chromatographic column: Thermo Scientific HYPERSIL GOLD C-18 UPLC column, 100*2.1mm, 1.9μm.
流动相：水(0.1％甲酸)-乙腈按下表进行梯度洗脱Mobile phase: water (0.1% formic acid)-acetonitrile for gradient elution according to the following table
时间(min)time (min) 水(含0.1％甲酸)Water (with 0.1% formic acid) 乙腈Acetonitrile
00 90％90% 10％10%
0.60.6 90％90% 10％10%
11 10％10% 90％90%
2.62.6 10％10% 90％90%
2.612.61 90％90% 10％10%
44 90％90% 10％10%
(3).数据处理(3). Data processing
LC-MS检测血药浓度后，采用WinNonlin 6.1软件，非房室模型法计算药动学参数，结果见表11。After LC-MS detection of blood drug concentration, WinNonlin 6.1 software was used to calculate pharmacokinetic parameters by non-compartmental model method. The results are shown in Table 11.
表11本发明化合物的大鼠药代动力学参数(IV及PO给药)Table 11 Rat pharmacokinetic parameters of compounds of the present invention (IV and PO administration)
Figure PCTCN2021105088-appb-000260
Figure PCTCN2021105088-appb-000260
结论：本发明化合物在大鼠口服给药后吸收较好，清除率慢于对照化合物，表观分布容积大于对照化合物，口服生物利用度好。Conclusion: The compound of the present invention has better absorption after oral administration in rats, the clearance rate is slower than that of the control compound, the apparent volume of distribution is larger than that of the control compound, and the oral bioavailability is good.
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, The simplification should be equivalent replacement manners, which are all included in the protection scope of the present invention.

Claims (18)

  1. 并三环类衍生物，其特征在于，所述衍生选自式(I)、(II)、(III)、(VI)的并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐：A tricyclic derivative, characterized in that the derivative is selected from the tricyclic derivative of formula (I), (II), (III), (VI) or its stereoisomers, tautomers In vivo, pharmaceutically acceptable salts:
    Figure PCTCN2021105088-appb-100001
    Figure PCTCN2021105088-appb-100001
    其中：in:
    X选自碳、氮；X is selected from carbon, nitrogen;
    Y选自碳、氮、氧；Y is selected from carbon, nitrogen, oxygen;
    Z选自碳、氮、氧；Z is selected from carbon, nitrogen, oxygen;
    T 1、T 2、T 3、T 4分别选自碳、氮、硫； T 1 , T 2 , T 3 and T 4 are respectively selected from carbon, nitrogen and sulfur;
    Figure PCTCN2021105088-appb-100002
    代表单键或者双键；
    Figure PCTCN2021105088-appb-100002
    Represents a single bond or a double bond;
    其中，A环和B环上未有取代基，或者A环和/或B环上一个以上氢独立的被一个或多个卤素、C 1-6的烷基、卤代C 1-6的烷基、C 1-6的烷氧基、卤代C 1-6的烷氧基所取代； Wherein, there is no substituent on ring A and ring B, or one or more hydrogens on ring A and/or ring B are independently replaced by one or more halogens, C 1-6 alkyl, halogenated C 1-6 alkyl substituted by alkoxy group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group;
    C环被一个以上R 1所取代，R 1选自： A C ring is substituted by R 1 above, R 1 is selected from:
    氢，hydrogen,
    卤素，halogen,
    氰基，cyano,
    C 1-6的烷基， C 1-6 alkyl,
    卤代C 1-6的烷基， halogenated C 1-6 alkyl,
    C 1-6的烷氧基， C 1-6 alkoxy,
    卤代C 1-6的烷氧基， Halogenated C 1-6 alkoxy,
    硝基，nitro,
    酰胺基，amide group,
    苯基，phenyl,
    卤代苯基，halophenyl,
    包含1、2或3个独立地选自N、O和S的杂原子的5-12元单环或稠合二环杂芳基、或其任选地被一个或多个独立选择的卤素、C 1-6烷基、C 1-6烷氧基取代，或 5-12 membered monocyclic or fused bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or optionally halogen, independently selected by one or more, C 1-6 alkyl, C 1-6 alkoxy substituted, or
    -NR 7gR 7h； -NR 7g R 7h ;
    R 2选自： R 2 is selected from:
    -氢，-hydrogen,
    C 1-6烷基或其任选地被一个或多个独立选择的R 3基团取代， Or C 1-6 alkyl optionally substituted with one or more independently selected R 3 groups,
    C 3-7单环环烷基或其任选地被一个或多个独立选择的R 3基团取代， C 3-7 monocyclic cycloalkyl or its optionally substituted with one or more independently selected R 3 groups,
    包含1至2个独立地选自N、O和S的杂原子的4-7元单环杂环烷基、或该单环杂环烷基任选地被一个或多个独立选择的C 1-6烷基、-C(＝O)C 1-6烷基或-C(＝O)OC 1-6烷基取代， Containing 1 to 2 substituents independently selected from N, 4-7 membered monocyclic heterocycloalkyl group of O and S, or the monocyclic heterocycloalkyl are optionally substituted with one or more independently selected a C 1 -6 alkyl, -C(=O)C 1-6 alkyl or -C(=O)OC 1-6 alkyl substituted,
    苯基或其任选地被一个或多个独立选择的R 4基团取代， Or phenyl optionally substituted with one or more independently selected R 4 groups,
    稠合至包含1、2或3个独立地选自N、O和S的杂原子的5-6元单环杂环烷基的苯基、或该杂环烷基任选地被一个或多个＝O取代，或phenyl fused to a 5-6 membered monocyclic heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or the heterocycloalkyl is optionally substituted by one or more =O substitution, or
    包含1或2个独立地选自N、O和S的杂原子的5-6元单环杂芳基、或该单环杂芳基任选地被一个或多个独立选择的R 4基团取代； Comprising 1 or 2 heteroatoms independently selected from N, 5-6 membered hetero atoms O and S, aryl, monocyclic heteroaryl, or monocyclic heteroaryl which is optionally substituted with one or more independently selected R 4 group replace;
    R 3选自： R 3 is selected from:
    卤素，halogen,
    羟基，hydroxyl,
    氰基，cyano,
    C 1-6烷基， C 1-6 alkyl,
    C 1-6烷氧基或其任选地被C 1-6烷氧基或苯基取代， C 1-6 alkoxy or optionally substituted by C 1-6 alkoxy or phenyl,
    C 1-6硫代烷氧基， C 1-6 thioalkoxy,
    包含一个或多个独立地选自N、S和O的杂原子的4-7元单环杂环烷基、或该单环杂环烷基任选地被一个或多个卤素或-C(＝O)OC 1-6烷基取代， A 4-7 membered monocyclic heterocycloalkyl containing one or more heteroatoms independently selected from N, S and O, or the monocyclic heterocycloalkyl optionally substituted by one or more halogen or -C( =O)OC 1-6 alkyl substitution,
    苯基，phenyl,
    -S(＝O) 2C 1-6烷基， -S(=O) 2 C 1-6 alkyl,
    -C(＝O)OR 5a， -C(=O)OR 5a ,
    -C(＝O)NR 5bR 5c， -C(=O)NR 5b R 5c ,
    -NHC(＝O)OR 5d， -NHC(=O)OR 5d ,
    -NHC(＝O)R 5e，或 -NHC(=O)R 5e , or
    -NR 6aR 6b； -NR 6a R 6b ;
    R 4选自： R 4 is selected from:
    卤素，halogen,
    羟基，hydroxyl,
    氰基，cyano,
    C 1-6烷基或其任选地被一个或多个独立选择的卤素、-NR 7aR 7b或-C(＝O)NR 7cR 7d取代， C 1-6 alkyl or optionally substituted with one or more independently selected halogen, -NR 7a R 7b or -C(=O)NR 7c R 7d ,
    C 1-6烷氧基或其任选地被-NR 7eR 7f取代，或 C 1-6 alkoxy or optionally substituted by -NR 7e R 7f , or
    -S(＝O) 2C 1-6烷基； -S(=O) 2 C 1-6 alkyl;
    R 5a、R 5b、R 5c、R 5d或R 5e独立地选自： R 5a , R 5b , R 5c , R 5d or R 5e are independently selected from:
    -氢，或- hydrogen, or
    -C 1-6烷基或其任选地被OH或C 1-6烷氧基取代， -C 1-6 alkyl or optionally substituted by OH or C 1-6 alkoxy,
    R 6a或R 6b独立地选自： R 6a or R 6b are independently selected from:
    -氢，或- hydrogen, or
    -C 1-6烷基或其任选地被OH、C 1-6烷氧基或苯基取代； -C 1-6 alkyl or optionally substituted with OH, C 1-6 alkoxy or phenyl;
    R 7a、R 7b、R 7c、R 7d、R 7e、R 7f、R 7g或R 7h独立地选自H或C 1-6烷基； R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g or R 7h are independently selected from H or C 1-6 alkyl;
    n＝0～2自然数；n=0～2 natural numbers;
    m＝0～4自然数。m=0～4 natural numbers.
  2. 根据权利要求1所述的并三环类衍生物，其特征在于，所述衍生物选自式(Ia)、(IIa)、(IIIa)、(VIa)的并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐，The no-tricyclic derivative according to claim 1, wherein the derivative is selected from the group consisting of the no-tricyclic derivatives of formula (Ia), (IIa), (IIIa), (VIa) or stereotaxic derivatives thereof Isomers, tautomers, pharmaceutically acceptable salts,
    Figure PCTCN2021105088-appb-100003
    Figure PCTCN2021105088-appb-100003
    其中，Y、Z、T 1、T 2、T 3、T 4、R 1、m、n如上定义。 Wherein, Y, Z, T 1 , T 2 , T 3 , T 4 , R 1 , m, and n are as defined above.
  3. 根据权利要求1所述的并三环类衍生物，其特征在于，所述衍生物选自式(Ib)、(IIb)、(IIIb)、(VIb)的并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐，The natricyclic derivative according to claim 1, wherein the derivative is selected from the natricyclic derivative of formula (Ib), (IIb), (IIIb), (VIb) or its stereotaxic Isomers, tautomers, pharmaceutically acceptable salts,
    Figure PCTCN2021105088-appb-100004
    Figure PCTCN2021105088-appb-100004
    其中，Y、Z、T 1、T 2、T 3、T 4、R 1、m、n如上定义。 Wherein, Y, Z, T 1 , T 2 , T 3 , T 4 , R 1 , m, and n are as defined above.
  4. 根据权利要求1所述的并三环类衍生物，其特征在于，所述衍生物选自式(Ic)、(Id)、(Ie)、(If)、(Ig)、(Ih)、(Ii)、(IIc)、(IId)、(IIIc)的并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐，The tricyclic derivative according to claim 1, wherein the derivative is selected from the group consisting of formula (Ic), (Id), (Ie), (If), (Ig), (Ih), ( Ii), (IIc), (IId), (IIIc) and tricyclic derivatives or stereoisomers, tautomers, pharmaceutically acceptable salts thereof,
    Figure PCTCN2021105088-appb-100005
    Figure PCTCN2021105088-appb-100005
    其中，R 1、m如上定义，R 8独立地选自H或C 1-6烷基。 wherein, R 1 and m are as defined above, and R 8 is independently selected from H or C 1-6 alkyl.
  5. 根据权利要求1所述的并三环类衍生物，其特征在于，所述衍生物选自式(Ij)、(Ik)的并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐，The no-tricyclic derivatives according to claim 1, wherein the derivatives are selected from the no-tricyclic derivatives of formula (Ij), (Ik) or their stereoisomers, tautomers body, a pharmaceutically acceptable salt,
    Figure PCTCN2021105088-appb-100006
    Figure PCTCN2021105088-appb-100006
    R 1、m如上定义。 R 1 , m are as defined above.
  6. 根据权利要求1所述的并三环类衍生物，其特征在于，The no-tricyclic derivative according to claim 1, wherein:
    所述卤素为氟、氯、溴、碘；Described halogen is fluorine, chlorine, bromine, iodine;
    所述C 1-6的烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、仲戊基、叔戊基、正己基、异己基、新己基、仲己基、叔己基； The C 1-6 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, new Amyl, sec-amyl, tert-amyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl;
    所述C 1-6的烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基、新戊氧基、仲戊氧基、叔戊氧基、正己氧基、异己氧基、新己氧基、仲己氧基、叔己氧基； The C 1-6 alkoxy is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-butoxy pentyloxy, isopentyloxy, neopentyloxy, sec-pentyloxy, tert-amyloxy, n-hexyloxy, isohexyloxy, neohexyloxy, sec-hexyloxy, tert-hexyloxy;
    所述C 3-7单环环烷基选自环丙基、环丁基、环戊基、环己基、环庚基； The C 3-7 monocyclic cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl;
    所述5-12元单环或稠合二环杂芳基选自吡咯基、呋喃基、噻吩基、咪唑基、呋咱基、噁唑基、噁二唑基、噁三唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、三唑基、四唑基；吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基；咪唑并噻唑基、咪唑并咪唑基；苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、异苯并噁唑基、苯并异唑基、苯并噻唑基、苯并异噻唑基、异苯并呋喃基、吲哚基、异吲哚基、吲哚嗪基、嘌呤基、吲唑基、吡唑并嘧啶基、三唑并嘧啶基和吡唑并吡啶基；喹啉基、异喹啉基、吡啶并吡啶基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基、萘啶基和喋啶基；以及基、吡咯基、苯并噻吩基、苯并呋喃基、吲哚基、吡啶基、喹啉基、咪唑基、噁唑基和吡嗪基。The 5-12-membered monocyclic or fused bicyclic heteroaryl is selected from pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxalyl azolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl; pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl; imidazothiazolyl, imidazoimidazolyl; benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl , indolyl, isoindolyl, indolazinyl, purinyl, indazolyl, pyrazolopyrimidinyl, triazolopyrimidyl and pyrazolopyridyl; quinolinyl, isoquinolinyl, pyridine pyridyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridyl; and radicals, pyrrolyl, benzothienyl, benzofuranyl, indolyl, Pyridyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.
  7. 根据权利要求1所述的并三环类衍生物，其特征在于，R 1选自氟、氯、溴，甲氧基、
    Figure PCTCN2021105088-appb-100007
    三氟甲基、氰基；R 2选自环丙基，n＝0～2自然数；m＝0～4自然数。     The tricyclic derivative according to claim 1, wherein R 1 is selected from fluorine, chlorine, bromine, methoxy,
    Figure PCTCN2021105088-appb-100007
    Trifluoromethyl group, cyano group; R 2 is selected from cyclopropyl group, n=0～2 natural number; m=0～4 natural number.
  8. 根据权利要求2或3所述的并三环类衍生物，其特征在于，Y选自碳；Z选自碳、氮、氧；T 1、T 2、T 3、T 4分别选自碳、硫；
    Figure PCTCN2021105088-appb-100008
    代表单键或者双键；R 1选自氢、氟、氯、溴，甲氧基、
    Figure PCTCN2021105088-appb-100009
    三氟甲基、氰基；n＝0～2自然数；m＝0～4自然数。     The tricyclic derivative according to claim 2 or 3, wherein Y is selected from carbon; Z is selected from carbon, nitrogen, oxygen; T 1 , T 2 , T 3 , T 4 are respectively selected from carbon, sulfur;
    Figure PCTCN2021105088-appb-100008
    Represents a single bond or a double bond; R 1 is selected from hydrogen, fluorine, chlorine, bromine, methoxy,
    Figure PCTCN2021105088-appb-100009
    Trifluoromethyl group, cyano group; n=0～2 natural number; m=0～4 natural number.
  9. 根据权利要求4所述的并三环类衍生物，其特征在于，R 1选自氢、氟、氯、溴，甲氧基、
    Figure PCTCN2021105088-appb-100010
    三氟甲基、氰基；m＝0～4自然数；R 8选自H、甲基。     The tricyclic derivative according to claim 4, wherein R 1 is selected from hydrogen, fluorine, chlorine, bromine, methoxy,
    Figure PCTCN2021105088-appb-100010
    Trifluoromethyl group, cyano group; m=0～4 natural number; R 8 is selected from H, methyl group.
  10. 根据权利要求5所述的并三环类衍生物，其特征在于，R 1选自氢、氟、氯、溴，甲氧基、
    Figure PCTCN2021105088-appb-100011
    三氟甲基、氰基；m＝0～4自然数。     The tricyclic derivative according to claim 5, wherein R 1 is selected from hydrogen, fluorine, chlorine, bromine, methoxy,
    Figure PCTCN2021105088-appb-100011
    Trifluoromethyl, cyano group; m=0～4 natural number.
  11. 根据权利要求1所述的并三环类衍生物，其特征在于，所述衍生物选自下表中所示并三环类衍生物或其立体异构体、互变异构体、药学上可接受的盐，The no-tricyclic derivatives according to claim 1, wherein the derivatives are selected from the no-tricyclic derivatives shown in the following table or their stereoisomers, tautomers, pharmaceutically acceptable salt,
    Figure PCTCN2021105088-appb-100012
    Figure PCTCN2021105088-appb-100012
    Figure PCTCN2021105088-appb-100013
    Figure PCTCN2021105088-appb-100013
    Figure PCTCN2021105088-appb-100014
    Figure PCTCN2021105088-appb-100014
    Figure PCTCN2021105088-appb-100015
    Figure PCTCN2021105088-appb-100015
    Figure PCTCN2021105088-appb-100016
    Figure PCTCN2021105088-appb-100016
  12. 根据权利要求1-11任意一项所述的并三环类衍生物，其特征在于，所述药学上可接受的盐选自无机酸或有机酸成盐。The no-tricyclic derivative according to any one of claims 1-11, wherein the pharmaceutically acceptable salt is selected from inorganic acid or organic acid salt.
  13. 根据权利要求1-12任意一项所述的并三环类衍生物，其特征在于，所述并三环类衍生物的一个或多个氢原子上被同位素氘取代。The no-tricyclic derivative according to any one of claims 1-12, wherein one or more hydrogen atoms of the no-tricyclic derivative are substituted with isotopic deuterium.
  14. 一种药物组合物，其特征在于，包括前述权利要求1-13任意一项所述并三环类衍生物和一种以上药学上可接受的载体。A pharmaceutical composition, characterized by comprising the tricyclic derivatives according to any one of the preceding claims 1-13 and one or more pharmaceutically acceptable carriers.
  15. 根据权利要求1-13任意一项所述并三环类衍生物在制备用于治疗和/或预防蛋白聚糖酶2抑制相关疾病的药物方面的用途。Use of the tricyclic derivatives according to any one of claims 1 to 13 in preparing a medicament for treating and/or preventing diseases related to proteoglycanase 2 inhibition.
  16. 根据权利要求14所述药物组合物在制备用于治疗和/或预防蛋白聚糖酶2抑制相关疾病的药物方面的用途。Use of the pharmaceutical composition according to claim 14 in preparing a medicament for the treatment and/or prevention of a disease related to proteoglycanase 2 inhibition.
  17. 根据权利要求15或16所述的用途，其中所述疾病涉及炎症状况和/或软骨退化和/或软骨稳态破坏。Use according to claim 15 or 16, wherein the disease involves an inflammatory condition and/or cartilage degeneration and/or disruption of cartilage homeostasis.
  18. 根据权利要求15或16所述的用途，其中所述疾病是骨质疏松、糖皮质激素诱导的骨质疏松、佩吉特氏病、骨更新异常增加、牙周疾病、牙损失、骨折、类风湿性关节炎、骨关节炎、假体周围骨质溶解、骨生成不完全、转移性骨疾病、恶性高钙血症或多发性骨髓瘤。Use according to claim 15 or 16, wherein the disease is osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, fractures, Rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, malignant hypercalcemia, or multiple myeloma.
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