WO2020015735A1 - Inhibiteurs de la tyrosine kinase de bruton - Google Patents

Inhibiteurs de la tyrosine kinase de bruton Download PDF

Info

Publication number
WO2020015735A1
WO2020015735A1 PCT/CN2019/096777 CN2019096777W WO2020015735A1 WO 2020015735 A1 WO2020015735 A1 WO 2020015735A1 CN 2019096777 W CN2019096777 W CN 2019096777W WO 2020015735 A1 WO2020015735 A1 WO 2020015735A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
alkyl
acceptable salt
Prior art date
Application number
PCT/CN2019/096777
Other languages
English (en)
Chinese (zh)
Inventor
张寅生
任景
吴喆阳
王庆璘
金超
徐胜
陆鹏
施伟
贺香依
田晓萌
汪杰
Original Assignee
正大天晴药业集团股份有限公司
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 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN201980047159.XA priority Critical patent/CN112424203B/zh
Publication of WO2020015735A1 publication Critical patent/WO2020015735A1/fr

Links

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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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

Definitions

  • the present application relates to an imidazopyrazine ring-containing compound as a BTK inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof in treating BTK-related diseases.
  • BTK Bruton's tyrosine kinase
  • Ibrutinib is the first BTK inhibitor approved for marketing, which is used for the treatment of CLL (chroniclymphoid leukemia) and MCL (mantle cells).
  • CLL chroniclymphoid leukemia
  • MCL mantle cells
  • the application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • Ring B is selected from 5-10 membered heteroaryl or C 6-10 aryl
  • R 1 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, or halogen-substituted C 1-6 alkyl;
  • p is selected from 0, 1, 2, 3, or 4;
  • L is selected from -C (O) NH-, -CH 2 NHC (O)-, -NHC (O)-, -O-, -NH-, -S-, -C (O) O-, -OC ( O)-, -S (O) 2 O- or -OS (O) 2- ;
  • R 2 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl or C 1-6 alkoxy, said C 1-6 alkyl or C 1-6 alkoxy any Elected to be replaced by halogen;
  • n is selected from 0, 1, 2, 3 or 4;
  • X 1 is independently selected from -NH-, -O-, -S- or -CH 2- ;
  • n1 is selected from 1, 2, 3, 4, 5 or 6;
  • n2 and n3 are independently selected from 1, 2 or 3;
  • n4 is selected from 0, 1, 2 or 3;
  • q1, q2, q3 and q4 are independently selected from 0, 1, 2 or 3;
  • X 2 is selected from N or CH;
  • X 3 is selected from -CH 2- , -O-, -S-, or -NH-.
  • the present application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof described in the present application.
  • the present application provides a method for treating a mammal and a BTK-related disease, comprising administering a therapeutically effective amount of a compound of formula (I) described herein or a pharmacological agent to a mammal, preferably a human, in need of the treatment.
  • a mammal preferably a human
  • the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof described in the present application, or a pharmaceutical composition described in the present application in the manufacture of a medicament for preventing or treating a disease associated with BTK. use.
  • the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof described in the present application, or a pharmaceutical composition described in the present application for the prevention or treatment of a disease associated with BTK.
  • the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in the present application, for preventing or treating a disease associated with BTK.
  • This application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • Ring B is selected from 5-10 membered heteroaryl or C 6-10 aryl
  • R 1 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, or halogen-substituted C 1-6 alkyl;
  • p is selected from 0, 1, 2, 3, or 4;
  • L is selected from -C (O) NH-, -CH 2 NHC (O)-, -NHC (O)-, -O-, -NH-, -S-, -C (O) O-, -OC ( O)-, -S (O) 2 O- or -OS (O) 2- ; or L is selected from -C (O) NH-, -NHC (O)-, -O-, -NH-, -S -, -C (O) O-, -OC (O)-, -S (O) 2 O- or -OS (O) 2- ;
  • R 2 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl or C 1-6 alkoxy, said C 1-6 alkyl or C 1-6 alkoxy any Elected to be replaced by halogen;
  • n is selected from 0, 1, 2, 3 or 4;
  • X 1 is independently selected from -NH-, -O-, -S- or -CH 2- ;
  • n1 is selected from 1, 2, 3, 4, 5 or 6;
  • n2 and n3 are independently selected from 1, 2 or 3;
  • n4 is selected from 0, 1, 2 or 3;
  • q1, q2, q3 and q4 are independently selected from 0, 1, 2 or 3;
  • X 2 is selected from N or CH;
  • X 3 is selected from -CH 2- , -O-, -S-, or -NH-.
  • ring B is selected from a 5-10 membered heteroaryl or phenyl group; in some embodiments, ring B is selected from a 5-6 membered heteroaryl or phenyl group; in some embodiments, ring B Is selected from pyridyl (eg, pyridin-2-yl) or phenyl.
  • R 1 is independently selected from halogen, -CN, C 1-6 alkoxy, or C 1-6 alkyl optionally substituted with halogen; in some embodiments, R 1 is independently selected From halogen, -CN, C 1-3 alkoxy, or C 1-3 alkyl optionally substituted with halogen; in some embodiments, R 1 is independently selected from chlorine, -CN, methoxy, methyl Radical or -CF 3 .
  • R 1 is independently selected from -F, -Cl, -Br, -I, -CN, C 1-3 alkoxy, or C 1-3 alkyl optionally substituted with halogen; In some embodiments, R 1 is independently selected from -F, -Cl, -CN, methoxy, methyl, or -CF 3 .
  • R 1 is independently selected from C 1-6 alkyl optionally substituted with halogen; in some embodiments, R 1 is independently selected from halogen substituted C 1-3 alkyl; in some embodiments In the scheme, R 1 is selected from -CF 3 .
  • p is selected from 0, 1, or 2; in some embodiments, p is selected from 0 or 1.
  • R 1 is independently selected from halogen, -CN, C 1-6 alkoxy, or C 1-6 alkyl optionally substituted with halogen, and p is selected from 0, 1 or 2; In some embodiments, R 1 is -F, -Cl, -CN, methoxy, methyl, or -CF 3 , and p is 1.
  • L is selected from -C (O) NH-, -NHC (O)-, -O-, -NH-, -S-, -C (O) O-, -OC (O)- , -S (O) 2 O- or -OS (O) 2- .
  • L is selected from -C (O) NH-, -CH 2 NHC (O)-, -NHC (O)-, or -O-; in some embodiments, L is selected from -C (O ) NH -, - CH 2 NHC (O) -, or -O-.
  • L is selected from -C (O) NH-, -NHC (O)-, or -O-; in some embodiments, L is selected from -C (O) NH- or -O-.
  • L is -C (O) NH-. In some embodiments, L is -CH 2 NHC (O) -. In some embodiments, L is -O-.
  • R 1 is in an ortho, meta, or para position relative to the attachment position of L to ring B.
  • Ring B is pyridyl, and R 1 is in the meta or para position relative to the attachment position of L to ring B.
  • Ring B is phenyl and R 1 is in the ortho or meta position relative to the position of attachment of L to ring B.
  • R 2 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-3 alkyl, or C 1-3 alkoxy, the C 1-3 alkyl or C 1 -3 alkoxy is optionally substituted with halogen; in some embodiments, R 2 is independently selected from -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, -CH 3 , or- CF 3 ; in some embodiments, R 2 is independently selected from -F, -Cl, -Br, or -I; in some embodiments, R 2 is independently selected from -F or -Cl.
  • n is selected from 0, 1 or 2; in some embodiments, m is selected from 0 or 1.
  • R 2 is -F or -Cl, and m is 1. In some embodiments, m is 0.
  • X 1 is independently selected from -NH-, -O-, or -CH 2- .
  • X 1 is independently selected from -NH-, -O-, or -CH 2- , wherein the H atom in -NH- and -CH 2 -is optionally substituted with R 3 .
  • n1 is selected from 1, 2, 3, or 4; in some embodiments, n1 is selected from 2, 3, or 4.
  • n1 is 2,3,4,5 or 6, wherein X 1 is selected from a -NH -, - O -, - S- , or -CH 2 -, -NH- wherein in H
  • the atom is optionally substituted with C 1-3 alkyl, and the remaining X 1 is -CH 2- .
  • n1 is 2, 3 or 4, wherein X 1 is selected from a -NH -, - O- or -CH 2 -, wherein the H atoms are optionally C 1-3 -NH- Alkyl substituted, the remaining X 1 is -CH 2- .
  • n1 is 2, 3 or 4, wherein X 1 is selected from a -NH -, - O -, - CH 2 -, wherein the H atom is optionally substituted with methyl -NH-, The remaining X 1 is -CH 2- .
  • n2 is selected from 1 or 2
  • n3 is selected from 2 or 3.
  • both n2 and n3 are two.
  • n2 is 1, and n3 is 2 or 3.
  • n4 is selected from 0, 1 or 2; in some embodiments, n4 is selected from 0 or 1; in some embodiments, n4 is selected from 1.
  • R is independently selected from -H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkane , 5-6 membered heteroaryl or phenyl; in some embodiments, R is independently selected from -H, C 1-3 alkyl, C 2-3 alkenyl, or C 2-3 alkynyl.
  • q1 is selected from 1 or 2
  • q3 is selected from 1; in some embodiments, q1 is selected from 2, and q3 is selected from 1.
  • q2 is selected from 1 or 2, and q4 is selected from 1; in some embodiments, q2 is selected from 2, and q4 is selected from 1.
  • X 2 is selected from N.
  • X 3 is selected from -O-, -S-, or -NH-; in some embodiments, X 3 is selected from -O-, -S-, or -NH-, wherein -NH- The H atom is optionally substituted with C 1-3 alkyl; in some embodiments, X 3 is selected from -NH-.
  • X 1 of the above five structures is selected from -NH-, -O-, -S-, -CH 2 -or -NH- substituted with C 1-3 alkyl, and the remaining X 1 is -CH 2- .
  • one X 1 of the above five structures is selected from -NH-, -O-, -CH 2 -or -NH- substituted with methyl, and the remaining X 1 is -CH 2- .
  • X 1 at a position alternate with the splice junction is -NH- or -NH- substituted with a methyl group, and the remaining X 1 is -CH 2- .
  • X 2 is N
  • X 3 is NH
  • / or R 5 0 in the above structure.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof,
  • R 1 , p, R 2 , and m are as defined above.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II-3) or a pharmaceutically acceptable salt thereof,
  • R 1 , p, R 2 , and m are as defined above.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), formula (II-1), formula (II-2), formula (II-3), or a specific compound described above, or a pharmacy Acceptable salt.
  • the pharmaceutical compositions of the present application further include a pharmaceutically acceptable excipient.
  • the present application relates to a method for treating mammalian and BTK-related diseases, which comprises administering a therapeutically effective amount of formula (I), formula (II-1), formula (II- 2) A compound of formula (II-3) or the above-mentioned specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present application relates to a compound of formula (I), formula (II-1), formula (II-2), formula (II-3) or the above specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof
  • a compound of formula (I), formula (II-1), formula (II-2), formula (II-3) or the above specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof Use of the substance in the preparation of a medicament for preventing or treating a disease related to BTK.
  • the present application relates to a compound of formula (I), formula (II-1), formula (II-2), formula (II-3) or the above specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof Use of substances in the prevention or treatment of diseases related to BTK.
  • the present application relates to a compound of formula (I), formula (II-1), formula (II-2), formula (II-3) or the above specific compound or a pharmaceutically acceptable compound thereof for preventing or treating a disease related to BTK. Accepted salts, or pharmaceutical compositions thereof.
  • the BTK-related disease is a BTK-mediated disease.
  • the BTK-related disease is selected from the group consisting of an autoimmune disease, an inflammatory disease, or cancer, wherein the cancer includes, but is not limited to, diffuse large B-cell lymphoma.
  • substituted means that any one or more hydrogen atoms on a specific group are substituted with a substituent, as long as the valence of the specific group is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted, and oxo does not occur on the aromatic group.
  • an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH 2 CH 3 ), mono-substituted (such as CH 2 CH 2 F), poly-substituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and / or cannot be synthesized will be introduced.
  • C mn is the part with an integer number of carbon atoms in a given range.
  • C 1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • any variable such as R
  • its definition in each case is independent. For example, if a group contains 2 Rs, each R has independent options.
  • linking group When the number of a linking group is 0, such as-(CH 2 ) 0- , it means that the linking group is a covalent bond.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxy refers to the -OH group.
  • amino refers to the -NH 2 group.
  • alkyl refers to a hydrocarbon of the formula C n H 2n + 1, e.g., C 1-6 alkyl, C 1-3 alkyl.
  • the alkyl group may be linear or branched.
  • C 1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • the alkyl portion (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definitions as described above.
  • alkoxy refers to -O-alkyl, for example, -OC 1-6 alkyl, -OC 1-3 alkyl.
  • alkylamino refers to -NH-alkyl, for example, -NH-C 1-6 alkyl, -NH-C 1-3 alkyl.
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group having at least one double bond consisting of a carbon atom and a hydrogen atom, for example, a C 2-6 alkenyl group, a C 2-3 alkenyl group.
  • alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to a linear or branched unsaturated aliphatic hydrocarbon group having at least one triple bond consisting of a carbon atom and a hydrogen atom, for example, a C 2-6 alkynyl group, a C 2-3 alkynyl group.
  • alkynyl include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-butadiynyl (-C ⁇ CC ⁇ CH) and the like.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is generally a 3- to 10-membered ring, and may also be a 3- to 6-membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantine Alkyl, etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocyclic ring is generally a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen.
  • a heterocycloalkyl group may be a 3 to 6 membered ring containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, ethylene oxide, epithioethane, and cycloazinyl.
  • Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetane
  • Examples of cyclic groups, thiobutane groups, and 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, and thiazolidine
  • Examples of imidazolyl, tetrahydropyrazolyl, and 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothyranyl, morpholinyl, piperazinyl, 1, Examples of 4-thiaoxaalkyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl,
  • aryl refers to a full-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system.
  • an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthalene, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, and S, the remaining ring atoms being C, and having at least one aromatic ring.
  • a heteroaryl group may contain 1, 2 or 3 heteroatoms selected from N, O, and S.
  • Preferred heteroaryl groups have a single 4- to 8-membered ring, especially a 5- to 8-membered ring, or a fused polycyclic ring containing 6 to 14, especially 6 to 10 ring atoms.
  • heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , Tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, particularly when Such mammals are susceptible to the disease state but have not yet been diagnosed as having the disease state.
  • terapéuticaally effective amount means (i) treats or prevents a specific disease, condition or disorder, (ii) reduces, improves or eliminates one or more symptoms of a specific disease, condition or disorder, or (iii) prevents or delays
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” depends on the compound, the state of the disease and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own Determined by the knowledge of this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without More toxic, irritating, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.
  • Examples of the pharmaceutically acceptable salt include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • composition refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant stimulating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • tautomers or “tautomeric forms” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton transfer tautomers include interconversions via migration of protons, such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogens.
  • Valence tautomers include interconversions through recombination of some bonding electrons.
  • This application also includes isotopically-labeled compounds of the present application that are the same as those described herein, but with one or more atoms replaced by an atomic weight or mass number different from the atomic weight or mass number usually found in nature.
  • isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl.
  • isotopically labeled compounds of the present application can be used in compound and / or substrate tissue distribution analysis. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
  • Positron emission isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present application can generally be prepared by the following procedures similar to those disclosed in the schemes and / or examples below by replacing isotopically labeled reagents with isotopically labeled reagents.
  • deuterium i.e., 2 H
  • replacement with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and therefore in some cases
  • deuterium substitution may be partial or complete
  • partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.
  • the compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers.
  • the compounds containing asymmetric carbon atoms of the present application can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with a suitable pharmaceutically acceptable excipient, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation, such as a tablet, pill, capsule, powder , Granules, creams, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • a suitable pharmaceutically acceptable excipient for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation, such as a tablet, pill, capsule, powder , Granules, creams, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering a compound of the present application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coated pills method, a grinding method, an emulsification method, a freeze-drying method, and the like.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, dragees, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets. Or the core of a sugar coating agent. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.
  • compositions are also suitable for parenteral administration, such as sterile unit solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • the daily dose is 0.01 to 200 mg / kg body weight, either alone or in divided doses.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those familiar to those skilled in the art. Equivalent alternatives. Preferred implementations include, but are not limited to, the examples of this application.
  • compounds of general formula (I) of the present application can be prepared by those skilled in the art of organic synthesis by the following routes using standard methods in the art:
  • PE petroleum ether
  • EA ethyl acetate
  • DMSO dimethyl sulfoxide
  • DMF N, N-dimethylformamide
  • DCM dichloromethane
  • NBS N-bromosuccinimide
  • DIPEA Diisopropylethylamine
  • MeOH for methanol
  • NMP for N-methylpyrrolidone
  • EDTA for ethylenediamine tetraacetic acid
  • DTT dithiothreitol
  • EGTA ethylene glycol bis (2-aminoethyl ether) Tetraacetic acid
  • ATP stands for adenosine triphosphate.
  • Step 1 N-((3-chloropyrazin-2-yl) methyl) formamide
  • Step 4 1,3-Dibromoimidazo [1,5-a] pyrazine-8-amine
  • intermediates 1-4 (20 g), sec-butanol (150 ml), and ammonia (169 g, 187 ml) were added in this order.
  • the reaction apparatus was sealed and heated to 90 ° C. for 4 hours to react. After the reaction solution was cooled to room temperature, most of the sec-butanol was removed by concentration. Water and EA were added to the residue, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 1-5 (17.35 g).
  • Step 5 8- (8-amino-1-bromoimidazo [1,5-a] pyrazin-3-yl) -2,8-diazaspiro [4.5] decane-1-one
  • Step 6 4- (8-Amino-3- (1-carbonyl-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazin-1-yl ) -3-fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • reaction solution was dissolved in 50 mL of water, extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • the concentrate was purified by silica gel column, eluting with DCM: MeOH (97: 3), to obtain compound 1 0.07g).
  • Step 1 8- (8-Amino-1-bromoimidazo [1,5-a] pyrazin-3-yl) hexahydro-2H-pyrazino [1,2-a] pyrazine-1 (6H )-ketone
  • Step 2 4- (8-Amino-3- (9-carbonyloctahydro-2H-pyrazino [1,2-a] pyrazin-2-yl) imidazo [1,5-a] pyrazine- 1-yl) -3-fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • the intermediate 2-6 was used instead of the intermediate 1-6 as the starting material to obtain the compound 2 (26 mg).
  • Step 1 4- (8-Amino-3- (1-carbonyl-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazin-1-yl ) -N- (pyridin-2-yl) benzamide
  • Step 1 8- (8-amino-1- (4-phenoxyphenyl) imidazo [1,5-a] pyrazin-3-yl) -2,8-diazaspiro [4.5] dec Alkane-1-one
  • Step 1 8- (8-amino-1- (2-chloro-4-phenoxyphenyl) imidazo [1,5-a] pyrazin-3-yl) -2,8-diazaspiro [4.5] Decane-1-one
  • Step 1 8- (8-Amino-1-bromoimidazo [1,5-a] pyrazin-3-yl) -2-oxa-8-azaspiro [4.5] decane-1-one
  • Step 2 4- (8-Amino-3- (1-carbonyl-2-oxa-8-azaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazine-1 -Yl) -3-fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • Step 2 8- (8-Amino-1-bromoimidazo [1,5-a] pyrazin-3-yl) -8-azaspiro [4.5] decane-1-one
  • Step 3 4- (8-Amino-3- (1-carbonyl-8-azaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazin-1-yl) -3 -Fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • Step 1 8- (8-Amino-1-bromoimidazo [1,5-a] pyrazin-3-yl) -1,8-diazaspiro [4.5] decane-2-one
  • Step 2 4- (8-Amino-3- (2-carbonyl-1,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazin-1-yl ) -3-fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • Step 1 8- (8-Amino-1-bromoimidazo [1,5-a] pyrazin-3-yl) -2,8-diazaspiro [4.5] decane-3-one
  • Step 2 4- (8-Amino-3- (3-carbonyl-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazin-1-yl ) -3-fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • Step 1 7- (8-Amino-1-bromoimidazo [1,5-a] pyrazin-3-yl) -2,7-diazaspiro [3.5] nonan-1-one
  • Step 2 4- (8-Amino-3- (1-carbonyl-2,7-diazaspiro [3.5] nonane-7-yl) imidazo [1,5-a] pyrazin-1-yl ) -3-fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • Step 1 9- (8-Amino-1-bromoimidazo [1,5-a] pyrazin-3-yl) -2,9-diazaspiro [5.5] undecane-1-one
  • Step 2 4- (8-Amino-3- (1-carbonyl-2,9-diazaspiro [5.5] undec-9-yl) imidazo [1,5-a] pyrazine-1- ) -3-fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • Step 1 7- (8-Amino-1-bromoimidazo [1,5-a] pyrazin-3-yl) -2,7-diazaspiro [4.4] nonan-1-one
  • Step 2 4- (8-Amino-3- (6-carbonyl-2,7-diazaspiro [4.4] nonane-2-yl) imidazo [1,5-a] pyrazin-1-yl ) -3-fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • reaction step 6 using intermediate 12-6 instead of intermediate 1-6 as the reaction raw material, compound 12 (102 mg) was obtained.
  • Step 1 7- (8-Amino-1-bromoimidazo [1,5-a] pyrazin-3-yl) -2,7-diazaspiro [4.5] decane-1-one
  • Step 2 4- (8-Amino-3- (1-carbonyl-2,7-diazaspiro [4.5] decane-7-yl) imidazo [1,5-a] pyrazin-1-yl ) -3-fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • Step 1 (4-((2-methoxybenzoylamino) methyl) phenyl) boronic acid
  • Step 2 N- (4- (8-amino-3- (1-carbonyl-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazine- 1-yl) benzyl) -2-methoxybenzamide
  • Step 1 (4-((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) boronic acid
  • Step 2 N- (4- (8-amino-3- (1-carbonyl-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazine- 1-yl) benzyl) -5-fluoro-2-methoxybenzamide
  • Step 1 8- (8-Amino-1-bromoimidazo [1,5-a] pyrazin-3-yl) -2,8-diazaspiro [4.5] decane-2-carboxylic acid tert-butyl ester
  • Step 2 8- (8-Amino-1- (2-fluoro-4-((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) imidazo [1,5-a ] Pyrazin-3-yl) tert-butyl-2,8-diazaspiro [4.5] decane-2-carboxylic acid methyl ester
  • Step 3 4- (8-Amino-3- (2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazin-1-yl) -3- Fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • Step 1 7- (8-Amino-1-bromoimidazo [1,5-a] pyrazin-3-yl) -2,7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester
  • Step 2 7- (8-amino-1- (2-fluoro-4-((4- (trifluoromethyl) pyridin-2-yl) carbamoyl) phenyl) imidazo [1,5-a ] Pyrazin-3-yl) tert-butyl-2,7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester
  • Step 3 4- (8-Amino-3- (2,7-diazaspiro [3.5] non-7-yl) imidazo [1,5-a] pyrazin-1-yl) -3-fluoro -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • Step 1 4- (8-Amino-3- (2-methyl-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazine-1- ) -3-fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • Step 1 4- (8-Amino-3- (2-methyl-2,7-diazaspiro [3.5] non-7-yl) imidazo [1,5-a] pyrazin-1-yl ) -3-fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • Step 1 2-methyl-1-oxo-2,8-diazaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
  • Step 3 8- (8-Amino-1-bromoimidazo [1,5-a] pyrazin-3-yl) -2-methyl-2,8-diazaspiro [4.5] dec-1- ketone
  • intermediate 20-2 was used as a reaction raw material to obtain intermediate 20-6 (98 mg).
  • Step 4 4- (8-Amino-3- (2-methyl-1-oxo-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] Pyrazin-1-yl) -3-fluoro-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • intermediate 20-6 was used instead of intermediate 1-6 as the reaction raw material to obtain compound 20 (47 mg).
  • Step 1 (2-Fluoro-4- (pyridin-2-ylcarbamoyl) phenyl) boronic acid
  • Step 2 4- (8-Amino-3- (1-oxo-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazine-1- ) -3-fluoro-N- (pyridin-2-yl) benzamide
  • the intermediate 21-7 was used instead of the intermediate 1-7 as the reaction raw material to obtain the compound 21 (154 mg).
  • Step 1 (2-Fluoro-4- (pyridin-2-ylcarbamoyl) phenyl) boronic acid
  • Step 2 4- (8-Amino-3- (1-oxo-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazine-1- ) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
  • the intermediate 22-7 was used instead of the intermediate 1-7 as the reaction raw material to obtain the compound 22 (105 mg).
  • Step 1 (2-fluoro-4-((4-methylpyridin-2-yl) carbamoyl) phenyl) boronic acid
  • Step 2 4- (8-Amino-3- (1-oxo-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazine-1- ) -3-fluoro-N- (4-methylpyridin-2-yl) benzamide
  • the intermediate 23-7 was used as the reaction raw material to obtain the compound 23 (193 mg).
  • Step 1 (2-fluoro-4-((4-methoxypyridin-2-yl) carbamoyl) phenyl) boronic acid
  • Step 2 4- (8-Amino-3- (1-oxo-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazine-1- ) -3-fluoro-N- (4-methoxypyridin-2-yl) benzamide
  • the intermediate 24-7 was used instead of the intermediate 1-7 as the reaction raw material to obtain the compound 24 (310 mg).
  • Step 1 (4-((5-chloropyridin-2-yl) carbamoyl) -2-fluorophenyl) boronic acid
  • Step 2 4- (8-Amino-3- (1-oxo-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazine-1- ) -N- (5-chloropyridin-2-yl) -3-fluorobenzamide
  • Step 1 (4-((4-cyanopyridine-2-yl) carbamoyl) -2-fluorophenyl) boronic acid
  • Step 2 4- (8-Amino-3- (1-oxo-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazine-1- ) -N- (4-cyanopyridine-2-yl) -3-fluorobenzamide
  • Step 1 (4-((5-chloro-4- (trifluoromethyl) pyridin-2-yl) carbamoyl) -2-fluorophenyl) boronic acid
  • Step 2 4- (8-Amino-3- (1-oxo-2,8-diazaspiro [4.5] decane-8-yl) imidazo [1,5-a] pyrazine-1- ) -N- (5-chloro-4- (trifluoromethyl) pyridin-2-yl) -3-fluorobenzamide
  • intermediate 27-7 was used instead of intermediate 1-7 as the reaction raw material to obtain compound 27 (11 mg).
  • Test example 1 in vitro activity
  • 8nM detection reagent (final concentration of 2nM, Ab), incubate for 1 hour at room temperature; read the plate (excitation 620nm, emission 665nm) with a PE Envision multifunctional microplate reader, and calculate the IC50 using four-parameter fitting.
  • 8nM detection reagent (final concentration of 2nM, Ab), incubate for 1 hour at room temperature; read the plate (excitation 620nm, emission 665nm) with a PE Envision multifunctional microplate reader, and calculate the IC50 using four-parameter fitting.
  • ⁇ 8nM detection reagent final concentration of 2nM, Eu-anti-phospho-tyrosine antibody
  • incubate for 1 hour at room temperature, and read the plate (excitation 320nm, emission 665nm) using a PE Envision microplate reader, using four-parameter fitting, Calculate IC50.
  • ⁇ 8nM detection reagent final concentration of 2nM, Eu-anti-phospho-tyrosine antibody
  • PE Envision multi-functional microplate reader was used to read the plate (excitation 320nm, emission 665nm), using four-parameter fitting, Calculate IC50.
  • TMD-8 cells in good exponential growth state, collect the cells into a centrifuge tube, low-speed desktop centrifuge, 1500 rpm, centrifuge for 3 min, discard the supernatant, and add 2 mL of seed plate medium (RPMI basic medium + 5% FBS + 0.05mM 2-mercaptoethanol) for cell resuspension.
  • seed plate medium RPMI basic medium + 5% FBS + 0.05mM 2-mercaptoethanol
  • Count with a cell counter take the required amount of cells to adjust the density to 5 ⁇ 104 cells / mL, inoculate on a 96-well plate with a row gun, 100 ⁇ L / well, and place in a cell incubator at 37 ° C and 5% saturated humidity ⁇ culturing. After 24 hours of incubation, compound loading was performed using a nanoliter sampler.
  • Test Example 2 Metabolic stability of liver microsomes in vitro

Abstract

L'invention concerne des inhibiteurs de la tyrosine kinase de Bruton, et concerne en particulier un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation de celui-ci, une composition pharmaceutique contenant le composé, et l'utilisation du composé dans le traitement de maladies associées à la tyrosine kinase de Bruton.
PCT/CN2019/096777 2018-07-20 2019-07-19 Inhibiteurs de la tyrosine kinase de bruton WO2020015735A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201980047159.XA CN112424203B (zh) 2018-07-20 2019-07-19 布鲁顿酪氨酸激酶抑制剂

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810802823.4 2018-07-20
CN201810802823 2018-07-20

Publications (1)

Publication Number Publication Date
WO2020015735A1 true WO2020015735A1 (fr) 2020-01-23

Family

ID=69163862

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/096777 WO2020015735A1 (fr) 2018-07-20 2019-07-19 Inhibiteurs de la tyrosine kinase de bruton

Country Status (2)

Country Link
CN (1) CN112424203B (fr)
WO (1) WO2020015735A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021008441A1 (fr) * 2019-07-12 2021-01-21 正大天晴药业集团股份有限公司 Inhibiteur de btk contenant du 5-azaspiroheptane
WO2021180107A1 (fr) * 2020-03-12 2021-09-16 Fochon Pharmaceuticals, Ltd. Composés utiles en tant qu'inhibiteurs de kinase
WO2022037649A1 (fr) * 2020-08-20 2022-02-24 Beijing Innocare Pharma Tech Co., Ltd. Composés hétérocycliques utilisés comme inhibiteurs de btk
CN114634512A (zh) * 2020-12-16 2022-06-17 江苏恒瑞医药股份有限公司 作为布鲁顿酪氨酸激酶抑制剂的化合物、其制备方法和医药应用
WO2023110970A1 (fr) 2021-12-14 2023-06-22 Netherlands Translational Research Center Holding B.V Inhibiteurs macrocycliques de btk

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104080789A (zh) * 2012-01-31 2014-10-01 南京奥昭生物科技有限公司 作为布鲁顿酪氨酸激酶抑制剂的环状分子
WO2016106625A1 (fr) * 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Inhibiteurs de btk
WO2016106623A1 (fr) * 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Composés benzamides et imidazopyrazines utilisés comme inhibiteurs de la btk
CN105916859A (zh) * 2014-02-03 2016-08-31 卡迪拉保健有限公司 杂环化合物
CN106831787A (zh) * 2017-01-20 2017-06-13 成都倍特药业有限公司 用作布鲁顿酪氨酸激酶抑制剂的化合物及其制备方法和应用
WO2018033091A1 (fr) * 2016-08-17 2018-02-22 深圳市塔吉瑞生物医药有限公司 Composé bicyclique fusionné pour inhiber l'activité de la tyrosine kinase

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104080789A (zh) * 2012-01-31 2014-10-01 南京奥昭生物科技有限公司 作为布鲁顿酪氨酸激酶抑制剂的环状分子
CN105916859A (zh) * 2014-02-03 2016-08-31 卡迪拉保健有限公司 杂环化合物
WO2016106625A1 (fr) * 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Inhibiteurs de btk
WO2016106623A1 (fr) * 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Composés benzamides et imidazopyrazines utilisés comme inhibiteurs de la btk
WO2018033091A1 (fr) * 2016-08-17 2018-02-22 深圳市塔吉瑞生物医药有限公司 Composé bicyclique fusionné pour inhiber l'activité de la tyrosine kinase
CN106831787A (zh) * 2017-01-20 2017-06-13 成都倍特药业有限公司 用作布鲁顿酪氨酸激酶抑制剂的化合物及其制备方法和应用

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021008441A1 (fr) * 2019-07-12 2021-01-21 正大天晴药业集团股份有限公司 Inhibiteur de btk contenant du 5-azaspiroheptane
CN113993871A (zh) * 2019-07-12 2022-01-28 正大天晴药业集团股份有限公司 含有5-氮杂螺庚烷的btk抑制剂
CN113993871B (zh) * 2019-07-12 2023-08-01 正大天晴药业集团股份有限公司 含有5-氮杂螺庚烷的btk抑制剂
WO2021180107A1 (fr) * 2020-03-12 2021-09-16 Fochon Pharmaceuticals, Ltd. Composés utiles en tant qu'inhibiteurs de kinase
CN115443277A (zh) * 2020-03-12 2022-12-06 重庆复尚源创医药技术有限公司 作为激酶抑制剂的化合物
WO2022037649A1 (fr) * 2020-08-20 2022-02-24 Beijing Innocare Pharma Tech Co., Ltd. Composés hétérocycliques utilisés comme inhibiteurs de btk
CN114634512A (zh) * 2020-12-16 2022-06-17 江苏恒瑞医药股份有限公司 作为布鲁顿酪氨酸激酶抑制剂的化合物、其制备方法和医药应用
CN114634512B (zh) * 2020-12-16 2023-11-14 江苏恒瑞医药股份有限公司 作为布鲁顿酪氨酸激酶抑制剂的化合物、其制备方法和医药应用
WO2023110970A1 (fr) 2021-12-14 2023-06-22 Netherlands Translational Research Center Holding B.V Inhibiteurs macrocycliques de btk

Also Published As

Publication number Publication date
CN112424203B (zh) 2022-07-26
CN112424203A (zh) 2021-02-26

Similar Documents

Publication Publication Date Title
WO2020015735A1 (fr) Inhibiteurs de la tyrosine kinase de bruton
EP3277689B1 (fr) Composés hétérocycliques utilisés en tant qu'inhibiteurs de lsd1
TWI503319B (zh) 吡啶酮和氮雜吡啶酮之化合物及其使用方法
KR101727264B1 (ko) 이미다조〔2,1-ｂ〕〔1,3,4〕티아디아졸 유도체
EP4119558A1 (fr) Composés de pyrazolopyridine et leurs utilisations
WO2021088945A1 (fr) Composé utilisé comme inhibiteur de shp2 et son utilisation
BRPI0622030A2 (pt) Derivados de purina 7-substituída, para imunossupressão
TWI707855B (zh) 咪唑并嗒類化合物及其用途
PL199615B1 (pl) Pochodne imidazo [1,2-a] pirydyny i pirazolo [2,3-a] pirydyny, sposób ich wytwarzania, zawierające je kompozycje farmaceutyczne oraz ich zastosowania
CN102762565A (zh) 吡啶并[3,2-d]嘧啶PI3δ抑制剂化合物及使用方法
KR20180006334A (ko) 신규한 4-아미노피라졸로[3,4-d]피리미디닐아자바이사이클로 유도체 및 이를 포함하는 약학 조성물
CN113754682B (zh) 具有大环结构的化合物及其用途
CA3174865A1 (fr) Compose de quinazoline et procede de preparation, utilisation et composition pharmaceutique correspondantes
AU2019237991A1 (en) JAK inhibitors
CA2634555A1 (fr) Diazepinones
CN116940573A (zh) 三环类化合物及其用途
EP4223759A1 (fr) Composé pyrazolopyridazinone, composition pharmaceutique le contenant et son utilisation
WO2018228275A1 (fr) Composé hétérocyclique utilisé en tant qu'inhibiteur de mnk
CN112805287B (zh) 含有呋喃并[3,4-b]吡咯的BTK抑制剂
TW202400581A (zh) 驅動蛋白kif18a抑制劑及其應用
CN109641909A (zh) 雷帕霉素信号通路抑制剂的机理靶标及其治疗应用
BR112020026337A2 (pt) Compostos tricíclicos
CA3174838A1 (fr) Inhibiteurs de kinase
KR20230022433A (ko) Gpr65의 조절제로서 n-(페닐아미노카보닐) 테트라하이드로-이소퀴놀린 및 관련 화합물
AU2020406056A1 (en) 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino]methyl)piperidin-3-ol compounds and their therapeutic use

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: 19837028

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19837028

Country of ref document: EP

Kind code of ref document: A1