WO2022007866A1 - Dérivé tricyclique condensé, son procédé de préparation et son application pharmaceutique - Google Patents

Dérivé tricyclique condensé, son procédé de préparation et son application pharmaceutique Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
tert
reaction
room temperature
synthesis
Prior art date
Application number
PCT/CN2021/105088
Other languages
English (en)
Chinese (zh)
Inventor
吴俊军
陆银锁
肖瑛
吴建立
洪泽新
段振芳
Original Assignee
深圳信立泰药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 深圳信立泰药业股份有限公司 filed Critical 深圳信立泰药业股份有限公司
Priority to CN202180044456.6A priority Critical patent/CN115720578A/zh
Publication of WO2022007866A1 publication Critical patent/WO2022007866A1/fr

Links

Images

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé tricyclique condensé relatif au domaine technique des médicaments chimiques, son procédé de préparation et une application pharmaceutique de celui-ci. Le dérivé tricyclique condensé est un inhibiteur de l'aggrécanase-2 (ADAMTS-5). L'invention concerne également une composition pharmaceutique comprenant le composé et une utilisation du composé dans la préparation d'un médicament pour le traitement de maladies telles que l'arthrose.
PCT/CN2021/105088 2020-07-09 2021-07-08 Dérivé tricyclique condensé, son procédé de préparation et son application pharmaceutique WO2022007866A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202180044456.6A CN115720578A (zh) 2020-07-09 2021-07-08 并三环类衍生物、其制备方法及其在医药上的应用

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202010657928.2 2020-07-09
CN202010657928 2020-07-09
CN202110171283.6 2021-02-07
CN202110171283 2021-02-07

Publications (1)

Publication Number Publication Date
WO2022007866A1 true WO2022007866A1 (fr) 2022-01-13

Family

ID=79552276

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/105088 WO2022007866A1 (fr) 2020-07-09 2021-07-08 Dérivé tricyclique condensé, son procédé de préparation et son application pharmaceutique

Country Status (2)

Country Link
CN (1) CN115720578A (fr)
WO (1) WO2022007866A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023137634A1 (fr) * 2022-01-19 2023-07-27 上海奕拓医药科技有限责任公司 Composé tricyclique, sa préparation, composition pharmaceutique et utilisation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1509286A (zh) * 2001-03-15 2004-06-30 金属蛋白酶抑制剂
WO2010036638A2 (fr) * 2008-09-24 2010-04-01 Schering Corporation Composés pour traiter des troubles inflammatoires
CN104755464A (zh) * 2012-10-26 2015-07-01 伊莱利利公司 聚蛋白多糖酶抑制剂
CN107108579A (zh) * 2014-12-22 2017-08-29 加拉帕戈斯股份有限公司 作为adamts抑制剂用于治疗骨关节炎的5‑[(哌嗪‑1‑基)‑3‑氧代‑丙基]‑咪唑烷‑2,4‑二酮衍生物
WO2017211666A1 (fr) * 2016-06-09 2017-12-14 Galapagos Nv Dérivés de 5-[3-[pipérazin-1-yl]-3-oxo-propyl]-imidazolidine-2,4-dione à utiliser en tant qu'inhibiteurs d'adamts 4 et 5 pour traiter par exemple l'arthrose

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1509286A (zh) * 2001-03-15 2004-06-30 金属蛋白酶抑制剂
WO2010036638A2 (fr) * 2008-09-24 2010-04-01 Schering Corporation Composés pour traiter des troubles inflammatoires
CN104755464A (zh) * 2012-10-26 2015-07-01 伊莱利利公司 聚蛋白多糖酶抑制剂
CN107108579A (zh) * 2014-12-22 2017-08-29 加拉帕戈斯股份有限公司 作为adamts抑制剂用于治疗骨关节炎的5‑[(哌嗪‑1‑基)‑3‑氧代‑丙基]‑咪唑烷‑2,4‑二酮衍生物
WO2017211666A1 (fr) * 2016-06-09 2017-12-14 Galapagos Nv Dérivés de 5-[3-[pipérazin-1-yl]-3-oxo-propyl]-imidazolidine-2,4-dione à utiliser en tant qu'inhibiteurs d'adamts 4 et 5 pour traiter par exemple l'arthrose

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 13 June 2012 (2012-06-13), ANONYMOUS : " 2,4-Imidazolidinedione, 5-[3-(8-chloro-1,3,4,5-tetrahydro-2H-pyrido[4,3- b]indol-2-yl)-3-oxopropyl]- (CA INDEX NAME) ", XP055885902, retrieved from STN Database accession no. 1377844-59-1 *
DATABASE REGISTRY 13 June 2012 (2012-06-13), ANONYMOUS : "2,4-Imidazolidinedione, 5-[3-(6-chloro-1,3,4,5-tetrahydro-2H-pyrido[4,3- b]indol-2-yl)-3-oxopropyl]- (CA INDEX NAME)", XP055885900, retrieved from STN Database accession no. 1377847-04-5 *
DATABASE REGISTRY 17 March 2013 (2013-03-17), ANONYMOUS : "2,4-Imidazolidinedione, 5-[3-oxo-3-(1,3,4,5-tetrahydro-6-methyl-2Hpyrido[4,3-b]indol-2-yl)propyl]- (CA INDEX NAME)", XP055885897, retrieved from STN Database accession no. 1422567-25-6 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023137634A1 (fr) * 2022-01-19 2023-07-27 上海奕拓医药科技有限责任公司 Composé tricyclique, sa préparation, composition pharmaceutique et utilisation

Also Published As

Publication number Publication date
CN115720578A (zh) 2023-02-28

Similar Documents

Publication Publication Date Title
KR100883003B1 (ko) 알츠하이머병의 치료를 위한 글라이신 수송체1(ｇｌｙｔ-1) 억제제로서 바이- 및 트라이사이클릭 치환된페닐 메탄온
KR102473481B1 (ko) 강력하고 선택적인 rock 억제제로서의 락탐, 시클릭 우레아 및 카르바메이트, 및 트리아졸론 유도체
AU2007248603B2 (en) Pyrido [2, 3-b] pyrazine and [1, 8] -naphthyridine derivatives as ALK and c-Met inhibitors
KR102491994B1 (ko) Rock의 억제제로서의 스피로락탐
CN105814047B (zh) 作为tnf活性调节剂的稠合三环咪唑衍生物
CA2477967C (fr) Derives de la purine en tant qu'inhibiteurs de la kinase
CA3016182A1 (fr) Inhibiteurs d'indoles mcl-1 substitues
US8183238B2 (en) Bicyclic and tricyclic compounds as KAT II inhibitors
CA3010900A1 (fr) Salicylamides de spiroheptane et composes associes utilises comme inhibiteurs de rock
ES2734268T3 (es) Derivados de urea y amida de aminoalquilpiperazinas y uso de los mismos
KR20160012194A (ko) 이미다조피롤리디논 유도체 및 질환의 치료에서의 그의 용도
AU2003221500B2 (en) Heteroaryl substituted 2-pyridinyl and 2-pyrimidinyl -6,7,8,9-tetrahydropyrimido[1,2-a] pyrimidin-4-one derivatives
JP2003533524A (ja) ホスホジエステラーゼ阻害剤として有効な置換ピロロピリジノン誘導体
NZ749946A (en) Novel compound or pharmaceutically acceptable salt thereof
CA3106513A1 (fr) Composes heteroaromatiques utilises en tant qu'inhibiteurs de vanine
CN109195969A (zh) 作为tnf活性调节剂的稠合五环咪唑衍生物
WO2022007866A1 (fr) Dérivé tricyclique condensé, son procédé de préparation et son application pharmaceutique
WO2021204185A1 (fr) Dérivé de benzo[d]azépine en tant qu'inhibiteur de l'aggrécanase-2, son procédé de préparation et son utilisation pharmaceutique
CN109195968A (zh) 作为tnf活性调节剂的稠合五环咪唑衍生物
CA2919147A1 (fr) Derives de pyrroloquinoline utilises comme antagonistes de 5-ht6, leur procede de preparation et leur utilisation
EP4055013B1 (fr) Inhibiteurs et modulateurs de wdr5
JP2011504878A (ja) イミダゾアゼピノン化合物の製造方法
JP2020530023A (ja) 糖尿病の治療のためのｐｄｅ１阻害剤としての［１，２，４］トリアゾロ誘導体
CA3212872A1 (fr) Derives d'indoline utilises en tant qu'inhibiteurs de ddr
TW202321232A (zh) 小分子sting拮抗劑

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21837183

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 15/05/2023)

122 Ep: pct application non-entry in european phase

Ref document number: 21837183

Country of ref document: EP

Kind code of ref document: A1