WO2020083377A1 - Dérivés de pyrrolidinyle-urée et leur application - Google Patents

Dérivés de pyrrolidinyle-urée et leur application Download PDF

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Publication number
WO2020083377A1
WO2020083377A1 PCT/CN2019/113278 CN2019113278W WO2020083377A1 WO 2020083377 A1 WO2020083377 A1 WO 2020083377A1 CN 2019113278 W CN2019113278 W CN 2019113278W WO 2020083377 A1 WO2020083377 A1 WO 2020083377A1
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compound
isomer
pharmaceutically acceptable
solution
acceptable salt
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Chinese (zh)
Inventor
张杨
伍文韬
滕明星
李志祥
李婕
龚珍
黎健
陈曙辉
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Medshine Discovery Inc
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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
    • 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
    • A61K31/415—1,2-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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of TrkA inhibitors and their application in the preparation of drugs for treating TrkA-related diseases. Specifically, it relates to the compounds represented by formula (I) and (II), their isomers and pharmaceutically acceptable salts thereof.
  • Promyosin-related kinase is a high-affinity receptor tyramine activated by a group of soluble growth factors called nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophic factor (NT) Acid kinase, whose family consists of three members (TrkA, TrkB, TrkC).
  • NGF, BDNF, NT-4 / 5 play an important role in many physiological adjustment processes such as signal maintenance of neuronal cells, signal transmission of neuronal cells, cell proliferation, cell differentiation, and cell survival through the receptor Trk.
  • TrkA inhibitors described in the present invention can solve the treatment needs of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
  • Patent WO2015175788 reports compounds having inhibitory activity against TrkA and pharmaceutically acceptable salts thereof (Reference Example 8: Reference compound D1).
  • the present invention provides compounds represented by formula (I), (II), isomers thereof or pharmaceutically acceptable salts thereof,
  • T 1 , T 2 and T 3 are independently selected from N and C (R 3 );
  • X 1 , X 2 and X 3 are independently selected from O, N (R 4 ) and C (R 5 ) (R 6 );
  • Z 1 , Z 2 and Z 3 are independently selected from N and CH;
  • R 1 is selected C 1-6 alkyl and C 1-6 alkoxy, said C 1-6 alkyl and C 1-6 alkoxy optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from C 1-3 alkyl optionally substituted with 1, 2 or 3 R b ;
  • R 3 is independently selected from H, F, Cl, Br, I, OH, and NH 2 ;
  • R 4 is independently selected from H and C 1-3 alkyl optionally substituted with 1, 2 or 3 R c ;
  • R 5 and R 6 are independently selected from H, F, Cl, Br, I, OH, and NH 2 ;
  • n is selected from 1, 2, and 3;
  • R a is selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkyl
  • the oxy group is optionally substituted with 1, 2 or 3 R;
  • R b and R c are independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R is selected from F, Cl, Br, I, OH and NH 2 ;
  • the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
  • the carbon atom with "#" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • R a is selected from H, F, Cl, Br,, OH, NH 2, CN, CH 3 , and CH 3 O, CH 3 a CH 3 O, and optionally substituted with 1,2 Or 3 R substitutions, other variables are as defined in the present invention.
  • R a is selected from H, F, Cl, Br, I, OH, NH 2, CN, CH 3, CH 2 F, CHF 2, CF 3 , and CH 3 O, other variables such as the present Definition of invention.
  • R 1 is selected from CH 3, CH 3 CH 2 and CH 3 O, the CH 3, CH 3 CH 2 and CH 3 O optionally substituted with 1, 2 or 3 R a, Other variables are as defined in the present invention.
  • R 1 is selected from Other variables are as defined in the present invention.
  • R 2 is selected from CH 3 and CH 3 CH 2 , and other variables are as defined in the invention.
  • R 4 is selected from H, CH 3 and CH 3 CH 2 , wherein the CH 3 and CH 3 CH 2 are optionally substituted with 1, 2 or 3 R c , and other variables are as described in the present invention definition.
  • R 4 is selected from H, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 3 CH 2 and Other variables are as defined in the present invention.
  • T 1 , T 2 and T 3 are independently selected from N, CH and CF, and other variables are as defined in the present invention.
  • X 1 , X 2 and X 3 are independently selected from O, N (CH 3 ), NH, CH 2 and Other variables are as defined in the present invention.
  • the above compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • T 1 , T 2 and T 3 are independently selected from N and C (R 3 );
  • D is selected from N (R 4 ) and O;
  • R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
  • the above compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • D is selected from N (R 4 ) and O;
  • R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
  • the present invention also provides the following compounds, isomers or pharmaceutically acceptable salts thereof, which are selected from
  • the above compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • the present invention also provides the use of the above-mentioned compound, its isomer or a pharmaceutically acceptable salt thereof in the preparation of drugs related to the treatment of TrkA inhibitors.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and / or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Bisulfate, hydroiodic acid, phosphorous acid, etc .; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also includes salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups and can be converted to any base or
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the term “isomer” is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers isomer.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers Isomers, (D) -isomers, (L) -isomers, and their racemic mixtures and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers in a mirror image relationship with each other.
  • cis-trans isomer or “geometric isomer” is caused by the fact that double bonds or single bonds of ring-forming carbon atoms cannot rotate freely.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and there is a non-mirror relationship between the molecules.
  • wedge-shaped solid line key And wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
  • using straight solid line keys And straight dotted keys Represents the relative configuration of the three-dimensional center
  • wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid line key And straight dotted keys
  • the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or (A-2) or as two isomers of formula (A-1) and formula (A-2) Exists in the form of a mixture;
  • the following formula (B) indicates that the compound exists as a single isomer of formula (B-1) or formula (B-2) or in both formula (B-1) and formula (B-2) There is a mixture of isomers.
  • the following formula (C) indicates that the compound exists as a single isomer of formula (C-1) or (C-2) or as two isomers of formula (C-1) and formula (C-2) In the form of a mixture.
  • tautomer or “tautomeric form” means that at room temperature, isomers of different functional groups are in dynamic equilibrium and can quickly convert to each other. If tautomers are possible (as in solution), the chemical equilibrium of tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • proton migration such as ketone-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include some recombination of bond-forming electrons for mutual conversion.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “rich in one isomer”, “isomer enriched”, “rich in one enantiomer” or “enantiomerically enriched” refer to one of the isomers or pairs
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater or equal 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the excess of isomer or enantiomer (ee value) is 80% .
  • optically active (R)-and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then by conventional methods known in the art The diastereomers are resolved and the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography, which uses a chiral stationary phase, and is optionally combined with chemical derivatization methods (for example, the formation of amino groups from amines) Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • the hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have lower toxicity and increase drug stability. , Strengthen the efficacy, extend the biological half-life of drugs and other advantages.
  • the conversion of all isotopic compositions of the compounds of the present invention, whether radioactive or not, is included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include heavy hydrogen and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable of.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical realization.
  • any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • R when any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R in each case has independent options.
  • combinations of substituents and / or variants thereof are only allowed if such combinations will produce stable compounds.
  • linking group When the number of a linking group is 0, such as-(CRR) 0- , it means that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is connected are directly connected. For example, when L represents a single bond in A-L-Z, it means that the structure is actually A-Z.
  • substituents listed do not indicate through which atom they are connected to the substituted group, such substituents can be bonded through any of their atoms.
  • substituents can be bonded through any of their atoms.
  • pyridyl can be used as a substituent through any of the pyridine rings. The carbon atom is attached to the substituted group.
  • connection direction is arbitrary, for example,
  • the linking group L in the middle is -MW-, then -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
  • Combinations of the linking group, substituents, and / or variants thereof are only allowed if such a combination will produce a stable compound.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups; etc .; Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl examples include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and so on.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc .; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine) .
  • Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
  • the term “leaving group” refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonate Ester, etc .; acyloxy, such as acetoxy, trifluoroacetoxy, etc.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through one oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy groups, etc. .
  • C 1-6 alkoxy groups include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy Oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, etc.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule by one oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C n-n + m or C n -C n + m includes any specific case of n to n + m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 11, and C 12, also including any one of n + m to n ranges, for example C 1- 3 comprises a C 1-12 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc .; similarly, n yuan to n + m member means that the number of atoms in the ring is n to n + m, for example, 3-12 member ring includes 3 member ring, 4 member ring, 5 member ring, 6 member ring, 7 member ring, 8 member ring, 9 member ring , 10-membered ring, 11-membered ring, and 12-membered
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonate Ester, etc .; acyloxy, such as acetoxy, trifluoroacetoxy, etc.
  • protecting group includes but is not limited to "amino protecting group", “hydroxy protecting group” or “mercapto protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyld
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of hydroxyl groups.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl groups (such as acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-flu
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalently, preferred embodiments include but are not limited to the embodiments of the present invention.
  • aq stands for water
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate Eq stands for equivalent and equivalent
  • DCM stands for dichloromethane
  • PE stands for petroleum ether
  • DMF stands for N, N-dimethylformamide
  • DMSO stands for dimethyl sulfoxide
  • EtOAc stands for ethyl acetate
  • EtOH stands for ethanol
  • MeOH stands for Methanol
  • CBz stands for benzyloxycarbonyl, an amine protecting group
  • BOC stands for tert-butoxycarbonyl, an amine protecting group
  • HOAc stands for acetic acid
  • rt stands for room temperature
  • O / N stands for overnight
  • THF stands for tetrahydrofuran
  • Boc 2 O stands for di-tert-butyl dicarbonate
  • the compound of the present invention has significant TrkA enzyme inhibitory activity; the compound of the present invention has a higher Caco-2 cell membrane penetration efflux ratio, which can better avoid the risk of entering the brain and reduce the movement caused by the inhibition of Trk target in the central nervous system Side effects such as disorders and sleep disturbances; the compound of the present invention has a higher free binding rate of human plasma proteins, lower risk of drug-drug interactions, and better metabolic stability of liver microsomes; a single drug administration in rats
  • the compound of the present invention had higher plasma exposure and higher oral bioavailability than the reference compound D1; in the rat model of CFA-induced mechanical pain, the same oral
  • the compound of the present invention has a longer-lasting analgesic effect than the reference compound D1; the compound of the present invention has a longer half-life and a shorter peak time, which indicates that the effect may be faster and have a longer time in vivo It has good pharmacokinetic properties and oral bioavail
  • the reaction solution was diluted with 1L of water, and the diluted reaction solution was extracted with ethyl acetate (1L ⁇ 3).
  • the organic phases were combined, and the organic phase was washed successively with water (800mL ⁇ 3), saturated brine (1L), organic
  • the phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness.
  • reaction solution was diluted with 100 mL of ethyl acetate and washed once with saturated brine (80.0 mL).
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness.
  • the obtained crude product was subjected to column chromatography (eluent: 20 -40% acetone / petroleum ether) was isolated and purified to obtain compound A1-5.
  • Compound A3-1 (38.50 g, 231.7 mmol) was dispersed in a mixed solvent of ethyl acetate (200.0 mL) and n-heptane (200.0 mL), followed by addition of trifluoroacetic acid (2.64 g, 23.2 mmol, 1.7 mL), and cooled to At 0 ° C, N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (137.53g, 579.3mmol) was slowly added dropwise. After the addition was completed, the temperature was naturally raised to 25 ° C and reacted for 20 hours.
  • reaction solution Concentrate the reaction solution to about 300.0mL, then add 300mL n-heptane, continue to concentrate to about 300.0mL, repeat the above operation 6 times, until the last time after adding 300mL n-heptane, filter, filter cake with n-heptane (100.0mL ⁇ 2) Wash and filter with suction twice, the filter cake is suction dried, and the filter cake is collected to obtain compound A3-2.
  • A3-2 (53.00 g, 177.06 mmol) was dispersed in toluene (400.0 mL), N, N-diisopropylethylamine (25.17 g, 194.77 mmol, 34.0 mL) was added, and protected with nitrogen, Subsequently, diphenyl azide phosphate (53.60g, 194.77mmol, 42.2mL) was slowly added dropwise. After the addition was completed, the reaction was performed at 25 ° C for 0.5 hours, followed by heating to 90 ° C for 3 hours, and then tert-butanol (80.0 mL), the reaction was continued for 16 hours at 90 ° C.
  • reaction solution was cooled to room temperature, 500.0 mL of saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate (600.0 mL ⁇ 2), the organic phases were combined, the organic phase was washed with saturated brine (800.0 mL), and the organic phase was anhydrous It was dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness.
  • the obtained crude product was separated and purified by column chromatography (eluent: 0-10% ethyl acetate / petroleum ether) to obtain compound A3-3.
  • A3-3 (29.40g, 79.36mmol) was dissolved in a mixed solvent of methanol (300.0mL) and tetrahydrofuran (75.0mL), followed by the addition of dry palladium carbon (3.00g, purity 10%), at 50psi Under hydrogen pressure, the reaction was carried out at 25 ° C for 18 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness to obtain A3-4.
  • A3-5 (16.50 g, 48.76 mmol) was suspended in ethyl acetate (50.0 mL), hydrochloric acid / ethyl acetate (4.0 M, 50.0 mL) was added, and the reaction was performed at 25 ° C. for 0.5 hour.
  • the reaction solution was concentrated to dryness, 15% sodium hydroxide solution (50.0 mL) was added to the obtained crude product, the aqueous phase was extracted with dichloromethane (60.0 mL ⁇ 3), the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate. Filter and concentrate the filtrate to dryness to give crude compound A3-6.
  • MS m / z 239.1 [M + 1] + .
  • the filter cake was washed with ethyl acetate (30.0mL ⁇ 2), the filter cake was drained, the filter cake was collected and suspended in 15% sodium hydroxide solution (100.0mL), and extracted with ethyl acetate (60.0mL ⁇ 3) Extract the aqueous phase, combine the organic phases, wash the organic phase once with saturated sodium chloride solution (150.0 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain compound A3.
  • n-butylamine (16.6g, 227.81mmol) was dropped into acetic acid (147.8g, 2.46mol), the internal temperature was controlled to be less than 15 ° C, and compound A4-1 (28.2g, 198.10mmol) and Nitromethane (36.3g, 594.30mmol), the reaction solution was heated to 85 °C and continued to stir for 4 hours. After cooling, the reaction solution was poured into ice water (150 mL), a solid was precipitated, dissolved with ethyl acetate (50 mL), the aqueous layer was separated, and the aqueous layer was extracted with ethyl acetate (20 mL).
  • Compound A4-4 (48.2g, 151.26mmol) was dissolved in a mixed solution of ethanol (700mL) and water (140mL), and amine chloride (80.9g, 1.51mol) and iron powder (84.5g, 1.51mol) were added. The reaction liquid was heated to 78 ° C and stirred for 4 hours.
  • compound C1-4 (1.50g, crude) and compound B1-3 (292mg, 910.56 ⁇ mol) were dissolved in a mixed solution of dioxane (15.0mL) and water (3.0mL), and sodium carbonate was added (193 mg, 1.82 mmol) and 1,1′-bis (diphenylphosphino) ferrocene palladium dichloride (74 mg, 91.06 ⁇ mol), the reaction solution was heated to 100 ° C. and stirring was continued for 4 hours.
  • reaction solution was diluted with 100.0 mL of ethyl acetate, filtered, and the filtrate was washed with 80.0 mL of saturated brine, dried over anhydrous sodium sulfate, and passed through column chromatography (eluent: 10-50% ethyl acetate / petroleum ether) After separation and purification, crude C1 was obtained.
  • aqueous phase was extracted with ethyl acetate (120.0 mL ⁇ 3), the organic phases were combined, the organic phase was washed with saturated brine (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and the resulting crude product was dissolved After cooling to 0 ° C in toluene (30.0mL), trifluoroacetic anhydride (27.4g, 130.29mmol, 18.1mL) was added dropwise, followed by heating to 25 ° C for 23.5 hours.
  • compound C4-4 (2.50 g, 10.00 mmol) was dissolved in tetrahydrofuran (25.0 mL), followed by addition of isopropanol pinacol borate (2.80 g, 15.00 mmol), the system was replaced with nitrogen for three times and then dropped A solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (1.3M, 7.7mL) was added, and the reaction was continued at 0 ° C for 4 hours. A saturated ammonium chloride solution (20.0 mL) was added to the reaction system to quench, and the aqueous phase was extracted with ethyl acetate (50.0 mL ⁇ 3).
  • reaction solution was slowly poured into ice water (50 mL), extracted with ethyl acetate (100 mL ⁇ 2), the combined organic phase was washed with water (100 mL), saturated aqueous sodium chloride solution (50 mL), anhydrous sodium sulfate It was dried, filtered, and the organic solvent was removed under reduced pressure.
  • the obtained crude product was separated and purified by silica gel column chromatography (eluent: 16.7-50% ethyl acetate / petroleum ether) to obtain compound C6-4.
  • the hydrochloride of compound 6 can be adjusted to pH 7-8 by saturated aqueous sodium bicarbonate solution, extracted with methylene chloride, and the organic solvent is removed under reduced pressure to obtain compound 6.
  • This experiment uses homogeneous time-resolved fluorescence conjugated energy transfer from Cisbio ( Method) Perform activity test.
  • enzyme, biotin-labeled peptide substrate, ATP and detection compound are mixed, and the reaction is incubated.
  • EDTA was added to terminate the reaction, and Eu-labeled antibody was added at the same time, and XL665 labeled with streptavidin was reacted and detected.
  • the data are represented by the readings of the fluorescent signals at 665nm and 620nm, respectively, where a high ratio of 665nm / 620nm indicates higher activity, and a low ratio of 665nm / 620nm indicates that activity is inhibited.
  • Compound dilution The compound to be tested is diluted 3 times, a total of 11 concentrations, the final system concentration is from 10 ⁇ M to 0.17 nM
  • Caco-2 cells are human colon cancer cells.
  • the monolayer Caco-2 cell model is widely used to evaluate the passive diffusion and active transport of test compounds in the small intestine.
  • the efflux transporters in the small intestine include P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). This experiment was used to determine the bidirectional permeability of the test compound through the Caco-2 cell model, and to investigate its efflux transport.
  • MEM Minimum Essential Media
  • FBS fetal bovine serum
  • penicillin-G 100 U / mL penicillin-G
  • 100 ⁇ g / mL streptomycin 100 ⁇ g / mL streptomycin was used.
  • the cell culture conditions are 37 ⁇ 1 °C, 5% CO 2 and saturation humidity.
  • trypsin 0.05%, w / v) / EDTA (0.02%, w / v) digestion solution to digest the cells and plant the plates.
  • the 38th generation Caco-2 cells were used.
  • the cells were seeded in BD Falcon's Transwell-96 well plate (Cat. No. 359274) with a seeding density of 1 ⁇ 105 cells / cm 2 .
  • the cells were placed in a carbon dioxide incubator for 22 days and used for transport experiments, during which the medium was changed every four to five days.
  • Hank's balanced salt buffer pH 7.40 ⁇ 0.05
  • HEPES Hank's balanced salt buffer
  • the concentration of DMSO in the incubation system is controlled below 1%.
  • liquid chromatography tandem mass spectrometry (LC / MS / MS) method was used to semi-quantitatively analyze the test compound and the control products fenoterol, propranolol, digoxin and digoxin Peak area ratio of internal standard.
  • dC r / d t is the cumulative concentration of the compound at the receiving end in unit time ( ⁇ M / s); V r is the volume of the receiving end solution (the volume of the solution at the top and basal end are 0.075mL and 0.250mL, respectively); A is the cell monolayer Relative surface area (0.0804cm 2 ); C 0 is the initial concentration (nM) of the test article at the administration end or the peak area ratio of the control article.
  • the efflux ratio is calculated using the following formula:
  • the recovery rate is calculated using the following formula:
  • C 0 is the initial concentration (nM) of the test article at the administration end or the peak area ratio of the reference substance
  • V d is the volume at the administration end (0.075 mL on the top side and 0.250 mL on the basal side)
  • C d and C r It is the final concentration (nM) of the test article at the administration end and the receiving end, respectively, or the peak area ratio of the control article.
  • the compound of the present invention has a higher Caco-2 cell membrane efflux efflux ratio, can better avoid the risk of entering the brain, and reduce side effects such as movement disorders and sleep disturbances caused by Trk target inhibition in the central nervous system.
  • test compounds in human, SD rat and Beagle dog plasma was measured.
  • test compound working solution 400 ⁇ M
  • warfarin working solution 400 ⁇ M
  • the final forest concentration was 2 ⁇ M. Mix the sample thoroughly.
  • the final concentration of the organic phase DMSO is 0.5%; pipette 50 ⁇ L of the test compound and warfarin plasma sample to the sample receiving plate, and immediately add the corresponding volume of corresponding blank plasma or buffer to make the final volume of each sample well 100 ⁇ L ,
  • the volume ratio of plasma: dialysis buffer is 1: 1, and then 400 ⁇ L of stop solution is added to these samples.
  • This sample will be used as a T 0 sample for recovery and stability determination.
  • the dialysis plate was sealed with a gas-permeable membrane, placed in a humidified 5% CO 2 incubator, and incubated at 37 ° C with shaking at 100 rpm for 4 hours. After dialysis, 50 ⁇ L of the dialyzed buffer sample and the dialyzed plasma sample were transferred to a new sample receiving plate.
  • F C is the concentration of the compound at the buffer end of the dialysis plate
  • T C is the concentration of the compound at the plasma end of the dialysis plate
  • T 0 is the concentration of the compound in the plasma sample at time zero.
  • the inhibitory activity of the test compounds on different isoforms of human cytochrome P450 isoenzyme was determined.
  • test compound Prepare the test compound, standard inhibitor (100 ⁇ final concentration) and mixed substrate working solution; remove the microsomes frozen in the refrigerator at -80 ° C and thaw.
  • NADPH coenzyme factor
  • Test article (10mM), testosterone (Testosterone, control substance, 10mM), diclofenac (Diclofenac, control substance, 10mM), propafenone (Propafenone, control substance, 10mM).
  • Working solution 450 ⁇ L of 100mM potassium phosphate buffer is used to dilute the intermediate solution.
  • liver microsome solution final concentration: 0.5 mg protein / mL
  • Dispense 680 ⁇ L / well liver microsome solution on a 96-well plate then add 80 ⁇ L / well to each plate, and place the above incubation plate at 37 ° C for pre-incubation for approximately 10 minutes.
  • Incubate for an appropriate time eg 5, 10, 20, 30 and 60 minutes.
  • liver weights of mice, rats, dogs, monkeys and humans are 88g / kg, 40g / kg, 32g / kg, 30g / kg and 20g / kg, respectively.
  • C t is the concentration at time t
  • t is the incubation time
  • C 0 is the concentration at 0
  • Ke is the elimination rate constant
  • Cl int (mic) is the intrinsic clearance of liver microparticles
  • Cl int (liver) is the intrinsic clearance of liver rate.
  • test compound was given by intragastric administration at 10 mg / kg.
  • the vehicle for intravenous administration is 10% ethanol + 20% castor oil polyoxyethylene ether + 70% physiological saline, and the vehicle for intragastric administration is 0.5% sodium carboxymethyl cellulose + 0.2% Tween 80.
  • Plasma samples were collected from animals in the intravenous group at 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration, while animals in the gavage group were at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 after administration. Plasma samples were collected at 8.0, 24 hours.
  • the plasma drug concentration was determined by LC-MS / MS method, and the relevant pharmacokinetic parameters were calculated by the non-compartment model linear log trapezoid method using WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software.
  • C 0 is the initial concentration
  • T 1/2 is the elimination half-life
  • Vd ss is the steady-state apparent volume of distribution
  • Cl is the total clearance
  • AUC 0-last is the plasma from time 0 to the last quantifiable time point Area under the concentration-time curve
  • AUC 0-inf is the area under the plasma concentration-time curve from time 0 to extrapolation to infinity
  • C max is the peak concentration
  • T max is the peak time.
  • CD-1 mice male, 20-40g, 6-9 weeks old, Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.
  • the test compound was formulated as a clear solution or a homogeneous suspension, and given to mice for single intravenous injection and oral administration.
  • the solvent is a certain proportion of ethanol, Cremophor EL and physiological saline solution, vortexed to prepare a 1 mg / mL clear solution, and the microporous filter is filtered for use;
  • the oral solvent is a certain ratio of methyl cellulose solution or a certain ratio Methyl cellulose and Tween 80 aqueous solution.
  • test compound After the test compound is mixed with the solvent, vortex to prepare a 10 mg / mL clear or homogeneous suspension for use. After 2 mg / kg intravenous administration or 100 mg / kg oral administration of mice, a certain amount of whole blood samples were collected, centrifuged at 3200 g for 10 minutes, and the supernatant plasma samples were separated, and the samples were diluted with blank plasma by a certain multiple according to actual needs.
  • Plasma samples were added to 20-fold volume of acetonitrile solution containing internal standard to precipitate protein, centrifuged to take supernatant, added 2 volumes of water and then centrifuged to take supernatant for injection, quantitative analysis of plasma drug concentration by LC-MS / MS analysis method, and Phoenix WinNonlin software (Pharsight, USA) calculates pharmacokinetic parameters, such as peak concentration, peak time, clearance rate, half-life, area under the curve of drug time, bioavailability, etc.
  • C 0 is the initial concentration
  • T 1/2 is the elimination half-life
  • Vd ss is the steady-state apparent volume of distribution
  • Cl is the total clearance
  • AUC 0-inf is the plasma concentration from time 0 to extrapolation to infinity -The area under the time curve
  • C max is the peak concentration
  • T max is the peak time.
  • Compound 12 of the present invention has a longer half-life and a shorter time to peak, which indicates that the body may have a faster effect and a longer period of drug efficacy, reducing the frequency of administration; it has good mouse pharmacokinetics Nature and oral bioavailability.
  • the blood concentration of the compound was measured after a single administration and the pharmacokinetic behavior was evaluated.
  • test The purpose of the test is to test the pharmacokinetic characteristics of the test compound after intravenous injection and oral administration.
  • the test compound is formulated into a clear solution or a uniform suspension, and the beagle dog is given a single intravenous injection or oral administration .
  • the solvent is a certain proportion of HP- ⁇ -cyclodextrin solution of dimethyl sulfoxide or a certain proportion of ethanol, polyethylene glycol 400 and physiological saline solution, vortex and ultrasound to prepare 2mg / mL or 1mg / kg Clarified solution, ready for use after filtration through microporous membrane; oral solvent is a certain proportion of HP- ⁇ of dimethyl sulfoxide Cyclodextrin solution or a certain proportion of sodium carboxymethylcellulose solution.
  • the test compound is mixed with the solvent, vortex and sonicate to prepare a 2 mg / mL clear solution or 1 mg / mL homogeneous suspension for use.
  • C 0 is the initial concentration
  • T 1/2 is the elimination half-life
  • Vd ss is the steady-state apparent volume of distribution
  • Cl is the total clearance
  • AUC 0-inf is the plasma concentration from time 0 to extrapolation to infinity -The area under the time curve
  • C max is the peak concentration
  • T max is the peak time.
  • the compound 12 of the present invention has a longer half-life and shorter peak time, which indicates that the body may have a faster effect and a longer period of drug effect, reducing the frequency of administration; it has good Beagle dog pharmacokinetics Academic properties and oral bioavailability.

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Abstract

La présente invention concerne une classe de dérivés de pyrrolidinyle-urée et une application de ceux-ci dans la préparation de médicaments pour le traitement de maladies associées à TrkA. L'invention concerne spécifiquement des composés représentés par les formules (I) et (II), un isomère de ceux-ci, et un sel pharmaceutiquement acceptable de ceux-ci.
PCT/CN2019/113278 2018-10-26 2019-10-25 Dérivés de pyrrolidinyle-urée et leur application Ceased WO2020083377A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106459013A (zh) * 2014-05-15 2017-02-22 阵列生物制药公司 作为trka激酶抑制剂的1‑((3s，4r)‑4‑(3‑氟苯基)‑1‑(2‑甲氧基乙基)吡咯烷‑3‑基)‑3‑(4‑甲基‑3‑(2‑甲基嘧啶‑5‑基)‑1‑苯基‑1h‑吡唑‑5‑基)脲
WO2017135399A1 (fr) * 2016-02-04 2017-08-10 塩野義製薬株式会社 Hétérocycle contenant de l'azote ayant une activité inhibitrice de trka et dérivé carbocyclique
US20170240512A1 (en) * 2014-08-06 2017-08-24 Shionogi & Co., Ltd. Heterocycle and carbocycle derivatives having trka inhibitory activity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106459013A (zh) * 2014-05-15 2017-02-22 阵列生物制药公司 作为trka激酶抑制剂的1‑((3s，4r)‑4‑(3‑氟苯基)‑1‑(2‑甲氧基乙基)吡咯烷‑3‑基)‑3‑(4‑甲基‑3‑(2‑甲基嘧啶‑5‑基)‑1‑苯基‑1h‑吡唑‑5‑基)脲
US20170240512A1 (en) * 2014-08-06 2017-08-24 Shionogi & Co., Ltd. Heterocycle and carbocycle derivatives having trka inhibitory activity
WO2017135399A1 (fr) * 2016-02-04 2017-08-10 塩野義製薬株式会社 Hétérocycle contenant de l'azote ayant une activité inhibitrice de trka et dérivé carbocyclique

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