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WO2023051648A1 - Composé utilisé comme inhibiteur de shp2, son procédé de préparation et son utilisation - Google Patents

Composé utilisé comme inhibiteur de shp2, son procédé de préparation et son utilisation 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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Chinese (zh)
Inventor
白进红
尹磊
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Gan and Lee Pharmaceuticals Co Ltd
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Gan and Lee Pharmaceuticals Co Ltd
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Priority to CN202280060269.1A priority Critical patent/CN118019743A/zh
Publication of WO2023051648A1 publication Critical patent/WO2023051648A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic 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

L'invention concerne un composé utilisé comme inhibiteur de SHP2, une composition pharmaceutique de celui-ci, et son utilisation dans la prévention ou le traitement de maladies médiées par l'activité de SHP2.
PCT/CN2022/122329 2021-09-28 2022-09-28 Composé utilisé comme inhibiteur de shp2, son procédé de préparation et son utilisation Ceased WO2023051648A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116514716A (zh) * 2023-05-10 2023-08-01 南京优氟医药科技有限公司 一种(s)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺-二盐酸盐的制备方法
CN118772157A (zh) * 2024-06-11 2024-10-15 浙江江北南海药业有限公司 一种6-氯-1h-吡唑并[3,4-b]吡嗪的合成方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016203404A1 (fr) * 2015-06-19 2016-12-22 Novartis Ag Composés et compositions pour inhiber l'activité de shp2
WO2018081091A1 (fr) * 2016-10-24 2018-05-03 Relay Therapeutics, Inc. Dérivés de pyrazolo [3,4-b] pyrazine en tant qu'inhibiteurs de la phosphatase shp2
WO2018218133A1 (fr) * 2017-05-26 2018-11-29 Relay Therapeutics, Inc. Dérivés de pyrazolo[3,4-b]pyrazine en tant qu'inhibiteurs de la phosphatase shp2
WO2019183364A1 (fr) * 2018-03-21 2019-09-26 Relay Therapeutics, Inc. Inhibiteurs de la phosphatase pyrazolo[3,4-b]pyrazine shp2 et leurs procédés d'utilisation
CN112166110A (zh) * 2018-03-21 2021-01-01 传达治疗有限公司 Shp2磷酸酶抑制剂及其使用方法
WO2021033153A1 (fr) * 2019-08-20 2021-02-25 Otsuka Pharmaceutical Co., Ltd. Inhibiteurs de pyrazolo[3,4-b]pyrazine shp2 phosphatase
CN112839935A (zh) * 2018-09-26 2021-05-25 北京加科思新药研发有限公司 可用作shp2抑制剂的新型杂环衍生物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016203404A1 (fr) * 2015-06-19 2016-12-22 Novartis Ag Composés et compositions pour inhiber l'activité de shp2
WO2018081091A1 (fr) * 2016-10-24 2018-05-03 Relay Therapeutics, Inc. Dérivés de pyrazolo [3,4-b] pyrazine en tant qu'inhibiteurs de la phosphatase shp2
WO2018218133A1 (fr) * 2017-05-26 2018-11-29 Relay Therapeutics, Inc. Dérivés de pyrazolo[3,4-b]pyrazine en tant qu'inhibiteurs de la phosphatase shp2
WO2019183364A1 (fr) * 2018-03-21 2019-09-26 Relay Therapeutics, Inc. Inhibiteurs de la phosphatase pyrazolo[3,4-b]pyrazine shp2 et leurs procédés d'utilisation
CN112166110A (zh) * 2018-03-21 2021-01-01 传达治疗有限公司 Shp2磷酸酶抑制剂及其使用方法
CN112839935A (zh) * 2018-09-26 2021-05-25 北京加科思新药研发有限公司 可用作shp2抑制剂的新型杂环衍生物
WO2021033153A1 (fr) * 2019-08-20 2021-02-25 Otsuka Pharmaceutical Co., Ltd. Inhibiteurs de pyrazolo[3,4-b]pyrazine shp2 phosphatase

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116514716A (zh) * 2023-05-10 2023-08-01 南京优氟医药科技有限公司 一种(s)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺-二盐酸盐的制备方法
CN116514716B (zh) * 2023-05-10 2025-07-25 南京优氟医药科技有限公司 一种(s)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺-二盐酸盐的制备方法
CN118772157A (zh) * 2024-06-11 2024-10-15 浙江江北南海药业有限公司 一种6-氯-1h-吡唑并[3,4-b]吡嗪的合成方法

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