WO2023051648A1 - Compound as shp2 inhibitor, and preparation method therefor and use thereof - Google Patents

Compound as shp2 inhibitor, and preparation method therefor and use thereof Download PDF

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Publication number
WO2023051648A1
WO2023051648A1 PCT/CN2022/122329 CN2022122329W WO2023051648A1 WO 2023051648 A1 WO2023051648 A1 WO 2023051648A1 CN 2022122329 W CN2022122329 W CN 2022122329W WO 2023051648 A1 WO2023051648 A1 WO 2023051648A1
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alkyl
ring
membered
compound
halogen
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PCT/CN2022/122329
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French (fr)
Chinese (zh)
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白进红
尹磊
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甘李药业股份有限公司
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Priority to CN202280060269.1A priority Critical patent/CN118019743A/en
Publication of WO2023051648A1 publication Critical patent/WO2023051648A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/4985Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12Heterocyclic 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 three hetero rings
    • C07D487/16Peri-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12Heterocyclic 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 three hetero rings
    • C07D498/16Peri-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D519/00Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a compound used as a SHP2 inhibitor, its pharmaceutical composition and its use in the treatment of diseases mediated by SHP2 activity.
  • SHP2 src homology 2 domain containing phosphotyrosine phosphatase 2 is a non-receptor protein tyrosine phosphatase encoded by gene PTPN11, which contains two N-terminal SH2 (Srchomology 2) domains and a protein tyrosine phosphatase acid phosphatase (PTP) catalytic domain and a C-terminal tail rich in proline groups and tyrosine phosphorylation sites.
  • PTPN11 non-receptor protein tyrosine phosphatase encoded by gene PTPN11, which contains two N-terminal SH2 (Srchomology 2) domains and a protein tyrosine phosphatase acid phosphatase (PTP) catalytic domain and a C-terminal tail rich in proline groups and tyrosine phosphorylation sites.
  • PTP protein tyrosine phosphatase acid phosphatase
  • the present invention provides a compound used as a SHP2 inhibitor, its pharmaceutical composition and its use in preventing or treating diseases mediated by SHP2 activity.
  • the present invention provides a compound represented by formula Q or a pharmaceutically acceptable salt thereof,
  • Z is CH or N;
  • Z 1 is CR 0 , N, O or S;
  • Ring D is a 5-6-membered monocyclic aryl group, a 5-6-membered monocyclic heteroaryl group with 1-4 heteroatoms independently selected from N, O, and S, and 1-5 independently selected heteroatoms
  • Ring E is a C 4-8 cycloalkyl group, or a 4-8 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O and S;
  • Substituents of -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; or, two independent R e and the atoms connected to them on the ring E form a 3-12 membered monocyclic or polycyclic hydrocarbon ring, a 3-12 membered monocyclic or polycyclic heterocyclic ring, a 3-12 membered hydrocarbon ring and a heterocyclic ring
  • L 1 is a covalent bond, or is a C1-4 divalent saturated or unsaturated straight-chain or branched chain hydrocarbon group, or, the C1-4 divalent saturated or unsaturated straight-chain or branched chain hydrocarbon group
  • One or two methylene groups in are independently selected from -O-, -C(O), -OC(O)-, -C(O)O-, -S-, -S(O)- and -S(O) 2 - the group formed after the group is replaced; k is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9; m is 0, 1, 2, 3, 4 or 5; and n is 0, 1, 2, 3, 4, 5, 6 or 7.
  • ring E is selected from:
  • the present invention further provides a compound or a pharmaceutically acceptable salt thereof, which has the structural formula Q 1 :
  • ring D is selected from
  • the present invention provides a general structure as shown in formula I or a pharmaceutically acceptable salt thereof:
  • W 1 , W 2 , and W 3 are each independently selected from CR 1 and N;
  • X 2 , X 3 , and X 4 are each independently selected from CR 2 and N;
  • Z is CH or N
  • X 1 is CR 8 or N
  • the ring A is selected from a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, a 5-8 membered heteroaryl ring or a 5-8 membered aromatic ring, and the hydrocarbon ring, heterocyclic ring, heteroaryl ring and aromatic
  • Ring A is a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, or a 5-8 membered heteroaromatic ring.
  • Ring A has 1, 2, 3 or 4 independently A 5-6 membered heterocyclic or heteroaryl ring with heteroatoms selected from N, O and S, preferably, ring A is a 5-6 membered heterocyclic ring with 1 or 2 heteroatoms independently selected from N and O or a heteroaromatic ring, preferably ring A is a 5-8 membered hydrocarbon ring or a 5-8 membered heterocyclic ring, preferably, ring A is a heterocyclic ring with 1, 2, 3 or 4 independently selected from N, O and S 5-6 membered heterocyclic rings with atoms, further preferably, ring A is selected from partially unsaturated morpholine rings, partially unsaturated pyrazolidine rings, partially unsaturated piperidine rings, partially unsaturated piperazine rings, partially unsaturation
  • R and f are as defined above.
  • each occurrence of R 1 is independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -OC 1-3 alkyl, -NH 2 , haloC 1-3 alkyl and C 3-4 cycloalkyl; in a preferred embodiment, each occurrence of R is independently selected from H, -CN, -CH and cyclopropyl.
  • each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -OC 1-3 alkyl, -NH 2 , -C( O)NH 2 , -COOH, -C(O)OC 1-3 alkyl, -C 1-3 alkylene-OH and halogenated C 1-3 alkyl; in a preferred embodiment, R 2 is at Each occurrence is independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -C(O)NH 2 and -C 1-3 alkylene-OH; in a more preferred embodiment In the scheme, each occurrence of R 2 is independently selected from H, F, -OH, -CN, -CH 3 , -C(O)NH 2 and -CH 2 -OH.
  • R and R are each independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -OC 1-3 alkyl, -C 1-3 alkylene- NH 2 , -NH 2 , -NH(C 1-3 alkyl) and -N(C 1-3 alkyl) 2 ; in a preferred embodiment, R 3 and R 4 are each independently selected from H, halogen , -OH, -CN, C 1-3 alkyl, -C 1-3 alkylene -NH 2 and -NH 2 ; in a preferred embodiment, R 3 and R 4 are each independently selected from H, - F, -OH, -CH2 - NH2 and -NH2 ; or
  • R 3 and R 4 form a 3, 4, 5 or 6-membered monocyclic hydrocarbon ring, or a 3, 4, 5 or 6-membered monocyclic heterocyclic ring together with the atoms they are connected to.
  • R 3 and R together with the atoms to which they are attached form a 5-6 membered monocyclic heterocycle having 1, 2, 3 or 4 heteroatoms selected from N, O or S, wherein each of the hydrocarbon ring and heterocycle is optionally One or more selected from halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -C(O)N(C 1-6 alkyl) 2 , -C 1-6 alkylene-OH and halogenated C 1-6 alkyl substituents, preferably substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, C 1-3 Alkyl, -OC 1-3 alkyl, -NH 2 , -C
  • Part is the following chemical structure:
  • Y1 is selected from O, S, C(R 6 ) 2 , or NR 6
  • each occurrence of R 6 is independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, - OC 1-3 alkyl, -NH 2 and halogenated C 1-3 alkyl
  • each occurrence of R is independently selected from H, halogen, -OH, -CN, - CH 3 , -OCH 3 , -NH 2 , -CH 2 -OH, -C(O)N(CH 3 ) 2 and -CF 3
  • g is 0, 1, 2, 3, 4, 5 or 6
  • R 3 and R 4 together with the atoms they connect form a bicyclic ring system formed by condensing a 5-6 membered hydrocarbon ring with a 5-6 membered heteroaromatic ring, a 5-6 membered hydrocarbon ring and
  • the compound of Formula I has the structure of Formula II:
  • W 1 , W 2 , W 3 , X 1 , X 2 , X 3 , X 4 , Z, m and n are as defined above
  • R 1 and R 2 are as defined above
  • W 4 , R 5 , p , q and f are as defined above
  • Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are as defined above; preferably, both X 1 and X 2 are N, and/or p is 1 or 2, q is 0 or 1.
  • the present invention provides a compound or a pharmaceutically acceptable salt thereof, the compound is selected from:
  • the present invention provides a preferred compound or a pharmaceutically acceptable salt thereof, the compound is selected from:
  • the present invention also provides an intermediate for preparing the above compound, or a salt thereof, wherein the intermediate is selected from:
  • the above-mentioned intermediates are selected from:
  • the present invention also provides a preparation method of the compound shown in formula II or a pharmaceutically acceptable salt thereof:
  • W 1 , W 2 , W 3 , Z, m and n are as defined above
  • R 1 and R 2 are as defined in claim 5, 6, 11, or 15, W 4 , R 5 , p, q and f are as defined above
  • Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are as defined above
  • X 1 , X 2 , X 3 , X 4 are all N
  • n is 0, including: using the corresponding The first key intermediate of the structure of part A, the second key intermediate corresponding to the structure of part B, and the third key intermediate corresponding to the structure of part C are subjected to substitution reactions to prepare the compound shown in formula II.
  • R 9 and R 10 are as defined above.
  • the first key intermediate corresponding to part A is selected from:
  • the second key intermediate corresponding to part B is selected from:
  • compositions, formulations and kits are provided.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injections. Pharmaceutically acceptable carriers include pharmaceutical excipients.
  • Suitable pharmaceutical excipients include, but are not limited to, starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol , water, ethanol, etc.
  • the composition may also contain small amounts of wetting agents, emulsifiers, lubricants, stabilizers or pH buffering agents, etc., as required.
  • Oral formulations can contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).
  • Another aspect of the present invention also relates to a pharmaceutical preparation comprising the compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, or the pharmaceutical composition of the present invention.
  • the formulation is in the form of a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.
  • compositions of the present invention can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated.
  • Topical e.g., transdermal, dermal, ocular, and mucous membranes, including intranasal, vaginal, and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal, intranasal
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, eg, intrathecal or intracerebroventricular, administration.
  • a further object of the present invention is to provide a product, for example in the form of a kit.
  • articles of manufacture are intended to include, but are not limited to, kits and packages.
  • the kit may also include instructions for use.
  • Another object of the present invention is to provide a use of a compound of formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating diseases mediated by SHP2 activity.
  • the present invention provides a method for preventing or treating a disease mediated by SHP2 activity, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof or the present invention to an individual in need thereof.
  • Invented pharmaceutical composition Invented pharmaceutical composition.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention for preventing or treating diseases mediated by SHP2 activity.
  • the diseases mediated by SHP2 activity which can be prevented or treated using the compounds of the invention are diseases which are sensitive or responsive to inhibition of the SHP2 enzyme.
  • the disease mediated by SHP2 activity is non-small cell lung cancer.
  • the present invention provides a new type of highly active SHP2 inhibitor, which can achieve at least one of the following technical effects:
  • compositions of the present invention may exist in free form or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, prodrugs, stereoisomers (including but not limited to diastereoisomers and enantiomers), Tautomers, solvates, polymorphs and isotopic compounds are capable of providing, directly or indirectly, a compound of formula I or its metabolites after their administration to a patient in need thereof. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acids and bases of the specified compound without adverse biological effects.
  • pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, etc.; Maleic acid, maleic acid, benzoic acid, phenylacetic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, glycolic acid, cinnamic acid, pyruvic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid , acrylic acid, mandelic acid, etc.; or (2) alkali addition salts, salts formed with alkali metals such as lithium, sodium, potassium, etc.; salts formed with alkaline earth metals such as calcium, magnesium, etc.; and organic
  • the prodrugs of the compounds of the present invention are included in the protection scope of the present invention.
  • the prodrugs refer to functional derivatives that are readily converted in vivo to the desired compound. Therefore, the term "administering" in the treatment method provided by the present invention includes administering the compound disclosed in the present invention, or although not explicitly disclosed but can be converted into the compound disclosed in the present invention after administration to the subject to treat the described compound. various diseases. Routine methods for selecting and preparing suitable prodrug derivatives are described, for example, in such books as Design of Prodrugs, H. Bundgaard, Elsevier, 1985.
  • the compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and optical isomers.
  • the present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
  • the above formula I does not exactly define the stereostructure of a certain position of the compound.
  • the present invention includes all stereoisomers of the compound represented by formula I and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. During the synthesis of such compounds, or during the use of racemization or epimerization procedures well known to those of ordinary skill in the art, the products obtained may be mixtures of stereoisomers.
  • the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and their mixtures.
  • the present invention includes any possible solvates and polymorphs.
  • the type of solvent forming a solvate is not particularly limited as long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone, and the like can be used.
  • the invention also includes all pharmaceutically acceptable isotopic compounds which are identical to the compounds of the invention except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass or mass prevailing in nature Atomic substitution of numbers.
  • isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g., 13C and 14C ); Isotopes (such as 37 Cl); isotopes of iodine (such as 125 I); isotopes of nitrogen (such as 13 N and 15 N); isotopes of oxygen (such as 17 O and 18 O); isotopes of phosphorus (such as 32 P); Isotopes of sulfur (eg 34 S).
  • isotopes of hydrogen e.g., deuterium ( 2H ), tritium ( 3H
  • C 1 -C 6 should be understood to cover any subrange therein as well as every point value, such as C 2 -C 5 , C 3 -C 4 , C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , etc., and C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , etc.
  • the expression "5-10 yuan” should also be understood in a similar manner, for example, can cover any sub-range and point value contained therein, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5- 9 yuan, 5-10 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 6-10 yuan, 7-8 yuan, etc. and 5, 6, 7, 8, 9, 10 yuan, etc.
  • alkyl refers to a saturated straight or branched chain hydrocarbon group.
  • C 1-6 alkyl refers to a saturated linear or branched hydrocarbon group having 1-6 carbon atoms (eg, 1, 2, 3, 4, 5 or 6 carbon atoms).
  • C 1-6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo Pentyl or n-hexyl etc.
  • alkylene refers to a saturated linear or branched divalent hydrocarbon group.
  • C 1-6 alkylene refers to a saturated linear or branched divalent hydrocarbon group having 1-6 carbon atoms.
  • methylene, ethylene, propylene or butylene and the like are examples of alkylenes.
  • cycloalkyl refers to a saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g. monocyclic, such as cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl; or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1] Heptyl, bicyclo [3.2.1] octyl or bicyclo [5.2.0] nonyl, decahydronaphthyl, etc.).
  • Cycloalkyl includes C 3-10 cycloalkyl, preferably C 3-6 cycloalkyl, more C 5-6 cycloalkyl is preferred.
  • C 3-10 cycloalkyl refers to a cycloalkyl group having 3-10 ring carbon atoms (eg, 3, 4, 5, 6, 7, 8, 9 or 10).
  • hydrocarbon ring when used alone or in combination with other groups herein, refers to the Saturated or partially unsaturated (ie having one or more double and/or triple bonds within the ring, but not forming an aromatic ring system) monocyclic or polycyclic hydrocarbon rings with preferably 5-6) ring carbon atoms, wherein Monocyclic rings include but are not limited to cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclohexyl rings, cycloheptyl rings, cyclooctyl rings, cyclononyl rings, cyclohexenyl rings, etc., and polycyclic hydrocarbon rings include Linked ring, spiro ring, parallel ring or bridged ring, which has 6-16 carbon atoms.
  • halo or halogen group, when used herein alone or in combination with other groups, means F, Cl, Br or I.
  • haloalkyl refers to an alkyl group as described above, wherein one or more hydrogen atoms are replaced by a halogen.
  • haloC 1-6 alkyl refers to a C 1-6 alkyl optionally substituted with one or more (eg, 1-3) halogen.
  • the halogens may be the same or different, and may be located on the same or different C atoms.
  • haloalkyl groups are for example -CH2F , -CHF2 , -CF3, -CCl3, -C2F5 , -C2Cl5 , -CH2CF3 , -CH2Cl or -CH2CH 2 CF 3 etc.
  • heterocycle when used herein alone or in combination with other groups, refers to a - 6, more preferably 5-6) ring atoms of monocyclic or polycyclic non-aromatic ring systems (eg 3-10, 4-10, 5-10, 6-10, 3-8 , 3-6 membered or 5-6 membered heterocyclic ring), wherein at least one ring atom (eg 1, 2 or 3) is a heteroatom selected from N, O and S, and the remaining ring atoms are C.
  • the ring system may be saturated (also understood as the corresponding "saturated heterocycloalkane") or unsaturated (ie have one or more double and/or triple bonds within the ring).
  • a heterocyclyl group is a group derived from a heterocyclic ring by removal of a hydrogen atom, examples of which include, but are not limited to: oxiranyl, cyclothioethyl, cycloazaethyl, azetidinyl, oxa Cyclobutyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl base, piperidinyl, morpholinyl, 1,4-thiaxanyl, 1,4-dioxanyl, dithianyl, tetrahydropyranyl base, piperidinyl, morpholinyl, 1,4-thiaxanyl, 1,4-dioxanyl, dithianyl,
  • aromatic ring refers to an all-carbon monocyclic or fused-ring polycyclic (eg, bicyclic) aromatic ring having a conjugated ⁇ -electron system.
  • An aryl group is a group derived from an aromatic ring by removal of one hydrogen atom.
  • C 6-10 aryl refers to an aromatic group derived from an aromatic ring containing 6-10 carbon atoms. Examples of aryl include, but are not limited to, phenyl, naphthyl, and the like.
  • heteroaryl group is a group derived from a heteroaryl ring by removal of one hydrogen atom.
  • a heteroaryl or heteroaryl ring can be characterized by the number of ring atoms.
  • a 5-10 membered heteroaryl group may contain 5-10 (eg 5, 6, 7, 8, 9 or 10) ring atoms, especially 5, 6, 9, 10 ring atoms, 5
  • a 6-membered heteroaryl group may contain, for example, 5 or 6 ring atoms.
  • the heteroaryl or heteroaryl ring may optionally be further benzo-fused.
  • heteroaryl groups are thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, tri Azolyl, thiadiazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolyl, benzofuryl, Benzothienyl, indolyl, isoindolyl, etc., and their benzo derivatives.
  • substituted and “substituted” mean that one or more (e.g., one, two, three or four) hydrogens on the indicated atom are replaced by a selection from the indicated group, provided that no more than the indicated Atoms are indicated at their normal valences at the present situation and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituent can be (1) unsubstituted, or (2) substituted. If an atom or group is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the atom or group may be independently selected, optional substituents substitute. If substituents are described as being “independently selected from” or “each independently being”, each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
  • a certain substituent or substituent position or different substituents or substituent positions may have the R groups indicated by the same or different symbols (such as but not limited to R 2 , R 3 , Rh , R i , R x and/or or R y ), each R is independently selected, and may be the same or different. The same goes for the choice of values such as d, g, m, n.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • “Pharmaceutically acceptable carrier” in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with the active ingredient, and it is suitable for contacting human beings and/or Tissues from other animals without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • active ingredient refers to a chemical entity that is effective in treating one or more symptoms of the targeted disorder or condition.
  • the term "effective amount” refers to the amount of the active ingredient which, when administered, will achieve to some extent the desired effect, such as alleviation of a part of the condition being treated. one or more symptoms or prevent the occurrence of a disorder or its symptoms.
  • treating means reversing, alleviating, inhibiting the progression of the disorder or condition to which the term applies or one or more symptoms of said disorder or condition, or preventing said disorder or condition.
  • Benzyl alcohol (17.0 g, 157.96 mmol) was dissolved in THF (300 mL), cooled to 0 °C, NaH (6.89 g, 172.32 mmol) was added in portions, and the resulting mixture was stirred at 0 °C for 1 hour. This mixture was then added to a solution of 3,5-dichloropyrazine-2-carbonitrile (25.0 g, 143.6 mmol) in THF (200 mL) at -78 °C. The resulting solution was stirred at -78°C for 2 hours, and the reaction was quenched by adding saturated ammonium chloride. The reaction mixture was diluted with EA and washed with saturated brine.
  • N-bromosuccinimide (13.8 g, 77.9 mmol) was added in portions to a solution of compound C2-4 (8 g, 51.9 mmol) in acetonitrile (150 mL), and stirred at RT for 3 hours. The solvent was distilled off under reduced pressure to obtain compound C2-5 (12 g of brown solid), without further purification. MS(ESI):233.0[M+H]+.
  • Example 12-4 (100mg, 0.154mmol) was dissolved in HCl/dioxane (4N, 2mL), stirred at RT for 1 hour, concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain Example 12 (21mg yellow solid, yield 24 %).
  • Example 29-2 (67mg, 0.089mmol) was dissolved in HCl/dioxane (4N, 2mL), stirred at RT for 1 hour, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (water/acetonitrile) to obtain Example 29 (10mg yellow solid).
  • Example 33 can be synthesized in a manner similar to Example 1.
  • Example 37-3 was used to replace compound 1-3 in Example 1, and Example 37 was synthesized in a manner similar to Example 1. MS(ESI):mass calcd.for C 31 H 33 N 7 O 2 535.3,m/z found 536.2[M+H] + .
  • Test example 1 SHP2 (protein tyrosine phosphatase) in vitro enzymatic activity inhibition test
  • SHP2 protein solution concentration 0.5nM; enzyme buffer solution: 55mM HEPES, 100mM NaCl, 0.2% BSA, 1mM EDTA, 1mM DTT, 0.1% Triton X-100; SHP2Activating Peptide solution concentration: 0.5 ⁇ M; DiFMUP solution concentration: 120 ⁇ M; Positive Concentration of DMSO solution of drug SHP099: 10000nM, 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, 0.15nM, 0nM, wherein the compound concentration of 0nM is the blank group; the DMSO solution concentration of the test compound : 10000nM, 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, 0.15nM, 0nM, wherein the compound concentration of 0nM is the blank group; the DMSO solution concentration of the
  • the inhibition rate of each compound at each concentration point was calculated according to the following formula, and the IC50 value was obtained by curve fitting with the software Graphpad Prism 8.0.
  • the inhibitory activity of the compounds on SHP2 activity was determined according to the above method, and the results are shown in the following table.
  • Example 1 5.46 Example 4 2.19 Example 5 35.50 Example 6 22.21 Example 7 32.80 Example 8 4.15 Example 9 17.73 Example 12 7.28 Example 19 8.27 Example 20 26.18 Example 21 3.56 Example 22 12.29 Example 23 4.99 Example 29 8.44 Example 30 3.33 Example 31 2.68 Example 32 7.36 Example 33 6.85 Example 52 7.17 Example 59 65.59 Example 60 13.28 Example 61 9.81 Example 63 4.7 Example 64 5.72 Example 65 11.26 Example 66 3.84 Example 67 8.79 Example 68 9.84 Example 69 6.54 Example 70 4.36 Example 71 18.42 Example 72 6.72 Example 73 4.17 Example 74 4.65 Example 75 2.51 Example 76 5.78 Example 77 5.73 Example 78 7.89 Example 79 13.9 Example 80 3.24
  • Example 81 3.09 Example 83 8.45 Example 84 1.7 Example 85 11.61
  • Example 86 6.87 Example 87 46.5
  • Example 88 7.19
  • Example 90 22.95
  • Example 91 11.5
  • Example 92 6.14 Example 93 15.13
  • Example 94 9.24
  • Example 95 10.56
  • Example 96 70.16 Example 97 7.82
  • Example 98 7.06 Example 99 8.86
  • Example 100 336.83
  • Example 101 277.66
  • Example 102 520.61
  • Example 103 205.46
  • Test Example 2 Compounds of the present invention inhibit the proliferation of non-small cell lung cancer H358 cells
  • DMSO solution concentration of positive drug SHP099 80000nM, 20000nM, 5000nM, 1250nM, 312.5nM, 78.13nM, 19.53nM, 4.88nM , 1.22nM and 0nM, wherein the compound concentration of 0nM is the blank group; the DMSO solution concentration of the test compound: 80000nM, 20000nM, 5000nM, 1250nM, 312.5nM, 78.13nM, 19.53nM, 4.88nM, 1.22nM and 0nM, where The compound concentration of 0nM group was the blank group.
  • H358 cells were cultured in the culture medium and placed at 37°C, 5% CO 2 culture conditions for culture. Take the H358 cells in the logarithmic growth phase, digest and resuspend the cells, count them, adjust the cell density and inoculate them into a transparent black plate at the bottom of 96 wells, inoculate 2,500 cells per well, and place them in an incubator at 37°C and 5% CO 2 Cultivate for 72h. After 72 hours, 20 ⁇ L of positive drug or test compound solution was added to each well, and incubated at a constant temperature of 37° C., 5% CO 2 and 90% relative humidity for 120 hours.
  • the inhibition rate of each compound at each concentration point was calculated according to the following formula, and the IC50 value was obtained by curve fitting with the software Graphpad Prism 8.0.
  • the inhibitory activity of the compounds on H358 cell proliferation was determined according to the above method, and the results are shown in the following table.
  • Example 1 6.70
  • Example 2 22.10
  • Example 3 25.75
  • Example 4 5.14
  • Example 8 7.17
  • Example 9 38.36
  • Example 12 25.96
  • Example 19 39.63
  • Example 21 54.11
  • Example 23 45.66
  • Example 29 5.35
  • Example 30 3.90
  • Example 32 14.82
  • Example 33 4.7
  • Example 34 50.22
  • Example 35 16.46
  • Example 52 39.24
  • Example 59 470.24
  • Example 60 224.3 Example 61 72.89 Example 63 216.9 Example 64 22.81 Example 65 29.1 Example 66 54.09 Example 67 159.5 Example 68 28.43 Example 69 13.18 Example 70 16.2 Example 71 8.51 Example 72 5.21 Example 73 1.98 Example 74 6.9 Example 75 11.32 Example 76 55.6 Example 77 42.71 Example 78 45.52 Example 79 40.51 Example 80 10.18 Example 81 8.31 Example 83 3.15 Example 84 13.33 Example 85 27.26 Example 86 8.23 Example 87 732.7 Example 88 30.38 Example 89 48.42 Example 90 32.85 Example 91 32.21 Example 92 30.26 Example 93 159.36 Example 94 54.04 Example 95 63.93 Example 96 578.5 Example 97 30.31 Example 98 27.25 Example 99 39.76 Example 100 1698 Example 101 752.2 Example 102 1265 Example 103 2851
  • Test Example 3 Compounds of the present invention inhibit test of hERG potassium ion channel
  • F-12 (HAM) medium 10% FBS buffer, 100U/mL penicillin/streptomycin, 100 ⁇ g/mL Hygronycin and 100 ⁇ g/mL G418;
  • NMDG 60 standard external solution (use HCl to adjust the pH to 7.4, infiltrate Pressure is 289mOsm/kg) 80mM sodium chloride, 60mM NMDG, 4mM potassium chloride, 2mM calcium chloride, 1mM magnesium chloride, 5mM polydextrose, 10mM HEPES;
  • the compound was first diluted with DMSO to 3.33, 1.11 and 0.37 mM stock solutions in a serial dilution manner, and then diluted with extracellular fluid to the final dilution of the compound into the following concentrations (30, 10, 3.33, 1.11 and 0.37 ⁇ M ) for testing.
  • the final concentration of DMSO in each concentration test solution was 0.1%. All stock and test solutions were sonicated and shaken for 5-10 minutes to ensure complete dissolution of the compound.
  • CHO cells were grown in the culture dish containing the above cell culture medium, and cultured at 37°C in an incubator containing 5% CO2. 24 to 48 hours before electrophysiological experiments, CHO cells were transferred to round glass slides placed in petri dishes, and grown in the same culture medium and culture conditions as above. The density of CHO cells on each circular slide needs to be such that most of the cells are independent and single.
  • the drug to be tested can be superimposed and perfused until the inhibitory effect of the drug on the hERG current reaches a steady state.
  • the coincidence of the latest three consecutive current recording lines is used as the criterion for judging whether it is in a stable state.
  • extracellular fluid was used to perfuse and wash until the hERG current returned to the size before adding drugs.
  • One or more drugs, or multiple concentrations of the same drug can be tested on a cell, but extracellular fluid washing is required between different drugs.
  • the hERG potassium ion channel inhibitory activity of the compounds was determined according to the above method, and the results are shown in the following table.
  • Example 5 9.2 Example 29 >30 Example 64 >30 Example 66 >30 Example 68 6.83 Example 69 19.12 Example 70 4.23 Example 71 4.55 Example 75 4.28 Example 76 7.02 Example 77 16.49 Example 78 6.13 Example 79 7.64 Example 94 4.65
  • the drug configuration is 5% DMSO+40% PEG400+55% NS, the drug is effective
  • the components are the compounds in Examples 80 and 81 respectively, and the administration frequency and administration volume are single, oral administration (p.o.) 10mg/kg; intravenous injection (i.v.) 2mg/kg, grouping and administration are as follows.
  • sample collection time points 15min, 30min, 1h, 2h, 4h, 8h, 12h, 24h; the distribution of sample collection points is shown in the table below.
  • mice/time point Whole blood was collected from the orbits of each dosing group, 3 mice/time point, the blood collection volume was 0.2ml/time point, EDTA anticoagulated whole blood, and centrifuged after the whole blood collection was completed to obtain the supernatant, the centrifugation speed was 4000rpm, and the centrifugation time was 10min.
  • the results of the mouse pharmacokinetic parameters of the examples detected by the LCMS/MS method are as follows.
  • NCI-H1975 human non-small cell lung adenocarcinoma cells were cultured in a single layer in vitro, and the culture conditions were 1640 medium plus 10% fetal bovine serum, cultured at 37°C and 5% CO 2 . Routine digestion with trypsin-EDTA was performed twice a week for passaging. When the cells are in the exponential growth phase, the cells are collected, counted, and inoculated.
  • mice 54 BALB/c female nude mice weighing about 15-18 g (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were selected for 6 weeks. Each mouse was subcutaneously inoculated with (2 x 10 6 ) NCI-H1975 cells at the posterior scapula, and the cell suspension was composed of serum-free medium mixed with 50% medium gel. The drug treatment was started after the average tumor volume reached the appropriate size.
  • TGI (%) [1-(Ti-T0)/(Vi-V0)] ⁇ 100, wherein Ti is the average tumor volume of a certain administration group on a certain day, and T0 is given for this purpose.
  • T and C represent the tumor weight of the administration group and the vehicle control group, respectively.

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Abstract

Provided are a compound as an SHP2 inhibitor, a pharmaceutical composition thereof, and the use thereof in the prevention or treatment of SHP2 activity-mediated diseases.

Description

可用作SHP2抑制剂的化合物及其制备方法和用途Compounds useful as SHP2 inhibitors and their preparation and use 技术领域technical field
本发明涉及药物化学领域,并且具体地涉及一种用作SHP2抑制剂的化合物、其药物组合物及其在治疗SHP2活性介导的疾病中的用途。The present invention relates to the field of medicinal chemistry, and in particular to a compound used as a SHP2 inhibitor, its pharmaceutical composition and its use in the treatment of diseases mediated by SHP2 activity.
背景技术Background technique
SHP2(src homology 2 domain containing phosphotyrosine phosphatase 2)是一种由基因PTPN11编码的非受体型蛋白酪氨酸磷酸酶,结构上含有两个N末端的SH2(Srchomology 2)结构域、一个蛋白酪氨酸磷酸酶(PTP)催化功能域和一个富含脯氨酸基团和酪氨酸磷酸化位点的C-末端尾巴。SHP2蛋白调节Ras/ERK、JAK-STAT3、NF-kB、PI3K/Akt、RHO和NFAT等多条信号通路,参与多种生长因子、细胞因子和整联蛋白受体下游信号的信号传导,促进增殖、分化、细胞周期维持和迀移等细胞功能。SHP2 (src homology 2 domain containing phosphotyrosine phosphatase 2) is a non-receptor protein tyrosine phosphatase encoded by gene PTPN11, which contains two N-terminal SH2 (Srchomology 2) domains and a protein tyrosine phosphatase acid phosphatase (PTP) catalytic domain and a C-terminal tail rich in proline groups and tyrosine phosphorylation sites. SHP2 protein regulates multiple signaling pathways such as Ras/ERK, JAK-STAT3, NF-kB, PI3K/Akt, RHO and NFAT, participates in the signal transduction of downstream signals of various growth factors, cytokines and integrin receptors, and promotes proliferation , differentiation, cell cycle maintenance and migration and other cellular functions.
研究表明,SHP2的激活突变与努南综合征、豹综合征、幼年稚型粒单核细胞白血病(JMML)、黑色素瘤和实体瘤等发病有密切的关系。SHP2的过表达会增加慢性粒细胞白血病、肥大细胞增多症、恶性胶质瘤、肺癌和乳腺癌等癌症的风险,提示SHP2在不同类型癌症及癌症的不同发展阶段中有广泛的作用(Higuchi M et al.Cancer Sci,2004,95:442-447;Bentires-Al j M et al.Cancer Res,2004,64:8816-8820;Martinelli S et al.Cancer Genet Cytogenet,2006,166:124-129)。因此,人类肿瘤中或其它疾病中活化的SHP2或者上调的SHP2蛋白成为新的治疗靶点。本发明中的化合物满足了对SHP2小分子抑制剂的需求。Studies have shown that activating mutations of SHP2 are closely related to the pathogenesis of Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia (JMML), melanoma and solid tumors. Overexpression of SHP2 increases the risk of chronic myelogenous leukemia, mastocytosis, malignant glioma, lung cancer and breast cancer, suggesting that SHP2 has a wide range of roles in different types of cancer and in different stages of cancer development (Higuchi M et al.Cancer Sci,2004,95:442-447; Bentires-Al j M et al.Cancer Res,2004,64:8816-8820; Martinelli S et al.Cancer Genet Cytogenet,2006,166:124-129) . Therefore, activated SHP2 or upregulated SHP2 protein in human tumors or other diseases has become a new therapeutic target. The compounds of the present invention fulfill the need for small molecule inhibitors of SHP2.
发明内容Contents of the invention
本发明提供了一种用作SHP2抑制剂的化合物、其药物组合物及其在预防或治疗SHP2活性介导的疾病中的用途。The present invention provides a compound used as a SHP2 inhibitor, its pharmaceutical composition and its use in preventing or treating diseases mediated by SHP2 activity.
本发明提供了式Q所示的化合物或其药学上可接受的盐,The present invention provides a compound represented by formula Q or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022122329-appb-000001
Figure PCTCN2022122329-appb-000001
其中,Z是CH或N;Z 1是CR 0、N、O或S; Wherein, Z is CH or N; Z 1 is CR 0 , N, O or S;
R 0选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、C 2-6炔基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; R 0 is selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0-2 -C 1-6 alkane Base, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N (C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1 -6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, - OC 1-6 alkyl, C 2-6 alkynyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2. Substituents of -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ;
环A选自5-8元的烃环、5-8元杂环、5-8元杂芳环和5-8元芳环,且所述烃环、杂环、杂芳环和芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、C 2-6炔基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基、C 3-6 环烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Ring A is selected from 5-8 membered hydrocarbon rings, 5-8 membered heterocyclic rings, 5-8 membered heteroaryl rings and 5-8 membered aromatic rings, and the hydrocarbon rings, heterocyclic rings, heteroaryl rings and aromatic rings are each Optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH (C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkane and -C(O)N(C 1-6 alkyl) substituents substituted with each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl optionally further substituted by One or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkane group, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl ) is replaced by a substituent of 2 ;
环B是包含N原子的5-8元杂环或5-8元杂芳环,且所述杂环和杂芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、C 2-6烯基、C 2-6炔基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Ring B is a 5-8 membered heterocyclic ring or a 5-8 membered heteroaryl ring containing N atoms, and each of the heterocyclic ring and heteroaryl ring is optionally replaced by one or more members selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered hetero Cyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkane group, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl ) 2 is substituted by a substituent, each of said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl being optionally further selected from one or more of halogen, -OH, =O, - OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O) Substituents of NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ;
环C选自5-8元芳环或含有各自独立选自N、O、和S的1-3个杂原子的5-8元杂芳环,且所述芳环或杂芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Ring C is selected from 5-8 membered aromatic rings or 5-8 membered heteroaromatic rings containing 1-3 heteroatoms independently selected from N, O, and S, and each of the aromatic rings or heteroaryl rings is optionally One or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl group, -CN, -NH 2 , - NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 Alkyl and -C (O) N (C 1-6 alkyl) substituent substitution, said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl each optionally further By one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, - N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituent substitution;
环D为5-6元的单环芳基、具有1-4个各自独立选自N、O、S的杂原子的5-6元的单环杂芳基,具有1-5个各自独立选自N、O、S的杂原子的8-10元双环杂芳基,或具有1-5个各自独立选自N、O、S的杂原子的杂烃环与杂芳环形成的8-10元稠合环基;Ring D is a 5-6-membered monocyclic aryl group, a 5-6-membered monocyclic heteroaryl group with 1-4 heteroatoms independently selected from N, O, and S, and 1-5 independently selected heteroatoms An 8-10 membered bicyclic heteroaryl group consisting of N, O, and S heteroatoms, or an 8-10 membered heterohydrocarbon ring and a heteroaryl ring having 1-5 heteroatoms independently selected from N, O, and S Member fused ring group;
环E为C 4-8环烷基,或含有1-3个各自独立选自N、O和S的杂原子的4-8元杂环烷基; Ring E is a C 4-8 cycloalkyl group, or a 4-8 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O and S;
R 1在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0 -2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl group, -NH 2 , -NH(C 1 -6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and - C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally selected from one or more halogen , -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl ) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 are substituted by substituents;
R 2在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0 -2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl group, -NH 2 , -NH(C 1 -6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and - C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally selected from one or more halogen , -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl ) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 are substituted by substituents;
R e每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代;或者,两个独立地R e与环E上与它们连接的原子一起形成3-12元的单环或多环烃环、3-12 元的单环或多环杂环、3-12元的烃环和杂环形成的多环环系、3-6元的烃环与5-8元的杂芳环稠合形成的多环环系、3-6元的烃环与5-8元的芳环稠合形成的多环环系、3-6元的杂环与5-8元的杂芳环稠合形成的多环环系、或3-6元的杂环与5-8元的芳环稠合形成的多环环系,且所述每个环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基、C 3-6环烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Each occurrence of R e is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0- 2 -C 1-6 alkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -OC 1-6 alkyl, -NH 2 , -NH(C 1- 6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C (O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2. Substituents of -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; or, two independent R e and the atoms connected to them on the ring E form a 3-12 membered monocyclic or polycyclic hydrocarbon ring, a 3-12 membered monocyclic or polycyclic heterocyclic ring, a 3-12 membered hydrocarbon ring and a heterocyclic ring The formed polycyclic ring system, the polycyclic ring system formed by the fusion of 3-6 membered hydrocarbon ring and 5-8 membered heteroaryl ring, the condensed form of 3-6 membered hydrocarbon ring and 5-8 membered aromatic ring A polycyclic ring system, a polycyclic ring system formed by the fusion of a 3-6-membered heterocycle and a 5-8-membered heteroaromatic ring, or a condensed 3-6-membered heterocycle and a 5-8-membered aromatic ring A polycyclic ring system, and each ring is optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, -S(=O ) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl group, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkyl and -C (O) N (C 1-6 alkyl) substituent substitution, the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl Each is optionally further represented by one or more selected from halogen, -OH, =O, -OC1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) substituted by substituents of 2 ;
L 1为共价键,或者,是C1-4的二价饱和或不饱和的直链或支链烃基,或者,将所述C1-4的二价饱和或不饱和的直链或支链烃基中的一个或两个亚甲基以独立地被选自-O-、-C(O)、-OC(O)-、-C(O)O-、-S-、-S(O)-和-S(O) 2-的基团替换后形成的基团;k为0、1、2、3、4、5、6、7、8或9;m为0、1、2、3、4或5;和n为0、1、2、3、4、5、6或7。 L 1 is a covalent bond, or is a C1-4 divalent saturated or unsaturated straight-chain or branched chain hydrocarbon group, or, the C1-4 divalent saturated or unsaturated straight-chain or branched chain hydrocarbon group One or two methylene groups in are independently selected from -O-, -C(O), -OC(O)-, -C(O)O-, -S-, -S(O)- and -S(O) 2 - the group formed after the group is replaced; k is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9; m is 0, 1, 2, 3, 4 or 5; and n is 0, 1, 2, 3, 4, 5, 6 or 7.
在根据本发明的一个实施方案中,环E选自:In one embodiment according to the invention, ring E is selected from:
Figure PCTCN2022122329-appb-000002
Figure PCTCN2022122329-appb-000002
Figure PCTCN2022122329-appb-000003
Figure PCTCN2022122329-appb-000003
本发明进一步提供了一种化合物或其药学上可接受的盐,其具有结构式Q 1The present invention further provides a compound or a pharmaceutically acceptable salt thereof, which has the structural formula Q 1 :
Figure PCTCN2022122329-appb-000004
Figure PCTCN2022122329-appb-000004
其中,R 3和R 4各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代;或者R 3和R 4与它们连接的原子一起形成3-12元的单环或多环烃环、3-12元的单环或多环杂环、3-12元的烃环和杂环形成的多环环系、3-6元的烃环与5-8元的杂芳环稠合形成的多环环系、3-6元的烃环与5-8元的芳环稠合形成的多环环系、3-6元的杂环与5-8元的杂芳环稠合形成的多环环系、或3-6元的杂环与5-8元的芳环稠合形成的多环环系,且所述每个环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基、C 3-6环烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代;k 1为1、2或3;k 2为1、2或3。 Wherein, R 3 and R 4 are each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), - N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O ) NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituents; or the atoms to which R 3 and R 4 are attached Together form a 3-12 membered monocyclic or polycyclic hydrocarbon ring, a 3-12 membered monocyclic or polycyclic heterocyclic ring, a polycyclic ring system formed by a 3-12 membered hydrocarbon ring and a heterocyclic ring, a 3-6 membered A polycyclic ring system formed by the fusion of a hydrocarbon ring and a 5-8 membered heteroaromatic ring, a polycyclic ring system formed by the fusion of a 3-6-membered hydrocarbon ring and a 5-8-membered aromatic ring, a 3-6-membered heteroaromatic ring A polycyclic ring system formed by condensing a ring with a 5-8 membered heteroaromatic ring, or a polycyclic ring system formed by condensing a 3-6 membered heterocyclic ring with a 5-8 membered aromatic ring, and each ring Each is optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkane radical), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkyl and -C(O )N(C 1-6 alkyl) substituted by a substituent, each of said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl optionally further being selected from one or more Halogen, -OH, =O, -OC1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1 Substituents of -6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; k 1 is 1, 2 or 3; k 2 is 1, 2 or 3.
在根据本发明的一个实施方案中,环D选自In one embodiment according to the invention, ring D is selected from
Figure PCTCN2022122329-appb-000005
Figure PCTCN2022122329-appb-000005
Figure PCTCN2022122329-appb-000006
Figure PCTCN2022122329-appb-000006
在另一个方面,本发明提供了具有如式I所示的通式结构或其药学上可接受的盐:In another aspect, the present invention provides a general structure as shown in formula I or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022122329-appb-000007
Figure PCTCN2022122329-appb-000007
其中,W 1,W 2,和W 3各自独立地选自CR 1和N; Wherein, W 1 , W 2 , and W 3 are each independently selected from CR 1 and N;
X 2,X 3,和X 4各自独立地选自CR 2和N; X 2 , X 3 , and X 4 are each independently selected from CR 2 and N;
Z是CH或N;Z is CH or N;
X 1是CR 8或N; X 1 is CR 8 or N;
R 8独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,所述烷基、烯基、杂环基、芳基、杂芳基、和环烷基各自任选被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; R 8 is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 Membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), -N( C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1- 6 alkyl) 2 , the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl are each optionally replaced by one or more selected from halogen, -OH, =O, -OC 1 -6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C( Substituents of O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ;
环A是5-8元的烃环、5-8元杂环、5-8元杂芳环或5-8元芳环,且所述烃环、杂环、杂芳环和芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基、C 3-6环烷基、和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环 烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Ring A is a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, a 5-8 membered heteroaryl ring or a 5-8 membered aromatic ring, and each of the hydrocarbon ring, heterocyclic ring, heteroaryl ring and aromatic ring is any Optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3- 10-membered heterocyclic group, 6-10-membered aryl group, 5-10-membered heteroaryl group, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl) , -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkyl, and -C(O) Substituents of N(C 1-6 alkyl) 2 , each of which is optionally further selected from the group consisting of halogen , -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1 Substituents of -6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ;
环B是包含N原子的5-8元杂环或5-8元杂芳环,且所述杂环和杂芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基、和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Ring B is a 5-8 membered heterocyclic ring or a 5-8 membered heteroaryl ring containing N atoms, and each of the heterocyclic ring and heteroaryl ring is optionally replaced by one or more members selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclyl, 6-10 membered Aryl, 5-10 membered heteroaryl, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1 Substituents of -6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , Each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl groups is optionally further replaced by one or more alkyl groups selected from halogen, -OH, =O, -OC , -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, Substituents of -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ;
R 1在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), - N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O ) NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituents;
R 2在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), - N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O ) NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituents;
R 3和R 4各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基、和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代;或者R 3和R 4与它们连接的原子一起形成3-12元的单环或多环烃环、3-12元的单环或多环杂环、3-12元的烃环和杂环形成的多环环系、3-6元的烃环与5-8元的杂芳环稠合形成的多环环系、3-6元的烃环与5-8元的芳环稠合形成的多环环系、3-6元的杂环与5-8元的杂芳环稠合形成的多环环系或3-6元的杂环与5-8元的芳环稠合形成的多环环系,且所述每个环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基、C 3-6环烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基、和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代;m为0、1、2或3;和n为0、1、2或3。 R 3 and R 4 are each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl , 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N( C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1- 6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, - OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O) Substituents of NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; or R 3 and R 4 together with the atoms to which they are attached Form 3-12 membered monocyclic or polycyclic hydrocarbon rings, 3-12 membered monocyclic or polycyclic heterocyclic rings, 3-12 membered hydrocarbon rings and polycyclic ring systems formed by heterocyclic rings, 3-6 membered hydrocarbons A polycyclic ring system formed by condensing a ring with a 5-8 membered heteroaromatic ring, a polycyclic ring system formed by condensing a 3-6-membered hydrocarbon ring with a 5-8-membered aromatic ring, and a 3-6-membered heterocyclic ring A polycyclic ring system formed by condensing a 5-8 membered heteroaromatic ring or a 3-6 membered heterocyclic ring condensed with a 5-8 membered aromatic ring, and each ring is independently Optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3- 10-membered heterocyclic group, 6-10-membered aryl group, 5-10-membered heteroaryl group, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl) , -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkyl and -C(O)N (C 1-6 alkyl) substituted by a substituent, each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl is optionally further selected from one or more halogen , -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1 Substituents of -6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; m is 0, 1, 2 or 3; and n is 0, 1, 2 or 3.
在一些实施方案中,R 8独立地选自H、卤素、-OH、-CN、C 1-6烷基、-OC 1-6烷基、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,所述烷基和环烷基任选被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、 -C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代;和/或 In some embodiments, R 8 is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NO 2 , -NH(C 1 -6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and - C(O)N(C 1-6 alkyl) 2 , the alkyl and cycloalkyl are optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN , -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH , -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) substituent substitution; and/or
所述环A选自5-8元的烃环、5-8元杂环、5-8元杂芳环或5-8元芳环,且所述烃环、杂环、杂芳环和芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)O C 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述C 1-6烷基任选进一步地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2和-NH(C 1-6烷基)的取代基取代;和/或 The ring A is selected from a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, a 5-8 membered heteroaryl ring or a 5-8 membered aromatic ring, and the hydrocarbon ring, heterocyclic ring, heteroaryl ring and aromatic Each ring is optionally replaced by one or more groups selected from halogen, -OH, =O, C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkane radical), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC C 1-6 alkyl and -C(O)N(C 1-6 alkane substituted by a substituent of C 1-6 alkyl, said C 1-6 alkyl being optionally further selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 and -NH(C 1-6 alkyl) substituent substitution; and/or
所述环B选自包含N原子的5-8元杂环或5-8元杂芳环,且所述杂环和杂芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、-OC 1-6烷基、-CN、-NH 2和-NH(C 1-6烷基)的取代基取代;和/或 The ring B is selected from a 5-8-membered heterocyclic ring or a 5-8-membered heteroaryl ring containing N atoms, and each of the heterocyclic ring and the heteroaryl ring is optionally replaced by one or more members selected from halogen, -OH, Substituents of =O, C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NH 2 and -NH(C 1-6 alkyl); and/or
R 1在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2和C 3-6环烷基,其中所述C 1-6烷基、和C 3-6环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2和-NH(C 1-6烷基)的取代基取代;和/或,R 2在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH和-C(O)OC 1-6烷基,其中所述C 1-6烷基任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2和-NH(C 1-6烷基)的取代基取代;和/或 Each occurrence of R 1 is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl ), -N(C 1-6 alkyl) 2 and C 3-6 cycloalkyl, wherein each of the C 1-6 alkyl and C 3-6 cycloalkyl is optionally selected from one or more Substituents from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH , and -NH(C 1-6 alkyl); and/or, R at each occurrence each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N(C 1 -6 alkyl) 2 , -C(O)NH 2 , -COOH and -C(O)OC 1-6 alkyl, wherein the C 1-6 alkyl is optionally selected from one or more halogen , -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 and -NH (C 1-6 alkyl) substituent substitution; and/or
R 3和R 4各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)和-N(C 1-6烷基) 2,其中所述C 1-6烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2和-NH(C 1-6烷基)的取代基取代;或者R 3和R 4与它们连接的原子一起形成3-6元的单环或多环烃环、3-6元的单环或多环杂环、3-6元的烃环和杂环形成的多环环系、3-6元的烃环与5-6元的杂芳环稠合形成的双环或更多环系、3-6元的烃环与5-6元的芳环稠合形成的双环或更多环系、3-6元的杂环与5-6元的杂芳环稠合形成的双环或更多环系、或3-6元的杂环与5-6元的芳环稠合形成的双环或更多环系。 R 3 and R 4 are each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 , wherein each of the C 1-6 alkyl groups is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN , -NH 2 and -NH (C 1-6 alkyl) substituent substitution; or R 3 and R 4 form a 3-6 membered monocyclic or polycyclic hydrocarbon ring together with the atoms they are connected to, 3-6 membered Monocyclic or polycyclic heterocyclic rings, polycyclic ring systems formed by 3-6 membered hydrocarbon rings and heterocyclic rings, bicyclic or more Ring system, a bicyclic or more ring system formed by condensing a 3-6-membered hydrocarbon ring with a 5-6-membered aromatic ring, a bicyclic ring formed by condensing a 3-6-membered heterocycle and a 5-6-membered heteroaromatic ring or more ring systems, or bicyclic or more ring systems formed by the fusion of 3-6 membered heterocycles and 5-6 membered aromatic rings.
在一些实施方案中,环A是5-8元的烃环、5-8元杂环、或5-8元杂芳环,优选地,环A是具有1、2、3或4个独立地选自N、O和S的杂原子的5-6元杂环或杂芳环,优选地,环A是具有1或2个独立地选自N和O的杂原子的5-6元杂环或杂芳环,优选环A是5-8元的烃环或5-8元杂环,优选地,环A是具有1、2、3或4个独立地选自N、O和S的杂原子的5-6元杂环,进一步优选,环A选自部分不饱和的吗啉环、部分不饱和的吡唑烷环、部分不饱和的哌啶环、部分不饱和的哌嗪环、部分不饱和的六氢嘧啶环、部分不饱和的吡咯烷环、吡唑环、吡咯环、咪唑环和部分不饱和的咪唑烷环;In some embodiments, Ring A is a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, or a 5-8 membered heteroaromatic ring. Preferably, Ring A has 1, 2, 3 or 4 independently A 5-6 membered heterocyclic or heteroaryl ring with heteroatoms selected from N, O and S, preferably, ring A is a 5-6 membered heterocyclic ring with 1 or 2 heteroatoms independently selected from N and O or a heteroaromatic ring, preferably ring A is a 5-8 membered hydrocarbon ring or a 5-8 membered heterocyclic ring, preferably, ring A is a heterocyclic ring with 1, 2, 3 or 4 independently selected from N, O and S 5-6 membered heterocyclic rings with atoms, further preferably, ring A is selected from partially unsaturated morpholine rings, partially unsaturated pyrazolidine rings, partially unsaturated piperidine rings, partially unsaturated piperazine rings, partially unsaturated piperazine rings, partially Unsaturated hexahydropyrimidine ring, partially unsaturated pyrrolidine ring, pyrazole ring, pyrrole ring, imidazole ring and partially unsaturated imidazolidine ring;
在一些实施方案中,环A任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、-OC 1-6烷基、-CN、-NH 2、-C(O)NH 2、-COOH、-C(O)N(C 1-6烷基) 2、-C 1-6亚烷基-OH和卤代C 1-6烷基的取代基取代,在优选的实施方案中,环A任选地被一个或多个选自F、Cl、Br、-OH、=O、C 1-3烷基、-OC 1-3烷基、-CN、-NH 2、-C(O)NH 2、-COOH、-C(O)N(C 1-3烷基) 2、-C 1-3亚烷基-OH和卤代C 1-3烷基的取代基取代,在更优选的实施方案中,环A任选地被一个或多个选自F、=O、-CH 3、-C(O)NH 2、-COOH、-C(O)N(CH 3) 2和-CH 2-OH的取代基取代。 In some embodiments, ring A is optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NH 2 , -C Substituents of (O)NH 2 , -COOH, -C(O)N(C 1-6 alkyl) 2 , -C 1-6 alkylene-OH and halogenated C 1-6 alkyl, in In a preferred embodiment, ring A is optionally replaced by one or more selected from F, Cl, Br, -OH, =O, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH 2. Substitution of -C(O)NH 2 , -COOH, -C(O)N(C 1-3 alkyl) 2 , -C 1-3 alkylene-OH and halogenated C 1-3 alkyl In a more preferred embodiment, ring A is optionally substituted by one or more selected from F, =O, -CH 3 , -C(O)NH 2 , -COOH, -C(O)N( Substituents of CH 3 ) 2 and -CH 2 -OH.
在一些实施方案中,环B选自包含N原子的5、6、7或8元杂环,优选地,环B是部分不饱和的哌啶环、部分不饱和的哌嗪环、部分不饱和的二氮杂环庚烷环、部分不饱和的咪唑啉环、部分不饱和的吗啉环或部分不饱和的吡唑烷环,且所述环B任选地被一个或多个选自卤素、-OH、=O、C 1-3烷基、-OC 1-3烷基、-CN、-NH 2、和-NH(C 1-3烷基)的取代基取代。 In some embodiments, ring B is selected from 5, 6, 7 or 8 membered heterocycles containing N atoms, preferably, ring B is a partially unsaturated piperidine ring, a partially unsaturated piperazine ring, a partially unsaturated A diazepane ring, a partially unsaturated imidazoline ring, a partially unsaturated morpholine ring or a partially unsaturated pyrazolidine ring, and the ring B is optionally selected from one or more halogen , -OH, =O, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH 2 , and -NH(C 1-3 alkyl) substituents.
在一些实施方案中,
Figure PCTCN2022122329-appb-000008
部分是如下的化学结构:
Figure PCTCN2022122329-appb-000009
其中,W 4选自C(R 5) 2、O、和NR 5;p为0、1或2;q为0或1;R 5在每次出现时各自独立地选自H、卤素、-OH、=O、C 1-6烷基、-OC 1-6烷基、-CN、-NH 2、-C(O)NH 2、-COOH、-C(O)N(C 1-6烷基) 2、-C 1-6亚烷基-OH、和卤代C 1-6烷基;在优选的实施方案中,R 5在每次出现时各自独立地选自H、F、Cl、Br、-OH、=O、C 1-3烷基、-OC 1-3烷基、-CN、-NH 2、-C(O)NH 2、-COOH、-C(O)N(C 1-3烷基) 2、-C 1-3亚烷基-OH、和卤代C 1-3烷基;在更优选的实施方案中,R 5在每次出现时各自独立地选自H、-F、=O、-CH 3、-C(O)NH 2、-COOH、-C(O)N(CH 3) 2、-CH 2-OH;和f为0、1、2、3、4或5。
In some embodiments,
Figure PCTCN2022122329-appb-000008
Part is the following chemical structure:
Figure PCTCN2022122329-appb-000009
Wherein, W 4 is selected from C(R 5 ) 2 , O, and NR 5 ; p is 0, 1 or 2; q is 0 or 1; R 5 is each independently selected from H, halogen, - OH, =O, C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NH 2 , -C(O)NH 2 , -COOH, -C(O)N(C 1-6 alkane group) 2 , -C 1-6 alkylene-OH, and halogenated C 1-6 alkyl; in a preferred embodiment, each occurrence of R 5 is independently selected from H, F, Cl, Br, -OH, =O, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH 2 , -C(O)NH 2 , -COOH, -C(O)N(C 1 -3 alkyl) 2 , -C 1-3 alkylene-OH, and haloC 1-3 alkyl; in a more preferred embodiment, each occurrence of R is independently selected from H, -F, =O, -CH 3 , -C(O)NH 2 , -COOH, -C(O)N(CH 3 ) 2 , -CH 2 -OH; and f is 0, 1, 2, 3, 4 or 5.
在一些实施方案中,
Figure PCTCN2022122329-appb-000010
部分选自如下的化学结构:
In some embodiments,
Figure PCTCN2022122329-appb-000010
Partially selected from the following chemical structures:
Figure PCTCN2022122329-appb-000011
Figure PCTCN2022122329-appb-000011
Figure PCTCN2022122329-appb-000012
Figure PCTCN2022122329-appb-000012
其中,R 5和f如上文所义。 Wherein, R and f are as defined above.
在一些实施方案中,R 1在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-3烷基、-OC 1-3烷基、-NH 2、卤代C 1-3烷基和C 3-4环烷基;在优选的实施方案中,R 1在每次出现时各自独立地选自H、-CN、-CH 3和环丙基。 In some embodiments, each occurrence of R 1 is independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -OC 1-3 alkyl, -NH 2 , haloC 1-3 alkyl and C 3-4 cycloalkyl; in a preferred embodiment, each occurrence of R is independently selected from H, -CN, -CH and cyclopropyl.
在一些实施方案中,R 2在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-3烷基、-OC 1-3烷基、-NH 2、-C(O)NH 2、-COOH、-C(O)OC 1-3烷基、-C 1-3亚烷基-OH和卤代C 1-3烷基;在优选的实施方案中,R 2在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-3烷基、-C(O)NH 2和-C 1-3亚烷基-OH;在更优选的实施方案中,R 2在每次出现时各自独立地选自H、F、-OH、-CN、-CH 3、-C(O)NH 2和-CH 2-OH。 In some embodiments, each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -OC 1-3 alkyl, -NH 2 , -C( O)NH 2 , -COOH, -C(O)OC 1-3 alkyl, -C 1-3 alkylene-OH and halogenated C 1-3 alkyl; in a preferred embodiment, R 2 is at Each occurrence is independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -C(O)NH 2 and -C 1-3 alkylene-OH; in a more preferred embodiment In the scheme, each occurrence of R 2 is independently selected from H, F, -OH, -CN, -CH 3 , -C(O)NH 2 and -CH 2 -OH.
在一些实施方案中,R 3和R 4各自独立地选自H、卤素、-OH、-CN、C 1-3烷基、-OC 1-3烷基、-C 1-3亚烷基-NH 2、-NH 2、-NH(C 1-3烷基)和-N(C 1-3烷基) 2;在优选的实施方案中,R 3和R 4各自独立地选自H、卤素、-OH、-CN、C 1-3烷基、-C 1-3亚烷基-NH 2和-NH 2;在优选的实施方案中,R 3和R 4各自独立地选自H、-F、-OH、-CH 2-NH 2和-NH 2;或 In some embodiments, R and R are each independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -OC 1-3 alkyl, -C 1-3 alkylene- NH 2 , -NH 2 , -NH(C 1-3 alkyl) and -N(C 1-3 alkyl) 2 ; in a preferred embodiment, R 3 and R 4 are each independently selected from H, halogen , -OH, -CN, C 1-3 alkyl, -C 1-3 alkylene -NH 2 and -NH 2 ; in a preferred embodiment, R 3 and R 4 are each independently selected from H, - F, -OH, -CH2 - NH2 and -NH2 ; or
R 3和R 4与它们连接的原子一起形成3、4、5或6元的单环烃环、或3、4、5或6元的单环杂环,在优选的实施方案中,R 3和R 4与它们连接的原子一起形成具有1、2、3或4个选自N、O或S杂原子的5-6元的单环杂环,其中所述烃环和杂环各自任选地被一个或多个选自卤素、-OH、-CN、C 1-6烷基、-OC 1-6烷基、-NH 2、-C(O)N(C 1-6烷基) 2、-C 1-6亚烷基-OH和卤代C 1-6烷基的取代基取代,优选地被一个或多个选自F、Cl、Br、-OH、-CN、C 1-3烷基、-OC 1-3烷基、-NH 2、-C 1-3亚烷基-OH、-C(O)N(C 1-3烷基) 2和卤代C 1-3烷基的取代基取代,优选地被一个或多个选自F、Cl、Br、-OH、-CN、-CH 3、-OCH 3、-NH 2、-CH 2-OH、-C(O)N(CH 3) 2 和-CF 3的取代基取代; R 3 and R 4 form a 3, 4, 5 or 6-membered monocyclic hydrocarbon ring, or a 3, 4, 5 or 6-membered monocyclic heterocyclic ring together with the atoms they are connected to. In a preferred embodiment, R 3 and R together with the atoms to which they are attached form a 5-6 membered monocyclic heterocycle having 1, 2, 3 or 4 heteroatoms selected from N, O or S, wherein each of the hydrocarbon ring and heterocycle is optionally One or more selected from halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -C(O)N(C 1-6 alkyl) 2 , -C 1-6 alkylene-OH and halogenated C 1-6 alkyl substituents, preferably substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, C 1-3 Alkyl, -OC 1-3 alkyl, -NH 2 , -C 1-3 alkylene-OH, -C(O)N(C 1-3 alkyl) 2 and halogenated C 1-3 alkyl substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -CH 3 , -OCH 3 , -NH 2 , -CH 2 -OH, -C(O)N Substituents of (CH 3 ) 2 and -CF 3 are substituted;
在更优选的实施方案中,
Figure PCTCN2022122329-appb-000013
部分是如下的化学结构:
Figure PCTCN2022122329-appb-000014
其中,Y1选自O、S、C(R 6) 2、或NR 6,R 6在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-3烷基、-OC 1-3烷基、-NH 2和卤代C 1-3烷基,在优选的实施方案中,R 6在每次出现时各自独立地选自H、卤素、-OH、-CN、-CH 3、-OCH 3、-NH 2、-CH 2-OH、-C(O)N(CH 3) 2和-CF 3,g为0、1、2、3、4、5或6;或R 3和R 4与它们连接的原子一起形成5-6元的烃环与5-6元的杂芳环稠合形成的双环系、5-6元的烃环与5-6元的芳环稠合形成的双环系、5-6元的杂环与5-6元的杂芳环稠合形成的双环系、或5-6元的杂环与5-6元的芳环稠合形成的双环系,其中所述烃环、杂环、杂芳环和芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、-OC 1-6烷基、-CN、-NH 2、-C(O)NH 2、-COOH、-C(O)N(C 1-6烷基) 2、-C 1-6亚烷基-OH、卤代C 1-6烷基的取代基取代,优选地被一个或多个选自卤素、-OH、C 1-3烷基、-OC 1-3烷基、-CN、-NH 2、-C(O)NH 2、-C 1-3亚烷基-OH、-C(O)N(C 1-3烷基) 2、和卤代C 1-3烷基的取代基取代,优选地被一个或多个选自F、Cl、Br、-OH、-CN、-CH 3、-OCH 3、-NH 2、-CH 2-OH、-C(O)N(CH 3) 2和-CF 3的取代基取代;还优选地,
Figure PCTCN2022122329-appb-000015
部分是如下的化学结构:
Figure PCTCN2022122329-appb-000016
其中,Y 2选自O、S、CH 2、和NH,优选选自O、和CH 2;Y 3、Y 4、Y 5、和Y 6各自独立地选自CR 7和N,在优选的实施方案中,Y 3、Y 4、Y 5、和Y 6各自独立地选自CH和N;R 7在每次出现时各自独立地选自H、卤素、-OH、C 1-3烷基、-OC 1-3烷基、-CN、-NH 2、-C(O)NH 2、-C 1-3亚烷基-OH、-C(O)N(C 1-3烷基) 2、和卤代C 1-3烷基,在优选的实施方案中,R 7在每次出现时各自独立地选自H、F、Cl、Br、-OH、-CN、-CH 3、-OCH 3、-NH 2、-CH 2-OH、-C(O)N(CH 3) 2和-CF 3;且h为0、1、2、3或4。
In a more preferred embodiment,
Figure PCTCN2022122329-appb-000013
Part is the following chemical structure:
Figure PCTCN2022122329-appb-000014
Wherein, Y1 is selected from O, S, C(R 6 ) 2 , or NR 6 , and each occurrence of R 6 is independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, - OC 1-3 alkyl, -NH 2 and halogenated C 1-3 alkyl, in a preferred embodiment, each occurrence of R is independently selected from H, halogen, -OH, -CN, - CH 3 , -OCH 3 , -NH 2 , -CH 2 -OH, -C(O)N(CH 3 ) 2 and -CF 3 , g is 0, 1, 2, 3, 4, 5 or 6; or R 3 and R 4 together with the atoms they connect form a bicyclic ring system formed by condensing a 5-6 membered hydrocarbon ring with a 5-6 membered heteroaromatic ring, a 5-6 membered hydrocarbon ring and a 5-6 membered aromatic ring A bicyclic ring system formed by fusion, a bicyclic system formed by the fusion of a 5-6 membered heterocyclic ring and a 5-6 membered heteroaryl ring, or a fused 5-6 membered heterocyclic ring and a 5-6 membered aromatic ring Bicyclic ring system, wherein said hydrocarbon ring, heterocycle, heteroaromatic ring and aromatic ring are each optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, -OC 1-6 alkane radical, -CN, -NH 2 , -C(O)NH 2 , -COOH, -C(O)N(C 1-6 alkyl) 2 , -C 1-6 alkylene-OH, halogenated C 1-6 alkyl substituents are substituted, preferably by one or more selected from halogen, -OH, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH 2 , -C(O ) NH 2 , -C 1-3 alkylene-OH, -C(O)N(C 1-3 alkyl) 2 , and substituents of halogenated C 1-3 alkyl, preferably substituted by one or Multiple selected from F, Cl, Br, -OH, -CN, -CH 3 , -OCH 3 , -NH 2 , -CH 2 -OH, -C(O)N(CH 3 ) 2 and -CF 3 Substituents are substituted; also preferably,
Figure PCTCN2022122329-appb-000015
Part is the following chemical structure:
Figure PCTCN2022122329-appb-000016
Wherein, Y 2 is selected from O, S, CH 2 , and NH, preferably selected from O, and CH 2 ; Y 3 , Y 4 , Y 5 , and Y 6 are each independently selected from CR 7 and N, in preferred In an embodiment, Y 3 , Y 4 , Y 5 , and Y 6 are each independently selected from CH and N; each occurrence of R 7 is independently selected from H, halogen, -OH, C 1-3 alkyl , -OC 1-3 alkyl, -CN, -NH 2 , -C(O)NH 2 , -C 1-3 alkylene-OH, -C(O)N(C 1-3 alkyl) 2 , and halogenated C 1-3 alkyl, in a preferred embodiment, each occurrence of R 7 is independently selected from H, F, Cl, Br, -OH, -CN, -CH 3 , -OCH 3 , -NH 2 , -CH 2 -OH, -C(O)N(CH 3 ) 2 and -CF 3 ; and h is 0, 1, 2, 3 or 4.
在一些实施方案中,式I化合物具有式II的结构:In some embodiments, the compound of Formula I has the structure of Formula II:
Figure PCTCN2022122329-appb-000017
Figure PCTCN2022122329-appb-000017
其中,W 1,W 2,W 3,X 1,X 2,X 3,X 4,Z,m和n如上文所定义,R 1和R 2如上文所定义,W 4、R 5、p、q和f如上文所定义,Y 2,Y 3,Y 4,Y 5和Y 6如上文所定义;优选地,X 1和X 2均为N,和/或p为1或2,q为0或1。 wherein, W 1 , W 2 , W 3 , X 1 , X 2 , X 3 , X 4 , Z, m and n are as defined above, R 1 and R 2 are as defined above, W 4 , R 5 , p , q and f are as defined above, Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are as defined above; preferably, both X 1 and X 2 are N, and/or p is 1 or 2, q is 0 or 1.
在一优选的实施方案中,本发明提供化合物或其药学上可接受的盐,所述化合物选自:In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, the compound is selected from:
Figure PCTCN2022122329-appb-000018
Figure PCTCN2022122329-appb-000018
Figure PCTCN2022122329-appb-000019
Figure PCTCN2022122329-appb-000019
Figure PCTCN2022122329-appb-000020
Figure PCTCN2022122329-appb-000020
Figure PCTCN2022122329-appb-000021
Figure PCTCN2022122329-appb-000021
进一步地,本发明提供优选地化合物或其药学上可接受的盐,所述化合物选自:Further, the present invention provides a preferred compound or a pharmaceutically acceptable salt thereof, the compound is selected from:
Figure PCTCN2022122329-appb-000022
Figure PCTCN2022122329-appb-000022
Figure PCTCN2022122329-appb-000023
Figure PCTCN2022122329-appb-000023
Figure PCTCN2022122329-appb-000024
Figure PCTCN2022122329-appb-000024
Figure PCTCN2022122329-appb-000025
Figure PCTCN2022122329-appb-000025
Figure PCTCN2022122329-appb-000026
Figure PCTCN2022122329-appb-000026
本发明还提供用于制备上述化合物的中间体,或其盐,所述中间体选自:The present invention also provides an intermediate for preparing the above compound, or a salt thereof, wherein the intermediate is selected from:
Figure PCTCN2022122329-appb-000027
Figure PCTCN2022122329-appb-000027
其中,R 9和R 10各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2, 其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代。 Wherein, R 9 and R 10 are each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), - N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O )NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 are substituted.
在优选地实施方案中,上述中间体选自:In a preferred embodiment, the above-mentioned intermediates are selected from:
Figure PCTCN2022122329-appb-000028
Figure PCTCN2022122329-appb-000028
本发明还提供了结构式如式II所示的化合物或其药学上可接受的盐的制备方法:The present invention also provides a preparation method of the compound shown in formula II or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022122329-appb-000029
Figure PCTCN2022122329-appb-000029
其中,W 1,W 2,W 3,Z,m和n如上文所定义,R 1和R 2如权利要求5、6、11、或15中所定义,W 4、R 5、p、q和f如上文中所定义,Y 2,Y 3,Y 4,Y 5和Y 6如上文所定义,X 1,X 2,X 3,X 4均为N,n为0,包括:利用对应于A部分结构的第一关键中间体、对应于B部分结构的第二关键中间体、对应于C部分结构的第三关键中间体进行取代反应制备得到式II所示的化合物。 wherein, W 1 , W 2 , W 3 , Z, m and n are as defined above, R 1 and R 2 are as defined in claim 5, 6, 11, or 15, W 4 , R 5 , p, q and f are as defined above, Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are as defined above, X 1 , X 2 , X 3 , X 4 are all N, and n is 0, including: using the corresponding The first key intermediate of the structure of part A, the second key intermediate corresponding to the structure of part B, and the third key intermediate corresponding to the structure of part C are subjected to substitution reactions to prepare the compound shown in formula II.
在优选地实施方案中,其中所述C部分对应的第三关键中间体结构式如式Ⅲ所示:In a preferred embodiment, the structural formula of the third key intermediate corresponding to the C part is shown in formula III:
Figure PCTCN2022122329-appb-000030
其中,R 9和R 10如上文所定义。
Figure PCTCN2022122329-appb-000030
Wherein, R 9 and R 10 are as defined above.
进一步地,其中所述第三关键中间体选自:Further, wherein the third key intermediate is selected from:
Figure PCTCN2022122329-appb-000031
Figure PCTCN2022122329-appb-000031
优选地,其中A部分对应的所述第一关键中间体选自:Preferably, the first key intermediate corresponding to part A is selected from:
Figure PCTCN2022122329-appb-000032
Figure PCTCN2022122329-appb-000032
优选地,其中所述B部分对应的第二关键中间体选自:Preferably, wherein the second key intermediate corresponding to part B is selected from:
Figure PCTCN2022122329-appb-000033
Figure PCTCN2022122329-appb-000033
在一些优选地实施方案中,(A)当化合物或其药学上可接受的盐具有结构式
Figure PCTCN2022122329-appb-000034
时,通过包括下述步骤的方法制备:
In some preferred embodiments, (A) when the compound or a pharmaceutically acceptable salt thereof has the structural formula
Figure PCTCN2022122329-appb-000034
, prepared by a method comprising the following steps:
(a1)将化合物
Figure PCTCN2022122329-appb-000035
溶解于DCM中,加入三氟乙酸,搅拌2小时,用饱和碳酸氢钠中和反应液,二氯甲烷萃取,合并有机相,减压浓缩,纯化得化合物
Figure PCTCN2022122329-appb-000036
(a1) compound
Figure PCTCN2022122329-appb-000035
Dissolve in DCM, add trifluoroacetic acid, stir for 2 hours, neutralize the reaction solution with saturated sodium bicarbonate, extract with dichloromethane, combine the organic phases, concentrate under reduced pressure, and purify the compound
Figure PCTCN2022122329-appb-000036
(a2)将
Figure PCTCN2022122329-appb-000037
溶于DMF,加入三乙胺和化合物
Figure PCTCN2022122329-appb-000038
50℃下搅拌,反应混合物用饱和食盐水稀释,萃取,有机层用无水硫酸钠干燥,过滤,减压浓缩得化合物
Figure PCTCN2022122329-appb-000039
(a2) will
Figure PCTCN2022122329-appb-000037
Dissolve in DMF, add triethylamine and compound
Figure PCTCN2022122329-appb-000038
Stir at 50°C, dilute the reaction mixture with saturated brine, extract, dry the organic layer with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the compound
Figure PCTCN2022122329-appb-000039
(a3)将化合物
Figure PCTCN2022122329-appb-000040
和化合物
Figure PCTCN2022122329-appb-000041
溶于甲苯,氮气保护下加入Pd 2(dba) 3,RuPhos和Cs 2CO 3,100℃搅拌16小时,冷却至RT并减压浓缩,通过制备TLC(DCM:MeOH=10:1)纯化残余物得化合物
Figure PCTCN2022122329-appb-000042
将化合物
Figure PCTCN2022122329-appb-000043
溶于HCl/Dioxane和甲醇中,搅拌1小时,减压浓缩,纯化得
Figure PCTCN2022122329-appb-000044
(a3) compound
Figure PCTCN2022122329-appb-000040
and compound
Figure PCTCN2022122329-appb-000041
Dissolve in toluene, add Pd 2 (dba) 3 , RuPhos and Cs 2 CO 3 under nitrogen protection, stir at 100°C for 16 hours, cool to RT and concentrate under reduced pressure, purify the residue by preparative TLC (DCM:MeOH=10:1) compound
Figure PCTCN2022122329-appb-000042
compound
Figure PCTCN2022122329-appb-000043
Dissolved in HCl/Dioxane and methanol, stirred for 1 hour, concentrated under reduced pressure, and purified to obtain
Figure PCTCN2022122329-appb-000044
和/或,(B)当化合物或其药学上可接受的盐具有结构式
Figure PCTCN2022122329-appb-000045
时,通过包括下述步骤的方法制备:
And/or, (B) when the compound or a pharmaceutically acceptable salt thereof has the formula
Figure PCTCN2022122329-appb-000045
, prepared by a method comprising the following steps:
(b1)将化合物
Figure PCTCN2022122329-appb-000046
溶于二氧六环中,氮气保护下加入化合物
Figure PCTCN2022122329-appb-000047
Pd 2(dba) 3,Xantphos和Cs 2CO 3,100℃下搅拌过夜,EA稀释,过滤,浓缩滤液,纯化得化合物
Figure PCTCN2022122329-appb-000048
(b1) compound
Figure PCTCN2022122329-appb-000046
Dissolve in dioxane, add compound under nitrogen protection
Figure PCTCN2022122329-appb-000047
Pd 2 (dba) 3 , Xantphos and Cs 2 CO 3 , stirred overnight at 100°C, diluted with EA, filtered, concentrated the filtrate, and purified the compound
Figure PCTCN2022122329-appb-000048
(b2)将化合物
Figure PCTCN2022122329-appb-000049
溶于THF/H 2O/MeOH中,加入钯/碳和甲酸铵,50℃搅拌过夜,反应液用EA稀释,过滤,滤液浓缩,纯化得化合物
Figure PCTCN2022122329-appb-000050
(b2) compound
Figure PCTCN2022122329-appb-000049
Dissolve in THF/H 2 O/MeOH, add palladium/carbon and ammonium formate, stir overnight at 50°C, dilute the reaction solution with EA, filter, concentrate the filtrate, and purify the compound
Figure PCTCN2022122329-appb-000050
(b3)将化合物
Figure PCTCN2022122329-appb-000051
溶于DCM中,加入对甲苯磺酰氯和DIEA,RT搅拌1.5小时,浓缩,纯化得化合物
Figure PCTCN2022122329-appb-000052
(b3) compound
Figure PCTCN2022122329-appb-000051
Dissolve in DCM, add p-toluenesulfonyl chloride and DIEA, stir at RT for 1.5 hours, concentrate, and purify the compound
Figure PCTCN2022122329-appb-000052
(b4)将化合物
Figure PCTCN2022122329-appb-000053
溶于DMF中,加入TEA和化合物
Figure PCTCN2022122329-appb-000054
50℃搅拌过夜,反应液用EA稀释,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,纯化得化合物
Figure PCTCN2022122329-appb-000055
(b4) compound
Figure PCTCN2022122329-appb-000053
Dissolve in DMF, add TEA and compound
Figure PCTCN2022122329-appb-000054
Stir overnight at 50°C, dilute the reaction solution with EA, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify the compound
Figure PCTCN2022122329-appb-000055
(b5)化合物
Figure PCTCN2022122329-appb-000056
溶于HCl/dioxane中,RT搅拌1小时,减压浓缩,纯化得
Figure PCTCN2022122329-appb-000057
(b5) compound
Figure PCTCN2022122329-appb-000056
Dissolved in HCl/dioxane, stirred at RT for 1 hour, concentrated under reduced pressure, and purified to obtain
Figure PCTCN2022122329-appb-000057
和/或,(C)当化合物或其药学上可接受的盐,具有结构式
Figure PCTCN2022122329-appb-000058
时,通过包括下述步骤的方法制备:
And/or, (C) when the compound or a pharmaceutically acceptable salt thereof has the structural formula
Figure PCTCN2022122329-appb-000058
, prepared by a method comprising the following steps:
(c1)化合物
Figure PCTCN2022122329-appb-000059
和化合物
Figure PCTCN2022122329-appb-000060
溶于甲苯中,氮气保护下,加入Pd 2(dba) 3,Ruphos和Cs 2CO 3,110℃搅拌,反应液减压浓缩,纯化得化合物
Figure PCTCN2022122329-appb-000061
(c1) compound
Figure PCTCN2022122329-appb-000059
and compound
Figure PCTCN2022122329-appb-000060
Dissolve in toluene, under nitrogen protection, add Pd 2 (dba) 3 , Ruphos and Cs 2 CO 3 , stir at 110°C, concentrate the reaction solution under reduced pressure, and purify the compound
Figure PCTCN2022122329-appb-000061
(c2)将化合物
Figure PCTCN2022122329-appb-000062
溶于NH 3/MeOH中,70℃搅拌4个小时,浓缩得化合物
Figure PCTCN2022122329-appb-000063
(c2) compound
Figure PCTCN2022122329-appb-000062
Dissolved in NH 3 /MeOH, stirred at 70°C for 4 hours, concentrated to give the compound
Figure PCTCN2022122329-appb-000063
(c3)将化合物
Figure PCTCN2022122329-appb-000064
溶于HCl/dioxane中,RT搅拌1小时,减压浓缩,纯化得
Figure PCTCN2022122329-appb-000065
(c3) compound
Figure PCTCN2022122329-appb-000064
Dissolved in HCl/dioxane, stirred at RT for 1 hour, concentrated under reduced pressure, and purified to obtain
Figure PCTCN2022122329-appb-000065
和/或,(D)当化合物或其药学上可接受的盐具有结构式
Figure PCTCN2022122329-appb-000066
时,通过包 括下述步骤的方法制备:
And/or, (D) when the compound or a pharmaceutically acceptable salt thereof has the formula
Figure PCTCN2022122329-appb-000066
, prepared by a method comprising the following steps:
(d1)将中间体
Figure PCTCN2022122329-appb-000067
溶于MeOH/DMSO,加入硝酸银和三氟乙酸,70℃搅拌1小时,加入(NH 4) 2S 2O 8和H 2O,70℃搅拌2小时,反应液用EA稀释,NaOH水溶液洗涤,有机相无水硫酸钠干燥,过滤,浓缩,纯化得化合物
Figure PCTCN2022122329-appb-000068
(d1) the intermediate
Figure PCTCN2022122329-appb-000067
Dissolve in MeOH/DMSO, add silver nitrate and trifluoroacetic acid, stir at 70°C for 1 hour, add (NH 4 ) 2 S 2 O 8 and H 2 O, stir at 70°C for 2 hours, dilute the reaction solution with EA, wash with NaOH aqueous solution , the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain the compound
Figure PCTCN2022122329-appb-000068
(d2)将化合物
Figure PCTCN2022122329-appb-000069
溶于DMF中,加入三乙胺和化合物
Figure PCTCN2022122329-appb-000070
50℃搅拌,反应液用EA稀释,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,纯化得化合物
Figure PCTCN2022122329-appb-000071
(d2) compound
Figure PCTCN2022122329-appb-000069
Dissolve in DMF, add triethylamine and compound
Figure PCTCN2022122329-appb-000070
Stir at 50°C, dilute the reaction solution with EA, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify the compound
Figure PCTCN2022122329-appb-000071
(d3)将化合物
Figure PCTCN2022122329-appb-000072
和化合物
Figure PCTCN2022122329-appb-000073
溶于甲苯中,氮气保护下加入Pd 2(dba) 3,RuPhos和Cs 2CO 3,100℃搅拌16小时,冷却至RT并减压浓缩,纯化得化合物
Figure PCTCN2022122329-appb-000074
(d3) compound
Figure PCTCN2022122329-appb-000072
and compound
Figure PCTCN2022122329-appb-000073
Dissolve in toluene, add Pd 2 (dba) 3 , RuPhos and Cs 2 CO 3 under nitrogen protection, stir at 100°C for 16 hours, cool to RT and concentrate under reduced pressure to obtain the compound
Figure PCTCN2022122329-appb-000074
(d4)将化合物
Figure PCTCN2022122329-appb-000075
溶于HCl/Dioxane和甲醇中,RT搅拌1小时,减压浓缩,纯化得
Figure PCTCN2022122329-appb-000076
(d4) compound
Figure PCTCN2022122329-appb-000075
Dissolved in HCl/Dioxane and methanol, stirred at RT for 1 hour, concentrated under reduced pressure, and purified to obtain
Figure PCTCN2022122329-appb-000076
和/或,(E)当化合物或其药学上可接受的盐具有结构式
Figure PCTCN2022122329-appb-000077
时,通过包括下述步骤的方法制备:
And/or, (E) when the compound or a pharmaceutically acceptable salt thereof has the formula
Figure PCTCN2022122329-appb-000077
, prepared by a method comprising the following steps:
(e1)将6-氯-1H-吡唑并[3,4-b]吡啶溶于DMF中,加入NIS,80℃搅拌4小时,反应液用水稀释,EA萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得化合物
Figure PCTCN2022122329-appb-000078
(e1) Dissolve 6-chloro-1H-pyrazolo[3,4-b]pyridine in DMF, add NIS, stir at 80°C for 4 hours, dilute the reaction solution with water, extract with EA, and wash the organic phase with saturated brine , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound
Figure PCTCN2022122329-appb-000078
(e2)将化合物
Figure PCTCN2022122329-appb-000079
溶于DCM中,加入DHP和对甲苯磺酸,RT搅拌3小时,减压浓缩,纯化得化合物
Figure PCTCN2022122329-appb-000080
(e2) compound
Figure PCTCN2022122329-appb-000079
Dissolved in DCM, added DHP and p-toluenesulfonic acid, stirred at RT for 3 hours, concentrated under reduced pressure, and purified to obtain the compound
Figure PCTCN2022122329-appb-000080
(e3)将化合物
Figure PCTCN2022122329-appb-000081
溶于DMF中,加入化合物
Figure PCTCN2022122329-appb-000082
和三乙胺,50℃搅拌12小时,水稀释,EA萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,纯化得化合物
Figure PCTCN2022122329-appb-000083
(e3) compound
Figure PCTCN2022122329-appb-000081
Dissolve in DMF, add compound
Figure PCTCN2022122329-appb-000082
and triethylamine, stirred at 50°C for 12 hours, diluted with water, extracted with EA, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain the compound
Figure PCTCN2022122329-appb-000083
(e4)将化合物
Figure PCTCN2022122329-appb-000084
和化合物
Figure PCTCN2022122329-appb-000085
溶于甲苯中,氮气保护下加入Pd 2(dba) 3,RuPhos和Cs 2CO 3,100℃搅拌16小时,冷却至RT并减压浓缩,纯化得化合物
Figure PCTCN2022122329-appb-000086
(e4) compound
Figure PCTCN2022122329-appb-000084
and compound
Figure PCTCN2022122329-appb-000085
Dissolve in toluene, add Pd 2 (dba) 3 , RuPhos and Cs 2 CO 3 under nitrogen protection, stir at 100°C for 16 hours, cool to RT and concentrate under reduced pressure to obtain the compound
Figure PCTCN2022122329-appb-000086
(e5)将化合物
Figure PCTCN2022122329-appb-000087
溶于HCl/Dioxane和甲醇中,RT搅拌1小时,减压浓缩,纯化得
Figure PCTCN2022122329-appb-000088
(e5) compound
Figure PCTCN2022122329-appb-000087
Dissolved in HCl/Dioxane and methanol, stirred at RT for 1 hour, concentrated under reduced pressure, and purified to obtain
Figure PCTCN2022122329-appb-000088
药物组合物、制剂和试剂盒Pharmaceutical compositions, formulations and kits
本发明还提供一种药物组合物,其包含式I的化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体。The present invention also provides a pharmaceutical composition, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体,例如水和油,包括那些石油、动物、植物或合成来源的油,例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时,水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体,特别是用于注射液。药学上可接受的载体包括药物赋形剂。适合的药物赋形剂包括但不限于淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂、润滑剂、稳定剂或pH缓冲剂等。口服制剂可以包含标准载体,如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(2005)中所述。Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injections. Pharmaceutically acceptable carriers include pharmaceutical excipients. Suitable pharmaceutical excipients include, but are not limited to, starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol , water, ethanol, etc. The composition may also contain small amounts of wetting agents, emulsifiers, lubricants, stabilizers or pH buffering agents, etc., as required. Oral formulations can contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).
本发明的另一方面还涉及一种药物制剂,其包含式I化合物或其药学上可接受的盐作为活性成分,或者本发明的药物组合物。在一些实施方案中,所述制剂的形式为固体制剂、半固体制剂、液体制剂或气态制剂。Another aspect of the present invention also relates to a pharmaceutical preparation comprising the compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, or the pharmaceutical composition of the present invention. In some embodiments, the formulation is in the form of a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.
可通过多种途径给予本发明的药物组合物,这取决于是否需要局部或全身治疗和所治疗的区域。可局部(例如,透皮、皮肤、眼和粘膜包括鼻内、阴道和直肠递药)、肺(例如,通过吸入或吹入粉末或气雾剂,包括通过喷雾器;气管内、鼻内)、口服或肠胃外给药。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注;或颅内例如鞘内或脑室内给药。The pharmaceutical compositions of the present invention can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated. Topical (e.g., transdermal, dermal, ocular, and mucous membranes, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal, intranasal), Oral or parenteral administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, eg, intrathecal or intracerebroventricular, administration.
本发明的进一步的目的在于提供一种制品,例如以试剂盒形式提供。本文所用的制品意图包括但不限于药盒和包装。所述试剂盒还可包括使用说明书。A further object of the present invention is to provide a product, for example in the form of a kit. As used herein, articles of manufacture are intended to include, but are not limited to, kits and packages. The kit may also include instructions for use.
治疗方法和用途Treatments and uses
本发明的另一目的在于提供一种式I的化合物或其药学上可接受的盐或者本发明的药物组合物在制备用于预防或治疗SHP2活性介导的疾病的药物中的用途。Another object of the present invention is to provide a use of a compound of formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating diseases mediated by SHP2 activity.
在另一方面,本发明提供一种用于预防或治疗SHP2活性介导的疾病的方法,所述方法包括向有此需要的个体给药式I的化合物或其药学上可接受的盐或者本发明的药物组合物。In another aspect, the present invention provides a method for preventing or treating a disease mediated by SHP2 activity, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof or the present invention to an individual in need thereof. Invented pharmaceutical composition.
在又一方面,本发明提供式I的化合物或其药学上可接受的盐或者本发明的药物组合物,用于预防或治疗SHP2活性介导的疾病。In yet another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention for preventing or treating diseases mediated by SHP2 activity.
根据本发明的一个实施方案,可使用本发明的化合物进行预防或治疗的SHP2活性介导的疾病为对SHP2酶抑制敏感或有响应的疾病。在进一步的实施方案中,所述SHP2活性介导的疾病为非小细胞肺癌。According to one embodiment of the invention, the diseases mediated by SHP2 activity which can be prevented or treated using the compounds of the invention are diseases which are sensitive or responsive to inhibition of the SHP2 enzyme. In a further embodiment, the disease mediated by SHP2 activity is non-small cell lung cancer.
有益效果Beneficial effect
本发明提供一类新型的高活性SHP2抑制剂,能够实现下述至少一种技术效果:The present invention provides a new type of highly active SHP2 inhibitor, which can achieve at least one of the following technical effects:
(1)对SHP2酶的高抑制活性。(1) High inhibitory activity against SHP2 enzyme.
(2)优异的肿瘤细胞抑制活性。(2) Excellent tumor cell inhibitory activity.
(3)优异的药物代谢动力学性质(例如良好的生物利用度、合适的半衰期和作用持续时间)。(3) Excellent pharmacokinetic properties (such as good bioavailability, suitable half-life and duration of action).
一般术语和定义General Terms and Definitions
除非在下文中另有定义,本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。Unless defined otherwise hereinafter, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
本发明的某些化合物可以游离形式存在,或适当时,以其药学上可接受的衍生物形式存在。在本发明中,药学上可接受的衍生物包括但不限于,药学上可接受的盐、前药、立体异构体(包括但不限于非对映异构体和对映异构体)、互变异构体、溶剂化物、多晶型物和同位素化合物,在将它们向需要其的患者给药后,能够直接或间接提供式I化合物或其代谢物。因此,当在本文中提及“本发明的化合物”时,也意在涵盖化合物的上述各种衍生物形式。Certain compounds of the present invention may exist in free form or, where appropriate, as pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, prodrugs, stereoisomers (including but not limited to diastereoisomers and enantiomers), Tautomers, solvates, polymorphs and isotopic compounds are capable of providing, directly or indirectly, a compound of formula I or its metabolites after their administration to a patient in need thereof. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
术语“药学上可接受的盐”指保留了特定化合物的游离酸和碱的生物学效力而没有生物学不良作用的盐。药学上可接受的盐的例子包括但不限于:(1)酸加成盐,和无机酸例如盐酸、硫酸、氢溴酸、硝酸、磷酸等形成的盐;或和有机酸例如苹果酸、富马酸、马来酸、苯甲酸、苯乙酸、琥珀酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、羟基乙酸、肉桂酸、丙酮酸、甲酸、乙酸、丙酸、草酸、丙二酸、丙烯酸、扁桃酸等形成的盐;或者(2)碱加成盐,和碱金属例如锂、钠、钾等形成的盐;和碱土金属例如钙、镁等形成的盐;和有机碱例如铵、胆碱、二乙醇胺、赖氨酸、乙二胺、叔丁胺、叔辛胺、三(羟甲基)氨基甲烷、N-甲基葡萄糖胺、三乙醇胺、脱氢松香胺等形成的盐。对于本领域的技术人员而言,其他的药学上可接受的盐是已知的。The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acids and bases of the specified compound without adverse biological effects. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, etc.; Maleic acid, maleic acid, benzoic acid, phenylacetic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, glycolic acid, cinnamic acid, pyruvic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid , acrylic acid, mandelic acid, etc.; or (2) alkali addition salts, salts formed with alkali metals such as lithium, sodium, potassium, etc.; salts formed with alkaline earth metals such as calcium, magnesium, etc.; and organic bases such as ammonium , choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris(hydroxymethyl)aminomethane, N-methylglucamine, triethanolamine, dehydroabietamine, etc. Other pharmaceutically acceptable salts are known to those skilled in the art.
本发明化合物的药物前体包含在本发明的保护范围内。通常,所述药物前体是指很容易在体内转化成所需要的化合物的功能性衍生物。因此,本发明提供的治疗方法中的术语“给药”包括施用本发明公开的化合物,或虽未明确公开但对受试者给药后能够在体内转化为本发明公开的化合物治疗所述的各种疾病。有关选择和制备合适药物前体衍生物的常规方法,已记载在例如《药物前体设计》(Design of Prodrugs,H.Bundgaard,Elsevier,1985)这类书中。The prodrugs of the compounds of the present invention are included in the protection scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted in vivo to the desired compound. Therefore, the term "administering" in the treatment method provided by the present invention includes administering the compound disclosed in the present invention, or although not explicitly disclosed but can be converted into the compound disclosed in the present invention after administration to the subject to treat the described compound. various diseases. Routine methods for selecting and preparing suitable prodrug derivatives are described, for example, in such books as Design of Prodrugs, H. Bundgaard, Elsevier, 1985.
本发明所述化合物可能含有一个或多个不对称中心,并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药学上可接受的盐。The compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and optical isomers. The present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
上述式I没有确切定义该化合物某一位置的立体结构。本发明包括式I所示化合物的所有立体异构体及其药学上可接受的盐。而且,立体异构体的混合物及分离出的特定的立体异构体也包括在本发明中。制备此类化合物的合成过程中,或使用本领域普通技术人员公知的外消旋化或差向异构化方法的过程中,制得的产品可以是立体异构体的混合物。The above formula I does not exactly define the stereostructure of a certain position of the compound. The present invention includes all stereoisomers of the compound represented by formula I and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. During the synthesis of such compounds, or during the use of racemization or epimerization procedures well known to those of ordinary skill in the art, the products obtained may be mixtures of stereoisomers.
当式I所示化合物存在互变异构体时,除非特别声明,本发明包括任何可能的互变异构体和其药学上可接受的盐,及它们的混合物。When the compound represented by formula I has tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and their mixtures.
当式I所示化合物及其药学上可接受的盐以溶剂化物或多晶型的形式存在时,本发明包括任何可能的溶剂化物和多晶型形式。形成溶剂化物的溶剂类型没有特别的限定,只要该溶剂是药理学上可以接受的。例如,水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。When the compound represented by formula I and its pharmaceutically acceptable salts exist in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent forming a solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.
本发明还包括所有药学上可接受的同位素化合物,其与本发明的化合物相同,除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘( 2H)、氚( 3H));碳的同位素(例如 13C及 14C);氯的同位素(例如 37Cl);碘的同位素(例如 125I);氮的同位素(例如 13N及 15N);氧的同位素(例如 17O及 18O);磷的同位素(例如 32P);及硫的同位素(例如 34S)。 The invention also includes all pharmaceutically acceptable isotopic compounds which are identical to the compounds of the invention except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass or mass prevailing in nature Atomic substitution of numbers. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g., 13C and 14C ); Isotopes (such as 37 Cl); isotopes of iodine (such as 125 I); isotopes of nitrogen (such as 13 N and 15 N); isotopes of oxygen (such as 17 O and 18 O); isotopes of phosphorus (such as 32 P); Isotopes of sulfur (eg 34 S).
例如,表述“C 1-C 6”应理解为涵盖其中的任意亚范围以及每个点值,例如C 2-C 5、C 3-C 4、 C 1-C 2、C 1-C 3、C 1-C 4、C 1-C 5等,以及C 1、C 2、C 3、C 4、C 5、C 6等。又例如,表述“5-10元”也应当以类似的方式理解,例如可以涵盖包含于其中的任意亚范围和点值,例如5-6元、5-7元、5-8元、5-9元、5-10元、6-7元、6-8元、6-9元、6-10元、7-8元等以及5、6、7、8、9、10元等。 For example, the expression "C 1 -C 6 " should be understood to cover any subrange therein as well as every point value, such as C 2 -C 5 , C 3 -C 4 , C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , etc., and C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , etc. As another example, the expression "5-10 yuan" should also be understood in a similar manner, for example, can cover any sub-range and point value contained therein, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5- 9 yuan, 5-10 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 6-10 yuan, 7-8 yuan, etc. and 5, 6, 7, 8, 9, 10 yuan, etc.
术语“烷基”,在本文中单独或与其他基团组合使用时,指饱和的直链或支链烃基。如本文中所使用,术语“C 1-6烷基”指具有1-6个碳原子(例如1、2、3、4、5或6个碳原子)的饱和直链或支链烃基。例如“C 1-6烷基”可以是甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基等。 The term "alkyl", as used herein alone or in combination with other groups, refers to a saturated straight or branched chain hydrocarbon group. As used herein, the term "C 1-6 alkyl" refers to a saturated linear or branched hydrocarbon group having 1-6 carbon atoms (eg, 1, 2, 3, 4, 5 or 6 carbon atoms). For example, "C 1-6 alkyl" can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo Pentyl or n-hexyl etc.
术语“亚烷基”指饱和的直链或支链的二价烃基。例如,如本文中所使用,术语“C 1-6亚烷基”指具有1-6个碳原子饱和的直链或支链的二价烃基。例如亚甲基、亚乙基、亚丙基或亚丁基等。 The term "alkylene" refers to a saturated linear or branched divalent hydrocarbon group. For example, as used herein, the term "C 1-6 alkylene" refers to a saturated linear or branched divalent hydrocarbon group having 1-6 carbon atoms. For example, methylene, ethylene, propylene or butylene and the like.
术语“环烷基”,在本文中单独或与其他基团组合使用时,指饱和的非芳族单环或多环(诸如双环)烃环(例如单环,如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基;或双环,包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)。环烷基包括C 3-10环烷基,优选C 3-6环烷基,更优选C 5-6环烷基。 The term "cycloalkyl", as used herein alone or in combination with other groups, refers to a saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g. monocyclic, such as cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl; or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1] Heptyl, bicyclo [3.2.1] octyl or bicyclo [5.2.0] nonyl, decahydronaphthyl, etc.). Cycloalkyl includes C 3-10 cycloalkyl, preferably C 3-6 cycloalkyl, more C 5-6 cycloalkyl is preferred.
例如,术语“C 3-10环烷基”指具有3-10个环碳原子(如3、4、5、6、7、8、9或10个)的环烷基。 For example, the term "C 3-10 cycloalkyl" refers to a cycloalkyl group having 3-10 ring carbon atoms (eg, 3, 4, 5, 6, 7, 8, 9 or 10).
术语“烃环”,在本文中单独或与其他基团组合使用时,指具有例如3-16个(例如4-10个、5-10个、6-10个,优选5-8个,更优选5-6个)环碳原子的饱和或部分不饱和的(即在环内具有一个或多个双键和/或三键,但未形成芳香环体系)单环或多环烃环,其中单环包括但不限于环丙基环、环丁基环、环戊基环、环己基环、环庚基环、环辛基环、环壬基环、环己烯基环等,多环烃环包括联环、螺环、并环或桥环,其具有6~16个碳原子。The term "hydrocarbon ring", when used alone or in combination with other groups herein, refers to the Saturated or partially unsaturated (ie having one or more double and/or triple bonds within the ring, but not forming an aromatic ring system) monocyclic or polycyclic hydrocarbon rings with preferably 5-6) ring carbon atoms, wherein Monocyclic rings include but are not limited to cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclohexyl rings, cycloheptyl rings, cyclooctyl rings, cyclononyl rings, cyclohexenyl rings, etc., and polycyclic hydrocarbon rings include Linked ring, spiro ring, parallel ring or bridged ring, which has 6-16 carbon atoms.
术语“卤代”或“卤素”基团,在本文中单独或与其他基团组合使用时,表示F、Cl、Br或I。The term "halo" or "halogen" group, when used herein alone or in combination with other groups, means F, Cl, Br or I.
术语“卤代烷基”,在本文中单独或与其他基团组合使用时,指上文所述的烷基,其中一个或多个氢原子被卤素代替。例如,术语“卤代C 1-6烷基”指任选地被一个或多个(如1-3个)卤素取代的C 1-6烷基。本领域技术人员应当理解,当卤素取代基多于一个时,卤素可以相同也可以不同,并且可以位于相同或不同的C原子上。卤代烷基的实例有例如-CH 2F、-CHF 2、-CF 3、-CCl 3、-C 2F 5、-C 2Cl 5、-CH 2CF 3、-CH 2Cl或-CH 2CH 2CF 3等。 The term "haloalkyl", as used herein alone or in combination with other groups, refers to an alkyl group as described above, wherein one or more hydrogen atoms are replaced by a halogen. For example, the term "haloC 1-6 alkyl" refers to a C 1-6 alkyl optionally substituted with one or more (eg, 1-3) halogen. Those skilled in the art should understand that when there is more than one halogen substituent, the halogens may be the same or different, and may be located on the same or different C atoms. Examples of haloalkyl groups are for example -CH2F , -CHF2 , -CF3, -CCl3, -C2F5 , -C2Cl5 , -CH2CF3 , -CH2Cl or -CH2CH 2 CF 3 etc.
术语“杂环”,在本文中单独或与其他基团组合使用时,指具有例如3-16个(例如4-10个、5-10个、6-10个、3-8个,优选3-6个,更优选5-6个)环原子的单环或多环的非芳香环体系(例如3-10元、4-10元、5-10元、6-10元、3-8元、3-6元或5-6元杂环),其中至少一个环原子(例如1、2或3个)是选自N、O和S的杂原子,且其余环原子是C。该环体系可以是饱和(也可以理解为相应的“饱和杂环烷”)或不饱和的(即在环内具有一个或多个双键和/或三键)。该术语还涵盖这样的情况,其中的C原子可以被(=O)取代和/或环上的S原子可以被1个或2个(=O)取代。杂环基是通过去除一个氢原子由杂环衍生的基团,其实例包括但不限于:环氧乙烷基、环硫乙烷基、环氮乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、四氢呋喃基、四氢噻吩基、二氧杂环戊烯基、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、1,4-噻噁烷基、1,4-二氧六环基、二噻烷基、四氢吡啶基、硫吗啉基、哌嗪基或三噻烷基等。The term "heterocycle", when used herein alone or in combination with other groups, refers to a - 6, more preferably 5-6) ring atoms of monocyclic or polycyclic non-aromatic ring systems (eg 3-10, 4-10, 5-10, 6-10, 3-8 , 3-6 membered or 5-6 membered heterocyclic ring), wherein at least one ring atom (eg 1, 2 or 3) is a heteroatom selected from N, O and S, and the remaining ring atoms are C. The ring system may be saturated (also understood as the corresponding "saturated heterocycloalkane") or unsaturated (ie have one or more double and/or triple bonds within the ring). The term also covers cases where a C atom may be substituted by (=0) and/or a ring S atom may be substituted by 1 or 2 (=0). A heterocyclyl group is a group derived from a heterocyclic ring by removal of a hydrogen atom, examples of which include, but are not limited to: oxiranyl, cyclothioethyl, cycloazaethyl, azetidinyl, oxa Cyclobutyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl base, piperidinyl, morpholinyl, 1,4-thiaxanyl, 1,4-dioxanyl, dithianyl, tetrahydropyridyl, thiomorpholinyl, piperazinyl or trithianyl Alkyl etc.
术语“芳环”,在本文中单独或与其他基团组合使用时,指具有共轭π电子系统的全碳单环或稠合环多环(如双环)芳族环。芳基是通过去除一个氢原子由芳环衍生的基团。如本文中所使用,术语“C 6-10芳基”指从含有6-10个碳原子的芳环衍生的芳族基团。芳基的实例包括但不限于苯基和萘基等。 The term "aromatic ring", as used herein alone or in combination with other groups, refers to an all-carbon monocyclic or fused-ring polycyclic (eg, bicyclic) aromatic ring having a conjugated π-electron system. An aryl group is a group derived from an aromatic ring by removal of one hydrogen atom. As used herein, the term "C 6-10 aryl" refers to an aromatic group derived from an aromatic ring containing 6-10 carbon atoms. Examples of aryl include, but are not limited to, phenyl, naphthyl, and the like.
术语“杂芳环”,在本文中单独或与其他基团组合使用时,指这样的芳族环,其中一个或多个(如1、2或3个)环原子是选自N、O和S的杂原子,其余的环原子为C。杂芳基是通过去除一个氢原子由杂芳环衍生的基团。杂芳基或杂芳环可以用环原子的数目表征。例如,5-10元杂芳基可以含有5-10个环原子(例如5、6、7、8、9或10个)环原子,特别是含有5、6、9、10个环原子,5-6元杂芳基可以含有例如5或6个环原子。并且在每一种情况下,杂芳基或杂芳环可任选为进一步苯并稠合的。例如,杂芳基的实例有噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、吡嗪基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等,以及它们的苯并衍生物;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、喹啉基、异喹啉基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等,以及它们的苯并衍生物。The term "heteroaromatic ring", as used herein alone or in combination with other groups, refers to an aromatic ring in which one or more (such as 1, 2 or 3) ring atoms are selected from N, O and S heteroatom, and the remaining ring atoms are C. A heteroaryl group is a group derived from a heteroaryl ring by removal of one hydrogen atom. A heteroaryl or heteroaryl ring can be characterized by the number of ring atoms. For example, a 5-10 membered heteroaryl group may contain 5-10 (eg 5, 6, 7, 8, 9 or 10) ring atoms, especially 5, 6, 9, 10 ring atoms, 5 A 6-membered heteroaryl group may contain, for example, 5 or 6 ring atoms. And in each case, the heteroaryl or heteroaryl ring may optionally be further benzo-fused. For example, examples of heteroaryl groups are thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, tri Azolyl, thiadiazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolyl, benzofuryl, Benzothienyl, indolyl, isoindolyl, etc., and their benzo derivatives.
术语“取代”和“取代的”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替,条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。The terms "substituted" and "substituted" mean that one or more (e.g., one, two, three or four) hydrogens on the indicated atom are replaced by a selection from the indicated group, provided that no more than the indicated Atoms are indicated at their normal valences at the present situation and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
如果取代基被描述为“任选地…被取代”,则取代基可(1)未被取代,或(2)被取代。如果某个原子或基团被描述为任选地被取代基列表中的一个或多个取代,则该原子或基团上的一个或多个氢可被独立地选择的、任选的取代基替代。如果取代基被描述为“独立地选自”或“各自独立地为”,则各取代基互相独立地加以选择。因此,各取代基可与另一(其他)取代基相同或不同。例如,某个取代基或取代位置或者不同的取代基或取代位置具有可能相同或不同符号指代的R基团(例如但不限于R 2、R 3、R h、R i、R x和/或R y)的选择时,各个R之间独立地加以选择,即可以相同也可以不同。关于数值如d、g、m、n的选择也是如此。 If a substituent is described as "optionally substituted," the substituent can be (1) unsubstituted, or (2) substituted. If an atom or group is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the atom or group may be independently selected, optional substituents substitute. If substituents are described as being "independently selected from" or "each independently being", each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent. For example, a certain substituent or substituent position or different substituents or substituent positions may have the R groups indicated by the same or different symbols (such as but not limited to R 2 , R 3 , Rh , R i , R x and/or or R y ), each R is independently selected, and may be the same or different. The same goes for the choice of values such as d, g, m, n.
除非指明,否则如本文中所使用,取代基的连接点可来自取代基的任意适宜位置。As used herein, unless otherwise indicated, the point of attachment of a substituent may be from any suitable position of the substituent.
当取代基的键显示为穿过环中连接两个原子的键时,则这样的取代基可键连至该可取代的环中的任一成环原子。When a bond for a substituent is shown as being through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring-forming atom in such a substitutable ring.
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的或开放式的,且不排除其它未列举的元素或方法步骤。本领域技术人员应当理解,上述术语如“包括”涵盖“由…组成”的含义。The terms "comprising", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude other unrecited elements or method steps . Those skilled in the art should understand that the above terms such as "comprising" cover the meaning of "consisting of".
本发明中“药学上可接受的载体”是指与活性成分一同给药的稀释剂、辅剂、赋形剂或媒介物,并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。术语“活性成分”、“治疗剂”,“活性物质”或“活性剂”是指一种化学实体,它可以有效地治疗目标病症或病况的一种或多种症状。"Pharmaceutically acceptable carrier" in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with the active ingredient, and it is suitable for contacting human beings and/or Tissues from other animals without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio. The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating one or more symptoms of the targeted disorder or condition.
如本文中所使用的术语“有效量”(例如“治疗有效量”或“预防有效量”)指给药后会在一定程度上实现预期效果的活性成分的量,例如缓解所治疗病症的一种或多种症状或预防病症或其症状的出现。As used herein, the term "effective amount" (eg, "therapeutically effective amount" or "prophylactically effective amount") refers to the amount of the active ingredient which, when administered, will achieve to some extent the desired effect, such as alleviation of a part of the condition being treated. one or more symptoms or prevent the occurrence of a disorder or its symptoms.
除非另外说明,否则如本文中所使用,术语“治疗”意指逆转、减轻、抑制该术语所应用的病症或病况或者所述病症或病况的一种或多种症状的进展,或预防所述病症或病况或者所述病症或病况的一种或多种症状。Unless otherwise stated, the term "treating" as used herein means reversing, alleviating, inhibiting the progression of the disorder or condition to which the term applies or one or more symptoms of said disorder or condition, or preventing said disorder or condition. A disorder or condition or one or more symptoms of said disorder or condition.
具体实施方式Detailed ways
下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的化学原料、试剂等,如无特殊说明,均为市售购买产品。The experimental methods in the following examples are conventional methods unless otherwise specified. The chemical raw materials and reagents used in the following examples are all commercially available products unless otherwise specified.
本文中出现的缩略语及其含义如下所示:Abbreviations and their meanings appearing in this document are as follows:
缩写abbreviation 含义meaning 缩写abbreviation 含义meaning
DMFDMF N,N-二甲基甲酰胺N,N-Dimethylformamide NBSNBS N-溴代丁二酰亚胺N-Bromosuccinimide
THFTHF 四氢呋喃Tetrahydrofuran NISNIS N-碘代丁二酰亚胺N-iodosuccinimide
MeCNMeCN 乙腈Acetonitrile TFATFA 三氟乙酸Trifluoroacetate
DioxaneDioxane 二氧六环Dioxane NaOEtNaOEt 乙醇钠sodium ethylate
TEATEA 三乙胺Triethylamine Na 2S 2O 3 Na 2 S 2 O 3 硫代硫酸钠Sodium thiosulfate
PEPE 石油醚petroleum ether NaHNaH 氢化钠sodium hydride
EAEA 乙酸乙酯ethyl acetate PPh 3 PPh 3 三苯基膦Triphenylphosphine
DCMDCM 二氯甲烷Dichloromethane XantPhosXantPhos 4,5-双(二苯基膦)-9,9-二甲基氧杂蒽4,5-bis(diphenylphosphine)-9,9-dimethylxanthene
DMSODMSO 二甲基亚砜Dimethyl sulfoxide RuPhosRuPhos 2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯2-Dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl
MeOHMeOH 甲醇Methanol Pd(PPh 3) 4 Pd(PPh 3 ) 4 四(三苯基膦)钯Tetrakis(triphenylphosphine)palladium
EtOHEtOH 乙醇ethanol Pd 2(dba) 3 Pd 2 (dba) 3 三(二亚苄基丙酮)二钯Tris(dibenzylideneacetone)dipalladium
Ti(OEt) 4 Ti(OEt) 4 钛酸乙酯Ethyl titanate Pd(OAc) 2 Pd(OAc) 2 醋酸钯palladium acetate
NMPNMP 1-甲基-2-吡咯烷酮1-methyl-2-pyrrolidone LDALDA 二异丙基氨基锂lithium diisopropylamide
RTRT 室温room temperature DIBAL-HDIBAL-H 二异丁基氢化铝Diisobutylaluminum hydride
TLCTLC 薄层色谱法TLC PPAPPAs 多聚磷酸polyphosphoric acid
(NH 4) 2S 2O 8 (NH 4 ) 2 S 2 O 8 过硫酸铵Ammonium persulfate HEPESHEPES 4-羟乙基呱嗪乙磺酸4-Hydroxyethylpiperazineethanesulfonic acid
DTTDTT 二硫苏糖醇Dithiothreitol BSABSA 牛血清白蛋白bovine serum albumin
DiFMUPDiFMUP 6,8-二氟-4-甲基伞形酮磷酸盐6,8-Difluoro-4-methylumbelliferone phosphate Triton X-100Triton X-100 聚乙二醇对异辛基苯基醚Polyethylene glycol p-isooctyl phenyl ether
PBSPBS 磷酸盐缓冲液Phosphate buffer FBSFBS 胎牛血清fetal bovine serum
中间体A1Intermediate A1
Figure PCTCN2022122329-appb-000089
Figure PCTCN2022122329-appb-000089
将2-氨基-3-硝基苯酚(5.0g,32.5mmol)溶于50mL四氢呋喃中,加入三乙胺(9.85g,97.5mmol),冷至0℃加入2-溴-2-甲基丙基溴(7.4g,32.5mmol),室温搅拌16小时。反应液用100mL饱和氯化铵淬灭,用乙酸乙酯萃取3次,每次100mL。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,粗品用硅胶柱色谱法(石油醚:乙酸乙酯=2:1)纯化,得化合物A1-1(3.6g白色固体,收率36%)。MS(ESI):303.0[M+H] +. Dissolve 2-amino-3-nitrophenol (5.0g, 32.5mmol) in 50mL tetrahydrofuran, add triethylamine (9.85g, 97.5mmol), cool to 0°C and add 2-bromo-2-methylpropyl Bromine (7.4g, 32.5mmol), stirred at room temperature for 16 hours. The reaction solution was quenched with 100 mL of saturated ammonium chloride and extracted three times with 100 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound A1-1 (3.6 g white solid, Yield 36%). MS(ESI):303.0[M+H] + .
将化合物A1-1(3.6g,11.9mmol)溶于40mL DMF中,加入碳酸铯(11.6g,35.7mmol),75℃搅拌1.5小时。反应混合物用100mL饱和氯化铵水溶液稀释,乙酸乙酯萃取3次,每次100mL。合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,粗品用硅胶柱层析(石油醚:乙酸乙酯=2:1)纯化,得化合物A1-2(2.5g黄色固体,收率96%)。MS(ESI):223.0[M+H] +. Compound A1-1 (3.6 g, 11.9 mmol) was dissolved in 40 mL of DMF, cesium carbonate (11.6 g, 35.7 mmol) was added, and stirred at 75° C. for 1.5 hours. The reaction mixture was diluted with 100 mL of saturated aqueous ammonium chloride, and extracted three times with 100 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound A1-2 (2.5 g yellow solid, obtained rate of 96%). MS(ESI):223.0[M+H] + .
在H 2气氛下向化合物A1-2(2.5g,11.3mmol)的甲醇(20mL)溶液中加入200mgPd/C,室温搅拌3小时。过滤,减压浓缩得化合物A1-3(2.0g黄色固体,收率93%)。MS(ESI):193.1[M+H] +. To a solution of compound A1-2 (2.5 g, 11.3 mmol) in methanol (20 mL) was added 200 mg Pd/C under H 2 atmosphere, and stirred at room temperature for 3 hours. Filter and concentrate under reduced pressure to obtain compound A1-3 (2.0 g yellow solid, yield 93%). MS(ESI):193.1[M+H] + .
将化合物A1-3(2.0g,10.4mmol)溶于20mL DMF中,加入1,2-二溴乙烷(2.95g,15.6mmol)和碳酸铯(10g,31.2mmol)。80℃搅拌5小时,用100mL饱和饱和氯化铵稀释,乙酸乙酯萃取3次,每次100mL。合并有机相,用100mL饱和食盐水洗涤,无水硫酸钠干燥,过滤,真空浓缩,粗品用硅胶柱层析(石油醚:乙酸乙酯=2:1)纯化,得中间体A1(700mg黄色固体,收率31%)。MS(ESI):219.1[M+H] +. Compound A1-3 (2.0 g, 10.4 mmol) was dissolved in 20 mL of DMF, and 1,2-dibromoethane (2.95 g, 15.6 mmol) and cesium carbonate (10 g, 31.2 mmol) were added. Stir at 80°C for 5 hours, dilute with 100 mL of saturated ammonium chloride, and extract with ethyl acetate three times, 100 mL each time. The organic phases were combined, washed with 100 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain intermediate A1 (700 mg yellow solid , yield 31%). MS(ESI):219.1[M+H] + .
使用上述合成方法或改进的方法,用相应的起始原料合成以下中间体。Using the above synthetic methods or modified methods, the following intermediates were synthesized from the corresponding starting materials.
Figure PCTCN2022122329-appb-000090
Figure PCTCN2022122329-appb-000090
中间体A2Intermediate A2
Figure PCTCN2022122329-appb-000091
Figure PCTCN2022122329-appb-000091
将2-羟基乙酸乙酯(3.6g,34.68mmol)溶于THF(100mL)中,冷却至0℃,分批加入NaH(11.39g,0.624mmo,分散于矿物油中,含量60%),室温反应2h。之后加入2-氯-3-硝基吡啶-4-胺(5g,28.9mmol)。所得混合物在80℃搅拌反应6h,冷却至室温,倒入冰水中淬灭,然后用EA(100mL x 3)萃取。用饱和食盐水(100mL)洗涤有机相,无水硫酸钠干燥,过滤,浓缩。通过反相柱色谱(H2O/ACN)纯化得到化合物A2-1(2.9g黄色固体,收率42%)。MS(ESI):242.1[M+H] +. Ethyl 2-hydroxyacetate (3.6g, 34.68mmol) was dissolved in THF (100mL), cooled to 0°C, NaH (11.39g, 0.624mmo, dispersed in mineral oil, content 60%) was added in batches, at room temperature Reaction 2h. Then 2-chloro-3-nitropyridin-4-amine (5 g, 28.9 mmol) was added. The resulting mixture was stirred at 80 °C for 6 h, cooled to room temperature, quenched by pouring into ice water, and then extracted with EA (100 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by reverse phase column chromatography (H2O/ACN) gave compound A2-1 (2.9 g yellow solid, yield 42%). MS(ESI):242.1[M+H] + .
将化合物A2-1(2.7g,11.2mmol)溶于MeOH(50mL)中,加入Pd/C(270mg),用氢气置换3次,并在氢气氛下室温反应7小时。混合物过滤,浓缩滤液得化合物A2-2(2.2g黄色固体,收率99%)。MS(ESI):212.1[M+H] +. Compound A2-1 (2.7 g, 11.2 mmol) was dissolved in MeOH (50 mL), Pd/C (270 mg) was added, replaced with hydrogen 3 times, and reacted at room temperature under hydrogen atmosphere for 7 hours. The mixture was filtered, and the filtrate was concentrated to obtain compound A2-2 (2.2 g of yellow solid, yield 99%). MS(ESI):212.1[M+H] + .
将化合物A2-2(2.7g,12.8mmol)溶于AcOH(30mL)中,搅拌10min,浓缩得固体,用石油醚/乙酸乙酯(20:1)打浆。过滤得到化合物A2-3(1.6g灰白色固体,76%)。MS(ESI):166.1[M+H] +. Compound A2-2 (2.7 g, 12.8 mmol) was dissolved in AcOH (30 mL), stirred for 10 min, concentrated to obtain a solid, and slurried with petroleum ether/ethyl acetate (20:1). Filtration afforded compound A2-3 (1.6 g off-white solid, 76%). MS(ESI):166.1[M+H] + .
将化合物A2-3(500mg,3mmol)溶于DMF(15mL)中,加入1,2-二溴乙烷(1.7g,9mmol)和碳酸铯(1.96g,6mmol),混合物在80℃反应18小时。用四氢呋喃(20mL)稀释,饱和食盐水洗涤3次,每次10mL。合并有机相,无水硫酸钠干燥,过滤,浓缩。粗品用反相柱层析(水/乙腈)和制备TLC(DCM:MeOH=15:1)纯化得到中间体A2(53mg白色固体,收率9%)。MS(ESI):192.2[M+H] +. Compound A2-3 (500mg, 3mmol) was dissolved in DMF (15mL), 1,2-dibromoethane (1.7g, 9mmol) and cesium carbonate (1.96g, 6mmol) were added, and the mixture was reacted at 80°C for 18 hours . Dilute with tetrahydrofuran (20 mL), and wash with saturated brine three times, 10 mL each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by reverse-phase column chromatography (water/acetonitrile) and preparative TLC (DCM:MeOH=15:1) to obtain intermediate A2 (53 mg white solid, yield 9%). MS(ESI):192.2[M+H] + .
使用上述合成方法或改进的方法,用相应的起始原料合成以下中间体。Using the above synthetic methods or modified methods, the following intermediates were synthesized from the corresponding starting materials.
Figure PCTCN2022122329-appb-000092
Figure PCTCN2022122329-appb-000092
中间体A3Intermediate A3
Figure PCTCN2022122329-appb-000093
Figure PCTCN2022122329-appb-000093
将2-氨基-3-硝基苯酚(20g,130mmol)溶于DMF(200mL)中,加入氟化钾(22g,390mmol)和2-溴-2-甲基丙二酸二乙酯(40g,156mmol)。将所得反应物室温搅拌30分钟,60℃搅拌过夜。反应液用EA稀释,饱和食盐水洗涤。有机相用无水硫酸钠干燥,过滤,浓缩,粗品用硅胶柱层析纯化(EA:PE=1:4)得化合物A3-1(19g黄色固体,收率52%)。MS(ESI):281.1[M+H] +. Dissolve 2-amino-3-nitrophenol (20g, 130mmol) in DMF (200mL), add potassium fluoride (22g, 390mmol) and diethyl 2-bromo-2-methylmalonate (40g, 156 mmol). The resulting reaction was stirred at room temperature for 30 minutes and at 60°C overnight. The reaction solution was diluted with EA and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (EA:PE=1:4) to obtain compound A3-1 (19 g yellow solid, yield 52%). MS(ESI):281.1[M+H] + .
将化合物A3-1(3g,10.67mmol)溶于甲醇(80ml)中,加入Pd/C(300mg),氢气置换3次。氢气氛下40℃搅拌2小时。过滤,甲醇洗涤,滤液浓缩得化合物A3-2(2.2g黄色固体,收率84%)。MS(ESI):251.1[M+H] +. Compound A3-1 (3 g, 10.67 mmol) was dissolved in methanol (80 ml), Pd/C (300 mg) was added, and hydrogen replacement was performed 3 times. Stir at 40°C for 2 hours under a hydrogen atmosphere. After filtering, washing with methanol, the filtrate was concentrated to obtain compound A3-2 (2.2 g yellow solid, yield 84%). MS(ESI):251.1[M+H] + .
将化合物A3-2(2.5g,9.9mmol)溶于DMF(20mL)中,加入碳酸钾(4.1g,29.7mmol)和1,2-二溴乙烷(2.4g,12.87mmol),80℃搅拌过夜。反应液用EA稀释,饱和食盐水洗涤。有机相用无水硫酸钠干燥,过滤,浓缩。粗品用反相柱色谱(乙腈/水)纯化得化合物A3-3(1.1g棕色固体,收率40%)。MS(ESI):277.1[M+H] +. Compound A3-2 (2.5g, 9.9mmol) was dissolved in DMF (20mL), potassium carbonate (4.1g, 29.7mmol) and 1,2-dibromoethane (2.4g, 12.87mmol) were added, stirred at 80°C overnight. The reaction solution was diluted with EA and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by reverse-phase column chromatography (acetonitrile/water) to obtain compound A3-3 (1.1 g brown solid, yield 40%). MS(ESI):277.1[M+H] + .
将化合物A3-3(600mg,2.16mmol)溶于四氢呋喃(10mL)中,降温至0℃,加入三乙基硼氢化锂(1N的THF溶液,5.4mL)。升至室温搅拌反应2小时。饱和氯化铵水溶液淬灭,乙酸乙酯萃取。有机相用无水硫酸钠干燥,过滤,浓缩。所得粗品用过硅胶柱层析纯化(EA:PE=1:2)得中间体A3(200mg白色固体,收率39%)。MS(ESI):235.1[M+H] +. Compound A3-3 (600mg, 2.16mmol) was dissolved in tetrahydrofuran (10mL), cooled to 0°C, and lithium triethylborohydride (1N solution in THF, 5.4mL) was added. Warm to room temperature and stir the reaction for 2 hours. Quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:2) to obtain intermediate A3 (200mg white solid, yield 39%). MS(ESI):235.1[M+H] + .
中间体A4Intermediate A4
Figure PCTCN2022122329-appb-000094
Figure PCTCN2022122329-appb-000094
将4-氯-1H-吡咯并[2,3-b]吡啶(5g,32.9mmol)溶于乙腈(100ml)中,加入N-碘代丁二酰亚胺(11.1g,49.4mmol),反应液升温至50℃搅拌2小时。减压除去溶剂,所得粗品用硅胶柱层析法(PE:EA=1:1)纯化得到化合物A4-1(8.7g浅棕色固体,收率95%)。MS(ESI):279.0[M+H] +. 4-Chloro-1H-pyrrolo[2,3-b]pyridine (5g, 32.9mmol) was dissolved in acetonitrile (100ml), N-iodosuccinimide (11.1g, 49.4mmol) was added, and the reaction The solution was heated to 50°C and stirred for 2 hours. The solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (PE:EA=1:1) to obtain compound A4-1 (8.7 g light brown solid, yield 95%). MS(ESI):279.0[M+H] + .
将化合物A4-1(8.3g,29.8mmol)溶于四氢呋喃(50mL)中,加入氢化钠(2.4g,59.7mmol,60%的矿物油混合物),室温搅拌1小时后,加入2-(三甲硅烷基)乙氧甲基氯(7.5g,44.7mmol)。室温搅拌1小时,加入饱和氯化铵水溶液(1ml)淬灭。减压除去溶剂,所得粗品用硅胶柱色谱法(PE:EA=7:1)纯化得化合物A4-2(5.4克黄色油状物,收率44%)。MS(ESI):409.2[M+H] +. Dissolve compound A4-1 (8.3g, 29.8mmol) in tetrahydrofuran (50mL), add sodium hydride (2.4g, 59.7mmol, 60% mineral oil mixture), stir at room temperature for 1 hour, add 2-(trimethylsilane yl) ethoxymethyl chloride (7.5 g, 44.7 mmol). Stir at room temperature for 1 hour, and quench with saturated aqueous ammonium chloride solution (1 ml). The solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (PE:EA=7:1) to obtain compound A4-2 (5.4 g of yellow oil, yield 44%). MS(ESI):409.2[M+H] + .
将化合物A4-2(5.4g,13.2mmol)溶于二氧六环(50mL)中,加入丙烯酸甲酯(1.7g,19.8mmol),三苯基膦(346mg,1.32mmol),醋酸钯(148mg,0.66mmol)和三乙胺(2.7g,26.4mmol)。氮气保护下,将混合物于100℃下搅拌18小时。过滤并浓缩,残余物用硅胶柱色谱法(PE:EA=9:1)纯化,得到化合物A4-3(3.16g黄色油状物,收率65%)。MS(ESI):367.1[M+H] +. Compound A4-2 (5.4g, 13.2mmol) was dissolved in dioxane (50mL), methyl acrylate (1.7g, 19.8mmol), triphenylphosphine (346mg, 1.32mmol), palladium acetate (148mg , 0.66mmol) and triethylamine (2.7g, 26.4mmol). Under nitrogen protection, the mixture was stirred at 100°C for 18 hours. After filtration and concentration, the residue was purified by silica gel column chromatography (PE:EA=9:1) to obtain compound A4-3 (3.16 g of yellow oil, yield 65%). MS(ESI):367.1[M+H] + .
将化合物A4-3(3.16g,8.6mmol)溶于乙酸乙酯(80mL)中,加入雷尼镍(3g)。体系用氢气置换3次,并在氢气氛下(氢气球)搅拌3小时。过滤并浓缩滤液,粗品用硅胶柱色谱法(PE:EA=10:1)纯化,得到化合物A4-4(2.7g黄色油状物,收率85%)。MS(ESI):368.2[M+H] +. Compound A4-3 (3.16 g, 8.6 mmol) was dissolved in ethyl acetate (80 mL), and Raney nickel (3 g) was added. The system was replaced with hydrogen 3 times, and stirred for 3 hours under a hydrogen atmosphere (hydrogen balloon). The filtrate was filtered and concentrated, and the crude product was purified by silica gel column chromatography (PE:EA=10:1) to obtain compound A4-4 (2.7 g yellow oil, yield 85%). MS(ESI):368.2[M+H] + .
将化合物A4-4(2.0g,5.4mmol)溶于氨的甲醇溶液中(7N,40ml),130℃下搅拌18小时。除去溶剂,粗品用硅胶柱色谱法(100%EA)纯化得到化合物A4-5(1.7g淡黄色固体,收率89%)。MS(ESI):354.2[M+H] +. Compound A4-4 (2.0 g, 5.4 mmol) was dissolved in methanolic ammonia solution (7N, 40 ml), and stirred at 130° C. for 18 hours. The solvent was removed, and the crude product was purified by silica gel column chromatography (100% EA) to obtain compound A4-5 (1.7 g light yellow solid, yield 89%). MS(ESI):354.2[M+H] + .
将化合物A4-5(580mg,1.6mmol)溶于乙腈(6ml)和水(6mL)中,加入醋酸碘苯 (1.6g,4.9mmol)。反应液于室温搅拌2小时。过滤得粗品溶液,用反相Flash快速色谱纯化得到化合物A4-6(440mg淡黄色固体,收率82%)。MS(ESI):326.1[M+H] +. Compound A4-5 (580 mg, 1.6 mmol) was dissolved in acetonitrile (6 ml) and water (6 mL), and iodobenzene acetate (1.6 g, 4.9 mmol) was added. The reaction was stirred at room temperature for 2 hours. The crude product solution was filtered and purified by reverse phase flash chromatography to obtain compound A4-6 (440 mg light yellow solid, yield 82%). MS(ESI):326.1[M+H] + .
将化合物A4-6(100mg,0.3mmol)溶于二甲基亚砜(3ml)中,加入碳酸铯(196mg,0.6mmol),碘化亚铜(57mg,0.3mmol)和L-脯氨酸(52mg,0.45mmol)。氮气保护下,将所得混合物在80℃下搅拌1小时。过滤,所得粗品溶液用反相Flash快速色谱纯化得到中间A4(60mg黄色油状物,收率69%)。MS(ESI):290.2[M+H] +. Compound A4-6 (100mg, 0.3mmol) was dissolved in dimethylsulfoxide (3ml), cesium carbonate (196mg, 0.6mmol), cuprous iodide (57mg, 0.3mmol) and L-proline ( 52 mg, 0.45 mmol). Under nitrogen protection, the resulting mixture was stirred at 80°C for 1 hour. After filtration, the resulting crude solution was purified by reverse-phase flash chromatography to obtain intermediate A4 (60 mg yellow oil, yield 69%). MS(ESI):290.2[M+H] + .
使用上述合成方法或改进的方法,用相应的起始原料合成以下中间体。Using the above synthetic methods or modified methods, the following intermediates were synthesized from the corresponding starting materials.
Figure PCTCN2022122329-appb-000095
Figure PCTCN2022122329-appb-000095
中间体A5Intermediate A5
Figure PCTCN2022122329-appb-000096
Figure PCTCN2022122329-appb-000096
将3-氟-2-硝基苯胺(20g,128.2mmol)溶于N,N-二甲基甲酰胺(40mL)中,加入碳酸铯(84g,256.4mmol)和丙二酸二乙酯(41g,256.4mmol),100℃回流6小时。冷却至室温,用乙酸乙酯(100mL)稀释,饱和食盐水(100ml x 3)洗涤。有机相用无水硫酸钠干燥,过滤,减压浓缩,所得粗品用反相快速色谱Flash纯化得到化合物A5-1(19g红色固体,收率50%)。MS(ESI):297.0[M+H] +. Dissolve 3-fluoro-2-nitroaniline (20g, 128.2mmol) in N,N-dimethylformamide (40mL), add cesium carbonate (84g, 256.4mmol) and diethyl malonate (41g , 256.4mmol), reflux at 100°C for 6 hours. Cool to room temperature, dilute with ethyl acetate (100 mL), and wash with saturated brine (100 ml x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by reverse-phase flash chromatography to obtain compound A5-1 (19 g of red solid, yield 50%). MS(ESI):297.0[M+H] + .
将化合物A5-1(4g,13.5mmol)溶于四氢呋喃(30mL)中,加入4-二甲氨基吡啶(4.1g,33.75mmol)和二碳酸二叔丁酯(7.4g,33.75mmol)。40℃下搅拌过夜,减压除去溶剂,所得粗品用柱层析色谱法纯化(EA:PE=1:2),得化合物A5-2(1.8g棕色固体,收率27%)。MS(ESI):497.2[M+H] +. Compound A5-1 (4 g, 13.5 mmol) was dissolved in tetrahydrofuran (30 mL), and 4-dimethylaminopyridine (4.1 g, 33.75 mmol) and di-tert-butyl dicarbonate (7.4 g, 33.75 mmol) were added. After stirring at 40°C overnight, the solvent was removed under reduced pressure, and the obtained crude product was purified by column chromatography (EA:PE=1:2) to obtain compound A5-2 (1.8 g brown solid, yield 27%). MS(ESI):497.2[M+H] + .
将化合物A5-2(1.8g,3.6mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入碘甲烷(2g,14.4mmol)和碳酸铯(2.3g,7.2mmol),室温搅拌3小时,用乙酸乙酯(100mL)稀释,饱和食盐水洗涤。有机相干燥,减压浓缩,所得粗品用柱色谱法(PE:EA=3:1)纯化得化合物A5-3(1.8g黄色油状物,收率99%)。MS(ESI):511.2[M+H] +. Dissolve compound A5-2 (1.8g, 3.6mmol) in N,N-dimethylformamide (10mL), add iodomethane (2g, 14.4mmol) and cesium carbonate (2.3g, 7.2mmol), stir at room temperature After 3 hours, it was diluted with ethyl acetate (100 mL), and washed with saturated brine. The organic phase was dried and concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE:EA=3:1) to obtain compound A5-3 (1.8 g yellow oil, yield 99%). MS(ESI):511.2[M+H] + .
将化合物A5-3(7.5g,14.67mmol)溶于乙醇/水(100mL/10mL)中,加入铁粉(8.2g, 146.7mmol)和氯化铵(3.8g,73.35mmol)。反应液于100℃下搅拌4小时。滤除固体,浓缩,用乙酸乙酯稀释,饱和食盐水洗涤。有机相浓缩得到化合物A5-4(4.5g棕色固体,收率95%)。MS(ESI):335.2[M+H] +. Compound A5-3 (7.5g, 14.67mmol) was dissolved in ethanol/water (100mL/10mL), iron powder (8.2g, 146.7mmol) and ammonium chloride (3.8g, 73.35mmol) were added. The reaction solution was stirred at 100°C for 4 hours. The solid was filtered off, concentrated, diluted with ethyl acetate, and washed with saturated brine. The organic phase was concentrated to obtain compound A5-4 (4.5 g brown solid, yield 95%). MS(ESI):335.2[M+H] + .
将化合物A5-4(4.9g,14.6mmol)溶于盐酸的二氧六环溶液中(4N,10mL),室温搅拌2小时。浓缩得到化合物A5-5(3.9g黄色固体)。MS(ESI):235.1[M+H] +. Compound A5-4 (4.9 g, 14.6 mmol) was dissolved in hydrochloric acid in dioxane (4N, 10 mL), and stirred at room temperature for 2 hours. Concentration gave compound A5-5 (3.9 g of yellow solid). MS(ESI):235.1[M+H] + .
将化合物A5-5(2g,7.38mmol)溶于N,N-二甲基甲酰胺(20ml)中,加入1,2-二溴乙烷(2.4g,12.75mmol)和碳酸钾(5.8g,42.5mmol)。反应液于85℃搅拌过夜。乙酸乙酯稀释,饱和食盐水洗涤。浓缩有机相,所得粗品用硅胶柱色谱法(EA:PE=1:1)纯化得到化合物A5-6(600mg黄色固体,收率27%)。MS(ESI):261.1[M+H] +. Compound A5-5 (2g, 7.38mmol) was dissolved in N,N-dimethylformamide (20ml), and 1,2-dibromoethane (2.4g, 12.75mmol) and potassium carbonate (5.8g, 42.5 mmol). The reaction solution was stirred overnight at 85°C. Diluted with ethyl acetate, washed with saturated brine. The organic phase was concentrated, and the obtained crude product was purified by silica gel column chromatography (EA:PE=1:1) to obtain compound A5-6 (600mg yellow solid, yield 27%). MS(ESI):261.1[M+H] + .
将化合物A5-6(200mg,0.76mmol)溶于四氢呋喃(3ml)中,冷却至0℃,加入硼烷-二甲硫醚溶液(10N,3ml)。反应液于70℃下搅拌3小时,甲醇猝灭,浓缩,所得粗品用制备TLC纯化(DCM:MeOH=10:1)得化合物A5(120mg,76%)。MS(ESI):205.1[M+H] +. Compound A5-6 (200mg, 0.76mmol) was dissolved in tetrahydrofuran (3ml), cooled to 0°C, and borane-dimethylsulfide solution (10N, 3ml) was added. The reaction solution was stirred at 70°C for 3 hours, quenched with methanol, concentrated, and the obtained crude product was purified by preparative TLC (DCM:MeOH=10:1) to obtain compound A5 (120 mg, 76%). MS(ESI):205.1[M+H] + .
使用上述合成方法或改进的方法,用相应的起始原料合成以下中间体。Using the above synthetic methods or modified methods, the following intermediates were synthesized from the corresponding starting materials.
Figure PCTCN2022122329-appb-000097
Figure PCTCN2022122329-appb-000097
中间体A6Intermediate A6
Figure PCTCN2022122329-appb-000098
Figure PCTCN2022122329-appb-000098
将2-氯-3-硝基吡啶-4-胺(5.0g,28.8mmol)溶于二氯甲烷(100ml)中,加入二碳酸二叔丁酯(7.5g,34.5mmol)和三乙胺(8.6g,86.1mmol)和4-二甲氨基吡啶(400mg,2.9mmol)。反应液室温搅拌5小时。减压浓缩,残余物用硅胶柱层析色谱法(PE:EA=10:1)纯化,得到化合物A6-1(7.8g黄色固体,收率99%)。MS(ESI):274.1[M+H] +. 2-Chloro-3-nitropyridin-4-amine (5.0g, 28.8mmol) was dissolved in dichloromethane (100ml), di-tert-butyl dicarbonate (7.5g, 34.5mmol) and triethylamine ( 8.6 g, 86.1 mmol) and 4-dimethylaminopyridine (400 mg, 2.9 mmol). The reaction solution was stirred at room temperature for 5 hours. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=10:1) to obtain compound A6-1 (7.8 g of yellow solid, yield 99%). MS(ESI):274.1[M+H] + .
将化合物A6-1(7.8g,28.6mmol)和苯甲胺(3.7g,34.3mmol)溶于乙醇(100ml)中,加入醋酸钾(7.2g,85.8mmol)。反应液于80℃下搅拌5小时。浓缩,所得粗品用硅胶柱色谱法(PE:EA=1:1)纯化得化合物A6-2(6.3g黄色固体,收率64%)。MS(ESI):345.2[M+H] +. Compound A6-1 (7.8g, 28.6mmol) and benzylamine (3.7g, 34.3mmol) were dissolved in ethanol (100ml), and potassium acetate (7.2g, 85.8mmol) was added. The reaction solution was stirred at 80°C for 5 hours. After concentration, the obtained crude product was purified by silica gel column chromatography (PE:EA=1:1) to obtain compound A6-2 (6.3 g yellow solid, yield 64%). MS(ESI):345.2[M+H] + .
将化合物A6-2(4.0g,11.6mmol)溶于乙酸乙酯(200ml)和冰醋酸(20ml)中,加入钯碳(800mg)。氢气氛(氢气球)下,反应液室温搅拌20小时。过滤,浓缩,所得粗品用硅胶柱色谱法(DCM:MeOH=10:1)纯化得到化合物A6-3(600mg黄色固体,收率23%)。MS(ESI):225.0[M+H] +. Compound A6-2 (4.0 g, 11.6 mmol) was dissolved in ethyl acetate (200 ml) and glacial acetic acid (20 ml), and palladium on carbon (800 mg) was added. Under a hydrogen atmosphere (hydrogen balloon), the reaction solution was stirred at room temperature for 20 hours. After filtration and concentration, the obtained crude product was purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain compound A6-3 (600mg yellow solid, yield 23%). MS(ESI):225.0[M+H] + .
将化合物A6-3(600mg,2.7mmol)溶于草酸二乙酯(3ml)中,80℃下搅拌8小时。 减压浓缩,残余物用硅胶柱色谱法(PE:EA=1:1)纯化得化合物A6-4(400mg黄色固体,收率54%)。MS(ESI):279.1[M+H] +. Compound A6-3 (600mg, 2.7mmol) was dissolved in diethyl oxalate (3ml), and stirred at 80°C for 8 hours. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain compound A6-4 (400 mg yellow solid, yield 54%). MS(ESI):279.1[M+H] + .
将化合物A6-4(400mg,1.4mmol)和1,2-二溴乙烷(404mg,2.2mmol)溶于DMF(5ml)中,加入碳酸铯(1.3g,4.2mmol)。反应液于80℃下搅拌8小时。乙酸乙酯稀释,饱和食盐水洗涤,无水硫酸钠干燥后过滤,减压浓缩,残余物用硅胶柱色谱法(PE:EA=1:1)纯化,得到化合物A6-5(80mg黄色固体,收率18%)。MS(ESI):305.3[M+H] +. Compound A6-4 (400 mg, 1.4 mmol) and 1,2-dibromoethane (404 mg, 2.2 mmol) were dissolved in DMF (5 ml), and cesium carbonate (1.3 g, 4.2 mmol) was added. The reaction solution was stirred at 80°C for 8 hours. Diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain compound A6-5 (80mg yellow solid, Yield 18%). MS(ESI):305.3[M+H] + .
将化合物A6-5(80mg,0.26mmol)溶于甲醇(2ml)中,加入盐酸二氧六环(4N,1.0ml)溶液,室温下搅拌4小时。反应液减压浓缩得中间体A6(50mg黄色固体,收率80%)。MS(ESI):205.2[M+H] +. Compound A6-5 (80mg, 0.26mmol) was dissolved in methanol (2ml), and a solution of dioxane hydrochloride (4N, 1.0ml) was added, and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate A6 (50mg yellow solid, yield 80%). MS(ESI):205.2[M+H] + .
中间体B1Intermediate B1
Figure PCTCN2022122329-appb-000099
Figure PCTCN2022122329-appb-000099
将(溴甲基)苯(5.0g,47.6mmol)溶于DMF(50mL)中,加入二乙醇胺(8.0g,47.6mmol)和三乙胺(9.6g,95.2mmol),室温搅拌2小时。反应液物用水(500ml)稀释,DCM萃取三次,每次100mL。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得化合物B1-1(13g棕色油物)。MS(ESI):196.2[M+H] +. Dissolve (bromomethyl)benzene (5.0 g, 47.6 mmol) in DMF (50 mL), add diethanolamine (8.0 g, 47.6 mmol) and triethylamine (9.6 g, 95.2 mmol), and stir at room temperature for 2 hours. The reaction liquid was diluted with water (500ml), and extracted three times with 100mL of DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound B1-1 (13 g of brown oil). MS(ESI):196.2[M+H] + .
将化合物B1-1(13g,66.7mmol)溶于甲苯(50mL)中,加入三溴化磷(27.1g,100mmol),100℃搅拌反应过夜。降温至0℃,用氢氧化钠水溶液淬灭,减压浓缩,二氯甲烷萃取3次,每次100mL,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩滤液得化合物B1-2(10.7g棕色油状物)。MS(ESI):320.0[M+H] +. Compound B1-1 (13g, 66.7mmol) was dissolved in toluene (50mL), phosphorus tribromide (27.1g, 100mmol) was added, and the reaction was stirred overnight at 100°C. Cool to 0°C, quench with aqueous sodium hydroxide solution, concentrate under reduced pressure, extract 3 times with dichloromethane, 100 mL each time, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound B1 -2 (10.7 g brown oil). MS(ESI):320.0[M+H] + .
将化合物B1-2(4.0g,31mmol)溶于DMF(100mL)中,冷至-20℃,分批加入氢化钠(3.1g,77.5mmol),继续搅拌30分钟,加入N,N-双(2-溴乙基)-3-(溴甲基)苯胺(10.6g,31mmol),升至0℃搅拌过夜。用水淬灭反应,反应液用乙酸乙酯萃取3次,每次100mL。合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩滤液,粗品用硅胶层析(EA:PE=1:1)纯化得化合物B1-3(4.9g土黄色固体,收率49%)。MS(ESI):322.2[M+H] +. Compound B1-2 (4.0g, 31mmol) was dissolved in DMF (100mL), cooled to -20°C, sodium hydride (3.1g, 77.5mmol) was added in batches, stirring was continued for 30 minutes, and N,N-bis( 2-Bromoethyl)-3-(bromomethyl)aniline (10.6g, 31mmol), raised to 0°C and stirred overnight. The reaction was quenched with water, and the reaction solution was extracted three times with ethyl acetate, 100 mL each time. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude product was purified by silica gel chromatography (EA:PE=1:1) to obtain compound B1-3 (4.9 g khaki solid, yield 49 %). MS(ESI):322.2[M+H] + .
将化合物B1-3(4.9g,15.2mmol)溶于二氯乙烷(50mL)中,加入1-氯乙基羰基氯酸盐(4.36g,30.5mmol),80℃搅拌6小时,浓缩反应液,甲醇(40mL)稀释,80℃搅拌1小时,冷却至室温,浓缩得化合物B1-4(5.1g黄色固体)。MS(ESI):232.2[M+H] +. Dissolve compound B1-3 (4.9g, 15.2mmol) in dichloroethane (50mL), add 1-chloroethylcarbonyl chlorate (4.36g, 30.5mmol), stir at 80°C for 6 hours, and concentrate the reaction solution , diluted with methanol (40 mL), stirred at 80° C. for 1 hour, cooled to room temperature, and concentrated to obtain compound B1-4 (5.1 g yellow solid). MS(ESI):232.2[M+H] + .
将化合物B1-4(5.2g,22.5mmol)溶于DCM(40mL)中,加入(Boc) 2O(7.36g,33.7mmol)和三乙胺(6.8g,67.5mmol),室温搅拌2小时。浓缩反应液,粗品用硅胶层析(EA:PE=1:3)纯化得化合物B1-5(5.0g黄色固体,67%)。MS(ESI):276.2[M+H-56] +. Compound B1-4 (5.2 g, 22.5 mmol) was dissolved in DCM (40 mL), (Boc) 2 O (7.36 g, 33.7 mmol) and triethylamine (6.8 g, 67.5 mmol) were added, and stirred at room temperature for 2 hours. The reaction solution was concentrated, and the crude product was purified by silica gel chromatography (EA:PE=1:3) to obtain compound B1-5 (5.0 g yellow solid, 67%). MS(ESI):276.2[M+H-56] + .
将化合物B1-5(5.0g,15.1mmol)溶于钛酸乙酯(100mL)中,加入(R)-2-甲基丙烷-2-亚硫酰胺(2.2g,18.1mmol),室温搅拌过夜。将反应液倒入EA和盐水混合物中,室 温搅拌15分钟。滤出固体并分液,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,粗品用硅胶层析(EA:PE=1:3)纯化得化合物B1-6(3.5g黄色固体,收率53%)。MS(ESI):435.2[M+H] +. Dissolve compound B1-5 (5.0 g, 15.1 mmol) in ethyl titanate (100 mL), add (R)-2-methylpropane-2-sulfinamide (2.2 g, 18.1 mmol), and stir overnight at room temperature . The reaction solution was poured into a mixture of EA and brine, and stirred at room temperature for 15 minutes. The solid was filtered off and separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (EA:PE=1:3) to obtain compound B1-6 (3.5g Yellow solid, yield 53%). MS(ESI):435.2[M+H] + .
将化合物B1-6(2.4g,5.5mmol)溶于THF(15mL)中,-70℃分批加入硼氢化钠(419mg,11mmol),搅拌70h,升至室温,反应液用EA稀释,饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,粗品用硅胶层析(EA:PE=1:1)纯化得化合物B1-7(1.0g白色固体,收率43%)。MS(ESI):337.2[M+H-100] + . Compound B1-6 (2.4g, 5.5mmol) was dissolved in THF (15mL), sodium borohydride (419mg, 11mmol) was added in batches at -70°C, stirred for 70h, raised to room temperature, the reaction solution was diluted with EA, saturated with salt Wash with water, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel chromatography (EA:PE=1:1) to obtain compound B1-7 (1.0 g white solid, yield 43%). MS(ESI):337.2[M+H-100] + .
将化合物B1-7(1.0g,2.3mmol)的HCl/Dioxane(4N,10.0mL)溶液于RT搅拌2小时,加入乙酸乙酯(5mL),抽滤,滤饼用乙酸乙酯洗涤,真空干燥得中间体B1(600mg白色固体)。MS(ESI):233.2[M+H] +. The HCl/Dioxane (4N, 10.0mL) solution of compound B1-7 (1.0g, 2.3mmol) was stirred at RT for 2 hours, ethyl acetate (5mL) was added, suction filtered, the filter cake was washed with ethyl acetate, and dried in vacuo Intermediate B1 (600 mg white solid) was obtained. MS(ESI):233.2[M+H] + .
使用上述合成方法或改进的方法,用相应的起始原料合成以下中间体。Using the above synthetic methods or modified methods, the following intermediates were synthesized from the corresponding starting materials.
Figure PCTCN2022122329-appb-000100
Figure PCTCN2022122329-appb-000100
中间体B2Intermediate B2
Figure PCTCN2022122329-appb-000101
Figure PCTCN2022122329-appb-000101
将3-溴-2-甲基吡啶(10g,58mmol)溶解于四氯化碳(50mL)中溶,加入过氧化苯甲酰(844mg,3.48mmol)和N-溴代丁二酰亚胺(11.35g,63.8mmol),90℃搅拌过夜。反应液用水稀释,二氯甲烷萃取3次,每次50mL。合并有机相,无水硫酸钠干燥,过滤,浓缩滤液,所得粗品用硅胶柱色谱(EA:PE=1:15)纯化得化合物B2-1(10g黄色液体,收率71%)。MS(ESI):249.8[M+H] +. 3-Bromo-2-picoline (10g, 58mmol) was dissolved in carbon tetrachloride (50mL), and benzoyl peroxide (844mg, 3.48mmol) and N-bromosuccinimide ( 11.35g, 63.8mmol), stirred overnight at 90°C. The reaction solution was diluted with water and extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:15) to obtain compound B2-1 (10 g yellow liquid, yield 71%). MS(ESI):249.8[M+H] + .
将化合物B2-1(8.4g,39.8mmol)溶于THF(300mL)中,氮气保护,-50℃滴加LDA(2N的THF溶液,39.8mL,79.6mmol),搅拌2小时,降温至-78℃,滴加3-溴-2-(溴甲基)吡啶(10g,39.8mmol)反应液搅拌过夜。饱和氯化铵水溶液猝灭,反应液用EA萃取萃取3次。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。所得粗品用硅胶层析(EA:PE=1:8)纯化得化合物B2-2(3.8g黄色液体,收率25%)。MS(ESI):324.0[M+H-56] +. Compound B2-1 (8.4g, 39.8mmol) was dissolved in THF (300mL), under nitrogen protection, LDA (2N THF solution, 39.8mL, 79.6mmol) was added dropwise at -50°C, stirred for 2 hours, and cooled to -78 °C, 3-bromo-2-(bromomethyl)pyridine (10 g, 39.8 mmol) was added dropwise to the reaction solution and stirred overnight. Saturated ammonium chloride aqueous solution was quenched, and the reaction solution was extracted three times with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (EA:PE=1:8) to obtain compound B2-2 (3.8 g yellow liquid, yield 25%). MS(ESI):324.0[M+H-56] + .
在二甲基乙酰胺和水(10:1,50mL)的混合溶剂中,加入化合物B2-2(3.8g,10mmol)、二氯二叔丁基-(4-二甲基氨基苯基)磷钯(II)(710mg,1mmol)和三乙胺(4g,40.1mmol),130℃搅拌过夜。反应液用EA稀释,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩滤液,所得粗品用硅胶层析(EA:PE=1:1)纯化,得化合物B2-3(2.5g棕色固体,收率83%)。MS(ESI):303.2[M+H] +. In a mixed solvent of dimethylacetamide and water (10:1, 50mL), add compound B2-2 (3.8g, 10mmol), dichlorodi-tert-butyl-(4-dimethylaminophenyl) phosphorus Palladium(II) (710mg, 1mmol) and triethylamine (4g, 40.1mmol) were stirred overnight at 130°C. The reaction solution was diluted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel chromatography (EA:PE=1:1) to obtain compound B2-3 (2.5 g brown solid, Yield 83%). MS(ESI):303.2[M+H] + .
向钛酸乙酯(50mL)中加入化合物B2-3(2.5g,8.27mmol)和(R)-2-甲基丙烷-2-亚硫酰胺(1.3g,10.76mmol),110℃搅拌过夜。冷却至室温,将反应液倒入乙酸乙酯/饱和 食盐水中,室温搅拌15分钟,滤出固体,分出有机相,用饱和食盐水冲洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得粗品用硅胶柱层析(EA:PE=1:2)纯化得化合物B2-4(3.2g黄色固体,收率95%)。MS(ESI):406.2[M+H] +. Compound B2-3 (2.5 g, 8.27 mmol) and (R)-2-methylpropane-2-sulfinamide (1.3 g, 10.76 mmol) were added to ethyl titanate (50 mL), and stirred overnight at 110°C. Cool to room temperature, pour the reaction solution into ethyl acetate/saturated brine, stir at room temperature for 15 minutes, filter out the solid, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting crude product was purified by silica gel column chromatography (EA:PE=1:2) to obtain compound B2-4 (3.2 g yellow solid, yield 95%). MS(ESI):406.2[M+H] + .
将化合物B2-4(3.7g,9.13mmol)溶于THF(15mL)中,降温至-70℃,分批加入硼氢化钠(694mg,18.27mmol),搅拌8小时,自热升至室温。用EA稀释反应液,饱和食盐水洗涤。有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,所得粗品用硅胶柱层析(EA:PE=1:2)纯化得化合物B2-5(600mg黄色固体,收率16%)。MS(ESI):408.2[M+H] +. Compound B2-4 (3.7g, 9.13mmol) was dissolved in THF (15mL), cooled to -70°C, sodium borohydride (694mg, 18.27mmol) was added in batches, stirred for 8 hours, then warmed to room temperature. The reaction solution was diluted with EA and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:2) to obtain compound B2-5 (600mg yellow solid, yield 16%). MS(ESI):408.2[M+H] + .
将化合物B2-5(500mg,1.2mmol)的HCl/Dioxane(4N,6.0mL)溶液于RT搅拌2小时,加入乙酸乙酯(3mL),抽滤,滤饼用乙酸乙酯洗涤,真空干燥得中间体B2(350mg白色固体)。MS(ESI):204.2[M+H] +. The HCl/Dioxane (4N, 6.0mL) solution of compound B2-5 (500mg, 1.2mmol) was stirred at RT for 2 hours, ethyl acetate (3mL) was added, filtered with suction, the filter cake was washed with ethyl acetate, and dried in vacuo to obtain Intermediate B2 (350 mg white solid). MS(ESI):204.2[M+H] + .
使用上述合成方法或改进的方法,用相应的起始原料合成以下中间体。Using the above synthetic methods or modified methods, the following intermediates were synthesized from the corresponding starting materials.
Figure PCTCN2022122329-appb-000102
Figure PCTCN2022122329-appb-000102
中间体B3Intermediate B3
Figure PCTCN2022122329-appb-000103
Figure PCTCN2022122329-appb-000103
将2-氟苯甲醛(5.0g,40mmol)溶于DCM(30mL)中,缓慢加入丙烷-1,3-二硫醇(4.35g,40mmol)和I 2(307mg,1.2mmol)。所得溶液室温搅拌过夜。将反应液倒入Na 2S 2O 3(aq)和NaOH(aq)中,用DCM萃取。合并有机相,饱和食盐水洗涤,干燥,过滤,浓缩得化合物B3-1(7.0g白色固体,收率81%)。MS(ESI):215.0[M+H] +. 2-Fluorobenzaldehyde (5.0 g, 40 mmol) was dissolved in DCM (30 mL), propane-1,3-dithiol (4.35 g, 40 mmol) and I2 (307 mg, 1.2 mmol) were added slowly. The resulting solution was stirred overnight at room temperature. The reaction solution was poured into Na 2 S 2 O 3 (aq) and NaOH (aq), extracted with DCM. The organic phases were combined, washed with saturated brine, dried, filtered, and concentrated to obtain compound B3-1 (7.0 g white solid, yield 81%). MS(ESI):215.0[M+H] + .
将化合物B3-1(6.2g,28.8mmol)溶于THF(50mL)中,降温至-78℃,滴加LDA(2N,28.8mL,57.6mmol),滴完后在-20℃搅拌30分钟,然后在-78℃加入4-氧哌啶-1-羧酸叔丁酯(5.7g,28.8mmol)的THF(50mL)溶液。反应液在-78℃下搅拌2小时。反应混合物用NH 4Cl饱和水溶液淬灭,EA萃取。有机相用无水硫酸钠干燥,过滤,浓缩。所得粗品用硅胶柱层析法(EA:PE=1:4)纯化得化合物B3-2(6.2g白色固体,收率52%)。MS(ESI):414.1[M+H] +. Compound B3-1 (6.2g, 28.8mmol) was dissolved in THF (50mL), cooled to -78°C, LDA (2N, 28.8mL, 57.6mmol) was added dropwise, and stirred at -20°C for 30 minutes after dropping, A solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.7 g, 28.8 mmol) in THF (50 mL) was then added at -78 °C. The reaction was stirred at -78°C for 2 hours. The reaction mixture was quenched with saturated aqueous NH 4 Cl and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:4) to obtain compound B3-2 (6.2 g white solid, yield 52%). MS(ESI):414.1[M+H] + .
将化合物B3-2(6.2g,14.97mmol)溶于DCM(100mL)/H 2O(25mL)中,加入吡啶(2.36g,29.94mmol)、三溴化吡啶(5.75g,17.96mmol)和四丁基溴化铵(482mg,1.49mmol),反应液室温搅拌过夜。将反应混合物倒入饱和氯化铵水溶液中,用EA萃取。有机层用无水硫酸钠干燥,过滤,浓缩。所得粗品用硅胶柱层析法(EA:PE=1:4)纯化,得化合物B3-3(2.6g黄色油状物,54%)。MS(ESI):324.2[M+H] +. Compound B3-2 (6.2g, 14.97mmol) was dissolved in DCM (100mL)/H 2 O (25mL), and pyridine (2.36g, 29.94mmol), pyridinium tribromide (5.75g, 17.96mmol) and four Butylammonium bromide (482mg, 1.49mmol), the reaction solution was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with EA. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:4) to obtain compound B3-3 (2.6 g yellow oil, 54%). MS(ESI):324.2[M+H] + .
将化合物B3-3(2.6g,8mmol)溶于THF(20mL)中,加入叔丁醇钾(1.35g,12mmol)。所得溶液在70℃搅拌2小时。反应液用EA稀释,饱和食盐水洗涤。有机层用无水硫酸钠干 燥,过滤,浓缩,所得粗品用硅胶柱层析法(EA:PE=1:4)纯化得化合物B3-4(1.2g白色固体,收率50%)。MS(ESI):304.1[M+H] +. Compound B3-3 (2.6 g, 8 mmol) was dissolved in THF (20 mL), and potassium tert-butoxide (1.35 g, 12 mmol) was added. The resulting solution was stirred at 70°C for 2 hours. The reaction solution was diluted with EA and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:4) to obtain compound B3-4 (1.2 g white solid, yield 50%). MS(ESI):304.1[M+H] + .
将化合物B3-4(1.2g,3.9mmol)溶于Ti(OEt) 4(30mL)和THF(5mL)中,加入(R)-2-甲基丙烷-2-亚磺酰胺(1.6g,13.65mmol)。反应液90℃下搅拌过夜。将混合物倒入冷水中。滤出固体,用EA洗涤。分出有机相,用无水硫酸钠干燥,浓缩。残余物用硅胶柱层析法(PE:EA=5:1)纯化,得化合物B3-5(1.5黄色油状物,收率93%)。MS(ESI):407.2[M+H] +. Compound B3-4 (1.2g, 3.9mmol) was dissolved in Ti(OEt) 4 (30mL) and THF (5mL), and (R)-2-methylpropane-2-sulfinamide (1.6g, 13.65 mmol). The reaction solution was stirred overnight at 90°C. Pour the mixture into cold water. The solid was filtered off and washed with EA. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (PE:EA=5:1) to obtain compound B3-5 (1.5 g yellow oil, yield 93%). MS(ESI):407.2[M+H] + .
将化合物B3-5(1.5g,3.68mmol)溶于THF(20mL)中,降温至-20℃,加入硼氢化钠(420mg,11.04mmol)。反应液升至室温并搅拌过夜。反应混合物用饱和氯化铵水溶液淬灭,EA萃取。有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,所得粗品用硅胶柱层析法(PE:EA=4:1)纯化得化合物B3-6(550mg白色固体,收率33%)。MS(ESI):409.2[M+H] +. Compound B3-5 (1.5 g, 3.68 mmol) was dissolved in THF (20 mL), cooled to -20°C, and sodium borohydride (420 mg, 11.04 mmol) was added. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with EA. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (PE:EA=4:1) to obtain compound B3-6 (550mg white solid, yield 33% ). MS(ESI):409.2[M+H] + .
将化合物B3-6(200mg,0.488mmol)溶于HCl/Dioxane(4N,5mL)中,RT搅拌1小时。将反应混合物浓缩,所得固体用EA洗涤,得中间体B3(100mg白色固体)。MS(ESI):205.2[M+H] +. Compound B3-6 (200 mg, 0.488 mmol) was dissolved in HCl/Dioxane (4N, 5 mL), stirred at RT for 1 hour. The reaction mixture was concentrated, and the resulting solid was washed with EA to give intermediate B3 (100 mg white solid). MS(ESI):205.2[M+H] + .
中间体C1Intermediate C1
Figure PCTCN2022122329-appb-000104
Figure PCTCN2022122329-appb-000104
将苄醇(17.0g,157.96mmol)溶于THF(300mL)中,降温至0℃,分批加入NaH(6.89g,172.32mmol),所得混合物在0℃下搅拌1小时。然后在-78℃将该混合物加入到3,5-二氯吡嗪-2-腈(25.0g,143.6mmol)的THF(200mL)溶液中。所得溶液在-78℃下搅拌2小时,加入饱和氯化铵淬灭反应。反应混合物用EA稀释并用饱和食盐水洗涤。有机层用无水硫酸钠干燥,过滤,减压浓缩。所得粗品用硅胶柱层析法(EA:PE=1:15)纯化得到化合物C1-1(25.0g白色固体,收率71%)。MS(ESI):246.1[M+H] +. Benzyl alcohol (17.0 g, 157.96 mmol) was dissolved in THF (300 mL), cooled to 0 °C, NaH (6.89 g, 172.32 mmol) was added in portions, and the resulting mixture was stirred at 0 °C for 1 hour. This mixture was then added to a solution of 3,5-dichloropyrazine-2-carbonitrile (25.0 g, 143.6 mmol) in THF (200 mL) at -78 °C. The resulting solution was stirred at -78°C for 2 hours, and the reaction was quenched by adding saturated ammonium chloride. The reaction mixture was diluted with EA and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:15) to obtain compound C1-1 (25.0 g white solid, yield 71%). MS(ESI):246.1[M+H] + .
将化合物C1-1(25.0g,101.6mmol)溶于THF(500mL)中,降温至-78℃,氮气保护下,滴加DIBAL-H(1N己烷溶液,305mL,304.8mmol)。Compound C1-1 (25.0 g, 101.6 mmol) was dissolved in THF (500 mL), cooled to -78°C, and DIBAL-H (1N hexane solution, 305 mL, 304.8 mmol) was added dropwise under nitrogen protection.
反应液在-78℃下搅拌2小时。用HOAc(10%水溶液)猝灭,EA萃取。依次用碳酸钠水溶液和饱和食盐水洗涤有机层,无水硫酸钠干燥,过滤,浓缩得化合物C1-2(26.0g,99%),无需进一步纯化。MS(ESI):249.0[M+H] +. The reaction was stirred at -78°C for 2 hours. Quenched with HOAc (10% aq) and extracted with EA. The organic layer was washed successively with aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound C1-2 (26.0 g, 99%) without further purification. MS(ESI):249.0[M+H] + .
将三乙胺(52g,57mmol)和一水合肼(15.6g,342mmol)加到化合物C1-2(26.0g,104mmol)的乙醇(400mL)溶液中。所得溶液在80℃下搅拌过夜。真空下除去溶剂,剩余物用EA稀释,饱和氯化铵洗涤。有机层用无水硫酸钠干燥,过滤,浓缩得化合物C1-3(22.0g棕色油状物,95%),无需进一步纯化。MS(ESI):227.1[M+H] +. Triethylamine (52 g, 57 mmol) and hydrazine monohydrate (15.6 g, 342 mmol) were added to a solution of compound C1-2 (26.0 g, 104 mmol) in ethanol (400 mL). The resulting solution was stirred overnight at 80°C. The solvent was removed in vacuo and the residue was diluted with EA and washed with saturated ammonium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give compound C1-3 (22.0 g brown oil, 95%) without further purification. MS(ESI):227.1[M+H] + .
将化合物C1-3(16.0g,70.48mmol)溶于DMF(200mL)中,加入N-碘代丁二酰亚胺(20.6g,91.6mmol)。所得溶液在85℃下搅拌3小时。EA稀释,依次用饱和亚硫酸钠溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩得化合物C1-4(22.0g,91%),无需进一步纯化。MS(ESI):353.0[M+H] +. Compound C1-3 (16.0 g, 70.48 mmol) was dissolved in DMF (200 mL), and N-iodosuccinimide (20.6 g, 91.6 mmol) was added. The resulting solution was stirred at 85°C for 3 hours. EA was diluted, washed successively with saturated sodium sulfite solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound C1-4 (22.0 g, 91%) without further purification. MS(ESI):353.0[M+H] + .
将化合物C1-4(22g,62.3mmol)溶于DCM(200mL)中,加入3,4-二氢吡喃(15.7g,186.9mmol)和对甲苯磺酸(3.5mg,18.69mmol)。所得溶液在室温下搅拌2小时。减压蒸 除溶剂,所得粗品用硅胶柱层析法(EA:PE=1:1)纯化得中间体C1(14.0g白色固体,52%)。MS(ESI):437.1[M+H] +. Compound C1-4 (22 g, 62.3 mmol) was dissolved in DCM (200 mL), 3,4-dihydropyran (15.7 g, 186.9 mmol) and p-toluenesulfonic acid (3.5 mg, 18.69 mmol) were added. The resulting solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (EA:PE=1:1) to obtain intermediate C1 (14.0 g white solid, 52%). MS(ESI):437.1[M+H] + .
中间体C2Intermediate C2
Figure PCTCN2022122329-appb-000105
Figure PCTCN2022122329-appb-000105
将3,5-二氯吡嗪-2-羧酸(25.0g,130mmol)溶于DMF(200mL)中,降温至0℃,加入碳酸氢钠(13.1g,156mmol)和碘甲烷(133g,937mmol),所得混合物在RT搅拌6小时。用水稀释,EA萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,所得粗品用硅胶柱层析法(EA:PE=1:10)纯化得化合物C2-1(26.0g白色固体,收率96%)。MS(ESI):207.1[M+H] +. Dissolve 3,5-dichloropyrazine-2-carboxylic acid (25.0g, 130mmol) in DMF (200mL), cool to 0°C, add sodium bicarbonate (13.1g, 156mmol) and iodomethane (133g, 937mmol ), and the resulting mixture was stirred at RT for 6 h. Diluted with water, extracted with EA, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (EA:PE=1:10) to obtain compound C2-1 ( 26.0 g white solid, 96% yield). MS(ESI):207.1[M+H] + .
将化合物C2-1(26g,126mmol)溶于四氢呋喃(250mL)和甲醇(28mL)中,降温至-20℃,滴加硼氢化锂(2N的THF溶液,76mL,151.4mmol)溶液。所得混合物在-20℃下搅拌2小时,用HCl(1N,aq.)淬灭反应。混合物用EA稀释,有机相用饱和食盐水洗涤无水硫酸钠干燥,减压浓缩,所得粗品用硅胶柱层析法(EA:PE=1:1)纯化得化合物C2-2(15g白色固体,收率68%)。MS(ESI):179.1[M+H] +. Compound C2-1 (26g, 126mmol) was dissolved in tetrahydrofuran (250mL) and methanol (28mL), cooled to -20°C, and a solution of lithium borohydride (2N in THF, 76mL, 151.4mmol) was added dropwise. The resulting mixture was stirred at -20°C for 2 hours, and the reaction was quenched with HCl (1 N, aq.). The mixture was diluted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (EA:PE=1:1) to obtain compound C2-2 (15 g white solid, Yield 68%). MS(ESI):179.1[M+H] + .
将化合物C2-2(22.6g,128mmol)溶于DCM(400mL)中,加入活性二氧化锰(161g,1.92mol),RT搅拌24小时。过滤,滤饼用DCM洗涤。滤液减压下浓缩,所得粗品用硅胶柱层析法(EA:PE=1:5)纯化得化合物C2-3(16.5g黄色油状物,收率72%)。MS(ESI):177.0[M+H] +. Compound C2-2 (22.6 g, 128 mmol) was dissolved in DCM (400 mL), and active manganese dioxide (161 g, 1.92 mol) was added, and stirred at RT for 24 hours. Filter and wash the filter cake with DCM. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (EA:PE=1:5) to obtain compound C2-3 (16.5 g yellow oil, yield 72%). MS(ESI):177.0[M+H] + .
将化合物C2-3(8g,45.4mmol)溶于NMP(20mL)中,降温至0℃,加入一水合肼(6.8g,136.3mmol),RT搅拌过夜。加入HCl(1N,aq.)淬灭反应,用EA稀释,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,所得粗品用硅胶柱层析法(DCM:MeOH=20:1)纯化得化合物C2-4(3.4g黄色固体,收率48%)。MS(ESI):155.1[M+H] +. Compound C2-3 (8 g, 45.4 mmol) was dissolved in NMP (20 mL), cooled to 0° C., added with hydrazine monohydrate (6.8 g, 136.3 mmol), and stirred overnight at RT. Add HCl (1N, aq.) to quench the reaction, dilute with EA, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained crude product is subjected to silica gel column chromatography (DCM: MeOH=20 : 1) Compound C2-4 (3.4 g yellow solid, yield 48%) was purified. MS(ESI):155.1[M+H] + .
将N-溴代丁二酰亚胺(13.8g,77.9mmol)分批加入化合物C2-4(8g,51.9mmol)的乙腈(150mL)溶液中,RT搅拌3小时。减压蒸去溶剂得化合物C2-5(12g棕色固体),无需进一步纯化。MS(ESI):233.0[M+H]+.N-bromosuccinimide (13.8 g, 77.9 mmol) was added in portions to a solution of compound C2-4 (8 g, 51.9 mmol) in acetonitrile (150 mL), and stirred at RT for 3 hours. The solvent was distilled off under reduced pressure to obtain compound C2-5 (12 g of brown solid), without further purification. MS(ESI):233.0[M+H]+.
将化合物C2-5(12g,51.9mmol)溶于DCM(300mL)中,加入3,4-二氢吡喃(13g,155.7mmol)和对甲苯磺酸(2.96g,15.5mmol),RT搅拌2小时。减压浓缩,所得粗品用硅胶柱层析法(EA:PE=1:1)纯化得中间体C2(9.5g白色固体,收率59%)。MS(ESI):317.1[M+H] +. Compound C2-5 (12g, 51.9mmol) was dissolved in DCM (300mL), added 3,4-dihydropyran (13g, 155.7mmol) and p-toluenesulfonic acid (2.96g, 15.5mmol), stirred at RT for 2 Hour. After concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography (EA:PE=1:1) to obtain intermediate C2 (9.5 g white solid, yield 59%). MS(ESI):317.1[M+H] + .
实施例1Example 1
Figure PCTCN2022122329-appb-000106
Figure PCTCN2022122329-appb-000106
将化合物1-1(12g,29.5mmol)溶解于DCM(90mL)中,加入三氟乙酸(30mL),RT搅拌2小时。用饱和碳酸氢钠(200mL)中和反应液(pH调节至8),用二氯甲烷萃取3次,每次100mL。合并有机相,减压浓缩,残余物用C18柱色谱(水/乙腈)纯化得化合物1-2(9g白色固体,收率99%)。MS(ESI):307.2[M+H] +. Compound 1-1 (12 g, 29.5 mmol) was dissolved in DCM (90 mL), added trifluoroacetic acid (30 mL), and stirred at RT for 2 hours. The reaction liquid was neutralized (pH adjusted to 8) with saturated sodium bicarbonate (200 mL), and extracted three times with dichloromethane, 100 mL each time. The organic phases were combined and concentrated under reduced pressure, and the residue was purified by C18 column chromatography (water/acetonitrile) to obtain compound 1-2 (9 g white solid, yield 99%). MS(ESI):307.2[M+H] + .
将中间体C2(3.0g,9.4mmol)溶于DMF(20mL)中,加入三乙胺(2.8g,28.2mmol)和化合物1-2(2.9g,9.4mmol),50℃下搅拌过夜。反应混合物用饱和食盐水稀释,用EA萃取,有机层用无水硫酸钠干燥,过滤,减压浓缩得化合物1-3(4.0g黄色固体,收率73%)。MS(ESI):587.2[M+H] +. Intermediate C2 (3.0 g, 9.4 mmol) was dissolved in DMF (20 mL), triethylamine (2.8 g, 28.2 mmol) and compound 1-2 (2.9 g, 9.4 mmol) were added, and stirred overnight at 50°C. The reaction mixture was diluted with saturated brine, extracted with EA, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-3 (4.0 g yellow solid, yield 73%). MS(ESI):587.2[M+H] + .
将化合物A1(37mg,0.17mmol)和化合物1-3(100mg,0.17mmol)溶于甲苯(2mL)中,氮气保护下加入Pd 2(dba) 3(16mg,0.017mmol),RuPhos(16mg,0.034mmol)和Cs 2CO 3(111mg,0.34mmol),100℃搅拌16小时。冷却至RT并减压浓缩,通过制备TLC(DCM:MeOH=10:1)纯化残余物得化合物1-4(100mg黄色固体,收率81%)。MS(ESI):725.3[M+H] +. Compound A1 (37 mg, 0.17 mmol) and compound 1-3 (100 mg, 0.17 mmol) were dissolved in toluene (2 mL), and Pd 2 (dba) 3 (16 mg, 0.017 mmol), RuPhos (16 mg, 0.034 mmol) and Cs 2 CO 3 (111 mg, 0.34 mmol), stirred at 100°C for 16 hours. After cooling to RT and concentrating under reduced pressure, the residue was purified by preparative TLC (DCM:MeOH=10:1) to obtain compound 1-4 (100 mg yellow solid, yield 81%). MS(ESI):725.3[M+H] + .
将化合物1-4(100mg,0.14mmol)溶于HCl/Dioxane(4N,3mL)和甲醇(1mL)中,RT搅拌1小时,减压浓缩,所得粗品用Pre-HPLC纯化得实施例1(20mg黄色固体,收率26%)。MS(ESI):mass calcd.for C 30H3 2N 8O 2 536.3,m/z found 537.2[M+H]+.1H-NMR(400MHz,DMSO-d6):δppm 12.63(brs,1H),8.35(s,1H),7.31-7.15(m,4H),6.94-6.91(m,1H),6.81-6.76(m,1H),6.51-6.48(m,1H),4.33-4.28(m,2H),4.06-4.03(m,2H),3.95-3.93(m,2H),3.88(s,1H),3.34-3.27(m,2H),3.11(d,J=15.6Hz,1H),2.68(d,J=15.6Hz,1H),1.89-1.52(m,3H),1.46(s,6H),1.13-1.05(m,1H). Compound 1-4 (100mg, 0.14mmol) was dissolved in HCl/Dioxane (4N, 3mL) and methanol (1mL), stirred at RT for 1 hour, concentrated under reduced pressure, and the obtained crude product was purified by Pre-HPLC to obtain Example 1 (20mg Yellow solid, yield 26%). MS(ESI):mass calcd.for C 30 H3 2 N 8 O 2 536.3,m/z found 537.2[M+H]+.1H-NMR(400MHz,DMSO-d6):δppm 12.63(brs,1H), 8.35(s,1H),7.31-7.15(m,4H),6.94-6.91(m,1H),6.81-6.76(m,1H),6.51-6.48(m,1H),4.33-4.28(m,2H ),4.06-4.03(m,2H),3.95-3.93(m,2H),3.88(s,1H),3.34-3.27(m,2H),3.11(d,J=15.6Hz,1H),2.68( d,J=15.6Hz,1H),1.89-1.52(m,3H),1.46(s,6H),1.13-1.05(m,1H).
使用上述方法或改进的方法,用相应的起始原料合成下列实施例。Using the above method or a modified method, the following examples were synthesized from the corresponding starting materials.
Figure PCTCN2022122329-appb-000107
Figure PCTCN2022122329-appb-000107
Figure PCTCN2022122329-appb-000108
Figure PCTCN2022122329-appb-000108
Figure PCTCN2022122329-appb-000109
Figure PCTCN2022122329-appb-000109
Figure PCTCN2022122329-appb-000110
Figure PCTCN2022122329-appb-000110
Figure PCTCN2022122329-appb-000111
Figure PCTCN2022122329-appb-000111
Figure PCTCN2022122329-appb-000112
Figure PCTCN2022122329-appb-000112
实施例12Example 12
Figure PCTCN2022122329-appb-000113
Figure PCTCN2022122329-appb-000113
将化合物A1(300mg,0.77mmol)溶于二氧六环(2mL)中,氮气保护下加入化合物C1(111mg,0.51mmol),Pd 2(dba) 3(47mg,0.051mmol),Xantphos(59mg,0.102mmol)和Cs 2CO 3(499mg,1.53mmol)。100℃下搅拌过夜,EA稀释,过滤,浓缩滤液。残余物用硅胶柱色谱法(EA:PE=1:10)纯化得化合物12-1(400mg棕色油状物,收率50%)。MS(ESI):527.2[M+H] +. Compound A1 (300mg, 0.77mmol) was dissolved in dioxane (2mL), and compound C1 (111mg, 0.51mmol), Pd 2 (dba) 3 (47mg, 0.051mmol), Xantphos (59mg, 0.102 mmol) and Cs 2 CO 3 (499 mg, 1.53 mmol). Stir overnight at 100°C, dilute with EA, filter, and concentrate the filtrate. The residue was purified by silica gel column chromatography (EA:PE=1:10) to obtain compound 12-1 (400 mg of brown oil, yield 50%). MS(ESI):527.2[M+H] + .
将化合物12-1(390mg,0.74mmol)溶于THF/H 2O/MeOH(2:1:0.5,共7mL)中,加入钯/碳(100mg)和甲酸铵(933mg,14.8mmol),50℃搅拌过夜,反应液用EA稀释,过滤,滤液浓缩,残余物用硅胶柱色谱法(DCM:MeOH=10:1)纯化得化合物12-2(300mg棕色固体,收率93%)。MS(ESI):437.2[M+H]+. Compound 12-1 (390 mg, 0.74 mmol) was dissolved in THF/H 2 O/MeOH (2:1:0.5, 7 mL in total), palladium/carbon (100 mg) and ammonium formate (933 mg, 14.8 mmol) were added, 50 Stirred at ℃ overnight, the reaction solution was diluted with EA, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain compound 12-2 (300mg brown solid, yield 93%). MS(ESI):437.2[M+H]+.
将化合物12-2(300mg,0.68mmol)溶于DCM(10mL)中,加入对甲苯磺酰氯(143.8mg,0.75mmol)和DIEA(105mg,0.816mmol),RT搅拌1.5小时。浓缩,残余物用硅胶柱层析法(EA:PE=1:5)纯化得化合物12-3(230mg棕色固体,56%)。MS(ESI):591.2[M+H] +. Compound 12-2 (300 mg, 0.68 mmol) was dissolved in DCM (10 mL), p-toluenesulfonyl chloride (143.8 mg, 0.75 mmol) and DIEA (105 mg, 0.816 mmol) were added, and stirred at RT for 1.5 hours. After concentration, the residue was purified by silica gel column chromatography (EA:PE=1:5) to obtain compound 12-3 (230 mg brown solid, 56%). MS(ESI):591.2[M+H] + .
将化合物12-3(200mg,0.338mmol)溶于DMF(5mL)中,加入TEA(171mg,1.695mmol)和化合物B1(103mg,0.338mmol),50℃搅拌过夜。Compound 12-3 (200 mg, 0.338 mmol) was dissolved in DMF (5 mL), TEA (171 mg, 1.695 mmol) and compound B1 (103 mg, 0.338 mmol) were added, and stirred overnight at 50°C.
反应液用EA稀释,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,残余物用C18反相柱色谱法(乙腈/水)纯化得化合物12-4(110mg黄色固体,收率50%)。MS(ESI):651.2[M+H] +. The reaction solution was diluted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by C18 reverse phase column chromatography (acetonitrile/water) to obtain compound 12-4 (110mg yellow solid, yield 50% ). MS(ESI):651.2[M+H] + .
化合物12-4(100mg,0.154mmol)溶于HCl/dioxane(4N,2mL)中,RT搅拌1小时,减压浓缩,残余物用prep-HPLC纯化得实施例12(21mg黄色固体,收率24%)。MS(ESI):mass calcd.for C 31H 34N 8O 3 566.3,m/z found 567.2[M+H] +.1H-NMR(400MHz,DMSO-d6):δppm 12.61(s,1H),8.35(s,1H),7.22-7.20(m,1H),6.94-6.91(m,1H),6.80-6.76(m,3H),6.51 -6.48(m,1H),4.32-4.29(m,2H),4.05-3.86(m,5H),3.72(s,3H),3.45-3.38(m,2H),3.05-3.11(m,1H),2.62-2.71(m,1H),1.82-1.60(m,2H),1.55-1.46(m,1H),1.45(s,6H),1.30-1.25(m,1H). Compound 12-4 (100mg, 0.154mmol) was dissolved in HCl/dioxane (4N, 2mL), stirred at RT for 1 hour, concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain Example 12 (21mg yellow solid, yield 24 %). MS(ESI):mass calcd.for C 31 H 34 N 8 O 3 566.3,m/z found 567.2[M+H] + .1H-NMR(400MHz,DMSO-d6):δppm 12.61(s,1H), 8.35(s,1H),7.22-7.20(m,1H),6.94-6.91(m,1H),6.80-6.76(m,3H),6.51-6.48(m,1H),4.32-4.29(m,2H ),4.05-3.86(m,5H),3.72(s,3H),3.45-3.38(m,2H),3.05-3.11(m,1H),2.62-2.71(m,1H),1.82-1.60(m ,2H),1.55-1.46(m,1H),1.45(s,6H),1.30-1.25(m,1H).
使用上述方法或改进的方法,用相应的起始原料合成下列实施例。Using the above method or a modified method, the following examples were synthesized from the corresponding starting materials.
Figure PCTCN2022122329-appb-000114
Figure PCTCN2022122329-appb-000114
Figure PCTCN2022122329-appb-000115
Figure PCTCN2022122329-appb-000115
Figure PCTCN2022122329-appb-000116
Figure PCTCN2022122329-appb-000116
Figure PCTCN2022122329-appb-000117
Figure PCTCN2022122329-appb-000117
Figure PCTCN2022122329-appb-000118
Figure PCTCN2022122329-appb-000118
Figure PCTCN2022122329-appb-000119
Figure PCTCN2022122329-appb-000119
Figure PCTCN2022122329-appb-000120
Figure PCTCN2022122329-appb-000120
Figure PCTCN2022122329-appb-000121
Figure PCTCN2022122329-appb-000121
Figure PCTCN2022122329-appb-000122
Figure PCTCN2022122329-appb-000122
Figure PCTCN2022122329-appb-000123
Figure PCTCN2022122329-appb-000123
Figure PCTCN2022122329-appb-000124
Figure PCTCN2022122329-appb-000124
实施例29Example 29
Figure PCTCN2022122329-appb-000125
Figure PCTCN2022122329-appb-000125
中间体A3-3(60mg,0.216mmol)和化合物1-3(127mg,0.216mmol)溶于甲苯(3mL)中,氮气保护下,加入Pd 2(dba) 3(20mg,0.0216mmol),Ruphos(20mg,0.0432mmol)和Cs 2CO 3(212mg,0.648mmol),110℃搅拌过夜。反应液减压浓缩,残余物用硅胶柱层析法(PE:EA=4:1)纯化得化合物29-1(90mg棕色固体,收率53%)。MS(ESI):783.2[M+H] +. Intermediate A3-3 (60mg, 0.216mmol) and compound 1-3 (127mg, 0.216mmol) were dissolved in toluene (3mL), under nitrogen protection, Pd 2 (dba) 3 (20mg, 0.0216mmol), Ruphos ( 20mg, 0.0432mmol) and Cs 2 CO 3 (212mg, 0.648mmol), stirred overnight at 110°C. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=4:1) to obtain compound 29-1 (90 mg brown solid, yield 53%). MS(ESI):783.2[M+H] + .
将化合物29-1(70mg,0.089mmol)溶于NH 3/MeOH(7N,3mL)中,70℃搅拌4个小时,浓缩得化合物29-2(67mg棕黄固体)。MS(ESI):754.2[M+H] +. Compound 29-1 (70mg, 0.089mmol) was dissolved in NH 3 /MeOH (7N, 3mL), stirred at 70°C for 4 hours, and concentrated to obtain Compound 29-2 (67mg brown solid). MS(ESI):754.2[M+H] + .
将化合物29-2(67mg,0.089mmol)溶于HCl/dioxane(4N,2mL)中,RT搅拌1小时,减压浓缩,残余物用Prep-HPLC(水/乙腈)纯化得实施例29(10mg黄色固体)。MS(ESI):mass calcd.for C 30H 31N 9O 3 565.3,m/z found 566.2[M+H]+.1H-NMR(400MHz,DMSO-d6):δppm 12.64(s,1H),8.35(s,1H),7.67(s,1H),7.45(s,1H),7.29(d,J=6.0Hz,1H),7.18-7.16(m,3H),6.93(d,J=8.4Hz,1H),6.82-6.77(m,1H),6.63(d,J=7.6Hz,1H),4.35-4.23(m,3H),4.15-4.11(m,1H),3.86-3.83(m,2H),3.67-3.63(m,1H),3.34-3.23(m,2H),3.12-3.08(m,1H),2.66-2.62(m,1H),1.81-1.69(m,1H),1.65-1.55(m,4H),1.52-1.43(m,1H),1.13-1.09(m,1H). Compound 29-2 (67mg, 0.089mmol) was dissolved in HCl/dioxane (4N, 2mL), stirred at RT for 1 hour, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (water/acetonitrile) to obtain Example 29 (10mg yellow solid). MS(ESI):mass calcd.for C 30 H 31 N 9 O 3 565.3,m/z found 566.2[M+H]+.1H-NMR(400MHz,DMSO-d6):δppm 12.64(s,1H), 8.35(s,1H),7.67(s,1H),7.45(s,1H),7.29(d,J=6.0Hz,1H),7.18-7.16(m,3H),6.93(d,J=8.4Hz ,1H),6.82-6.77(m,1H),6.63(d,J=7.6Hz,1H),4.35-4.23(m,3H),4.15-4.11(m,1H),3.86-3.83(m,2H ),3.67-3.63(m,1H),3.34-3.23(m,2H),3.12-3.08(m,1H),2.66-2.62(m,1H),1.81-1.69(m,1H),1.65-1.55 (m,4H),1.52-1.43(m,1H),1.13-1.09(m,1H).
使用上述方法或改进的方法,用相应的起始原料合成下列实施例。Using the above method or a modified method, the following examples were synthesized from the corresponding starting materials.
Figure PCTCN2022122329-appb-000126
Figure PCTCN2022122329-appb-000126
Figure PCTCN2022122329-appb-000127
Figure PCTCN2022122329-appb-000127
Figure PCTCN2022122329-appb-000128
Figure PCTCN2022122329-appb-000128
实施例33Example 33
Figure PCTCN2022122329-appb-000129
Figure PCTCN2022122329-appb-000129
将中间体C2(810mg,2.5mmol)溶于MeOH/DMSO(1mL/10mL),加入硝酸银(174 mg,1.0mmol)和三氟乙酸(0.19mL),70℃搅拌1小时,加入(NH 4) 2S 2O 8(1.45g,6.4mmol)和H 2O(3mL),70℃搅拌2小时,反应液用EA稀释,NaOH水溶液洗涤,有机相无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱色谱法(EA:PE=1:5)纯化得化合物33-1(340mg白色固体,收率39%)。MS(ESI):347.0[M+H] +. Dissolve intermediate C2 (810mg, 2.5mmol) in MeOH/DMSO (1mL/10mL), add silver nitrate (174 mg, 1.0mmol) and trifluoroacetic acid (0.19mL), stir at 70°C for 1 hour, add (NH 4 ) 2 S 2 O 8 (1.45g, 6.4mmol) and H 2 O (3mL), stirred at 70°C for 2 hours, the reaction solution was diluted with EA, washed with NaOH aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue The compound was purified by silica gel column chromatography (EA:PE=1:5) to obtain compound 33-1 (340mg white solid, yield 39%). MS(ESI):347.0[M+H] + .
将化合物33-1(300mg,0.8mmol)溶于DMF(5mL)中,加入三乙胺(0.6mL,4.3mmol)和化合物1-2(265mg,0.8mmol),50℃搅拌过夜。反应液用EA稀释,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,所得粗品用硅胶柱色谱法(EA:PE=2:1)纯化得化合物33-2(260mg黄色固体,收率48%)。MS(ESI):617.2[M+H] +. Compound 33-1 (300 mg, 0.8 mmol) was dissolved in DMF (5 mL), triethylamine (0.6 mL, 4.3 mmol) and compound 1-2 (265 mg, 0.8 mmol) were added, and stirred overnight at 50°C. The reaction solution was diluted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (EA:PE=2:1) to obtain compound 33-2 (260mg yellow solid, yield 48%). MS(ESI):617.2[M+H] + .
用化合物33-2代替实施例1中的化合物1-3,可以用类似实施例1的方式合成实施例33。MS(ESI):mass calcd.for C 31H 34N 8O 3 566.3,m/z found567.2[M+H] +.1H-NMR(400MHz,DMSO-d6):δ12.95(brs,1H),7.32(d,J=6.4Hz,1H),7.17(d,J=6.8Hz,3H),6.91(d,J=8.4Hz,1H),6.81-6.79(m,1H),6.52-6.50(m,1H),5.29(m,1H),4.58(d,J=5.6Hz,2H),4.10-4.08(m,2H),3.97-3.94(m,2H),3.87(s,1H),3.76-3.72(m,2H),3.08-3.04(m,1H),2.64(s,1H),1.85-1.82(m,2H),1.56(d,J=8Hz,1H),1.46(s,6H),1.18-1.14(m,1H). Using Compound 33-2 instead of Compound 1-3 in Example 1, Example 33 can be synthesized in a manner similar to Example 1. MS(ESI):mass calcd.for C 31 H 34 N 8 O 3 566.3,m/z found567.2[M+H] + .1H-NMR(400MHz,DMSO-d6):δ12.95(brs,1H ), 7.32(d, J=6.4Hz, 1H), 7.17(d, J=6.8Hz, 3H), 6.91(d, J=8.4Hz, 1H), 6.81-6.79(m, 1H), 6.52-6.50 (m,1H),5.29(m,1H),4.58(d,J=5.6Hz,2H),4.10-4.08(m,2H),3.97-3.94(m,2H),3.87(s,1H), 3.76-3.72(m,2H),3.08-3.04(m,1H),2.64(s,1H),1.85-1.82(m,2H),1.56(d,J=8Hz,1H),1.46(s,6H ),1.18-1.14(m,1H).
使用上述方法或改进的方法,用相应的起始原料合成下列实施例。Using the above method or a modified method, the following examples were synthesized from the corresponding starting materials.
Figure PCTCN2022122329-appb-000130
Figure PCTCN2022122329-appb-000130
Figure PCTCN2022122329-appb-000131
Figure PCTCN2022122329-appb-000131
实施例37Example 37
Figure PCTCN2022122329-appb-000132
Figure PCTCN2022122329-appb-000132
将6-氯-1H-吡唑并[3,4-b]吡啶(100mg,0.65mmol)溶于DMF(2ml)中,加入NIS(189mg,0.84mmol),80℃搅拌4小时。反应液用水稀释,EA萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得化合物37-1(160mg黄色固体,88%)。MS(ESI):280.0[M+H] +. 6-Chloro-1H-pyrazolo[3,4-b]pyridine (100mg, 0.65mmol) was dissolved in DMF (2ml), NIS (189mg, 0.84mmol) was added, and stirred at 80°C for 4 hours. The reaction solution was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 37-1 (160 mg yellow solid, 88%). MS(ESI):280.0[M+H] + .
将化合物37-1溶于DCM(4mL)中,加入DHP(144mg,1.71mmol)和对甲苯磺酸(11.4mg,0.057mmol),RT搅拌3小时,减压浓缩,残余物用硅胶柱色谱法(PE:EA=10:1)纯化得化合物37-2(130mg白色固体,收率63%)。MS(ESI):364.0[M+H] +. Compound 37-1 was dissolved in DCM (4mL), DHP (144mg, 1.71mmol) and p-toluenesulfonic acid (11.4mg, 0.057mmol) were added, stirred at RT for 3 hours, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (PE:EA=10:1) was purified to obtain compound 37-2 (130mg white solid, yield 63%). MS(ESI):364.0[M+H] + .
将化合物37-2(130mg,0.36mmol)溶于DMF(2mL)中,加入化合物1-2(109mg,0.36mmol)和三乙胺(181mg,1.80mmol),50℃搅拌12小时。水稀释,EA萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱层析法(PE:EA=1:1)纯化得化合物37-3(70mg白色固体,收率31%)。MS(ESI):634.2[M+H] +Compound 37-2 (130 mg, 0.36 mmol) was dissolved in DMF (2 mL), compound 1-2 (109 mg, 0.36 mmol) and triethylamine (181 mg, 1.80 mmol) were added, and stirred at 50°C for 12 hours. Diluted with water, extracted with EA, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain compound 37-3 (70mg white solid, yield 31%). MS (ESI): 634.2 [M+H] + .
用化合物37-3代替实施例1中的化合物1-3,用类似实施例1的方式合成实施例37。MS(ESI):mass calcd.for C 31H 33N 7O 2 535.3,m/z found 536.2[M+H] +. 1H-NMR(400MHz,DMSO-d6):δppm 12.47(s,1H),7.54(d,J=9.2Hz,1H),7.30(d,J=6.4Hz,1H),7.19-7.16(m,3H),6.80-6.73(m,2H),6.53-6.46(m,2H),4.26-4.25(m,2H),3.94-3.92(m,2H),3.85-3.81(m,3H),3.11-2.97(m,3H),2.65-2.61(m,1H),1.85-1.50(m,3H),1.46(s,6H),1.19-1.10(m,1H).使用上述方法或改进的方法,用相应的起始原料合成下列实施例。 Compound 37-3 was used to replace compound 1-3 in Example 1, and Example 37 was synthesized in a manner similar to Example 1. MS(ESI):mass calcd.for C 31 H 33 N 7 O 2 535.3,m/z found 536.2[M+H] + . 1 H-NMR(400MHz,DMSO-d6):δppm 12.47(s,1H) ,7.54(d,J=9.2Hz,1H),7.30(d,J=6.4Hz,1H),7.19-7.16(m,3H),6.80-6.73(m,2H),6.53-6.46(m,2H ),4.26-4.25(m,2H),3.94-3.92(m,2H),3.85-3.81(m,3H),3.11-2.97(m,3H),2.65-2.61(m,1H),1.85-1.50 (m, 3H), 1.46 (s, 6H), 1.19-1.10 (m, 1H). Using the above method or a modified method, the following examples were synthesized from the corresponding starting materials.
Figure PCTCN2022122329-appb-000133
Figure PCTCN2022122329-appb-000133
Figure PCTCN2022122329-appb-000134
Figure PCTCN2022122329-appb-000134
Figure PCTCN2022122329-appb-000135
Figure PCTCN2022122329-appb-000135
Figure PCTCN2022122329-appb-000136
Figure PCTCN2022122329-appb-000136
Figure PCTCN2022122329-appb-000137
Figure PCTCN2022122329-appb-000137
Figure PCTCN2022122329-appb-000138
Figure PCTCN2022122329-appb-000138
Figure PCTCN2022122329-appb-000139
Figure PCTCN2022122329-appb-000139
Figure PCTCN2022122329-appb-000140
Figure PCTCN2022122329-appb-000140
Figure PCTCN2022122329-appb-000141
Figure PCTCN2022122329-appb-000141
Figure PCTCN2022122329-appb-000142
Figure PCTCN2022122329-appb-000142
Figure PCTCN2022122329-appb-000143
Figure PCTCN2022122329-appb-000143
Figure PCTCN2022122329-appb-000144
Figure PCTCN2022122329-appb-000144
Figure PCTCN2022122329-appb-000145
Figure PCTCN2022122329-appb-000145
Figure PCTCN2022122329-appb-000146
Figure PCTCN2022122329-appb-000146
Figure PCTCN2022122329-appb-000147
Figure PCTCN2022122329-appb-000147
Figure PCTCN2022122329-appb-000148
Figure PCTCN2022122329-appb-000148
Figure PCTCN2022122329-appb-000149
Figure PCTCN2022122329-appb-000149
Figure PCTCN2022122329-appb-000150
Figure PCTCN2022122329-appb-000150
Figure PCTCN2022122329-appb-000151
Figure PCTCN2022122329-appb-000151
Figure PCTCN2022122329-appb-000152
Figure PCTCN2022122329-appb-000152
Figure PCTCN2022122329-appb-000153
Figure PCTCN2022122329-appb-000153
Figure PCTCN2022122329-appb-000154
Figure PCTCN2022122329-appb-000154
Figure PCTCN2022122329-appb-000155
Figure PCTCN2022122329-appb-000155
试验例1:SHP2(蛋白酪氨酸磷酸酶)体外酶学活性抑制试验 Test example 1 : SHP2 (protein tyrosine phosphatase) in vitro enzymatic activity inhibition test
1.1试验材料和仪器1.1 Test materials and instruments
试验材料和仪器Test Materials and Instruments 厂家factory 货号Item No.
SHP099SHP099 SelleckSelleck S8278S8278
DMSODMSO SigmaSigma D2650D2650
SHP2蛋白(PTPN11)SHP2 protein (PTPN11) ORIGENEORIGENE TP320029TP320029
SHP2 Activating PeptideSHP2 Activating Peptide BioscienceBioscience 79319-279319-2
DiFMUPDiFMUP ThermoThermo 21132942113294
NaClNaCl SigmaSigma S9888S9888
BSABSA SigmaSigma V900933V900933
HEPESHEPES gibcogibco 15630-08015630-080
DTTDTT SigmaSigma 4381643816
EDTAEDTA SCRSCR 1000971710009717
Triton X-100Triton X-100 SigmaSigma T9284T9284
多功能酶联免疫仪Spark M1000proMultifunctional ELISA Spark M1000pro TECANTECAN ----
96孔U底黑板96-hole U-bottom blackboard ThermoThermo 237108237108
1.2试验系统1.2 Test system
SHP2蛋白溶液浓度:0.5nM;酶缓冲液:55mM HEPES,100mM NaCl,0.2%BSA,1mM EDTA,1mM DTT,0.1%Triton X-100;SHP2Activating Peptide溶液浓度:0.5μM;DiFMUP溶液浓度:120μM;阳性药SHP099的DMSO溶液浓度:10000nM,2500nM,625nM,156.25nM,39.06nM,9.77nM,2.44nM,0.61nM,0.15nM,0nM,其中化合物浓度为0nM组为空白组;供试化合物的DMSO溶液浓度:10000nM,2500nM,625nM,156.25nM,39.06nM,9.77nM,2.44nM,0.61nM,0.15nM,0nM,其中化合物浓度为0nM组为空白组。SHP2 protein solution concentration: 0.5nM; enzyme buffer solution: 55mM HEPES, 100mM NaCl, 0.2% BSA, 1mM EDTA, 1mM DTT, 0.1% Triton X-100; SHP2Activating Peptide solution concentration: 0.5μM; DiFMUP solution concentration: 120μM; Positive Concentration of DMSO solution of drug SHP099: 10000nM, 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, 0.15nM, 0nM, wherein the compound concentration of 0nM is the blank group; the DMSO solution concentration of the test compound : 10000nM, 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, 0.15nM, 0nM, wherein the compound concentration of 0nM is the blank group.
1.3试验步骤1.3 Test steps
取96孔U底黑板,每孔依次加入30μL酶缓冲液、5μL SHP2蛋白溶液以及5μL SHP2 Activating Peptide,室温25℃摇板机孵育30min;每孔加入5μL阳性药或供试化合物溶液,室温25℃摇板机孵育30min;每孔加入5μL DiFMUP作为反应底物启动反应(体系总体积为50μL),室温25℃摇板机孵育30min后,使用多功能酶联免疫仪检测检测反应液的荧光强度(激发光340nm,发射光450nm)。Take a 96-well U-bottom black plate, add 30 μL of enzyme buffer, 5 μL of SHP2 protein solution and 5 μL of SHP2 Activating Peptide to each well, and incubate on a shaker at room temperature 25°C for 30 minutes; add 5 μL of positive drug or test compound solution to each well, at room temperature of 25°C Shaking plate machine was incubated for 30 min; 5 μL DiFMUP was added to each well as the reaction substrate to start the reaction (the total volume of the system was 50 μL), and after 30 min incubation with shaking plate machine at room temperature of 25 °C, the fluorescence intensity of the reaction solution was detected using a multifunctional enzyme-linked immunosorbent assay ( Excitation light 340nm, emission light 450nm).
1.4数据处理1.4 Data processing
按如下公式计算各化合物在各浓度点的抑制率,并通过软件Graphpad Prism 8.0进行曲线拟合得到IC50值。The inhibition rate of each compound at each concentration point was calculated according to the following formula, and the IC50 value was obtained by curve fitting with the software Graphpad Prism 8.0.
Figure PCTCN2022122329-appb-000156
Figure PCTCN2022122329-appb-000156
1.5试验结果1.5 Test results
按照上述方法测定化合物对SHP2活性的抑制活性,结果如下表中所示。The inhibitory activity of the compounds on SHP2 activity was determined according to the above method, and the results are shown in the following table.
化合物compound IC50(nM)IC50(nM)
SHP099SHP099 107.81107.81
实施例1Example 1 5.465.46
实施例4Example 4 2.192.19
实施例5Example 5 35.5035.50
实施例6Example 6 22.2122.21
实施例7Example 7 32.8032.80
实施例8Example 8 4.154.15
实施例9Example 9 17.7317.73
实施例12Example 12 7.287.28
实施例19Example 19 8.278.27
实施例20Example 20 26.1826.18
实施例21Example 21 3.563.56
实施例22Example 22 12.2912.29
实施例23Example 23 4.994.99
实施例29Example 29 8.448.44
实施例30Example 30 3.333.33
实施例31Example 31 2.682.68
实施例32Example 32 7.367.36
实施例33Example 33 6.856.85
实施例52Example 52 7.177.17
实施例59Example 59 65.5965.59
实施例60Example 60 13.2813.28
实施例61Example 61 9.819.81
实施例63Example 63 4.74.7
实施例64Example 64 5.725.72
实施例65Example 65 11.2611.26
实施例66Example 66 3.843.84
实施例67Example 67 8.798.79
实施例68Example 68 9.849.84
实施例69Example 69 6.546.54
实施例70Example 70 4.364.36
实施例71Example 71 18.4218.42
实施例72Example 72 6.726.72
实施例73Example 73 4.174.17
实施例74Example 74 4.654.65
实施例75Example 75 2.512.51
实施例76Example 76 5.785.78
实施例77Example 77 5.735.73
实施例78Example 78 7.897.89
实施例79Example 79 13.913.9
实施例80Example 80 3.243.24
实施例81Example 81 3.093.09
实施例83Example 83 8.458.45
实施例84Example 84 1.71.7
实施例85Example 85 11.6111.61
实施例86Example 86 6.876.87
实施例87Example 87 46.546.5
实施例88Example 88 7.197.19
实施例89Example 89 13.0213.02
实施例90Example 90 22.9522.95
实施例91Example 91 11.511.5
实施例92Example 92 6.146.14
实施例93Example 93 15.1315.13
实施例94Example 94 9.249.24
实施例95Example 95 10.5610.56
实施例96Example 96 70.1670.16
实施例97Example 97 7.827.82
实施例98Example 98 7.067.06
实施例99Example 99 8.868.86
实施例100Example 100 336.83336.83
实施例101Example 101 277.66277.66
实施例102Example 102 520.61520.61
实施例103Example 103 205.46205.46
结论:在SHP2酶活抑制试验中,与阳性药SHP099相比,本发明的化合物表现出了更优的抑制活性。Conclusion: In the SHP2 enzyme activity inhibition test, compared with the positive drug SHP099, the compound of the present invention shows better inhibitory activity.
试验例2本发明化合物对非小细胞肺癌H358细胞增殖活性抑制试验 Test Example 2 Compounds of the present invention inhibit the proliferation of non-small cell lung cancer H358 cells
2.1试验材料和仪器2.1 Test materials and instruments
Figure PCTCN2022122329-appb-000157
Figure PCTCN2022122329-appb-000157
2.2试验系统2.2 Test system
培养基:1640高糖培养基+10%FBS+1%(青霉素/链霉素);阳性药SHP099的DMSO溶液浓度:80000nM、20000nM、5000nM、1250nM、312.5nM、78.13nM、19.53nM、4.88nM、1.22nM和0nM,其中化合物浓度为0nM组为空白组;供试化合物的DMSO溶液浓度:80000nM、20000nM、5000nM、1250nM、312.5nM、78.13nM、19.53nM、4.88nM、1.22nM和0nM,其中化合物浓度为0nM组为空白组。Medium: 1640 high glucose medium + 10% FBS + 1% (penicillin/streptomycin); DMSO solution concentration of positive drug SHP099: 80000nM, 20000nM, 5000nM, 1250nM, 312.5nM, 78.13nM, 19.53nM, 4.88nM , 1.22nM and 0nM, wherein the compound concentration of 0nM is the blank group; the DMSO solution concentration of the test compound: 80000nM, 20000nM, 5000nM, 1250nM, 312.5nM, 78.13nM, 19.53nM, 4.88nM, 1.22nM and 0nM, where The compound concentration of 0nM group was the blank group.
2.3试验步骤2.3 Test steps
将H358细胞培养在培养基中,放置在37℃,5%CO 2培养条件下进行培养。取处于对数生长期的H358细胞,消化重悬细胞后计数,调整细胞密度后接种到96孔底部透明黑板中,每孔接种2500个细胞,置于37℃、5%CO 2的培养箱中培养72h。72h后,每孔加入20μL阳性药或供试化合物溶液,恒温37℃,5%CO 2和90%相对湿度下培养120h。120h后,每孔加入60μL的检测试剂
Figure PCTCN2022122329-appb-000158
3D Cell Viability溶液,置于摇板机上室温孵育30min,之后使用多功能酶联免疫仪读取各孔的数值。
H358 cells were cultured in the culture medium and placed at 37°C, 5% CO 2 culture conditions for culture. Take the H358 cells in the logarithmic growth phase, digest and resuspend the cells, count them, adjust the cell density and inoculate them into a transparent black plate at the bottom of 96 wells, inoculate 2,500 cells per well, and place them in an incubator at 37°C and 5% CO 2 Cultivate for 72h. After 72 hours, 20 μL of positive drug or test compound solution was added to each well, and incubated at a constant temperature of 37° C., 5% CO 2 and 90% relative humidity for 120 hours. After 120 hours, add 60 μL of detection reagent to each well
Figure PCTCN2022122329-appb-000158
The 3D Cell Viability solution was placed on a shaker and incubated at room temperature for 30 minutes, and then the value of each well was read using a multifunctional enzyme-linked immunosorbent analyzer.
2.4数据处理2.4 Data processing
按如下公式计算各化合物在各浓度点的抑制率,并通过软件Graphpad Prism 8.0进行曲线拟合得到IC50值。The inhibition rate of each compound at each concentration point was calculated according to the following formula, and the IC50 value was obtained by curve fitting with the software Graphpad Prism 8.0.
Figure PCTCN2022122329-appb-000159
Figure PCTCN2022122329-appb-000159
2.5试验结果2.5 Test results
按照上述方法测定化合物对H358细胞增殖的抑制活性,结果如下表中所示。The inhibitory activity of the compounds on H358 cell proliferation was determined according to the above method, and the results are shown in the following table.
化合物compound IC50(nM)IC50(nM)
SHP099SHP099 631.22631.22
实施例1Example 1 6.706.70
实施例2Example 2 22.1022.10
实施例3Example 3 25.7525.75
实施例4Example 4 5.145.14
实施例6Example 6 14.9214.92
实施例8Example 8 7.177.17
实施例9Example 9 38.3638.36
实施例12Example 12 25.9625.96
实施例19Example 19 39.6339.63
实施例21Example 21 54.1154.11
实施例23Example 23 45.6645.66
实施例25Example 25 76.5276.52
实施例29Example 29 5.355.35
实施例30Example 30 3.903.90
实施例32Example 32 14.8214.82
实施例33Example 33 4.74.7
实施例34Example 34 50.2250.22
实施例35Example 35 16.4616.46
实施例52Example 52 39.2439.24
实施例59Example 59 470.24470.24
实施例60Example 60 224.3224.3
实施例61Example 61 72.8972.89
实施例63Example 63 216.9216.9
实施例64Example 64 22.8122.81
实施例65Example 65 29.129.1
实施例66Example 66 54.0954.09
实施例67Example 67 159.5159.5
实施例68Example 68 28.4328.43
实施例69Example 69 13.1813.18
实施例70Example 70 16.216.2
实施例71Example 71 8.518.51
实施例72Example 72 5.215.21
实施例73Example 73 1.981.98
实施例74Example 74 6.96.9
实施例75Example 75 11.3211.32
实施例76Example 76 55.655.6
实施例77Example 77 42.7142.71
实施例78Example 78 45.5245.52
实施例79Example 79 40.5140.51
实施例80Example 80 10.1810.18
实施例81Example 81 8.318.31
实施例83Example 83 3.153.15
实施例84Example 84 13.3313.33
实施例85Example 85 27.2627.26
实施例86Example 86 8.238.23
实施例87Example 87 732.7732.7
实施例88Example 88 30.3830.38
实施例89Example 89 48.4248.42
实施例90Example 90 32.8532.85
实施例91Example 91 32.2132.21
实施例92Example 92 30.2630.26
实施例93Example 93 159.36159.36
实施例94Example 94 54.0454.04
实施例95Example 95 63.9363.93
实施例96Example 96 578.5578.5
实施例97Example 97 30.3130.31
实施例98Example 98 27.2527.25
实施例99Example 99 39.7639.76
实施例100Example 100 16981698
实施例101Example 101 752.2752.2
实施例102Example 102 12651265
实施例103Example 103 28512851
结论:在非小细胞肺癌H358细胞增殖活性抑制试验中,与阳性药SHP099相比,本发明的化合物表现出了更优的抑制活性。Conclusion: In the non-small cell lung cancer H358 cell proliferation inhibition test, compared with the positive drug SHP099, the compound of the present invention exhibits better inhibitory activity.
试验例3本发明化合物对hERG钾离子通道抑制试验 Test Example 3 Compounds of the present invention inhibit test of hERG potassium ion channel
3.1试验材料和仪器3.1 Test materials and instruments
试验材料和仪器Test Materials and Instruments 厂家或机构Manufacturer or organization 货号Item No.
CHO细胞CHO cells B’SYS GmbHB’SYS GmbH ----
其他试验材料和仪器来源参照上述试验例。未注明具体来源的试剂,为市场购买的常规试剂。For other test materials and instruments, refer to the above test examples. Reagents without specific sources indicated are conventional reagents purchased in the market.
3.2试验系统3.2 Test system
F-12(HAM)培养基:10%FBS缓冲液、100U/mL青霉素/链霉素、100μg/mL Hygronycin和100μg/mL G418;NMDG 60标准外液:(使用HCl将pH调至7.4,渗透压为289mOsm/kg)80mM氯化钠、60mM NMDG、4mM氯化钾、2mM氯化钙、1mM氯化镁、5mM多聚葡萄糖、10mM HEPES;NMDG 60细胞封接液:(使用HCl将pH调至7.4,渗透压为313mOsm/kg)80mM氯化钠、60mM NMDG、4mM氯化钾、10mM氯化钙、1mM氯化镁、5mM多聚葡萄糖、10mM HEPES;芯片填充液:(使用NaOH将pH调至7.4,渗透压为289mOsm/kg)140mM氯化钠、4mM氯化钾、5mM多聚葡萄糖、10mM HEPES;Standard标准外液:(使用NaOH将pH调至7.4,渗透压为298mOsm/kg)140mM氯化钠、4mM氯化钾、2mM氯化钙、1mM氯化镁、5mM多聚葡萄糖、10mM HEPES;KF110细胞内液:(使用KOH调节pH至7.2,渗透压大于280mOsm/kg)10mM EGTA、10mM HEPES、10mM氯化钾、10mM氯化钠、110mM氟化钾。F-12 (HAM) medium: 10% FBS buffer, 100U/mL penicillin/streptomycin, 100μg/mL Hygronycin and 100μg/mL G418; NMDG 60 standard external solution: (use HCl to adjust the pH to 7.4, infiltrate Pressure is 289mOsm/kg) 80mM sodium chloride, 60mM NMDG, 4mM potassium chloride, 2mM calcium chloride, 1mM magnesium chloride, 5mM polydextrose, 10mM HEPES; NMDG 60 cell sealing solution: (use HCl to adjust the pH to 7.4 , osmotic pressure is 313mOsm/kg) 80mM sodium chloride, 60mM NMDG, 4mM potassium chloride, 10mM calcium chloride, 1mM magnesium chloride, 5mM polydextrose, 10mM HEPES; chip filling solution: (use NaOH to adjust the pH to 7.4, The osmotic pressure is 289mOsm/kg) 140mM sodium chloride, 4mM potassium chloride, 5mM polydextrose, 10mM HEPES; Standard standard external solution: (use NaOH to adjust the pH to 7.4, the osmotic pressure is 298mOsm/kg) 140mM sodium chloride , 4mM potassium chloride, 2mM calcium chloride, 1mM magnesium chloride, 5mM polydextrose, 10mM HEPES; KF110 intracellular fluid: (use KOH to adjust pH to 7.2, osmotic pressure greater than 280mOsm/kg) 10mM EGTA, 10mM HEPES, 10mM chlorine Potassium chloride, 10mM sodium chloride, 110mM potassium fluoride.
3.3试验步骤3.3 Test steps
在试验之前,首先用DMSO以梯度稀释的方式稀释成3.33,1.11和0.37mM的贮备液,再用细胞外液稀释成最终的将化合物稀释成下列浓度(30,10,3.33,1.11和0.37μM)来作测试。各浓度测试溶液中DMSO的最终浓度为0.1%。所有的贮备液和测试溶液都经过5-10分钟的超声和振荡以保证化合物完全溶解。Before the test, the compound was first diluted with DMSO to 3.33, 1.11 and 0.37 mM stock solutions in a serial dilution manner, and then diluted with extracellular fluid to the final dilution of the compound into the following concentrations (30, 10, 3.33, 1.11 and 0.37 μM ) for testing. The final concentration of DMSO in each concentration test solution was 0.1%. All stock and test solutions were sonicated and shaken for 5-10 minutes to ensure complete dissolution of the compound.
CHO细胞生长于含上述细胞培养液的培养皿中,并在37℃、含5%CO2的培养箱中进行培养。电生理实验之前24到48小时,CHO细胞被转移到放置于培养皿中的圆形玻璃片上,并在以上相同的培养液及培养条件下生长。每个圆形玻片上CHO细胞的密度需要达到绝大多数细胞是独立、单个的要求。CHO cells were grown in the culture dish containing the above cell culture medium, and cultured at 37°C in an incubator containing 5% CO2. 24 to 48 hours before electrophysiological experiments, CHO cells were transferred to round glass slides placed in petri dishes, and grown in the same culture medium and culture conditions as above. The density of CHO cells on each circular slide needs to be such that most of the cells are independent and single.
本实验采用手动膜片钳系统作全细胞电流的记录。表面生长有CHO细胞的圆形玻片被放置于倒置显微镜下的电生理记录槽中。记录槽内以细胞外液作持续灌流(大约每分钟1毫升)。实验过程采用常规全细胞膜片钳电流记录技术。如无特殊说明,实验都是在常规室温下进行(~25℃)。细胞钳制在-90mV的电压下。细胞钳制电压去极化到+30mV以激活hERG钾通道,5秒后再钳制到-50mV以消除失活并产生尾电流。尾电流峰值用作hERG电流大小的数值。上述步骤所记录的hERG钾电流在记录槽内持续的细胞外液灌流下达到稳定后则可以叠加灌流待测试的药物,直到药物对hERG电流的抑制作用达到稳定状态。一般以最近的连续3个电流记录线重合作为判断是否稳定状态的标准。达到稳定态势以后以细胞外液灌流冲洗直到hERG电流回复到加药物之前的大小。一个细胞上可以测试一个或多个药物,或者同一种药物的多个浓度,但是在不同药物之间需要以细胞外液冲洗。In this experiment, a manual patch clamp system was used to record whole-cell currents. A circular glass slide with CHO cells grown on the surface was placed in the electrophysiological recording tank under an inverted microscope. The recording tank was continuously perfused with extracellular fluid (about 1 ml per minute). The experimental process used conventional whole-cell patch-clamp current recording technique. Unless otherwise specified, experiments were performed at normal room temperature (~25°C). Cells were clamped at a voltage of -90 mV. Cell voltage clamps were depolarized to +30mV to activate hERG potassium channels, and then clamped to -50mV after 5 seconds to eliminate inactivation and generate tail currents. The peak tail current was used as a measure of hERG current magnitude. After the hERG potassium current recorded in the above steps reaches a steady state under the continuous perfusion of extracellular fluid in the recording tank, the drug to be tested can be superimposed and perfused until the inhibitory effect of the drug on the hERG current reaches a steady state. Generally, the coincidence of the latest three consecutive current recording lines is used as the criterion for judging whether it is in a stable state. After reaching a steady state, extracellular fluid was used to perfuse and wash until the hERG current returned to the size before adding drugs. One or more drugs, or multiple concentrations of the same drug, can be tested on a cell, but extracellular fluid washing is required between different drugs.
3.4数据处理3.4 Data processing
参照试验例2的公式计算结果。Refer to the formula of Test Example 2 to calculate the result.
3.5试验结果3.5 Test results
按照上述方法测定化合物的hERG钾离子通道抑制活性,结果如下表中所示。The hERG potassium ion channel inhibitory activity of the compounds was determined according to the above method, and the results are shown in the following table.
化合物compound IC50(nM)IC50(nM)
实施例5Example 5 9.29.2
实施例29Example 29 >30>30
实施例64Example 64 >30>30
实施例66Example 66 >30>30
实施例68Example 68 6.836.83
实施例69Example 69 19.1219.12
实施例70Example 70 4.234.23
实施例71Example 71 4.554.55
实施例75Example 75 4.284.28
实施例76Example 76 7.027.02
实施例77Example 77 16.4916.49
实施例78Example 78 6.136.13
实施例79Example 79 7.647.64
实施例94Example 94 4.654.65
试验例4本发明化合物在BALB/C小鼠体内的药代动力学试验 Pharmacokinetic test of test example 4 compounds of the present invention in BALB/C mice
取BALB/C雄性小鼠45只(购自北京维通利华实验动物技术有限公司)进行药代动力学试验,药品配置(溶剂)为5%DMSO+40%PEG400+55%NS,药品有效成分分别为实施例80和81中的化合物,给药频率和给药体积为单次,口服给药(p.o.)10mg/kg;静脉注射(i.v.)2mg/kg,分组和给药如下表。Take 45 BALB/C male mice (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) for pharmacokinetic test, the drug configuration (solvent) is 5% DMSO+40% PEG400+55% NS, the drug is effective The components are the compounds in Examples 80 and 81 respectively, and the administration frequency and administration volume are single, oral administration (p.o.) 10mg/kg; intravenous injection (i.v.) 2mg/kg, grouping and administration are as follows.
Figure PCTCN2022122329-appb-000160
Figure PCTCN2022122329-appb-000160
给药后进行样品采集,样品采集时间点:15min,30min,1h,2h,4h,8h,12h,24h;样品采点分布见下表。Samples were collected after administration, sample collection time points: 15min, 30min, 1h, 2h, 4h, 8h, 12h, 24h; the distribution of sample collection points is shown in the table below.
组/时间group/time 15min15min 30min30min 1h1h 2h2 hours 4h4h 8h8 hours 12h12h 24h24 hours
11
22
33  the  the  the  the  the
44  the  the  the  the  the
55  the  the  the  the  the
66  the  the  the  the  the
77  the  the  the  the  the
88  the  the  the  the  the
99  the  the  the  the  the
1010  the  the  the  the  the
1111  the  the  the  the  the
1212  the  the  the  the  the
各给药组眼眶采集全血,3只/时间点,采血体积为0.2ml/时间点,EDTA抗凝全血,全血采集完成后离心取上清,离心速度4000rpm,离心时间10min。用LCMS/MS方法检测实施例的小鼠药代动力学参数结果如下。Whole blood was collected from the orbits of each dosing group, 3 mice/time point, the blood collection volume was 0.2ml/time point, EDTA anticoagulated whole blood, and centrifuged after the whole blood collection was completed to obtain the supernatant, the centrifugation speed was 4000rpm, and the centrifugation time was 10min. The results of the mouse pharmacokinetic parameters of the examples detected by the LCMS/MS method are as follows.
化合物80Compound 80
Figure PCTCN2022122329-appb-000161
Figure PCTCN2022122329-appb-000161
化合物81Compound 81
Figure PCTCN2022122329-appb-000162
Figure PCTCN2022122329-appb-000162
试验例5本发明化合物在NCI-H1975皮下移植瘤模型的体内药效学试验 Experimental example 5 in vivo pharmacodynamics test of the compound of the present invention in NCI-H1975 subcutaneous xenograft model
NCI-H1975人非小细胞肺腺癌细胞体外单层培养,培养条件为1640培养基中加10%胎牛血清,37℃、5%CO 2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞呈指数生长期时,收取细胞,计数,接种。 NCI-H1975 human non-small cell lung adenocarcinoma cells were cultured in a single layer in vitro, and the culture conditions were 1640 medium plus 10% fetal bovine serum, cultured at 37°C and 5% CO 2 . Routine digestion with trypsin-EDTA was performed twice a week for passaging. When the cells are in the exponential growth phase, the cells are collected, counted, and inoculated.
取BALB/c雌性,6周,体重约15-18g的裸小鼠54只(购自北京维通利华实验动物技术有限公司)。每只小鼠后肩胛部位皮下接种(2 x 10 6)NCI-H1975细胞,细胞悬液混有50%介质胶的无血清培养基构成。肿瘤平均体积达到合适大小后开始给药治疗。 54 BALB/c female nude mice weighing about 15-18 g (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were selected for 6 weeks. Each mouse was subcutaneously inoculated with (2 x 10 6 ) NCI-H1975 cells at the posterior scapula, and the cell suspension was composed of serum-free medium mixed with 50% medium gel. The drug treatment was started after the average tumor volume reached the appropriate size.
动物饲养3-7天后开始实验。笼具、饲料及饮水每周更换两次。温度:20~26℃,湿度:40~70%,光照周期:12小时光照,12小时无光照。饲料符合实验动物食物鉴定标准。污染物最高含量在可控范围内并由生产厂家负责例检。饮水采用高压灭菌的饮用水。The experiments were started after the animals were fed for 3-7 days. Cages, feed and drinking water were changed twice a week. Temperature: 20-26°C, humidity: 40-70%, photoperiod: 12 hours with light, 12 hours with no light. The feed meets the food identification standards for experimental animals. The maximum content of pollutants is within the controllable range and the manufacturer is responsible for the routine inspection. Drinking water was autoclaved drinking water.
给药前称重动物,测量瘤体积。根据瘤体积随机分组(见下表)。Animals were weighed before administration, and tumor volume was measured. Randomized grouping according to tumor volume (see table below).
Figure PCTCN2022122329-appb-000163
Figure PCTCN2022122329-appb-000163
用GraphPad Prism 8进行数据分析。p<0.05认为有显著性差异。肿瘤生长抑制率用下列公式计算:TGI(%)=[1-(Ti-T0)/(Vi-V0)]×100,其中Ti为某一天某给药组的平均肿瘤体积,T0为此给药组在开始给药时的平均肿瘤体积;Vi为某一天(与Ti同一天)溶媒对照组的平均肿瘤体积,V0为溶媒对照组在给开始药时的平均肿瘤体积。TGI(%)<40%,认为此药无效,≥40%且P<0.05,认为此药有效。在实验结束后将检测肿瘤重量,并计算T/C百分比,T和C分别表示给药组和溶媒对照组的瘤重。结果如下表所示,本发明实施例80和81的化合物均对肿瘤生长产生了显著地抑制效果:Data analysis was performed with GraphPad Prism 8. p<0.05 considered significant difference. The tumor growth inhibition rate is calculated with the following formula: TGI (%)=[1-(Ti-T0)/(Vi-V0)]×100, wherein Ti is the average tumor volume of a certain administration group on a certain day, and T0 is given for this purpose. The average tumor volume of the drug group at the beginning of administration; Vi is the average tumor volume of the vehicle control group on a certain day (the same day as Ti), and V0 is the average tumor volume of the vehicle control group at the beginning of drug administration. If TGI (%)<40%, the drug is considered ineffective; if ≥40% and P<0.05, the drug is considered effective. After the end of the experiment, the tumor weight will be detected, and the T/C percentage will be calculated. T and C represent the tumor weight of the administration group and the vehicle control group, respectively. The results are shown in the following table, the compounds of Examples 80 and 81 of the present invention all had a significant inhibitory effect on tumor growth:
化合物compound TGITGI PP
实施例81Example 81 90%90% <0.0001<0.0001
实施例80Example 80 91%91% <0.0001<0.0001
本发明已经通过上述实施例进行了说明,但应当理解的是,上述实施例只是用于举例和说明的目的,而非意在将本发明限制于所描述的实施例范围内。此外本领域技术人员可以理解的是,本发明并不局限于上述实施例,根据本发明的教导还可以做出更多种的变型和修改,这些变型和修改均落在本发明所要求保护的范围以内。本发明的保护范围由附属的权利要求书及其等效范围所界定。The present invention has been described through the above-mentioned embodiments, but it should be understood that the above-mentioned embodiments are only for the purpose of illustration and description, and are not intended to limit the present invention to the scope of the described embodiments. In addition, those skilled in the art can understand that the present invention is not limited to the above-mentioned embodiments, and more variations and modifications can be made according to the teachings of the present invention, and these variations and modifications all fall within the claimed scope of the present invention. within the range. The protection scope of the present invention is defined by the appended claims and their equivalent scope.

Claims (28)

  1. 式Q所示的化合物或其药学上可接受的盐,A compound represented by formula Q or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022122329-appb-100001
    Figure PCTCN2022122329-appb-100001
    其中,Z是CH或N;Wherein, Z is CH or N;
    Z 1是CR 0、N、O或S; Z 1 is CR 0 , N, O or S;
    R 0选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、C 2-6炔基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; R 0 is selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0-2 -C 1-6 alkane Base, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N (C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1 -6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, - OC 1-6 alkyl, C 2-6 alkynyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2. Substituents of -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ;
    环A选自5-8元的烃环、5-8元杂环、5-8元杂芳环和5-8元芳环,且所述烃环、杂环、杂芳环和芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、C 2-6炔基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基、C 3-6环烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Ring A is selected from 5-8 membered hydrocarbon rings, 5-8 membered heterocyclic rings, 5-8 membered heteroaryl rings and 5-8 membered aromatic rings, and the hydrocarbon rings, heterocyclic rings, heteroaryl rings and aromatic rings are each Optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH (C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkane and -C(O)N(C 1-6 alkyl) substituents substituted with each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl optionally further substituted by One or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkane group, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl ) is replaced by a substituent of 2 ;
    环B是包含N原子的5-8元杂环或5-8元杂芳环,且所述杂环和杂芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、C 2-6烯基、C 2-6炔基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环 烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Ring B is a 5-8 membered heterocyclic ring or a 5-8 membered heteroaryl ring containing N atoms, and each of the heterocyclic ring and heteroaryl ring is optionally replaced by one or more members selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered hetero Cyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkane group, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl ) 2 is substituted by a substituent, each of said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl being optionally further selected from one or more of halogen, -OH, =O, - OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O) Substituents of NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ;
    环C选自5-8元芳环或含有各自独立选自N、O、和S的1-3个杂原子的5-8元杂芳环,且所述芳环或杂芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Ring C is selected from 5-8 membered aromatic rings or 5-8 membered heteroaromatic rings containing 1-3 heteroatoms independently selected from N, O, and S, and each of the aromatic rings or heteroaryl rings is optionally One or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl group, -CN, -NH 2 , - NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 Alkyl and -C (O) N (C 1-6 alkyl) substituent substitution, said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl each optionally further By one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, - N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituent substitution;
    环D为5-6元的单环芳基、具有1-4个各自独立选自N、O、S的杂原子的5-6元的单环杂芳基,具有1-5个各自独立选自N、O、S的杂原子的8-10元双环杂芳基,或具有1-5个各自独立选自N、O、S的杂原子的杂烃环与杂芳环形成的8-10元稠合环基;Ring D is a 5-6-membered monocyclic aryl group, a 5-6-membered monocyclic heteroaryl group with 1-4 heteroatoms independently selected from N, O, and S, and 1-5 independently selected heteroatoms An 8-10 membered bicyclic heteroaryl group consisting of N, O, and S heteroatoms, or an 8-10 membered heterohydrocarbon ring and a heteroaryl ring having 1-5 heteroatoms independently selected from N, O, and S Member fused ring group;
    环E为C 4-8环烷基,或含有1-3个各自独立选自N、O和S的杂原子的4-8元杂环烷基; Ring E is a C 4-8 cycloalkyl group, or a 4-8 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O and S;
    R 1在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0 -2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl group, -NH 2 , -NH(C 1 -6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and - C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally selected from one or more halogen , -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl ) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 are substituted by substituents;
    R 2在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0 -2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl group, -NH 2 , -NH(C 1 -6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and - C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally selected from one or more halogen , -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl ) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 are substituted by substituents;
    R e每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、 -NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代;或者,两个独立地R e与环E上与它们连接的原子一起形成3-12元的单环或多环烃环、3-12元的单环或多环杂环、3-12元的烃环和杂环形成的多环环系、3-6元的烃环与5-8元的杂芳环稠合形成的多环环系、3-6元的烃环与5-8元的芳环稠合形成的多环环系、3-6元的杂环与5-8元的杂芳环稠合形成的多环环系、或3-6元的杂环与5-8元的芳环稠合形成的多环环系,且所述每个环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基、C 3-6环烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Each occurrence of R e is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0- 2 -C 1-6 alkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -OC 1-6 alkyl, -NH 2 , -NH(C 1- 6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C (O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2. Substituents of -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; or, two independent R e and the atoms connected to them on the ring E form a 3-12 membered monocyclic or polycyclic hydrocarbon ring, a 3-12 membered monocyclic or polycyclic heterocyclic ring, a 3-12 membered hydrocarbon ring and a heterocyclic ring The formed polycyclic ring system, the polycyclic ring system formed by the fusion of 3-6 membered hydrocarbon ring and 5-8 membered heteroaryl ring, the condensed form of 3-6 membered hydrocarbon ring and 5-8 membered aromatic ring A polycyclic ring system, a polycyclic ring system formed by the fusion of a 3-6-membered heterocycle and a 5-8-membered heteroaromatic ring, or a condensed 3-6-membered heterocycle and a 5-8-membered aromatic ring A polycyclic ring system, and each ring is optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, -S(=O ) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl group, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkyl and -C (O) N (C 1-6 alkyl) substituent substitution, the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl Each is optionally further represented by one or more selected from halogen, -OH, =O, -OC1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) substituted by substituents of 2 ;
    L 1为共价键,或者,是C1-4的二价饱和或不饱和的直链或支链烃基,或者,将所述C1-4的二价饱和或不饱和的直链或支链烃基中的一个或两个亚甲基以独立地被选自-O-、-C(O)、-OC(O)-、-C(O)O-、-S-、-S(O)-和-S(O) 2-的基团替换后形成的基团; L 1 is a covalent bond, or is a C1-4 divalent saturated or unsaturated straight-chain or branched chain hydrocarbon group, or, the C1-4 divalent saturated or unsaturated straight-chain or branched chain hydrocarbon group One or two methylene groups in are independently selected from -O-, -C(O), -OC(O)-, -C(O)O-, -S-, -S(O)- and -S(O) 2 - the group formed after the group is replaced;
    k为0、1、2、3、4、5、6、7、8或9;k is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
    m为0、1、2、3、4或5;和m is 0, 1, 2, 3, 4 or 5; and
    n为0、1、2、3、4、5、6或7。n is 0, 1, 2, 3, 4, 5, 6 or 7.
  2. 根据权利要求1所述的化合物或其药学上可接受的盐,其中,环E选自:The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring E is selected from:
    Figure PCTCN2022122329-appb-100002
    Figure PCTCN2022122329-appb-100002
    Figure PCTCN2022122329-appb-100003
    Figure PCTCN2022122329-appb-100003
  3. 根据权利要求1所述的化合物或其药学上可接受的盐,其具有结构式Q 1The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula Q 1 :
    Figure PCTCN2022122329-appb-100004
    Figure PCTCN2022122329-appb-100004
    其中,R 3和R 4各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2, 其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代;或者R 3和R 4与它们连接的原子一起形成3-12元的单环或多环烃环、3-12元的单环或多环杂环、3-12元的烃环和杂环形成的多环环系、3-6元的烃环与5-8元的杂芳环稠合形成的多环环系、3-6元的烃环与5-8元的芳环稠合形成的多环环系、3-6元的杂环与5-8元的杂芳环稠合形成的多环环系、或3-6元的杂环与5-8元的芳环稠合形成的多环环系,且所述每个环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基、C 3-6环烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Wherein, R 3 and R 4 are each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), - N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O ) NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituents; or the atoms to which R 3 and R 4 are attached Together form a 3-12 membered monocyclic or polycyclic hydrocarbon ring, a 3-12 membered monocyclic or polycyclic heterocyclic ring, a polycyclic ring system formed by a 3-12 membered hydrocarbon ring and a heterocyclic ring, a 3-6 membered A polycyclic ring system formed by the fusion of a hydrocarbon ring and a 5-8 membered heteroaromatic ring, a polycyclic ring system formed by the fusion of a 3-6-membered hydrocarbon ring and a 5-8-membered aromatic ring, a 3-6-membered heteroaromatic ring A polycyclic ring system formed by condensing a ring with a 5-8 membered heteroaromatic ring, or a polycyclic ring system formed by condensing a 3-6 membered heterocyclic ring with a 5-8 membered aromatic ring, and each ring Each is optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkane radical), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkyl and -C(O )N(C 1-6 alkyl) substituted by a substituent, each of said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl optionally further being selected from one or more Halogen, -OH, =O, -OC1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1 Substituents of -6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ;
    k 1为1、2或3; k 1 is 1, 2 or 3;
    k 2为1、2或3。 k 2 is 1, 2 or 3.
  4. 根据权利要求1所述的化合物或其药学上可接受的盐,其中,环D选自The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring D is selected from
    Figure PCTCN2022122329-appb-100005
    Figure PCTCN2022122329-appb-100005
    Figure PCTCN2022122329-appb-100006
    Figure PCTCN2022122329-appb-100006
  5. 式I所示的化合物或其药学上可接受的盐:The compound shown in formula I or its pharmaceutically acceptable salt:
    Figure PCTCN2022122329-appb-100007
    Figure PCTCN2022122329-appb-100007
    其中,W 1,W 2,和W 3各自独立地选自CR 1和N; Wherein, W 1 , W 2 , and W 3 are each independently selected from CR 1 and N;
    X 2,X 3,和X 4各自独立地选自CR 2和N; X 2 , X 3 , and X 4 are each independently selected from CR 2 and N;
    Z是CH或N;Z is CH or N;
    X 1是CR 8或N; X 1 is CR 8 or N;
    R 8独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; R 8 is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 Membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), -N( C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1- 6 alkyl) 2 , the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl are each optionally replaced by one or more selected from halogen, -OH, =O, -OC 1- 6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O ) NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituents;
    环A是5-8元的烃环、5-8元杂环、5-8元杂芳环或5-8元芳环,且所述烃环、杂环、杂芳环和芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基、C 3-6环烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Ring A is a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, a 5-8 membered heteroaryl ring or a 5-8 membered aromatic ring, and each of the hydrocarbon ring, heterocyclic ring, heteroaryl ring and aromatic ring is any Optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3- 10-membered heterocyclic group, 6-10-membered aryl group, 5-10-membered heteroaryl group, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl) , -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkyl and -C(O)N (C 1-6 alkyl) substituted by a substituent, each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally further selected from one or more halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1- 6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 are substituted by substituents;
    环B是包含N原子的5-8元杂环或5-8元杂芳环,且所述杂环和杂芳环各自任选地被 一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Ring B is a 5-8 membered heterocyclic ring or a 5-8 membered heteroaryl ring containing N atoms, and each of the heterocyclic ring and heteroaryl ring is optionally replaced by one or more members selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclyl, 6-10 membered Aryl, 5-10 membered heteroaryl, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1 Substituents of -6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , Each of said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally further replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, - Substituents of C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ;
    R 1在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), - N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O ) NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituents;
    R 2在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; Each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), - N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O ) NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituents;
    R 3和R 4各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代;或者R 3和R 4与它们连接的原子一起形成3-12元的单环或多环烃环、3-12元的单环或多环杂环、3-12元的烃环和杂环形成的多环环系、3-6元的烃环与5-8元的杂芳环稠合形成的多环环系、3-6元的烃环与5-8元的芳环稠合形成的多环环系、3-6元的杂环与5-8元的杂芳环稠合形成的多环环系、或3-6元的杂环与5-8元的芳环稠合形成的多环环系,且所述每个环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、 -C(O)NH 2、-COOH、-C(O)OC 1-6烷基、C 3-6环烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选进一步地被一个或多个选自卤素、-OH、=O、-OC1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代; R 3 and R 4 are each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl , 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N( C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1- 6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2. Substituents of -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; or R 3 and R 4 form together with the atoms they are attached to 3-12 membered monocyclic or polycyclic hydrocarbon ring, 3-12 membered monocyclic or polycyclic heterocyclic ring, polycyclic ring system formed by 3-12 membered hydrocarbon ring and heterocyclic ring, 3-6 membered hydrocarbon ring A polycyclic ring system formed by condensing a 5-8-membered heteroaromatic ring, a polycyclic ring system formed by condensing a 3-6-membered hydrocarbon ring with a 5-8-membered aromatic ring, a 3-6-membered heterocyclic ring and A polycyclic ring system formed by condensing a 5-8 membered heteroaromatic ring, or a polycyclic ring system formed by condensing a 3-6 membered heterocyclic ring and a 5-8 membered aromatic ring, and each ring is independently Optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3- 10-membered heterocyclic group, 6-10-membered aryl group, 5-10-membered heteroaryl group, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl) , -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkyl and -C(O)N (C 1-6 alkyl) substituted by a substituent, each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally further selected from one or more halogen, -OH, =O, -OC1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 Alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 are substituted by substituents;
    m为0、1、2或3;和m is 0, 1, 2 or 3; and
    n为0、1、2或3。n is 0, 1, 2 or 3.
  6. 根据权利要求5所述的式I化合物或其药学上可接受的盐,其中The formula I compound or its pharmaceutically acceptable salt according to claim 5, wherein
    R 8独立地选自H、卤素、-OH、-CN、C 1-6烷基、-OC 1-6烷基、-NH 2、-NO 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2,所述烷基和环烷基任选被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NO 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代;和/或 R 8 is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N( C 1-6 alkyl) 2 , the alkyl and cycloalkyl are optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , - NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O) OC 1-6 alkyl and -C (O) N (C 1-6 alkyl) substituent substitution; and/or
    所述环A是5-8元的烃环、5-8元杂环、5-8元杂芳环或5-8元芳环,且所述烃环、杂环、杂芳环和芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代,所述C 1-6烷基任选进一步地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2和-NH(C 1-6烷基)的取代基取代;和/或 The ring A is a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, a 5-8 membered heteroaryl ring or a 5-8 membered aromatic ring, and the hydrocarbon ring, heterocyclic ring, heteroaryl ring and aromatic ring Each is optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl ), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl ) 2 is substituted by a substituent, the C 1-6 alkyl is optionally further selected from one or more halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 and - Substituent substitution of NH(C 1-6 alkyl); and/or
    所述环B是包含N原子的5-8元杂环或5-8元杂芳环,且所述杂环和杂芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、-OC 1-6烷基、-CN、-NH 2和-NH(C 1-6烷基)的取代基取代;和/或 The ring B is a 5-8 membered heterocyclic ring or a 5-8 membered heteroaryl ring containing N atoms, and each of the heterocyclic ring and the heteroaryl ring is optionally replaced by one or more members selected from halogen, -OH, = Substituent substitution of O, C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NH 2 and -NH(C 1-6 alkyl); and/or
    R 1在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2和C 3-6环烷基,其中所述C 1-6烷基、和C 3-6环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2和-NH(C 1-6烷基)的取代基取代;和/或 Each occurrence of R 1 is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl ), -N(C 1-6 alkyl) 2 and C 3-6 cycloalkyl, wherein each of the C 1-6 alkyl and C 3-6 cycloalkyl is optionally selected from one or more Substituents from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 and -NH(C 1-6 alkyl); and/or
    R 2在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH和-C(O)OC 1-6烷基,其中所述C 1-6烷基任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2和-NH(C 1-6烷基)的取代基取代;和/或 Each occurrence of R 2 is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl ), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH and -C(O)OC 1-6 alkyl, wherein the C 1-6 alkyl is optionally One or more substituents selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 and -NH(C 1-6 alkyl); and/or
    R 3和R 4各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)和-N(C 1-6烷基) 2,其中所述C 1-6烷基各自任选地被一个或多个选自卤素、-OH、=O、 -OC 1-6烷基、-CN、-NH 2和-NH(C 1-6烷基)的取代基取代;或者R 3和R 4与它们连接的原子一起形成3-6元的单环或多环烃环、3-6元的单环或多环杂环、3-6元的烃环和杂环形成的多环环系、3-6元的烃环与5-6元的杂芳环稠合形成的双环或更多环系、3-6元的烃环与5-6元的芳环稠合形成的双环或更多环系、3-6元的杂环与5-6元的杂芳环稠合形成的双环或更多环系、或3-6元的杂环与5-6元的芳环稠合形成的双环或更多环系。 R 3 and R 4 are each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 , wherein each of the C 1-6 alkyl groups is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN , -NH 2 and -NH (C 1-6 alkyl) substituent substitution; or R 3 and R 4 form a 3-6 membered monocyclic or polycyclic hydrocarbon ring together with the atoms they are connected to, 3-6 membered Monocyclic or polycyclic heterocyclic rings, polycyclic ring systems formed by 3-6 membered hydrocarbon rings and heterocyclic rings, bicyclic or more Ring system, a bicyclic or more ring system formed by condensing a 3-6-membered hydrocarbon ring with a 5-6-membered aromatic ring, a bicyclic ring formed by condensing a 3-6-membered heterocycle and a 5-6-membered heteroaromatic ring or more ring systems, or bicyclic or more ring systems formed by the fusion of 3-6 membered heterocycles and 5-6 membered aromatic rings.
  7. 根据权利要求5或6所述的式I化合物或其药学上可接受的盐,其中环A是5-8元的烃环、5-8元杂环、或5-8元杂芳环,优选地,环A是具有1、2、3或4个独立地选自N、O和S的杂原子的5-6元杂环或杂芳环,优选地,环A是具有1或2个独立地选自N和O的杂原子的5-6元杂环或杂芳环,优选环A是5-8元的烃环或5-8元杂环,优选地,环A是具有1、2、3或4个独立地选自N、O和S的杂原子的5-6元杂环,进一步优选,环A选自部分不饱和的吗啉环、咪唑环、吡唑环、吡咯环、部分不饱和的吡唑烷环、部分不饱和的哌啶环、部分不饱和的哌嗪环、部分不饱和的六氢嘧啶环、部分不饱和的吡咯烷环和部分不饱和的咪唑烷环;和/或The compound of formula I according to claim 5 or 6 or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, or a 5-8 membered heteroaromatic ring, preferably Preferably, ring A is a 5-6 membered heterocyclic or heteroaromatic ring having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, preferably, ring A is having 1 or 2 independently A 5-6-membered heterocyclic or heteroaryl ring of heteroatoms selected from N and O, preferably ring A is a 5-8-membered hydrocarbon ring or a 5-8-membered heterocyclic ring, preferably, ring A has 1, 2 , 3 or 4 5-6 membered heterocyclic rings independently selected from N, O and S heteroatoms, further preferably, ring A is selected from partially unsaturated morpholine rings, imidazole rings, pyrazole rings, pyrrole rings, partially unsaturated pyrazolidine ring, partially unsaturated piperidine ring, partially unsaturated piperazine ring, partially unsaturated hexahydropyrimidine ring, partially unsaturated pyrrolidine ring and partially unsaturated imidazolidine ring; and / or
    环A任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、-OC 1-6烷基、-CN、-NH 2、-C(O)NH 2、-COOH、-C(O)N(C 1-6烷基) 2、-C 1-6亚烷基-OH和卤代C 1-6烷基的取代基取代,优选地,环A任选地被一个或多个选自F、Cl、Br、-OH、=O、C 1-3烷基、-OC 1-3烷基、-CN、-NH 2、-C(O)NH 2、-COOH、-C(O)N(C 1-3烷基) 2、-C 1-3亚烷基-OH和卤代C 1-3烷基的取代基取代,更优选地环A任选地被一个或多个选自F、=O、-CH 3、-C(O)NH 2、-COOH、-C(O)N(CH 3) 2和-CH 2-OH的取代基取代。 Ring A is optionally replaced by one or more members selected from halogen, -OH, =O, C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NH 2 , -C(O)NH 2 , Substituents of -COOH, -C(O)N(C 1-6 alkyl) 2 , -C 1-6 alkylene-OH and halogenated C 1-6 alkyl, preferably, ring A is optionally is one or more selected from F, Cl, Br, -OH, =O, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH 2 , -C(O)NH 2 , Substituents of -COOH, -C(O)N(C 1-3 alkyl) 2 , -C 1-3 alkylene-OH and halogenated C 1-3 alkyl, more preferably ring A is optionally is substituted with one or more substituents selected from F, =O, -CH 3 , -C(O)NH 2 , -COOH, -C(O)N(CH 3 ) 2 and -CH 2 -OH.
  8. 根据权利要求5-7任一项所述的式I化合物或其药学上可接受的盐,其中环B选自包含N原子的5、6、7或8元杂环,优选地,环B是部分不饱和的哌啶环、部分不饱和的哌嗪环、部分不饱和的二氮杂环庚烷环、部分不饱和的咪唑啉环、部分不饱和的吗啉环或部分不饱和的吡唑烷环,且所述环B任选地被一个或多个选自卤素、-OH、=O、C 1-3烷基、-OC 1-3烷基、-CN、-NH 2、和-NH(C 1-3烷基)的取代基取代。 The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 5-7, wherein ring B is selected from 5, 6, 7 or 8-membered heterocycles containing N atoms, preferably, ring B is A partially unsaturated piperidine ring, a partially unsaturated piperazine ring, a partially unsaturated diazepane ring, a partially unsaturated imidazoline ring, a partially unsaturated morpholine ring, or a partially unsaturated pyrazole ring alkane ring, and the ring B is optionally replaced by one or more selected from halogen, -OH, =O, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH 2 , and - NH (C 1-3 alkyl) substituent substitution.
  9. 根据权利要求5-8任一项所述的式I化合物或其药学上可接受的盐,A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 5-8,
    其中
    Figure PCTCN2022122329-appb-100008
    部分是如下的化学结构:
    in
    Figure PCTCN2022122329-appb-100008
    Part is the following chemical structure:
    Figure PCTCN2022122329-appb-100009
    Figure PCTCN2022122329-appb-100009
    其中,W 4选自C(R 5) 2、O、和NR 5Wherein, W 4 is selected from C(R 5 ) 2 , O, and NR 5 ;
    p为0、1或2;p is 0, 1 or 2;
    q为0或1;q is 0 or 1;
    R 5在每次出现时各自独立地选自H、卤素、-OH、=O、C 1-6烷基、-OC 1-6烷基、-CN、-NH 2、-C(O)NH 2、-COOH、-C(O)N(C 1-6烷基) 2、-C 1-6亚烷基-OH、和卤代C 1-6烷基;优选地,R 5在每次出现时各自独立地选自H、F、Cl、Br、-OH、=O、C 1-3烷基、-OC 1-3烷基、-CN、-NH 2、-C(O)NH 2、-COOH、-C(O)N(C 1-3烷基) 2、-C 1-3亚烷基-OH、和卤代C 1-3烷基;更优选地,R 5在每次出现时各自独立地选自H、-F、=O、-CH 3、-C(O)NH 2、-COOH、-C(O)N(CH 3) 2、和-CH 2-OH;和 Each occurrence of R is independently selected from H, halogen, -OH, =O, C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NH 2 , -C(O)NH 2 , -COOH, -C(O)N(C 1-6 alkyl) 2 , -C 1-6 alkylene-OH, and halogenated C 1-6 alkyl; preferably, R 5 in each When present, each is independently selected from H, F, Cl, Br, -OH, =O, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH 2 , -C(O)NH 2 , -COOH, -C(O)N(C 1-3 alkyl) 2 , -C 1-3 alkylene-OH, and halogenated C 1-3 alkyl; more preferably, R 5 in each each occurrence is independently selected from H, -F, =O, -CH3 , -C(O) NH2 , -COOH, -C(O)N( CH3 ) 2 , and -CH2 - OH; and
    f为0、1、2、3、4或5。f is 0, 1, 2, 3, 4 or 5.
  10. 根据权利要求9所述的式I化合物或其药学上可接受的盐,The compound of formula I according to claim 9 or a pharmaceutically acceptable salt thereof,
    其中,
    Figure PCTCN2022122329-appb-100010
    部分选自如下的化学结构:
    in,
    Figure PCTCN2022122329-appb-100010
    Partially selected from the following chemical structures:
    Figure PCTCN2022122329-appb-100011
    Figure PCTCN2022122329-appb-100011
    Figure PCTCN2022122329-appb-100012
    Figure PCTCN2022122329-appb-100012
    其中,R 5和f如权利要求9中所定义。 wherein R and f are as defined in claim 9.
  11. 根据权利要求5-10中任一项所述的式I化合物或其药学上可接受的盐,其中R 1在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-3烷基、-OC 1-3烷基、-NH 2、卤代C 1-3烷基和C 3-4环烷基;优选地,R 1在每次出现时各自独立地选自H、-CN、-CH 3和环丙基。 A compound of formula I according to any one of claims 5-10, or a pharmaceutically acceptable salt thereof, wherein R is each independently selected from H, halogen, -OH, -CN, C at each occurrence -3 alkyl, -OC 1-3 alkyl, -NH 2 , halogenated C 1-3 alkyl and C 3-4 cycloalkyl; preferably, each occurrence of R is independently selected from H , -CN, -CH 3 and cyclopropyl.
  12. 根据权利要求5-11任一项所述的式I化合物或其药学上可接受的盐,其中R 2在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-3烷基、-OC 1-3烷基、-NH 2、-C(O)NH 2、-COOH、-C(O)OC 1-3烷基、-C 1-3亚烷基-OH和卤代C 1-3烷基;优选地,R 2在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-3烷基、-C(O)NH 2和-C 1-3亚烷基-OH;还优选地,R 2在每次出现时各自独立地选自H、F、-OH、-CN、-CH 3、-C(O)NH 2和-CH 2-OH。 The compound of formula I according to any one of claims 5-11, or a pharmaceutically acceptable salt thereof, wherein R 2 are each independently selected from H, halogen, -OH, -CN, C 1- 3 alkyl, -OC 1-3 alkyl, -NH 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-3 alkyl, -C 1-3 alkylene-OH and Halogenated C 1-3 alkyl; preferably, each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -C(O)NH 2 and - C 1-3 alkylene-OH; also preferably, each occurrence of R 2 is independently selected from H, F, -OH, -CN, -CH 3 , -C(O)NH 2 and -CH 2 -OH.
  13. 根据权利要求5-12任一项所述的式I化合物或其药学上可接受的盐,其中:The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 5-12, wherein:
    R 3和R 4各自独立地选自H、卤素、-OH、-CN、C 1-3烷基、-OC 1-3烷基、-C 1-3亚烷 基-NH 2、-NH 2、-NH(C 1-3烷基)和-N(C 1-3烷基) 2;优选地,R 3和R 4各自独立地选自H、卤素、-OH、-CN、C 1-3烷基、-C 1-3亚烷基-NH 2和-NH 2;还优选地,R 3和R 4各自独立地选自H、-F、-OH、-CH 2-NH 2和-NH 2;或 R 3 and R 4 are each independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -OC 1-3 alkyl, -C 1-3 alkylene -NH 2 , -NH 2 , -NH(C 1-3 alkyl) and -N(C 1-3 alkyl) 2 ; preferably, R 3 and R 4 are each independently selected from H, halogen, -OH, -CN, C 1- 3 alkyl, -C 1-3 alkylene -NH 2 and -NH 2 ; also preferably, R 3 and R 4 are each independently selected from H, -F, -OH, -CH 2 -NH 2 and - NH2 ; or
    R 3和R 4与它们连接的原子一起形成3、4、5或6元的单环烃环、或3、4、5或6元的单环杂环,优选地,R 3和R 4与它们连接的原子一起形成具有1、2、3或4个选自N、O或S杂原子的5-6元的单环杂环,其中所述烃环和杂环各自任选地被一个或多个选自卤素、-OH、-CN、C 1-6烷基、-OC 1-6烷基、-NH 2、-C(O)N(C 1-6烷基) 2、-C 1-6亚烷基-OH和卤代C 1-6烷基的取代基取代,优选地被一个或多个选自F、Cl、Br、-OH、-CN、C 1-3烷基、-OC 1-3烷基、-NH 2、-C 1-3亚烷基-OH、-C(O)N(C 1-3烷基) 2和卤代C 1-3烷基的取代基取代,优选地被一个或多个选自F、Cl、Br、-OH、-CN、-CH 3、-OCH 3、-NH 2、-CH 2-OH、-C(O)N(CH 3) 2和-CF 3的取代基取代;更优选地,
    Figure PCTCN2022122329-appb-100013
    部分是如下的化学结构:
    Figure PCTCN2022122329-appb-100014
    其中,Y 1选自O、S、C(R 6) 2、或NR 6,R 6在每次出现时各自独立地选自H、卤素、-OH、-CN、C 1-3烷基、-OC 1-3烷基、-NH 2和卤代C 1-3烷基,优选,R 6在每次出现时各自独立地选自H、卤素、-OH、-CN、-CH 3、-OCH 3、-NH 2、-CH 2-OH、-C(O)N(CH 3) 2和-CF 3,g为0、1、2、3、4、5或6;或
    R 3 and R 4 form a 3, 4, 5 or 6-membered monocyclic hydrocarbon ring, or a 3, 4, 5 or 6-membered monocyclic heterocyclic ring together with the atoms they are connected to, preferably, R 3 and R 4 are combined with The atoms they connect together form a 5-6 membered monocyclic heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from N, O or S, wherein the hydrocarbon ring and heterocyclic ring are each optionally replaced by one or Multiple selected from halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -C(O)N(C 1-6 alkyl) 2 , -C 1 -6 alkylene-OH and halogenated C 1-6 alkyl substituents are preferably substituted by one or more selected from F, Cl, Br, -OH, -CN, C 1-3 alkyl, - Substituents of OC 1-3 alkyl, -NH 2 , -C 1-3 alkylene-OH, -C(O)N(C 1-3 alkyl) 2 and halogenated C 1-3 alkyl , preferably one or more selected from F, Cl, Br, -OH, -CN, -CH 3 , -OCH 3 , -NH 2 , -CH 2 -OH, -C(O)N(CH 3 ) 2 and the substituents of -CF 3 are substituted; more preferably,
    Figure PCTCN2022122329-appb-100013
    Part is the following chemical structure:
    Figure PCTCN2022122329-appb-100014
    Wherein, Y 1 is selected from O, S, C(R 6 ) 2 , or NR 6 , and each occurrence of R 6 is independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -OC 1-3 alkyl, -NH 2 and halogenated C 1-3 alkyl, preferably, each occurrence of R is independently selected from H, halogen, -OH, -CN, -CH 3 , - OCH 3 , -NH 2 , -CH 2 -OH, -C(O)N(CH 3 ) 2 and -CF 3 , g is 0, 1, 2, 3, 4, 5 or 6; or
    R 3和R 4与它们连接的原子一起形成5-6元的烃环与5-6元的杂芳环稠合形成的双环系、5-6元的烃环与5-6元的芳环稠合形成的双环系、5-6元的杂环与5-6元的杂芳环稠合形成的双环系、或5-6元的杂环与5-6元的芳环稠合形成的双环系,其中所述烃环、杂环、杂芳环和芳环各自任选地被一个或多个选自卤素、-OH、=O、C 1-6烷基、-OC 1-6烷基、-CN、-NH 2、-C(O)NH 2、-COOH、-C(O)N(C 1-6烷基) 2、-C 1-6亚烷基-OH、和卤代C 1-6烷基的取代基取代,优选地被一个或多个选自卤素、-OH、C 1-3烷基、-OC 1-3烷基、-CN、-NH 2、-C(O)NH 2、-C 1-3亚烷基-OH、-C(O)N(C 1-3烷基) 2、和卤代C 1-3烷基的取代基取代,优选地被一个或多个选自F、Cl、Br、-OH、-CN、-CH 3、-OCH 3、-NH 2、-CH 2-OH、-C(O)N(CH 3) 2和-CF 3 的取代基取代;还优选地,
    Figure PCTCN2022122329-appb-100015
    部分是如下的
    R 3 and R 4 together with the atoms they connect form a bicyclic ring system formed by condensing a 5-6 membered hydrocarbon ring with a 5-6 membered heteroaromatic ring, a 5-6 membered hydrocarbon ring and a 5-6 membered aromatic ring A bicyclic ring system formed by fusion, a bicyclic system formed by the fusion of a 5-6 membered heterocyclic ring and a 5-6 membered heteroaryl ring, or a fused 5-6 membered heterocyclic ring and a 5-6 membered aromatic ring Bicyclic ring system, wherein said hydrocarbon ring, heterocycle, heteroaromatic ring and aromatic ring are each optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, -OC 1-6 alkane radical, -CN, -NH 2 , -C(O)NH 2 , -COOH, -C(O)N(C 1-6 alkyl) 2 , -C 1-6 alkylene-OH, and halo Substituents of C 1-6 alkyl are preferably substituted by one or more selected from halogen, -OH, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH 2 , -C( Substituents of O)NH 2 , -C 1-3 alkylene-OH, -C(O)N(C 1-3 alkyl) 2 , and halogenated C 1-3 alkyl are preferably substituted by one or more selected from F, Cl, Br, -OH, -CN, -CH 3 , -OCH 3 , -NH 2 , -CH 2 -OH, -C(O)N(CH 3 ) 2 and -CF 3 Substituents are substituted; also preferably,
    Figure PCTCN2022122329-appb-100015
    part is as follows
    化学结构:
    Figure PCTCN2022122329-appb-100016
    其中,Y 2选自O、S、CH 2、和NH,优选地,选自O、和CH 2;Y 3、Y 4、Y 5、和Y 6各自独立地选自CR 7和N,优选Y 3、Y 4、Y 5、和Y 6各自独立地选自CH和N;R 7在每次出现时各自独立地选自H、卤素、-OH、C 1-3烷基、-OC 1-3烷基、-CN、-NH 2、-C(O)NH 2、-C 1-3亚烷基-OH、-C(O)N(C 1-3烷基) 2、和卤代C 1-3烷基,优选R 7在每次出现时各自独立地选自H、F、Cl、Br、-OH、-CN、-CH 3、-OCH 3、-NH 2、-CH 2-OH、-C(O)N(CH 3) 2和-CF 3;且h为0、1、2、3或4。
    Chemical structure:
    Figure PCTCN2022122329-appb-100016
    Wherein, Y 2 is selected from O, S, CH 2 , and NH, preferably, selected from O, and CH 2 ; Y 3 , Y 4 , Y 5 , and Y 6 are each independently selected from CR 7 and N, preferably Y 3 , Y 4 , Y 5 , and Y 6 are each independently selected from CH and N; each occurrence of R 7 is independently selected from H, halogen, -OH, C 1-3 alkyl, -OC 1 -3 alkyl, -CN, -NH 2 , -C(O)NH 2 , -C 1-3 alkylene-OH, -C(O)N(C 1-3 alkyl) 2 , and halo C 1-3 alkyl, preferably each occurrence of R 7 is independently selected from H, F, Cl, Br, -OH, -CN, -CH 3 , -OCH 3 , -NH 2 , -CH 2 - OH, -C(O)N( CH3 ) 2 and -CF3 ; and h is 0, 1, 2, 3 or 4.
  14. 根据权利要求5-13任一项所述的式I化合物或其药学上可接受的盐,其中式I化合物具有式II的结构:The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 5-13, wherein the compound of formula I has the structure of formula II:
    Figure PCTCN2022122329-appb-100017
    Figure PCTCN2022122329-appb-100017
    其中,W 1,W 2,W 3,X 1,X 2,X 3,X 4,Z,m和n如权利要求5中所定义,R 1和R 2如权利要求5、6、11、或12中所定义,W 4、R 5、p、q和f如权利要求9中所定义,Y 2,Y 3,Y 4,Y 5和Y 6如权利要求13中所定义; Wherein, W 1 , W 2 , W 3 , X 1 , X 2 , X 3 , X 4 , Z, m and n are as defined in claim 5, R 1 and R 2 are as defined in claim 5, 6, 11, or 12, W 4 , R 5 , p, q and f are as defined in claim 9, Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are as defined in claim 13;
    优选地,X 1和X 2均为N,和/或p为1或2,q为0或1。 Preferably, both X1 and X2 are N, and/or p is 1 or 2, and q is 0 or 1.
  15. 化合物或其药学上可接受的盐,所述化合物选自:A compound or a pharmaceutically acceptable salt thereof, the compound being selected from:
    Figure PCTCN2022122329-appb-100018
    Figure PCTCN2022122329-appb-100018
    Figure PCTCN2022122329-appb-100019
    Figure PCTCN2022122329-appb-100019
    Figure PCTCN2022122329-appb-100020
    Figure PCTCN2022122329-appb-100020
    Figure PCTCN2022122329-appb-100021
    Figure PCTCN2022122329-appb-100021
  16. 如权利要求15所述的化合物或其药学上可接受的盐,所述化合物选自:The compound or a pharmaceutically acceptable salt thereof as claimed in claim 15, which is selected from the group consisting of:
    Figure PCTCN2022122329-appb-100022
    Figure PCTCN2022122329-appb-100022
    Figure PCTCN2022122329-appb-100023
    Figure PCTCN2022122329-appb-100023
    Figure PCTCN2022122329-appb-100024
    Figure PCTCN2022122329-appb-100024
    Figure PCTCN2022122329-appb-100025
    Figure PCTCN2022122329-appb-100025
    Figure PCTCN2022122329-appb-100026
    Figure PCTCN2022122329-appb-100026
  17. 用于制备如权利要求1-16中任一项所述化合物的中间体,或其盐,选自:An intermediate for the preparation of the compound according to any one of claims 1-16, or a salt thereof, selected from:
    Figure PCTCN2022122329-appb-100027
    Figure PCTCN2022122329-appb-100027
    其中,R 9和R 10各自独立地选自H、卤素、-OH、-CN、C 1-6烷基、C 2-6烯基、-S(=O) 0-2-C 1-6烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基、-OC 1-6烷基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 3-6环烷基、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2, 其中所述烷基、烯基、杂环基、芳基、杂芳基和环烷基各自任选地被一个或多个选自卤素、-OH、=O、-OC 1-6烷基、-CN、-NH 2、-NH(C 1-6烷基)、C 3-6环烷基、-N(C 1-6烷基) 2、-C(O)NH 2、-COOH、-C(O)OC 1-6烷基和-C(O)N(C 1-6烷基) 2的取代基取代。 Wherein, R 9 and R 10 are each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), - N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O )NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 are substituted.
  18. 如权利要求17中所述的中间体,或其盐,选自:The intermediate as claimed in claim 17, or a salt thereof, selected from:
    Figure PCTCN2022122329-appb-100028
    Figure PCTCN2022122329-appb-100028
  19. 结构式如式II所示的化合物或其药学上可接受的盐的制备方法:The preparation method of the compound whose structural formula is shown as formula II or its pharmaceutically acceptable salt:
    Figure PCTCN2022122329-appb-100029
    Figure PCTCN2022122329-appb-100029
    其中,W 1,W 2,W 3,Z,m和n如权利要求1中所定义,R 1和R 2如权利要求5、6、11、或15中所定义,W 4、R 5、p、q和f如权利要求5中所定义,Y 2,Y 3,Y 4,Y 5和Y 6如权利要求13中所定义,X 1,X 2,X 3,X 4均为N,n为0, Wherein, W 1 , W 2 , W 3 , Z, m and n are as defined in claim 1, R 1 and R 2 are as defined in claim 5, 6, 11, or 15, W 4 , R 5 , p, q and f are as defined in claim 5, Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are as defined in claim 13, X 1 , X 2 , X 3 , and X 4 are all N, n is 0,
    其特征在于,包括,利用对应于A部分结构的第一关键中间体、对应于B部分结构的第二关键中间体、对应于C部分结构的第三关键中间体进行取代反应制备得到式II所示的化合物。It is characterized in that, comprising, using the first key intermediate corresponding to the structure of part A, the second key intermediate corresponding to the structure of part B, and the third key intermediate corresponding to the structure of part C to perform substitution reactions to prepare the formula II the indicated compounds.
  20. 如权利要求19所述的制备方法,其中所述第三关键中间体结构式如式Ⅲ所示:The preparation method according to claim 19, wherein the structural formula of the third key intermediate is shown in formula III:
    Figure PCTCN2022122329-appb-100030
    其中,R 9和R 10如权利要求17中所定义。
    Figure PCTCN2022122329-appb-100030
    wherein R 9 and R 10 are as defined in claim 17.
  21. 如权利要求20所述的制备方法,其中所述第三关键中间体选自:The preparation method according to claim 20, wherein the third key intermediate is selected from:
    Figure PCTCN2022122329-appb-100031
    Figure PCTCN2022122329-appb-100031
  22. 如权利要求19-21中任一项所述的制备方法,其中所述第一关键中间体选自:The preparation method according to any one of claims 19-21, wherein the first key intermediate is selected from:
    Figure PCTCN2022122329-appb-100032
    Figure PCTCN2022122329-appb-100032
  23. 如权利要求19-21所述的制备方法,其中所述第二关键中间体选自:The preparation method according to claims 19-21, wherein the second key intermediate is selected from:
    Figure PCTCN2022122329-appb-100033
    Figure PCTCN2022122329-appb-100033
  24. 如权利要求19-23所述的制备方法,其特征在于,包括:The preparation method according to claims 19-23, characterized in that it comprises:
    (A)当化合物或其药学上可接受的盐具有结构式
    Figure PCTCN2022122329-appb-100034
    时,通过包括下述步骤的方法制备:
    (A) When the compound or its pharmaceutically acceptable salt has the structural formula
    Figure PCTCN2022122329-appb-100034
    , prepared by a method comprising the following steps:
    (a1)将化合物
    Figure PCTCN2022122329-appb-100035
    溶解于DCM中,加入三氟乙酸,搅拌2小时,用饱和碳酸氢钠中和反应液,二氯甲烷萃取,合并有机相,减压浓缩,纯化得化合物
    Figure PCTCN2022122329-appb-100036
    (a1) compound
    Figure PCTCN2022122329-appb-100035
    Dissolve in DCM, add trifluoroacetic acid, stir for 2 hours, neutralize the reaction solution with saturated sodium bicarbonate, extract with dichloromethane, combine the organic phases, concentrate under reduced pressure, and purify the compound
    Figure PCTCN2022122329-appb-100036
    (a2)将
    Figure PCTCN2022122329-appb-100037
    溶于DMF,加入三乙胺和化合物
    Figure PCTCN2022122329-appb-100038
    50℃下搅拌,反应混合物用饱和食盐水稀释,萃取,有机层用无水硫酸钠干燥,过滤,减压浓缩得化合物
    Figure PCTCN2022122329-appb-100039
    (a2) will
    Figure PCTCN2022122329-appb-100037
    Dissolve in DMF, add triethylamine and compound
    Figure PCTCN2022122329-appb-100038
    Stir at 50°C, dilute the reaction mixture with saturated brine, extract, dry the organic layer with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the compound
    Figure PCTCN2022122329-appb-100039
    (a3)将化合物
    Figure PCTCN2022122329-appb-100040
    和化合物
    Figure PCTCN2022122329-appb-100041
    溶于甲苯,氮气保护下加入Pd 2(dba) 3,RuPhos和Cs 2CO 3,100℃搅拌16小时,冷却至室温并减压浓缩,通过制备TLC(DCM:MeOH=10:1)纯化残余物得化合物
    Figure PCTCN2022122329-appb-100042
    将化合物
    Figure PCTCN2022122329-appb-100043
    溶于HCl/Dioxane和甲醇中,搅拌1小时,减压浓缩,纯化得
    Figure PCTCN2022122329-appb-100044
    (a3) compound
    Figure PCTCN2022122329-appb-100040
    and compounds
    Figure PCTCN2022122329-appb-100041
    Dissolve in toluene, add Pd 2 (dba) 3 , RuPhos and Cs 2 CO 3 under nitrogen protection, stir at 100°C for 16 hours, cool to room temperature and concentrate under reduced pressure, and purify the residue by preparative TLC (DCM:MeOH=10:1) compound
    Figure PCTCN2022122329-appb-100042
    compound
    Figure PCTCN2022122329-appb-100043
    Dissolved in HCl/Dioxane and methanol, stirred for 1 hour, concentrated under reduced pressure, and purified to obtain
    Figure PCTCN2022122329-appb-100044
    和/或,(B)当化合物或其药学上可接受的盐具有结构式
    Figure PCTCN2022122329-appb-100045
    时,通过包括下述步骤的方法制备:
    And/or, (B) when the compound or a pharmaceutically acceptable salt thereof has the formula
    Figure PCTCN2022122329-appb-100045
    , prepared by a method comprising the following steps:
    (b1)将化合物
    Figure PCTCN2022122329-appb-100046
    溶于二氧六环中,氮气保护下加入化合物
    Figure PCTCN2022122329-appb-100047
    Pd 2(dba) 3,Xantphos和Cs 2CO 3,100℃下搅拌过夜,EA稀释,过滤,浓缩滤液,纯化得化合物
    Figure PCTCN2022122329-appb-100048
    (b1) compound
    Figure PCTCN2022122329-appb-100046
    Dissolve in dioxane, add compound under nitrogen protection
    Figure PCTCN2022122329-appb-100047
    Pd 2 (dba) 3 , Xantphos and Cs 2 CO 3 , stirred overnight at 100°C, diluted with EA, filtered, concentrated the filtrate, and purified the compound
    Figure PCTCN2022122329-appb-100048
    (b2)将化合物
    Figure PCTCN2022122329-appb-100049
    溶于THF/H 2O/MeOH中,加入钯/碳和甲酸铵,50℃搅拌过夜,反应液用EA稀释,过滤,滤液浓缩,纯化得化合物
    Figure PCTCN2022122329-appb-100050
    (b2) compound
    Figure PCTCN2022122329-appb-100049
    Dissolve in THF/H 2 O/MeOH, add palladium/carbon and ammonium formate, stir overnight at 50°C, dilute the reaction solution with EA, filter, concentrate the filtrate, and purify the compound
    Figure PCTCN2022122329-appb-100050
    (b3)将化合物
    Figure PCTCN2022122329-appb-100051
    溶于二氯甲烷(DCM)中,加入对甲苯磺酰氯和N,N-二异丙基乙胺(DIEA),室温搅拌1.5小时,浓缩,纯化得化合物
    Figure PCTCN2022122329-appb-100052
    (b3) compound
    Figure PCTCN2022122329-appb-100051
    Dissolve in dichloromethane (DCM), add p-toluenesulfonyl chloride and N,N-diisopropylethylamine (DIEA), stir at room temperature for 1.5 hours, concentrate, and purify the compound
    Figure PCTCN2022122329-appb-100052
    (b4)将化合物
    Figure PCTCN2022122329-appb-100053
    溶于DMF中,加入三乙胺(TEA)和化合物
    Figure PCTCN2022122329-appb-100054
    50℃搅拌过夜,反应液用EA稀释,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,纯化得化合物
    Figure PCTCN2022122329-appb-100055
    (b4) compound
    Figure PCTCN2022122329-appb-100053
    Dissolve in DMF, add triethylamine (TEA) and compound
    Figure PCTCN2022122329-appb-100054
    Stir overnight at 50°C, dilute the reaction solution with EA, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify the compound
    Figure PCTCN2022122329-appb-100055
    (b5)化合物
    Figure PCTCN2022122329-appb-100056
    溶于HCl/dioxane中,室温搅拌1小时,减压浓缩,纯化得
    Figure PCTCN2022122329-appb-100057
    (b5) compound
    Figure PCTCN2022122329-appb-100056
    Dissolved in HCl/dioxane, stirred at room temperature for 1 hour, concentrated under reduced pressure, and purified to obtain
    Figure PCTCN2022122329-appb-100057
    和/或,(C)当化合物或其药学上可接受的盐,具有结构式
    Figure PCTCN2022122329-appb-100058
    时,通过包括下述步骤的方法制备:
    And/or, (C) when the compound or a pharmaceutically acceptable salt thereof has the structural formula
    Figure PCTCN2022122329-appb-100058
    , prepared by a method comprising the following steps:
    (c1)化合物
    Figure PCTCN2022122329-appb-100059
    和化合物
    Figure PCTCN2022122329-appb-100060
    溶于甲苯中,氮气保护下,加入Pd 2(dba) 3,Ruphos和Cs 2CO 3,110℃搅拌,反应液减压浓缩,纯化得化合物
    Figure PCTCN2022122329-appb-100061
    (c1) compound
    Figure PCTCN2022122329-appb-100059
    and compounds
    Figure PCTCN2022122329-appb-100060
    Dissolve in toluene, under nitrogen protection, add Pd 2 (dba) 3 , Ruphos and Cs 2 CO 3 , stir at 110°C, concentrate the reaction solution under reduced pressure, and purify the compound
    Figure PCTCN2022122329-appb-100061
    (c2)将化合物
    Figure PCTCN2022122329-appb-100062
    溶于NH 3/MeOH中,70℃搅拌4个小时,浓缩得化合物
    Figure PCTCN2022122329-appb-100063
    (c2) compound
    Figure PCTCN2022122329-appb-100062
    Dissolved in NH 3 /MeOH, stirred at 70°C for 4 hours, concentrated to give the compound
    Figure PCTCN2022122329-appb-100063
    (c3)将化合物
    Figure PCTCN2022122329-appb-100064
    溶于HCl/dioxane中,室温搅拌1小时,减压浓缩,纯化得
    Figure PCTCN2022122329-appb-100065
    (c3) compound
    Figure PCTCN2022122329-appb-100064
    Dissolved in HCl/dioxane, stirred at room temperature for 1 hour, concentrated under reduced pressure, and purified to obtain
    Figure PCTCN2022122329-appb-100065
    和/或,(D)当化合物或其药学上可接受的盐具有结构式
    Figure PCTCN2022122329-appb-100066
    时,通过包括下述步骤的方法制备:
    And/or, (D) when the compound or a pharmaceutically acceptable salt thereof has the formula
    Figure PCTCN2022122329-appb-100066
    , prepared by a method comprising the following steps:
    (d1)将中间体
    Figure PCTCN2022122329-appb-100067
    溶于MeOH/DMSO,加入硝酸银和三氟乙酸,70℃搅拌1小时,加入(NH 4) 2S 2O 8和H 2O,70℃搅拌2小时,反应液用EA稀释,NaOH水溶液洗涤,有机相无水硫酸钠干燥,过滤,浓缩,纯化得化合物
    Figure PCTCN2022122329-appb-100068
    (d1) the intermediate
    Figure PCTCN2022122329-appb-100067
    Dissolve in MeOH/DMSO, add silver nitrate and trifluoroacetic acid, stir at 70°C for 1 hour, add (NH 4 ) 2 S 2 O 8 and H 2 O, stir at 70°C for 2 hours, dilute the reaction solution with EA, wash with NaOH aqueous solution , the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain the compound
    Figure PCTCN2022122329-appb-100068
    (d2)将化合物
    Figure PCTCN2022122329-appb-100069
    溶于DMF中,加入三乙胺和化合物
    Figure PCTCN2022122329-appb-100070
    50℃搅拌,反应液用EA稀释,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,纯化得化合物
    Figure PCTCN2022122329-appb-100071
    (d2) compound
    Figure PCTCN2022122329-appb-100069
    Dissolve in DMF, add triethylamine and compound
    Figure PCTCN2022122329-appb-100070
    Stir at 50°C, dilute the reaction solution with EA, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify the compound
    Figure PCTCN2022122329-appb-100071
    (d3)将化合物
    Figure PCTCN2022122329-appb-100072
    和化合物
    Figure PCTCN2022122329-appb-100073
    溶于甲苯中,氮气保护下加入Pd 2(dba) 3,RuPhos和Cs 2CO 3,100℃搅拌16小时,冷却至室温并减压浓缩,纯化得化合物
    Figure PCTCN2022122329-appb-100074
    (d3) compound
    Figure PCTCN2022122329-appb-100072
    and compounds
    Figure PCTCN2022122329-appb-100073
    Dissolve in toluene, add Pd 2 (dba) 3 , RuPhos and Cs 2 CO 3 under nitrogen protection, stir at 100°C for 16 hours, cool to room temperature and concentrate under reduced pressure to obtain compound
    Figure PCTCN2022122329-appb-100074
    (d4)将化合物
    Figure PCTCN2022122329-appb-100075
    溶于HCl/Dioxane和甲醇中,室温搅拌1小时,减压 浓缩,纯化得
    Figure PCTCN2022122329-appb-100076
    (d4) compound
    Figure PCTCN2022122329-appb-100075
    Dissolved in HCl/Dioxane and methanol, stirred at room temperature for 1 hour, concentrated under reduced pressure, and purified to obtain
    Figure PCTCN2022122329-appb-100076
    和/或,(E)当化合物或其药学上可接受的盐具有结构式
    Figure PCTCN2022122329-appb-100077
    时,通过包括下述步骤的方法制备:
    And/or, (E) when the compound or a pharmaceutically acceptable salt thereof has the formula
    Figure PCTCN2022122329-appb-100077
    , prepared by a method comprising the following steps:
    (e1)将6-氯-1H-吡唑并[3,4-b]吡啶溶于二甲基甲酰胺(DMF)中,加入(N-碘代丁二酰亚胺)NIS,80℃搅拌4小时,反应液用水稀释,EA萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得化合物
    Figure PCTCN2022122329-appb-100078
    (e1) Dissolve 6-chloro-1H-pyrazolo[3,4-b]pyridine in dimethylformamide (DMF), add (N-iodosuccinimide)NIS, stir at 80°C For 4 hours, the reaction solution was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound
    Figure PCTCN2022122329-appb-100078
    (e2)将化合物
    Figure PCTCN2022122329-appb-100079
    溶于DCM中,加入邻苯二甲酸二己酯(DHP)和对甲苯磺酸,室温搅拌3小时,减压浓缩,纯化得化合物
    Figure PCTCN2022122329-appb-100080
    (e2) compound
    Figure PCTCN2022122329-appb-100079
    Dissolve in DCM, add dihexyl phthalate (DHP) and p-toluenesulfonic acid, stir at room temperature for 3 hours, concentrate under reduced pressure, and purify the compound
    Figure PCTCN2022122329-appb-100080
    (e3)将化合物
    Figure PCTCN2022122329-appb-100081
    溶于DMF中,加入化合物
    Figure PCTCN2022122329-appb-100082
    和三乙胺,50℃搅拌12小时,水稀释,EA萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,纯化得化合物
    Figure PCTCN2022122329-appb-100083
    (e3) compound
    Figure PCTCN2022122329-appb-100081
    Dissolve in DMF, add compound
    Figure PCTCN2022122329-appb-100082
    and triethylamine, stirred at 50°C for 12 hours, diluted with water, extracted with EA, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain the compound
    Figure PCTCN2022122329-appb-100083
    (e4)将化合物
    Figure PCTCN2022122329-appb-100084
    和化合物
    Figure PCTCN2022122329-appb-100085
    溶于甲苯中,氮气保护下加入Pd 2(dba) 3,RuPhos和Cs 2CO 3,100℃搅拌16小时,冷却至室温并减压浓缩,纯化得化合物
    Figure PCTCN2022122329-appb-100086
    (e4) compound
    Figure PCTCN2022122329-appb-100084
    and compounds
    Figure PCTCN2022122329-appb-100085
    Dissolve in toluene, add Pd 2 (dba) 3 , RuPhos and Cs 2 CO 3 under nitrogen protection, stir at 100°C for 16 hours, cool to room temperature and concentrate under reduced pressure to obtain compound
    Figure PCTCN2022122329-appb-100086
    (e5)将化合物
    Figure PCTCN2022122329-appb-100087
    溶于HCl/二氧六环(Dioxane)和甲醇中,室温搅拌1小时,减压浓缩,纯化得
    Figure PCTCN2022122329-appb-100088
    (e5) compound
    Figure PCTCN2022122329-appb-100087
    Dissolved in HCl/Dioxane (Dioxane) and methanol, stirred at room temperature for 1 hour, concentrated under reduced pressure, and purified to obtain
    Figure PCTCN2022122329-appb-100088
  25. 一种药物组合物,其包含权利要求1-16中任一项所述的化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体。A pharmaceutical composition comprising the compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
  26. 权利要求1-16中任一项所述的化合物或其药学上可接受的盐或者权利要求25所述的药物组合物在制备用于预防或治疗SHP2活性介导的疾病的药物中的用途;Use of the compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 25 in the preparation of a medicament for preventing or treating a disease mediated by SHP2 activity;
    优选地,所述SHP2活性介导的疾病为对SHP2抑制敏感或有响应的疾病;Preferably, the disease mediated by SHP2 activity is a disease that is sensitive or responsive to SHP2 inhibition;
    还优选地,所述SHP2活性介导的疾病为非小细胞肺癌。Also preferably, the disease mediated by SHP2 activity is non-small cell lung cancer.
  27. 一种预防或治疗SHP2活性介导的疾病的方法,包括对有需要的受试者给予有效量的权利要求1-16中任一项所述的化合物或其药学上可接受的盐,或权利要求25所述的药物组合物;A method for preventing or treating a disease mediated by SHP2 activity, comprising administering to a subject in need an effective amount of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof, or the subject the pharmaceutical composition described in claim 25;
    优选地,所述SHP2活性介导的疾病为对SHP2抑制敏感或有响应的疾病;Preferably, the disease mediated by SHP2 activity is a disease that is sensitive or responsive to SHP2 inhibition;
    还优选地,所述SHP2活性介导的疾病为非小细胞肺癌。Also preferably, the disease mediated by SHP2 activity is non-small cell lung cancer.
  28. 权利要求1-16中任一项所述的化合物或其药学上可接受的盐或权利要求25所述的药物组合物,其用于预防或治疗SHP2活性介导的疾病;The compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 25, which is used for preventing or treating diseases mediated by SHP2 activity;
    优选地,所述SHP2活性介导的疾病为对SHP2抑制敏感或有响应的疾病;Preferably, the disease mediated by SHP2 activity is a disease that is sensitive or responsive to SHP2 inhibition;
    还优选地,所述SHP2活性介导的疾病为非小细胞肺癌。Also preferably, the disease mediated by SHP2 activity is non-small cell lung cancer.
PCT/CN2022/122329 2021-09-28 2022-09-28 Compound as shp2 inhibitor, and preparation method therefor and use thereof WO2023051648A1 (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016203404A1 (en) * 2015-06-19 2016-12-22 Novartis Ag Compounds and compositions for inhibiting the activity of shp2
WO2018081091A1 (en) * 2016-10-24 2018-05-03 Relay Therapeutics, Inc. Pyrazolo[3,4-b]pyrazine derivatives as shp2 phosphatase inhibitors
WO2018218133A1 (en) * 2017-05-26 2018-11-29 Relay Therapeutics, Inc. Pyrazolo[3,4-b]pyrazine derivatives as shp2 phosphatase inhibitors
WO2019183364A1 (en) * 2018-03-21 2019-09-26 Relay Therapeutics, Inc. Pyrazolo[3,4-b]pyrazine shp2 phosphatase inhibitors and methods of use thereof
CN112166110A (en) * 2018-03-21 2021-01-01 传达治疗有限公司 SHP2 phosphatase inhibitors and methods of use thereof
WO2021033153A1 (en) * 2019-08-20 2021-02-25 Otsuka Pharmaceutical Co., Ltd. Pyrazolo[3,4-b]pyrazine shp2 phosphatase inhibitors
CN112839935A (en) * 2018-09-26 2021-05-25 北京加科思新药研发有限公司 Novel heterocyclic derivatives useful as SHP2 inhibitors

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016203404A1 (en) * 2015-06-19 2016-12-22 Novartis Ag Compounds and compositions for inhibiting the activity of shp2
WO2018081091A1 (en) * 2016-10-24 2018-05-03 Relay Therapeutics, Inc. Pyrazolo[3,4-b]pyrazine derivatives as shp2 phosphatase inhibitors
WO2018218133A1 (en) * 2017-05-26 2018-11-29 Relay Therapeutics, Inc. Pyrazolo[3,4-b]pyrazine derivatives as shp2 phosphatase inhibitors
WO2019183364A1 (en) * 2018-03-21 2019-09-26 Relay Therapeutics, Inc. Pyrazolo[3,4-b]pyrazine shp2 phosphatase inhibitors and methods of use thereof
CN112166110A (en) * 2018-03-21 2021-01-01 传达治疗有限公司 SHP2 phosphatase inhibitors and methods of use thereof
CN112839935A (en) * 2018-09-26 2021-05-25 北京加科思新药研发有限公司 Novel heterocyclic derivatives useful as SHP2 inhibitors
WO2021033153A1 (en) * 2019-08-20 2021-02-25 Otsuka Pharmaceutical Co., Ltd. Pyrazolo[3,4-b]pyrazine shp2 phosphatase inhibitors

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