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WO2025011568A1 - 用作shp2抑制剂的杂环化合物、包含其的药物组合物及其制备方法和用途 - Google Patents

用作shp2抑制剂的杂环化合物、包含其的药物组合物及其制备方法和用途 Download PDF

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WO2025011568A1
WO2025011568A1 PCT/CN2024/104630 CN2024104630W WO2025011568A1 WO 2025011568 A1 WO2025011568 A1 WO 2025011568A1 CN 2024104630 W CN2024104630 W CN 2024104630W WO 2025011568 A1 WO2025011568 A1 WO 2025011568A1
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alkyl
membered
cycloalkyl
aryl
haloalkyl
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PCT/CN2024/104630
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English (en)
French (fr)
Inventor
王奎锋
张贵平
李家鹏
郑计岳
张涛
徐浩杰
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勤浩医药（苏州）有限公司
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Publication of WO2025011568A1 publication Critical patent/WO2025011568A1/zh

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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
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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 application relates to a heterocyclic compound, a pharmaceutical composition containing the heterocyclic compound, a preparation method thereof, and use thereof as a SHP2 inhibitor.
  • SHP2 (Src homology-2 protein tyrosine phosphatase) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which catalyzes protein tyrosine dephosphorylation reactions. It is generally believed that the N-terminus of SHP2 contains two SH2 domains, including N-src homology 2 domain (SH2) and C-SH2, and the C-terminus contains a catalytic PTP domain. In the inactivated state, SHP2 is in an autoinhibitory state, and the binding of N-SH2 and C-PTP inhibits the phosphatase activity.
  • SH2 N-src homology 2 domain
  • C-SH2 catalytic PTP domain
  • Ras-Erk In the presence of extracellular stimuli, they bind to related receptors and activate multiple downstream signaling pathways, such as Ras-Erk, Ras-MAPK, PI3K-AKT, Jak-Stat, Met, FGFR, EGFR, as well as insulin receptor and NF-kB pathways, regulating cell proliferation, differentiation, apoptosis and survival as well as migration.
  • signaling pathways such as Ras-Erk, Ras-MAPK, PI3K-AKT, Jak-Stat, Met, FGFR, EGFR, as well as insulin receptor and NF-kB pathways, regulating cell proliferation, differentiation, apoptosis and survival as well as migration.
  • Hyperactivation of SHP2 due to germline or somatic mutations has been found in Noonan Syndrome, Leopard Syndrome, Juvenile myelomonocytic leukemia, myelodysplastic syndrome, B cell acute lymphoblastic leukemia, and acute myeloid leukemia.
  • activating mutations of PTPN11 have also been found in solid tumors such as lung cancer, colon cancer, melanoma, neuroblastoma, and liver cancer. Therefore, activated SHP2 or upregulated SHP2 proteins in human tumors or other diseases have become new therapeutic targets.
  • PD-1 programmed death 1
  • ITIM immunoreceptor tyrosine-based inhibitory motif
  • ITMS immunoreceptor tyrosine-based switch motif
  • the present invention provides heterocyclic compounds that can be used as SHP2 inhibitors to prevent or treat SHP2 activity-mediated diseases, disorders and conditions.
  • the compounds of the present invention have high selectivity for the target.
  • the compounds of the present invention have better physicochemical properties (e.g., solubility, physical and/or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiac toxicity) and/or fewer side effects), less prone to drug resistance and other more excellent properties.
  • the present invention provides a compound of formula (I) as defined below:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof and one or more pharmaceutically acceptable carriers, wherein the pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention in the preparation of Use in a medicament for preventing or treating a disease, disorder or condition mediated by SHP2 activity.
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention for use in preventing or treating a disease, disorder or condition mediated by SHP2 activity.
  • the present invention provides a method for preventing or treating a disease, disorder or condition mediated by SHP2 activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.
  • the invention provides methods of preparing the compounds of the invention.
  • alkylene refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • alkoxy refers to -O-alkyl, which is as defined above.
  • C 1-6 alkoxy refers to a linear or branched alkoxy group of 1 to 6 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy or n-hexoxy), which is optionally substituted with 1 or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group is referred to as a "haloalkoxy”) (e.g., -OCF 3 , -OC 2 F 5 , -OCHF 2 , -OCH 2 F, -OCH 2 CF 3 , -OCH 2 Cl or -OCH 2 CH 2 CF 3, etc.).
  • C 1-4 alkoxy refers to a linear or branched alkoxy group of 1 to 4 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2 to 6 carbon atoms (“ C2-6 alkenyl”).
  • alkynyl refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc.
  • the alkynyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents.
  • alkynylene is a corresponding divalent group, including, for example, “C 2-8 alkynylene", “C 2 -6 alkynylene", “C 2-4 alkynylene", etc. Examples thereof include, but are not limited to The alkynylene group is optionally substituted with one or more (such as 1 to 3) identical or different substituents.
  • cycloalkylene refers to saturated (i.e., “cycloalkylene” and “cycloalkyl") or partially unsaturated (i.e., having one or more double bonds and/or triple bonds within the ring) monocyclic or polycyclic (e.g., bicyclic or tricyclic) hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including, but not limited to, (cyclo)propyl (ring), (cyclo)butyl (ring), (cyclo)pentyl (ring), (cyclo)hexyl (ring), (cyclo)heptyl (ring), (cyclo)octyl (ring), (cyclo)nonyl (ring), (cyclo)hexenyl (ring), etc.
  • Cycloalkyl includes monocyclic, spirocyclic, fused or bridged systems.
  • fused ring means that two rings in a ring system share two adjacent ring atoms (e.g., in the case of cycloalkyl, the two ring atoms are both C; or in the case of heterocyclyl, the two ring atoms can be both C or N, or one is C and the other is N).
  • Spirocyclic means that two rings in a ring system share one ring atom (e.g., C).
  • “Bridged ring” means that two rings in a ring system share two ring atoms that are not directly connected (e.g., in the case of cycloalkyl, the two ring atoms are both C; or in the case of heterocyclyl, the two ring atoms can be both C or N, or one is C and the other is N).
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including a spirocyclic, fused or bridged system (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
  • the cycloalkyl has 3 to 15 carbon atoms, suitably 3 to 10 carbon atoms.
  • C " 3-6 cycloalkyl” refers to a saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) of 3 to 6 ring carbon atoms.
  • the cycloalkyl is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.
  • monospirocycloalkyl refers to two monocyclic cycloalkyl groups having only one carbon atom in common.
  • Monospirocycloalkyl groups can have 6 to 14 ( C6-14 ), for example 6-11 ( C6-11 ) or 7-10 ( C7-10 ) carbon atoms.
  • Monospirocycloalkyl groups can include, for example, 3-yuan/5-yuan ring systems, 4-yuan/4-yuan ring systems, 4-yuan/5-yuan ring systems, 4-yuan/6-yuan ring systems, 5-yuan/5-yuan ring systems, 5-yuan/6-yuan ring systems, and 6-yuan/6-yuan ring systems, wherein the count of each ring includes spiral atoms.
  • Non-limiting examples of monospirocycloalkyl groups include: The monospirocycloalkyl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • the heterocyclyl group may be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom, if present, in the ring.
  • a 3-10 membered heterocyclyl group is a group having 3-10 (e.g., 4-6 or 5-6) carbon atoms and heteroatoms in the ring, such as, but not limited to, an oxirane, an aziridine, an azetidinyl, an oxetanyl, a tetrahydrofuranyl, a dioxolinyl, a pyrrolidinyl, a pyrrolidonyl, an imidazolidinyl, a pyrazolidinyl, a pyrrolinyl, a tetrahydropyranyl, a piperidinyl, a morpholinyl, a dithianyl, a thiomorpholinyl, a piperazinyl or a trithianyl.
  • 3-10 e.g., 4-6 or 5-6 carbon atoms and heteroatoms in the ring
  • an oxirane an aziridine
  • heterocyclyl encompasses fused ring structures, and the connection point of the fused ring structure to the other groups can be on any ring in the fused ring structure. Therefore, the heterocyclyl of the present invention also includes, but is not limited to, heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, such as 3-7 membered (mono) heterocyclyl and 3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclyl and (mono) cycloalkyl, 3-7 membered (mono) heterocyclyl and C 4-6 (mono) cycloalkyl, examples of which include, but are not limited to, pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and
  • heterocyclyl encompasses bridged heterocyclyls and spiro heterocyclyls.
  • one of the two rings forming the bridged heterocycle is a saturated ring and the other is a partially unsaturated ring. In some embodiments, both rings forming the bridged heterocycle are partially unsaturated rings.
  • bridged heterocycles include but are not limited to The "nitrogen-containing bridged heterocycle", “oxygen-containing bridged heterocycle” and “sulfur-containing bridged heterocycle” optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • the term "monospiro heterocycloalkyl” refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, sulfur atoms) formed by two or more saturated rings sharing one ring atom, including but not limited to 5-11-membered monospiro heterocycloalkyl, 6-10-membered monospiro heterocycloalkyl, 7-10-membered monocyclic heterocycloalkyl, 6-10-membered nitrogen-containing spiro heterocycloalkyl, 6-10-membered oxygen-containing spiro heterocycloalkyl, 6-10-membered sulfur-containing spiro heterocycloalkyl, etc.
  • heteroatoms e.g., oxygen atoms, nitrogen atoms, sulfur atoms
  • Monospiro heterocycloalkyl can include, for example, 3-membered/5-membered ring systems, 4-membered/4-membered ring systems, 4-membered/5-membered ring systems, 4-membered/6-membered ring systems, 5-membered/5-membered ring systems, 5-membered/6-membered ring systems, and 6-membered/6-membered ring systems, wherein the count of each ring includes the spiro atom.
  • nitrogen-containing monospiro heterocycloalkyl examples include, but are not limited to The "nitrogen-containing monospiro heterocycloalkyl", “oxygen-containing monospiro heterocycloalkyl”, “sulfur-containing monospiro heterocycloalkyl” optionally further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.
  • the term "6-10 membered nitrogen-containing monospiro heterocycloalkyl” refers to a spiro heterocycloalkyl containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ electron system.
  • C 6-14 aryl means an aromatic group containing 6 to 14 (e.g., 6 to 12) carbon atoms, such as phenyl or naphthyl.
  • the aryl group is optionally substituted with 1 or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • aralkyl preferably refers to an alkyl substituted with an aryl group, wherein the aryl group and the alkyl group are as defined herein.
  • the aryl group may have 6-14 carbon atoms
  • the alkyl group may have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • heteroaryl refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case, may additionally be benzo-fused.
  • heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), thiadiazolyl and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and benzo derivatives thereof.
  • halo or halogen group is defined to include F, Cl, Br, or I.
  • haloalkyl refers to an alkyl group substituted by one or more (such as 1 to 3) the same or different halogen atoms, the alkyl group being as defined herein.
  • C 1-8 haloalkyl refers to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1-4 carbon atoms, respectively, such as -CF 3 , -C 2 F 5 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 Cl or -CH 2 CH 2 CF 3 , etc.
  • alkylthio refers to an alkyl group as defined above attached to the parent molecular moiety through a sulfur atom.
  • Representative examples of C 1-6 alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio and hexylthio.
  • the nitrogen-containing heterocycle is connected to the rest of the molecule through a carbon atom.
  • the nitrogen-containing heterocycle is connected to the rest of the molecule through a nitrogen atom.
  • the nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring.
  • the 3- to 14-membered nitrogen-containing heterocycle is a group having 3-14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as aziridine), a four-membered nitrogen-containing heterocycle (such as azetidinyl), a five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), a six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidinyl ring), morpholinyl, thiomorpholinyl, piperazinyl), seven-membered nitrogen-containing heterocyclic ring, etc.
  • substituted means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and/or together, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); isotopes of carbon (e.g., 11 C, 13 C, and 14 C); isotopes of chlorine (e.g., 36 Cl); isotopes of fluorine (e.g., 18 F); isotopes of iodine (e.g., 123 I and 125 I); isotopes of nitrogen (e.g., 13 N and 15 N); isotopes of oxygen (e.g., 15 O, 17 O, and 18 O); isotopes of phosphorus (e.g., 32 P); and isotopes of sulfur (e.g., 35 S).
  • isotopes of hydrogen e.g., deuterium (D, 2 H), tritium (T, 3 H)
  • Certain isotopically labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (e.g., assays).
  • the radioisotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because they are easily incorporated and easily detected.
  • Substitution with positron emitting isotopes e.g., 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the invention can be prepared by methods similar to those described in the accompanying routes and/or in the examples and preparations by using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed.
  • Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
  • stereoisomer means an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc.
  • solid lines can be used Solid wedge Virtual wedge Depicting chemical bonds of the compounds of the invention.
  • the use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown are present. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry.
  • the compounds of the invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereoisomer pairs).
  • compositions of the present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof. Therefore, when referring to "compounds of the present invention" herein, the above-mentioned various derivative forms of the compounds are also intended to be covered.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrobromide, salts of bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A. These salts are also known as anhydrous bisphenol A. Bromide, Hydroiodide, Iodide, Maleate, Malonate, Methylsulfate, Naphthylate, Nicotinate, Nitrate, Orotate, Oxalate, Palmitate and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.
  • esters means an ester derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form).
  • physiologically hydrolyzable esters which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form.
  • the compounds of the present invention themselves may also be esters.
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • the compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • the amount of polar solvents, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.
  • metabolites of the compounds of the present invention i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc. of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity when administered into or onto the body, for example, by hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E. B. Roche, ed., American Pharmaceutical Association).
  • Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties” (e.g. as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).
  • the present invention also encompasses compounds of the present invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.
  • the protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • the term "about” means within ⁇ 10% of the stated numerical value, preferably within ⁇ 5%, and more preferably within ⁇ 2%.
  • the present invention provides a compound of formula (I):
  • X1 and X2 are each independently N or CR9 , and at least one of X1 and X2 is N;
  • X 3 is N
  • X 4 is N or CR 10 ;
  • L is selected from O, S, CR 7a R 7b , C(O) and S(O) p ;
  • p 1 or 2;
  • R 1 and R 10 are each independently selected from H, D, halogen, OH, NH 2 , CN, NO 2 , COOH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, saturated or partially unsaturated C 3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl are optionally each independently substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, NO 2 , oxo, C 1-6 alkyl, -COC 1-6 alkyl;
  • R 2 is selected from H, D, halogen, OH, NH 2 , CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl are optionally each independently substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, NO 2 , oxo, C 1-6 alkyl and -COC 1-6 alkyl;
  • the ring B is selected from a partially unsaturated C 3-10 cycloalkyl, a partially unsaturated 3-10 membered heterocyclyl, a C 6-10 aryl and a 5-14 membered heteroaryl, wherein the C 3-10 cycloalkyl, the 3-10 membered heterocyclyl, the C 6-10 aryl and the 5-14 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH 2 , CN, NO 2 , COOH, -NHR 8a , -NR 8a R 8b , -CONH 2 , -CONHR 8a , -CONR 8a R 8b , -COR 8a , -COOR 8a , -NHCOR 8a , -N(R 8a )COR 8b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2
  • R3 and R5 are each independently selected from H, D, halogen, OH, NH2 , CN, NO2 , C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C6-10 aryl and 5-14 membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-14 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2 , CN, NO2 , oxo, C1-6 alkyl and -COC 1-6 alkyl substituents are substituted
  • R4 and R9 are each independently selected from H, D, halogen, OH, NH2 , CN, NO2 , COOH, -NHR8a , -NR8aR8b , -CONH2 , -CONHR8a , -CONR8aR8b , -COR8a , -COOR8a , -NHCOR8a , -N( R8a ) COR8b , -COC1-6alkyl -OC1-6alkyl, C1-6alkyl , C1-6haloalkyl , C1-6alkoxy , C2-6alkenyl , C2-6alkynyl , saturated or partially unsaturated monocyclic or condensed C3-10cyclic hydrocarbon group, saturated or partially unsaturated monocyclic or condensed 3-10 membered heterocyclic group, C6-10aryl , 5-14 membered heteroaryl, C1-6alkyl, C2-6haloalkyl,
  • U is selected from O, S, CR 11a R 11b and NR 12 ;
  • V and W are each independently selected from O, S, CR 13a R 13b and NR 12 , and m is 0;
  • ring A is selected from saturated or partially unsaturated C 3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered Heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group,
  • V and W are each independently selected from C, N or CR 11a ,
  • R 6 is selected from H, D, halogen, OH, NH 2 , CN, NO 2 , -NHR 8a , -NR 8a R 8b , -CONH 2 , -CONHR 8a , -CONR 8a R 8b , -COR 8a , -COOH, -S(O) n C 1-6 alkyl, C 1-6 alkyl and C 1-6 alkoxy, wherein said -S(O) n C 1-6 alkyl, C 1-6 alkyl and C 1-6 alkoxy are optionally each independently substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, NO 2 , oxo, C 1-6 alkyl and -COC 1-6 alkyl,
  • n 1, 2, 3, or 4
  • n 0, 1 or 2;
  • R 7a , R 7b , R 11a , R 11b , R 12 , R 13a and R 13b are each independently selected from H, D, halogen, OH, NH 2 , CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl , C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10- membered aryl and 5-14-membered heteroaryl are optionally each independently substituted with one or more substituents independently
  • R 8a and R 8b are each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, saturated or partially unsaturated C 3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , CN, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, saturated or partially unsaturated C 3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 member
  • the conditions are:
  • the present invention provides compounds of formula (I), wherein when ring A is absent, R 2 together with L and the carbon atoms indicated by “a” and "b" to which they are attached form ring B.
  • the present invention provides compounds of formula (I), wherein when ring A is present, R 2 together with L and the carbon atoms indicated by “a” and "b" to which they are attached form ring B.
  • the present invention provides compounds of formula (I), wherein:
  • X1 is N, and X2 is CR9 ;
  • X1 is CR9
  • X2 is N.
  • R 9, at each occurrence, is independently selected from H, D, halogen, OH, NH 2 , CN, NO 2 , COOH, -NHR 8a , -NR 8a R 8b , -CONH 2 , -CONHR 8a , -CONR 8a R 8b , -COR 8a , -COOR 8a , -NHCOR 8a , -N(R 8a )COR 8b , -COC 1-6 alkyl-OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic or condensed ring C 3-10 cycloalkyl, monocyclic or condensed ring 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 6-11 membered monospirocyclo
  • R 9 is independently selected from H, D, F, Cl, OH, NH 2 , CN, NO 2 , COOH, -CONH 2 , -CONHR 8a , -CONR 8a R 8b , -COR 8a , -COOR 8a , -COC 1-4 alkyl-OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, monocyclic C 3-6 cycloalkyl, monocyclic 4-6 membered heterocycloalkyl, C 7-10 monospirocycloalkyl and 7-10 membered monospiroheterocycloalkyl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, monocyclic C 3-6 cycloalkyl, monocyclic 4-6 membered heterocycloalkyl, C 7-10 monospirocycloalkyl, C 7-10 monospirocycloal
  • R 9 is independently selected from H, D, F, Cl, CN, COOH, -CONH 2 , -CONHR 8a , -CONR 8a R 8b , -COR 8a , -COOR 8a , -COC 1-4 alkyl-OC 1-4 alkyl, C 2-4 alkenyl, monocyclic C 3-6 cycloalkyl, monocyclic 4-6 membered heterocycloalkyl, C 7 monospirocycloalkyl, 7-membered monospiroheterocycloalkyl, and C 1-4 alkyl substituted with OH, wherein the monospirocycloalkyl and monospiroheterocycloalkyl include 4-membered/4-membered ring systems, wherein the count of each ring includes the spiro atom; and wherein R 8a and R 8b , at each occurrence, are each independently selected from C 1-4 alky
  • R 9, at each occurrence, is independently selected from H, D, F, Cl, CN, -CH 2 OH, vinyl, cyclopropyl, COOH, -COOCH 3 , -COOCH 2 CH 3 , -CONH 2 , -COCH 3 , -COCH 2 OCH 3 , -COCH 2 F, -COCH 2 OH, -COCH 2 NH 2 , -COCH 2 N(CH 3 ) 2 ,
  • R 9 is independently H at each occurrence.
  • the present invention provides compounds of formula (I), wherein both X 1 and X 2 are N.
  • the present invention provides a compound of formula (I), wherein L is selected from O, S or CR 7a R 7b , wherein R 7a and R 7b are each independently selected from H, D, halogen, OH, NH 2 , CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH,
  • L is selected from O, S or CR 7a R 7b , wherein R 7a and R 7b are each independently selected from H, D, F, Cl, OH, NH 2 , CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl are optionally each independently replaced by one or more independently selected from F, Cl, OH, NH 2 , CN, NO 2 , C 1-4
  • L is selected from O, S and CH 2. In some more preferred embodiments, L is S.
  • the present invention provides a compound of formula (I), wherein R 2 is selected from H, D, halogen, OH, NH 2 , CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally each independently substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, NO 2 , oxo, C 1-6 alkyl and
  • R 2 is selected from H, D, halogen, OH, NH 2 , CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally each independently substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, NO 2 , oxo, C 1-4 alkyl and -COC 1-4 alkyl.
  • R 2 is selected from H, D, F, Cl, OH, NH 2 , CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 3-6 cycloalkyl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 3-6 cycloalkyl are optionally each independently substituted with one or more substituents independently selected from F, Cl, OH, NH 2 , CN, NO 2 , C 1-4 alkyl and -COC 1-4 alkyl.
  • R 2 is selected from H, D, OH, NH 2 and C 1-4 alkyl.
  • R 2 is selected from H, OH, NH 2 and CH 3 .
  • R2 is H.
  • the present invention provides a compound of formula (I), wherein R 2 together with L and the carbon atoms indicated by “a” and "b” to which they are attached form a ring B represented by the following formula:
  • the ring B is selected from a partially unsaturated C 3-6 cycloalkyl, a partially unsaturated 4-6 membered heterocyclyl, a C 6-10 aryl and a 5-10 membered heteroaryl, wherein the C 3-6 cycloalkyl, the 4-6 membered heterocyclyl, the C 6-10 aryl and the 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH 2 , CN, NO 2 , COOH, -NHR 8a , -NR 8a R 8b , -CONH 2 , -CONHR 8a , -CONR 8a R 8b , -COR 8a , -COOR 8a , -NHCOR 8a , -N(R 8a )COR 8b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2
  • the ring B is selected from phenyl and 5-6 membered heteroaryl, more preferably selected from 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally each independently substituted by one or more substituents independently selected from halogen, OH, NH 2 , CN, NO 2 , COOH, -NHR 8a , -NR 8a R 8b , -CONH 2 , -CONHR 8a , -CONR 8a R 8b , -COR 8a , -COOR 8a , -NHCOR 8a , -N(R 8a )COR 8b , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl, and
  • the ring B is selected from pyrrolyl, pyrazolyl, 1,2,3-triazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, more preferably pyrazolyl, each of the above groups is optionally independently substituted by one or more independently selected from halogen, OH, NH 2 , CN, NO 2 , COOH, -NHR 8a , -NR 8a R 8b , -CONH 2 , -CONHR 8a , -CONR 8a R 8b , -COR 8a , -COOR 8a , -NHCOR 8a , -N(R 8a )COR 8b , C 1-4 alky
  • the bond indicated by "c" in the above structures is attached to an available ring atom of Ring B.
  • R 2 together with L and the carbon atoms indicated by “a” and "b” to which they are attached form a structure represented by the following formula:
  • R 14 is selected from H, halogen, OH, NH 2 , CN, NO 2 , COOH, —NHR 8a , —NR 8a R 8b , —CONH 2 , —CONHR 8a , —CONR 8a R 8b , —COR 8a , —COOR 8a , —NHCOR 8a , —N(R 8a )COR 8b , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclo
  • R 14 is H.
  • the present invention provides compounds of formula (I), wherein Selected from:
  • the present invention provides a compound of formula (I), wherein R 5 is selected from H, D, halogen, OH, NH 2 , CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally each independently substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, NO 2 , oxo, C 1-6 alkyl and
  • R 5 is selected from H, D, F, Cl, OH, NH 2 , CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl are optionally each independently substituted with one or more substituents independently selected from F, Cl, OH, NH 2 , CN, NO 2 , C 1-4 alkyl and -COC 1-4 alkyl.
  • R 5 is selected from OH and NH 2 .
  • R 5 is OH
  • the present invention provides a compound of formula (I), wherein R 6 is selected from H, D, halogen, OH, NH 2 , CN, NO 2 , -NHR 8a , -NR 8a R 8b , -CONH 2 , -CONHR 8a , -CONR 8a R 8b , -COR 8a , -COOH, -S(O) n C 1-6 alkyl, C 1-6 alkyl and C 1-6 alkoxy, wherein the -S ( O ) n C 1-6 alkyl, C 1-6 alkyl and C 1-6 alkoxy are optionally each independently substituted with one or more substituents independently selected from halogen , OH, NH 2 , CN, NO 2 , oxo, C 1-6 alkyl and -COC 1-6 alkyl .
  • C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted independently by one or more substituents independently selected from halogen, OH, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl ) 2 , CN, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl.
  • substituents independently selected from halogen, OH, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl ) 2 ,
  • R 6 is selected from H, D, halogen, OH, NH 2 , CN, NO 2 , -NHR 8a , -NR 8a R 8b , -CONH 2 , -CONHR 8a , -CONR 8a R 8b , -COR 8a , -COOH, -S(O) n C 1-4 alkyl, C 1-4 alkyl and C 1-4 alkoxy, wherein said -S(O) n C 1-4 alkyl, C 1-4 alkyl and C 1-4 alkoxy are optionally each independently substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, NO 2 , oxo, C 1-4 alkyl and -COC 1-4 alkyl, and wherein R 8a and R 8b , at each occurrence, are each independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 The C 1-4
  • m is 1, 2, or 3.
  • n 0, 1, or 2.
  • R 6 is H, and m is 1;
  • the present invention provides a compound of formula (I), wherein X 4 is N.
  • the present invention provides a compound of formula (I), wherein X 4 is CR 10 , wherein R 10 is selected from H, D, halogen, OH, NH 2 , CN, NO 2 , COOH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen,
  • the substituents may be OH, NH 2 , CN, NO 2 , oxo, C 1-6 alkyl, or -COC 1-6 alkyl.
  • R 10 is selected from H, D, F, Cl, OH, NH 2 , CN, NO 2 , COOH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl are optionally each independently substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, NO 2 , C 1-4 alkyl, -COC 1-4 alkyl.
  • R 10 is H.
  • the present invention provides a compound of formula (I), wherein the compound has a structure of formula II:
  • Ring A is present.
  • the present invention provides a compound of formula (I), wherein the compound has a structure of formula III:
  • the present invention provides compounds of formula (I), wherein R 1 is each independently selected from H, D, halogen, OH, NH 2 , CN, NO 2 , COOH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally each independently substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, NO 2 , oxo, C 1-6 alkyl, -COC 1-6 alkyl.
  • R 1 is selected from H, D, F, Cl, OH, NH 2 , CN, NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 3-6 cycloalkyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 3-6 cycloalkyl are optionally each independently substituted with one or more substituents independently selected from F, Cl, OH, NH 2 , CN and NO 2 .
  • R 1 is selected from the group consisting of F, Cl, OH, NH 2 , CN, NO 2 , methyl, ethyl, propyl, isopropyl, CH 2 F, CHF 2 and CF 3 .
  • R 1 is selected from Cl and CF 3 .
  • the present invention provides a compound of formula (I), wherein R 3 is selected from H, D, halogen, OH, NH 2 , CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally each independently substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, NO 2 , oxo, C 1-6 alkyl and
  • R 3 is selected from H, D, F, Cl, OH, NH 2 , CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl,
  • the C 6-10 aryl and 5-6 membered heteroaryl are optionally each independently substituted with one or more substituents independently selected from F, Cl, OH, NH 2 , CN, NO 2 , C 1-4 alkyl and -COC 1-4 alkyl.
  • R 3 is selected from H, D, F, Cl, OH, NH 2 , CN, NO 2 and C 1-4 alkyl.
  • R 3 is H.
  • the present invention provides a compound of formula (I), wherein R 4 is selected from H, D, halogen, OH, NH 2 , CN, NO 2 , COOH, -NHR 8a , -NR 8a R 8b , -CONH 2 , -CONHR 8a , -CONR 8a R 8b , -COR 8a , -COOR 8a , -NHCOR 8a , -N(R 8a )COR 8b , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, monocyclic or condensed ring C 3-10 cycloalkyl, monocyclic or condensed ring 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 7-10 monospirocycloalkyl and 7-10 membered monospiroheterocycloalkyl, wherein the
  • R 4 is selected from H, D, F, Cl, OH, NH 2 , CN, NO 2 , C 1-4 alkyl, and C 3-6 cycloalkyl.
  • R4 is H.
  • the present invention provides a compound of formula (I), wherein R 12 , at each occurrence, is independently selected from H, D, F, Cl, OH, NH 2 , CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally each independently replaced by one or more independently selected from F, Cl, OH, NH 2 , CN, NO 2 , oxo, C 1-6
  • the present invention provides a compound of formula (I), wherein U is selected from O, S and CR 11a R 11b , wherein R 11a and R 11b are each independently selected from H, D, halogen, OH, NH 2 , CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally each independently replaced by one or more independently selected from halogen, OH, NH
  • U is O or CH 2 .
  • the present invention provides compounds of formula (I), wherein:
  • V and W are each independently selected from O, S and CR 13a R 13b , wherein R 13a and R 13b are each independently selected from H, D, halogen, OH, NH 2 , CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently substituted by one or more substituted alkyl groups independently selected from halogen, OH, NH 2 ,
  • R 13a and R 13b are each independently selected from H, F , Cl, methyl and ethyl.
  • V and W are each independently selected from O, CH 2 , CHCH 3 , CHCH 2 CH 3 , CHF 2 and CH 2 F.
  • V is selected from O, CH 2 , CHF 2 and CHCH 3 , preferably O.
  • W is selected from CH 2 , CH 2 F, CHCH 3 and CHCH 2 CH 3 , preferably CHCH 3 .
  • the part when ring A is absent, has the following structure:
  • the present invention provides compounds of formula (I), wherein:
  • V and W are each C, and said ring A is selected from phenyl and 5-6 membered heteroaryl.
  • the ring A is selected from phenyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.
  • the ring A is phenyl or pyridinyl.
  • Ring A when Ring A is present, The part has the following structure:
  • the present invention provides compounds of formula (I), wherein The part has the following structure:
  • the present invention provides compounds of formula (I), wherein The part has the following structure:
  • the present invention encompasses compounds resulting from any combination of the various embodiments.
  • the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound is selected from:
  • compositions and methods of treatment are provided.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a preventive or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.
  • the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention for preparing a medicament.
  • the compound of the invention, the pharmaceutical composition of the invention, or the medicament is used to prevent or treat cancer, cancer metastasis, cardiovascular disease, immune disorder or visual disorder.
  • the present invention also provides a method for preventing or treating a disease, disorder or condition, alleviating its symptoms, delaying its development or onset, which comprises administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, wherein the disease, disorder or condition is cancer, cancer metastasis, cardiovascular disease, immune disorder or visual disorder.
  • the present invention also provides the use of the compound of the present invention or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug, or the pharmaceutical composition of the present invention for preparing a medicament as a SHP2 inhibitor.
  • the present invention provides a method for inhibiting SHP2 activity in an individual, comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer Use of a polymorph, polymorph, solvate, metabolite, isotope-labeled compound or prodrug, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating a disease, disorder or condition mediated by SHP2 activity.
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention for use in preventing or treating a disease, disorder or condition mediated by SHP2 activity.
  • the present invention provides a method for preventing or treating a disease, disorder or condition mediated by SHP2 activity, alleviating its symptoms, delaying its development or onset, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.
  • the disease, disorder, or condition mediated by SHP2 activity is selected from Noonan's syndrome, Leopard syndrome, and cancer.
  • the cancer includes solid cancer and blood cancer.
  • the solid cancer includes neuroblastoma, melanoma, head cancer, head and neck squamous cell carcinoma, breast cancer, esophageal cancer, liver cancer, pancreatic cancer, gastric cancer, colon cancer, lung cancer (preferably non-small cell lung cancer), anaplastic large cell lymphoma and glioblastoma.
  • the blood cancer includes leukemia, preferably juvenile myelomonocytic leukemia, acute myeloid leukemia.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle that is administered together with a therapeutic agent and is suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic reaction or other problems or complications corresponding to a reasonable benefit/risk ratio within the scope of reasonable medical judgment.
  • “individual” includes humans or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.
  • A1-1 100 mg, 0.22 mmol, synthesized according to the synthesis method of patent CN111647000A
  • A1-2 79 mg, 0.29 mmol
  • potassium phosphate 190 mg, 0.88 mmol
  • LC-MS showed that the product was generated
  • the reaction solution was returned to room temperature
  • silica gel was added
  • the inhibitory activity of the compounds of the present application on SHP2 was evaluated by enzyme activity experiment.
  • the test compound was prepared with DMSO, and the test compound was diluted in multiples so that the final starting concentration in the reaction system was 1000nM (1:5 multiple dilution, 9 gradients in total).
  • the test compounds of different concentrations were transferred to a 384-well plate.
  • Prepare the experimental buffer 60mM HEPES, pH 7.2, 75mM NaCl, 75mM KCl, 1mM EDTA, 0.05% Tween-20, 5mM DTT).
  • 4 ⁇ SHP2 recombinant protein, 4 ⁇ IRS1 peptide, and 4 ⁇ DiFMUP were prepared with buffer respectively, added to 384-well plates, so that the final concentrations in the reaction system were 2.5nM, 0.5 ⁇ M, and 200 ⁇ M, respectively, and reacted at room temperature for 45 minutes.
  • the CCL method was used to evaluate the antiproliferative activity of the compounds of the present application on human non-small cell lung cancer NCI-H358 (ATCC: CRL-5807) and human oral squamous tumor cells HSC-2 (Kebai: CBP60260). Take the above-mentioned normal growth cells, digest them with trypsin cell digestion solution, centrifuge, count, and spread them into a 96-well plate (3000 cells/well) at a suitable cell density, 180 ⁇ L per well. After 24 hours, the test compound is first prepared with DMSO and then diluted with culture medium so that the final starting concentration in the reaction system is 1000nM, 1:5 dilution ratio, a total of 9 gradients.
  • the above-mentioned prepared compound is added to each well, three replicate wells are set for each concentration point, and a corresponding DMSO negative treatment control group is also set.
  • a corresponding DMSO negative treatment control group is also set.
  • all the liquid in the 96-well plate of adherent culture was tapped out, and 100 ⁇ L of a solution of a 1:1 mixture of cell proliferation detection reagent CellCounting-Lite (CCL) and culture medium was added to each well.
  • the plates were shaken for 3 minutes and then allowed to stand for 10 minutes.
  • the chemiluminescence value was read using a Thermo Varioskan LUX-3020 multifunctional microplate reader and converted into a proliferation index to calculate the inhibition rate of the compound on tumor cell proliferation.
  • the inhibition rate value and the logarithm of the compound concentration were fitted using nonlinear regression (dose response-variable slope) using GraphPad Prism 7.0 software to obtain the IC50 value of the compound.
  • compound A1 has excellent enzyme activity and cell proliferation inhibition activity, which is far superior to the known SHP2 inhibitor TNO-155 (Batoprotafib).
  • the first-phase metabolic stability of the test compounds was assessed in liver microsomes of CD-1 mice, Sprague-Dawley rats, beagle dogs, cynomolgus monkeys and humans.
  • the animal and human liver microsomes used in this test system were purchased from Xenotech, Corning or other qualified suppliers and stored in a freezer below -60°C before use.
  • test sample and the control compound were incubated with animal and human liver microsomes at 37 ⁇ 1°C for a certain period of time, with the longest incubation time being 60 minutes. Samples were taken out at the specified time point and the reaction was terminated with acetonitrile or other organic solvents containing internal standards. After centrifugation, the resulting supernatant was detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • test sample powder is prepared into a stock solution of a certain concentration using DMSO or other organic solvents, and then further diluted with a suitable organic solvent.
  • control compounds testosterone, diclofenac and propafenone were prepared as 10 mM stock solutions in DMSO and then further diluted in appropriate organic solvents.
  • NADP nicotinamide adenine dinucleotide phosphate
  • ISO isocitrate
  • the stop solution is prepared with acetonitrile or other organic solvents containing an internal standard (tolbutamide or other suitable compounds).
  • the prepared stop solution is stored in a refrigerator at 2-8°C.
  • Incubations will be done in 96-well plates. Prepare 8 incubation plates, named T0, T5, T15, T30, T45, T60, Blank60, and NCF60. The first 6 plates correspond to reaction time points of 0, 5, 15, 30, 45, and 60 minutes, respectively. No test or control compound is added to the Blank60 plate, and samples are taken after 60 minutes of incubation. In the NCF60 plate, potassium phosphate buffer is used instead of NADPH regeneration system solution for incubation for 60 minutes. All condition samples are three parallels.
  • the reaction temperature is 37 ⁇ 1°C
  • the final reaction volume is 200 ⁇ L
  • the reaction system includes 0.5mg/mL microsomes, 1.0 ⁇ M substrate, 1mM NADP, 6mM ISO and 1unit/mL IDH.
  • the CV of the internal standard peak area in each matrix should be within 20% for each analytical run.
  • the in vitro elimination rate constant ke of the compound was obtained by converting the ratio of the peak area of the compound to the internal standard into the residual rate in the following formula:
  • CL int(mic) 0.693/T 1/2 /microsomal protein content (microsomal concentration during incubation mg/mL)
  • CL int(liver) CL int(mic) ⁇ amount of microsomal protein in liver (mg/g) ⁇ liver weight to body weight ratio
  • the hepatic intrinsic clearance and hepatic clearance can be converted by the following formula.
  • This experiment was used to test the metabolic stability of compounds in hepatocytes.
  • Plasma concentrations were determined using LC-MS/MS.
  • the plasma drug concentration data of the compounds were processed using WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software with a non-compartmental model.
  • the linear-log trapezoidal method was used to calculate the relevant pharmacokinetic parameters.
  • the compound of the present invention has good oral exposure and oral bioavailability in rats, which is significantly better than the control compound C.
  • the structure of the control compound C is It is compound 1 in international patent application WO2022089389, and is synthesized according to the method of the patent application.
  • mice On the day of administration, the actual body weight of the mice was weighed and the administration volume was calculated. There were 9 mice in each group, and two groups of tests were performed for each compound, one group was administered with a single intravenous injection, and the other group of mice was administered with a single oral gavage.
  • Whole blood samples were collected at the specified time (0.25, 0.5, 1, 2, 4, 8, 24h after administration) by orbital blood sampling. After blood sample collection, it was immediately transferred to a labeled commercial sample tube containing K2-EDTA (0.85-1.15mg), followed by centrifugation (3200xg, 4°C, 10 minutes) and plasma was collected. The plasma was transferred to a pre-cooled centrifuge tube, quick-frozen in dry ice, and then stored in an ultra-low temperature refrigerator at -60°C or lower until LC-MS/MS analysis.
  • Plasma concentrations were determined using LC-MS/MS.
  • the plasma drug concentration data of the compounds were processed using WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software with a non-compartmental model.
  • the linear-log trapezoidal method was used to calculate the relevant pharmacokinetic parameters.
  • HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum and 0.8mg/mL G418 at 37°C and 5% CO2 .
  • the cells were digested with TrypLE TM Express and centrifuged to adjust the cell density to 2 ⁇ 10 6 cells/mL.
  • the cells were then gently mixed on a room temperature balanced shaker for 15-20min and then put on the machine for patch clamp detection.
  • the culture medium of the prepared cells was replaced with extracellular fluid.
  • the intracellular and extracellular fluids were drawn from the liquid pool and added to the intracellular fluid pool, cell and test substance pool of the QPlate chip respectively.
  • the whole-cell patch clamp recorded the voltage stimulation of the whole-cell hERG potassium current, and the experimental data were collected and stored by Qpatch.
  • the compound started at 30 ⁇ M, diluted 3 times, and 6 concentration points were set. Each drug concentration was set to be administered twice for at least 5 minutes. The current detected in the external solution without the compound for each cell was used as its own control group. At least two cells were used for each concentration and the detection was repeated twice independently. All electrophysiological experiments were performed at room temperature.
  • the compounds of the present invention have no obvious inhibitory risk on hERG and are significantly better than the control compound B.
  • the structure of the control compound B is It is the compound of Example 30 in patent application CN110143949A, and is synthesized according to the method of the patent application.
  • 100mM K-Buffer Mix 9.5mL of stock solution A into 40.5mL of stock solution B, adjust the total volume to 500mL with ultrapure water, and titrate the buffer to pH 7.4 with KOH or H 3 PO 4 .
  • Raw material A (1M potassium dihydrogen phosphate): 136.5 g potassium dihydrogen phosphate in 1 L water;
  • test substance powder is prepared into a stock solution of a certain concentration using DMSO or other organic solvents, and then further diluted with a suitable organic solvent.
  • the in vitro incubation system of liver microsomes for the study of CYP450 enzyme metabolic phenotype is a biochemical reaction carried out under conditions simulating physiological temperature and physiological environment, with the prepared liver microsomes supplemented with redox coenzymes and enzyme-specific selective inhibitors.
  • the concentration of parent drug or its metabolites in the incubation solution was determined by LC-MS/MS.
  • the experimental animals were randomly divided into groups, and the drugs were administered according to the weight of the experimental animals at 10 ml/kg.
  • Whole blood and required tissues were collected at the time points required by the experimental protocol; the whole blood was placed in a centrifuge tube containing an anticoagulant, placed on wet ice, centrifuged (8000rpm/10min/4°C), and the supernatant was taken to obtain plasma, which was stored in a -80°C refrigerator for drug concentration analysis; each tissue was fully rinsed with physiological saline after sampling, dried with filter paper, weighed and quickly frozen in liquid nitrogen, and the tissue samples were stored in a -80°C refrigerator for drug concentration analysis.
  • Tissue samples were added to the tissue homogenate according to the corresponding volume of 2mL/g, and ground at 60Hz for 10min for homogenization. Take 20 ⁇ L of tissue homogenate in a 96-well plate, add 80 ⁇ L of acetonitrile solution containing internal standard, vortex oscillate for 10min, centrifuge at 4000rpm for 20min, and take the supernatant for LC-MS/MS analysis.

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Abstract

本申请涉及式(I)的杂环化合物、包含其的药物组合物及其制备方法和作为SHP2抑制剂的用途。

Description

用作SHP2抑制剂的杂环化合物、包含其的药物组合物及其制备方法和用途 技术领域
本申请涉及杂环化合物、包含其的药物组合物及其制备方法和作为SHP2抑制剂的用途。
背景技术
SHP2(Src同源区-2蛋白质酪氨酸磷酸酶，The Src Homolgy-2phosphatease)是一个由PTPN11基因编码的非受体蛋白酪氨酸磷酸酶，催化蛋白质酪氨酸去磷酸化反应。通常认为，SHP2的N端包含N-src同源2域(SH2)和C-SH2在内的2个SH2结构域，C端包含1个具有催化活性的PTP结构域。在未激活状态下，SHP2处于自抑制状态，N-SH2与C-PTP相互结合抑制了磷酸酶活性。在存在细胞外刺激的情况下，它们与相关受体结合，激活下游多种信号通路，如包括Ras-Erk、Ras-MAPK、PI3K-AKT、Jak-Stat、Met、FGFR、EGFR，以及胰岛素受体和NF-kB通路，调节细胞增殖、分化、凋亡和存活以及迁移。
由种系或体细胞突变引起的SHP2的超活化已经在努南氏症候群(Noonan Syndrome)、豹皮症候群(Leopard Syndrome)、青少年骨髓单核细胞白血病(Juvenile myelomonocytic leukemia)、骨髓增生异常症候群(myelodysplastic syndrome)、B细胞急性淋巴细胞白血病(B cell acute lymphoblastic leukemia)和急性骨髓性白血病中发现。另外，PTPN11的活化突变也在实体瘤中发现，如肺癌、结肠癌、黑色素瘤、神经母细胞瘤和肝癌。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。
此外，研究表明(Sci Adv.2020.6(5):eaay 4458)，程序性死亡1(PD-1)也参与介导和激活SHP2。在癌症中，PD-1抑制T细胞刺激并介导免疫逃逸，刺激后，PD-1在其基于免疫受体酪氨酸的抑制基序(ITIM)和基于免疫受体酪氨酸的开关基序(ITSM)处被磷酸化，然后结合SHP2，启动T细胞失活。因此，SHP2抑制剂可以刺激肿瘤微环境中的适应性免疫和先天免疫活性，具有恢复已被癌细胞沉默的抗肿瘤免疫应答的潜力。
因此，亟需用作SHP2抑制剂的化合物以治疗和预防通过SHP2活性介导的疾病、病症和病况。
发明内容
本发明提供杂环化合物，其可用作SHP2抑制剂，用来预防或治疗SHP2活性介导疾病、病症和病况。本发明的化合物对靶点具有高选择性。此外，本发明的化合物具有更好的物理化学性质(例如溶解度、物理和/或化学稳定性)、改善的药物代谢动力学性质(例如改善的生物利用度、改善的代谢稳定性、合适的半衰期和作用持续时间)、改善的安全性(较低的毒性(例如降低的心脏毒性)和/或较少的副作用)、较不易产生耐药性等更优异的性质。
在一个方面，本发明提供如下文所定义的式(I)的化合物：
或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药。
在另一方面，本发明提供药物组合物，其包含本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选是固体制剂、液体制剂或透皮制剂。
在另一方面，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药、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、病症或病况的药物中的用途。
在另一方面，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物，其用于预防或治疗SHP2活性介导的疾病、病症或病况。
在另一方面，本发明提供预防或治疗SHP2活性介导的疾病、病症或病况的方法，所述方法包括向有需要的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物。
在另一方面，本发明提供制备本发明的化合物的方法。
具体实施方式
定义
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。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
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(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤(即，这些术语也涵盖术语“基本上由……组成”和“由……组成”)。
如本文中所使用，术语“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。
如本文中所使用，术语“烷基”定义为直链或支链饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CF3、C2F5、CHF2、CH2F、CH2CF3、CH2Cl或-CH2CH2CF3等)。术语“C1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本所使用，术语“烷氧基”指-O-烷基，所述烷基如上文所定义术语“C1-6烷氧基”指1至6个碳原子的线性或支化的烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基、正戊氧基或正己氧基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷氧基”)(例如-OCF3、-OC2F5、-OCHF2、-OCH2F、-OCH2CF3、-OCH2Cl或-OCH2CH2CF3等)。术语“C1-4烷氧基”指1至4个碳原子的线性或支化的烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基)。
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个或多个双键，且具有2-6个碳原子(“C2-6烯基”)。所述烯基为例如-CH＝CH2、-CH2CH＝CH2、-C(CH3)＝CH2、-CH2-CH＝CH-CH3、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。术语“亚烯基”为相应的二价基团，包括例如“C2-6亚烯基”、“C2-4亚烯基”等，其具体实例包括但不限于：-CH＝CH-、-CH2CH＝CH-、-C(CH3)＝CH-、亚丁烯基、亚戊烯基、亚己烯基、亚环戊烯基、亚环己烯基等。
如本文中所使用，术语“炔基”表示包含一个或多个三键的单价烃基，其优选具有2、3、4、5或6个碳原子，例如乙炔基、2-丙炔基、2-丁炔基、1,3-丁二炔基等。所述炔基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。术语“亚炔基”为相应的二价基团，包括例如“C2-8亚炔基”、“C2-6亚炔基”、“C2-4亚炔基”等。其实例包括但不限于等，所述亚炔基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。
如本文中所使用，术语“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或部分不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环(例如双环或三环)烃环，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。环烃基包括单环、螺环、稠环或桥连系统。
如本文中所使用，“稠环”意指环系统中两个环共用相邻的两个环原子(例如，在环烃基的情况下，所述两个环原子均为C；或者在杂环基的情况下，所述两个环原子可以均为C或N，或一个为C而另一个为N)。“螺环”意指环系统中两个环共用一个环原子(例如C)。“桥环”意指环系统中两个环共用两个不直接相连的环原子(例如，在环烃基的情况下，所述两个环原子均为C；或者在杂环基的情况下，所述两个环原子可以均为C或N，或一个为C而另一个为N)。
如本文中所使用，术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环，诸如环丙基、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)，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子，适合地具有3至10个碳原子。例如，术语“C3-6环烷基”指3至6个成环碳原子的饱和的非芳族单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)。所述环烷基任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
术语“单螺环烷基”指仅共有一个碳原子的两个单环环烷基。单螺环烷基可以具有6至14个(C6-14)，例如6-11(C6-11)或7-10(C7-10)个碳原子。单螺环烷基可以包括例如3元/5元环系、4元/4元环系、4元/5元环系、4元/6元环系、5元/5元环系、5元/6元环系和6元/6元环系，其中每个环的计数均包括螺原子。单螺环烷基的非限制性实例包括：等。所述单螺环烷基任选地被1或多个(诸如1至3个)适合的取代基取代。
如本文中所使用，术语“杂环基”指饱和(即，“杂环烷基”)或部分不饱和的一价单环或双环基团，其在环中具有2、3、4、5、6、7、8或9个碳原子和一个或多个(例如一个、两个、三个或四个)选自C(＝O)、O、S、S(＝O)、S(＝O)2和NRa的含杂原子的基团，其中Ra表示氢原子或C1-6烷基或卤代-C1-6烷基。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，3-10元杂环基为在环中具有3-10个(例如4-6或5-6个)碳原子及杂原子的基团，例如但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、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、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。
如本文中所使用，术语“杂环基”涵盖稠环结构，所述稠环结构与其他基团的连接点可以在稠环结构中的任一环上。因此，本发明的杂环基还包括但不限于杂环基并杂环基、杂环基并环烷基、单杂环基并单杂环基、单杂环基并单环烷基，例如3-7元(单)杂环基并3-7元(单)杂环基、3-7元(单)杂环基并(单)环烷基、3-7元(单)杂环基并C4-6(单)环烷基，其实例包括但不限于吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、哌啶基并吗啉基、
如本文中所使用，术语“杂环基”涵盖桥杂环基和螺杂环基。
如本文中所使用，术语“桥杂环”是指两个环共用两个不直接相连的环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子和/或硫原子)的环状结构，包括但不限于7-10元桥杂环、8-10元桥杂环、7-10元含氮桥杂环、7-10元含氧桥杂环、7-10元含硫桥杂环等。在一些实施方案中，形成桥杂环的两个环都是饱和环。在另一些实施方案中，形成桥杂环的两个环中的一个是饱和环，另一个是部分不饱和环。在一些实施方案中，形成桥杂环的两个环都是部分不饱和环。桥杂环的实例包括但不限于 等。所述“含氮桥杂环”、“含氧桥杂环”、“含硫桥杂环”任选地还含有一个或多个选自氧、氮和硫的其他杂原子。
如本文中所使用，术语“单螺杂环烷基”是指由两个或两个以上饱和环共用一个环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子、硫原子)的环状结构，包括但不限于5-11元单螺杂环烷基、6-10元单螺杂环烷基、7-10元单环杂环烷基、6-10元含氮螺杂环烷基、6-10元含氧螺杂环烷基、6-10元含硫螺杂环烷基等。单螺杂环烷基可以包括例如3元/5元环系、4元/4元环系、4元/5元环系、4元/6元环系、5元/5元环系、5元/6元环系和6元/6元环系，其中每个环的计数均包括螺原子。实例包括、但不限于 所述“含氮单螺杂环烷基”、“含氧单螺杂环烷基”、“含硫单螺杂环烷基”任选地还含有一个或多个选自氧、氮、硫的其他杂原子。术语“6-10元含氮单螺杂环烷基”是指含有共计6-10个环原子并且其中至少一个环原子为氮原子的螺杂环烷基。
如本文中所使用，术语“芳基”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C6-14芳基”意指含有6至14个(例如6至12个)碳原子的芳族基团，诸如苯基或萘基。芳基任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO2、C1-6烷基等)取代。
术语“芳烷基”优选表示芳基取代的烷基，其中所述芳基和所述烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。
如本文中所使用，术语“杂芳基”指一价单环、双环或三环芳族环系，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基(包括1,2,3-三唑基、1,2,4-三唑基)、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、三嗪基等，以及它们的苯并衍生物。
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用，术语“卤代烷基”是指被一个或多个(诸如1至3个)相同或不同的卤素原子取代的烷基，所述烷基如本文中所定义。术语“C1-8卤代烷基”、“C1-6卤代烷基”和“C1-4卤代烷基”分别指具有1至8个碳原子、1至6个碳原子和1-4个碳原子的卤代烷基，例如-CF3、-C2F5、-CHF2、-CH2F、-CH2CF3、-CH2Cl或-CH2CH2CF3等。
如本文中所使用，术语“烷基硫基”意指通过硫原子连接至母体分子部分的如上文所定义的烷基。C1-6烷基硫基的代表性实例包括但不限于甲硫基、乙硫基、叔丁硫基及己硫基。
如本文中所使用，术语“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O)2的环成员。在一些实施方案中，所述含氮杂环通过碳原子与分子的其余部分连接。在一些实施方案中，所述含氮杂环通过氮原子与分子的其余部分连接。所述含氮杂环优选为饱和含氮单环。特别地，3至14元含氮杂环为在环中具有3-14个碳原子及杂原子(其中至少一个为氮原子)的基团，其包括但不限于三元含氮杂环(如氮丙啶基)、四元含氮杂环(如氮杂环丁烷基)、五元含氮杂环(如吡咯基、吡咯烷基(吡咯烷环)、吡咯啉基、吡咯烷酮基、咪唑基、咪唑烷基、咪唑啉基、吡唑基、吡唑啉基)、六元含氮杂环(如哌啶基(哌啶环)、 吗啉基、硫吗啉基、哌嗪基)、七元含氮杂环等。
术语“取代”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。
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。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自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”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。
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。
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。
本发明还包括所有药学上可接受的同位素标记的化合物，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(D，2H)、氚(T，3H))；碳的同位素(例如11C、13C及14C)；氯的同位素(例如36Cl)；氟的同位素(例如18F)；碘的同位素(例如123I及125I)；氮的同位素(例如13N及15N)；氧的同位素(例如15O、17O及18O)；磷的同位素(例如32P)；及硫的同位素(例如35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即3H)及碳-14(即14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如11C、18F、15O及13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D2O、丙酮-d6或DMSO-d6。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如1个、2个、3个或4个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本文中可使用实线实楔形或虚楔形描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键旨在表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键旨在表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，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、酯、溶剂合物、代谢物或前药，在将它们向有需要的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。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。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括天冬氨酸盐、苯甲酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、氢溴 酸盐/溴化物、氢碘酸盐/碘化物、顺丁烯二酸盐、丙二酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐及其它类似的盐。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、二乙胺盐、赖氨酸盐、镁盐、葡甲胺盐、钾盐及其它类似的盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑，American Pharmaceutical Association)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
如本文中所使用，术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
化合物
在第一方面，本发明提供式(I)的化合物：
或者其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，
其中：
X1和X2各自独立地为N或CR9，并且X1和X2中至少有一个为N；
X3为N；
X4为N或CR10；
L选自O、S、CR7aR7b、C(O)和S(O)p；
p为1或2；
R1和R10各自独立地选自H、D、卤素、OH、NH2、CN、NO2、COOH、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-10环烃基、3-10元杂环基、C6-10芳基和5-14元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基、-COC1-6烷基的取代基取代；
R2选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烃基、3-10元杂环基、C6-10芳基和5-14元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代；或者，
R2与L以及它们所连接的以“a”和“b”指示的碳原子一起形成由下式表示的环B：
所述环B选自部分不饱和的C3-10环烃基、部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基，其中所述C3-10环烃基、3-10元杂环基、C6-10芳基和5-14元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基的取代基取代；
R3和R5各自独立地选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烃基、3-10元杂环基、C6-10芳基和5-14元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代；
R4和R9各自独立地选自H、D、卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、-COC1-6烷基-O-C1-6烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、饱和或部分不饱和的单环或稠环C3-10环烃基、饱和或部分不饱和的单环或稠环3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-11单螺环烷基和6-11元单螺杂环烷基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-11单螺环烷基和6-11元单螺杂环烷基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、-NR8aR8b、CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基的取代基取代；
U选自O、S、CR11aR11b和NR12；以及
环A存在或不存在，
其中当环A不存在时，V和W各自独立地选自O、S、CR13aR13b和NR12，并且m为0；
或者
其中当环A存在时，环A选自饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元 杂环基、C6-10芳基和5-10元杂芳基，
V和W各自独立地选自C、N或CR11a，
R6选自H、D、卤素、OH、NH2、CN、NO2、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOH、-S(O)nC1-6烷基、C1-6烷基和C1-6烷氧基，其中所述-S(O)nC1-6烷基、C1-6烷基和C1-6烷氧基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代，
m为1、2、3或4，并且
n为0、1或2；
R7a、R7b、R11a、R11b、R12、R13a和R13b，在每次出现时，各自独立地选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烃基、3-10元杂环基、C6-10芳基和5-14元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代；
R8a和R8b，在每次出现时，各自独立地选自C1-6烷基、C1-6卤代烷基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C3-10环烃基、3-10元杂环基、C6-10芳基和5-14元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-6烷基)、N(C1-6烷基)2、CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基的取代基取代；以及
表示单键或双键；并且
条件是：
(1)所有原子的化合价都被满足；以及
(2)所述式(I)的化合物不包括以下化合物：

在一些实施方案中，本发明提供所述式(I)的化合物，其中当环A不存在时，R2与L以及它们所连接的以“a”和“b”指示的碳原子一起形成所述环B。
在另一些实施方案中，本发明提供所述式(I)的化合物，其中当环A存在时，R2与L以及它们所连接的以“a”和“b”指示的碳原子一起形成所述环B。
在一些实施方案中，本发明提供所述式(I)的化合物，其中：
X1为N，并且X2为CR9；或者
X1为CR9，并且X2为N。
在一些此类实施方案中，在每次出现时，R9独立地选自H、D、卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、-COC1-6烷基-O-C1-6烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、单环或稠环C3-10环烷基、单环或稠环3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C6-11单螺环烷基和6-11元单螺杂环烷基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、单环或稠环C3-10环烷基、单环或稠环3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C6-11单螺环烷基和6-11元单螺杂环烷基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、-NR8aR8b、 CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基的取代基取代；其中所述单螺环烷基和单螺杂环烷基任选地包括3元/5元环系、4元/4元环系、4元/5元环系、4元/6元环系、5元/5元环系、5元/6元环系和6元/6元环系，其中每个环的计数均包括螺原子；并且其中R8a和R8b，在每次出现时，各自独立地选自C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中关于R8a和R8b所述的C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-6烷基)、N(C1-6烷基)2、CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基的取代基取代。
在一些优选的实施方案中，在每次出现时，R9独立地选自H、D、F、Cl、OH、NH2、CN、NO2、COOH、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-COC1-4烷基-O-C1-4烷基、C1-4烷基、C1-4卤代烷基、C2-4烯基、单环C3-6环烷基、单环4-6元杂环烷基、C7-10单螺环烷基和7-10元单螺杂环烷基，其中所述C1-4烷基、C1-4卤代烷基、C2-4烯基、单环C3-6环烷基、单环4-6元杂环烷基、C7-10单螺环烷基和7-10元单螺杂环烷基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、-NR8aR8b、CN和NO2的取代基取代；其中所述单螺环烷基和单螺杂环烷基任选地包括3元/5元环系、4元/4元环系、4元/5元环系、4元/6元环系、5元/5元环系和5元/6元环系，其中每个环的计数均包括螺原子；并且其中R8a和R8b，在每次出现时，各自独立地选自C1-4烷基、C3-6环烷基和苯基，其中关于R8a和R8b所述的C1-4烷基任选地被一个或多个独立地选自F、Cl、OH、NH2、NH(C1-4烷基)、N(C1-4烷基)2、CN、NO2、C3-6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基的取代基取代。
在一些更优选的实施方案中，在每次出现时，R9独立地选自H、D、F、Cl、CN、COOH、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-COC1-4烷基-O-C1-4烷基、C2-4烯基、单环C3-6环烷基、单环4-6元杂环烷基、C7单螺环烷基、7元单螺杂环烷基和被OH取代的C1-4烷基，其中所述单螺环烷基和单螺杂环烷基包括4元/4元环系，其中每个环的计数均包括螺原子；并且其中R8a和R8b，在每次出现时，各自独立地选自C1-4烷基、C3-6环烷基和苯基，其中关于R8a和R8b所述的C1-4烷基任选地被一个或多个独立地选自F、Cl、OH、NH2、NHCH3、N(CH3)2、环丙基、氮杂环丁烷基和苯基的取代基取代。
在一些更优选的实施方案中，在每次出现时，R9独立地选自H、D、F、Cl、CN、-CH2OH、乙烯基、环丙基、COOH、-COOCH3、-COOCH2CH3、-CONH2、-COCH3、-COCH2OCH3、-COCH2F、-COCH2OH、-COCH2NH2、-COCH2N(CH3)2、
在一些更优选的实施方案中，在每次出现时，R9独立地为H。
在一些实施方案中，本发明提供所述式(I)的化合物，其中X1和X2二者都为N。
在一些实施方案中，本发明提供所述式(I)的化合物，其中L选自O、S或CR7aR7b，其中R7a和R7b各自独立地选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代。
在一些优选的实施方案中，L选自O、S或CR7aR7b，其中R7a和R7b各自独立地选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、CN、NO2、C1-4烷基和-COC1-4烷基的取代基取代。
在一些优选的实施方案中，L选自O、S和CH2。在一些更优选的实施方案中，L为S。
在一些实施方案中，本发明提供所述式(I)的化合物，其中R2选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代。
在一些优选的实施方案中，R2选自H、D、卤素、OH、NH2、CN、NO2、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-4烷基和-COC1-4烷基的取代基取代。
在一些更优选的实施方案中，R2选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C3-6环烷基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C3-6环烷基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、CN、NO2、C1-4烷基和-COC1-4烷基的取代基取代。
在一些更优选的实施方案中，R2选自H、D、OH、NH2和C1-4烷基。
在一些更优选的实施方案中，R2选自H、OH、NH2和CH3。
在一些更优选的实施方案中，R2为H。
在一些实施方案中，本发明提供所述式(I)的化合物，其中R2与L以及它们所连接的以“a”和“b”指示的碳原子一起形成由下式表示的环B：
所述环B选自部分不饱和的C3-6环烃基、部分不饱和的4-6元杂环基、C6-10芳基和5-10元杂芳基，其中所述C3-6环烃基、4-6元杂环基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基的取代基取代，并且其中R8a和R8b，在每次出现时，各自独立地选自C1-6烷基、C1-6卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-10元杂芳基，其中关于R8a和R8b所述的C1-6烷基、C1-6卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-6烷基)、N(C1-6烷基)2、CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-10元杂芳基的取代基取代。
在一些优选的实施方案中，所述环B选自苯基和5-6元杂芳基，更优选地选自5-6元杂芳基，其中所述苯基和杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、5-6元杂环烷基、C6-10芳基和5-6元杂芳基的取代基取代，并且其中R8a和R8b，在每次出现时，各自独立地选自C1-4烷基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中关于R8a和R8b所述的C1-4烷基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-4烷基)、N(C1-4烷基)2、CN、NO2、氧代基、C1-4烷基、C1-4烷氧基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基的取代基取代。
在一些更优选的实施方案中，所述环B选自吡咯基、吡唑基、1,2,3-三唑基、呋喃基、噁唑基、 异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡啶基、吡嗪基、哒嗪基和嘧啶基，更优选地为吡唑基，上述基团中的每一个任选地独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、5-6元杂环烷基、C6-10芳基和5-6元杂芳基的取代基取代，并且其中R8a和R8b，在每次出现时，各自独立地选自C1-4烷基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中关于R8a和R8b所述的C1-4烷基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-4烷基)、N(C1-4烷基)2、CN、NO2、C1-4烷基、C1-4烷氧基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基的取代基取代。
在一些实施方案中，以上结构中以“c”指示的键连接至所述环B的可用环原子。
在一些优选的实施方案中，R2与L以及它们所连接的以“a”和“b”指示的碳原子一起形成由下式表示的结构：
其中R14选自H、卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、5-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、5-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-4烷基)、N(C1-4烷基)2、CN、NO2、氧代基、C1-4烷基、C1-4烷氧基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基的取代基取代。
在一些优选的实施方案中，R14为H。
在一些实施方案中，本发明提供所述式(I)的化合物，其中选自：
在一些优选的实施方案中，为
在另一些实施方案中，本发明提供所述式(I)的化合物，其中R2与L以及它们所连接的以“a”和 “b”指示的碳原子一起形成环，从而形成由下式表示的结构：
在一些实施方案中，本发明提供所述式(I)的化合物，其中R5选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代。
在一些优选的实施方案中，R5选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、CN、NO2、C1-4烷基和-COC1-4烷基的取代基取代。
在一些优选的实施方案中，R5选自OH和NH2。
在一些更优选的实施方案中，R5为OH。
在一些实施方案中，本发明提供所述式(I)的化合物，其中R6选自H、D、卤素、OH、NH2、CN、NO2、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOH、-S(O)nC1-6烷基、C1-6烷基和C1-6烷氧基，其中所述-S(O)nC1-6烷基、C1-6烷基和C1-6烷氧基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代，并且其中R8a和R8b，在每次出现时，各自独立地选自C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-6烷基)、N(C1-6烷基)2、CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基的取代基取代。
在一些优选的实施方案中，R6选自H、D、卤素、OH、NH2、CN、NO2、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOH、-S(O)nC1-4烷基、C1-4烷基和C1-4烷氧基，其中所述-S(O)nC1-4烷基、C1-4烷基和C1-4烷氧基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-4烷基和-COC1-4烷基的取代基取代，并且其中R8a和R8b，在每次出现时，各自独立地选自C1-4烷基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-4烷基)、N(C1-4烷基)2、CN、NO2、C1-4烷基、C1-4烷氧基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基的取代基取代。
在一些实施方案中，m为1、2或3。
在一些实施方案中，n为0、1或2。
在一些优选的实施方案中，R6为H，并且m为1；
在一些实施方案中，本发明提供所述式(I)的化合物，其中X4为N。
在一些实施方案中，本发明提供所述式(I)的化合物，其中X4为CR10，其中R10选自H、D、卤素、OH、NH2、CN、NO2、COOH、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、 OH、NH2、CN、NO2、氧代基、C1-6烷基、-COC1-6烷基的取代基取代。
在一些优选的实施方案中，R10选自H、D、F、Cl、OH、NH2、CN、NO2、COOH、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中所述C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、C1-4烷基、-COC1-4烷基的取代基取代。
在一些更优选的实施方案中，R10为H。
在一些实施方案中，本发明提供所述式(I)的化合物，其中所述化合物具有式II的结构：
在一些优选的实施方案中，环A存在。
在一些实施方案中，本发明提供所述式(I)的化合物，其中所述化合物具有式III的结构：
其中环A存在或不存在。
在一些实施方案中，本发明提供所述式(I)的化合物，其中R1各自独立地选自H、D、卤素、OH、NH2、CN、NO2、COOH、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基、-COC1-6烷基的取代基取代。
在一些优选的实施方案中，R1选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基、C1-4烷氧基、C1-4卤代烷基和C3-6环烷基，其中所述C1-4烷基、C1-4烷氧基、C1-4卤代烷基和C3-6环烷基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、CN和NO2的取代基取代。
在一些更优选的实施方案中，R1选自F、Cl、OH、NH2、CN、NO2、甲基、乙基、丙基、异丙基、CH2F、CHF2和CF3。
在一些更优选的实施方案中，R1选自Cl和CF3。
在一些实施方案中，本发明提供所述式(I)的化合物，其中R3选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代。
在一些优选的实施方案中，R3选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、 C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、CN、NO2、C1-4烷基和-COC1-4烷基的取代基取代。
在一些更优选的实施方案中，R3选自H、D、F、Cl、OH、NH2、CN、NO2和C1-4烷基。
在一些更优选的实施方案中，R3为H。
在一些实施方案中，本发明提供所述式(I)的化合物，其中R4选自H、D、卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、单环或稠环C3-10环烷基、单环或稠环3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C7-10单螺环烷基和7-10元单螺杂环烷基，其中所述C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、单环或稠环C3-10环烷基、单环或稠环3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C7-10单螺环烷基和7-10元单螺杂环烷基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、-NR8aR8b、CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基的取代基取代，并且其中R8a和R8b，在每次出现时，各自独立地选自C1-6烷基、C1-6卤代烷基、C3-6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基，其中关于R8a和R8b所述的C1-6烷基、C1-6卤代烷基、C3-6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-6烷基)、N(C1-6烷基)2、CN、NO2、C1-6烷基、C1-6烷氧基、C3-6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基的取代基取代。
在一些优选的实施方案中，R4选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基和C3-6环烷基。
在一些更优选的实施方案中，R4为H。
在一些实施方案中，本发明提供所述式(I)的化合物，其中R12，在每次出现时，独立地选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代。
在一些实施方案中，本发明提供所述式(I)的化合物，其中U选自O、S和CR11aR11b，其中R11a和R11b各自独立地选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代。在一些优选的实施方案中，R11a和R11b各自为H。
在一些优选的实施方案中，U为O或CH2。
在一些实施方案中，本发明提供所述式(I)的化合物，其中：
当环A不存在时，V和W各自独立地选自O、S和CR13aR13b，其中R13a和R13b各自独立地选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代。在一些优选的实施方案中，R13a和R13b各自独立地选自H、卤素、C1-4烷基。在一些更优选的实施方案中，R13a和R13b各自独立地选自H、F、Cl、甲基和乙基。在一些优选的此类实施方案中，V和W各自独立地选自O、CH2、CHCH3、CHCH2CH3、CHF2和CH2F。
在一些更优选的实施方案中，当环A不存在时，V选自O、CH2、CHF2和CHCH3，优选为O。在一些更优选的实施方案中，W选自CH2、CH2F、CHCH3和CHCH2CH3，优选为CHCH3。
在一些更优选的实施方案中，当环A不存在时，部分具有下式的结构：
在另一些实施方案中，本发明提供所述式(I)的化合物，其中：
当环A存在时，V和W各自为C，并且所述环A选自苯基和5-6元杂芳基。
在一些优选的实施方案中，所述环A选自苯基、吡咯基、吡唑基、1,2,3-三唑基、呋喃基、噁唑基、异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡啶基、吡嗪基、哒嗪基和嘧啶基。在一些更优选的实施方案中，所述环A为苯基或吡啶基。
在一些更优选的实施方案中，当环A存在时，部分具有下式的结构：
在一些实施方案中，本发明提供所述式(I)的化合物，其中部分具有下式的结构：
在另一些实施方案中，本发明提供所述式(I)的化合物，其中部分具有下式的结构：
本发明涵盖对各个实施方案进行任意组合所得的化合物。
在优选的实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：


药物组合物和治疗方法
在另一方面，本发明提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药以及一种或多种药学上可接受的载体。所述药物组合物优选是固体制剂、液体制剂或透皮制剂。
在另一方面，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物用于制备药物的用途。
在一些实施方案中，本发明的化合物、本发明的药物组合物、或者所述药物用于预防或治疗癌症、癌症转移、心血管疾病、免疫紊乱或视觉紊乱。
在另一方面，本发明还提供预防或治疗疾病、病症或病况、减轻其症状、延缓其发展或发作的方法，其包括向有需要的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物，其中所述疾病、病症或病况是癌症、癌症转移、心血管疾病、免疫紊乱或视觉紊乱。
在另一方面，本发明还提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物用于制备作为SHP2抑制剂的药物的用途。
在又一方面，本发明提供抑制个体中SHP2活性的方法，其包括向有需要的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物。
在又一方面，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构 体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物在制备用于预防或治疗通过SHP2活性介导的疾病、病症或病况的药物中的用途。
在又一方面，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物，其用于预防或治疗通过SHP2活性介导的疾病、病症或病况。
在又一方面，本发明提供预防或治疗通过SHP2活性介导的疾病、病症或病况、减轻其症状、延缓其发展或发作的方法，所述方法包括向有需要的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药、或者本发明的药物组合物。
在一些实施方案中，所述通过SHP2活性介导的疾病、病症或病况选自努南氏综合征、豹皮综合征和癌症。
在一些实施方案中，所述癌症包括实体癌和血液癌。在一些实施方案中，所述实体癌包括神经母细胞瘤、黑色素瘤、头癌、头颈部鳞状细胞癌、乳腺癌、食道癌、肝癌、胰腺癌、胃癌、结肠癌、肺癌(优选非小细胞肺癌)、间变性大细胞淋巴瘤和成胶质细胞瘤。在一些实施方案中，所述血液癌包括白血病，优选青少年骨髓单核细胞白血病、急性髓性白血病。
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、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。
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、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
在另种实施方案中，本发明的药物组合物还可以包含一种或多种另外的治疗剂或预防剂。
实施例
以下结合实施例进一步描述本发明，但提供这些实施例并非意在限制本发明的范围。
实施例1：化合物A1的合成
A1-1(100mg,0.22mmol，根据专利CN111647000A的合成方法合成得到)，A1-2(79mg,0.29mmol)，磷酸钾(190mg,0.88mmol)加入到N,N-二甲基甲酰胺(3mL)中，氮气保护下80℃搅拌12小时，LC-MS显示有产品生成，反应液恢复至室温，加入硅胶，柱层析(二氯甲烷:甲醇＝0-15％)纯化，浓缩得到白色固体，经制备HPLC(水/乙腈＝80％)纯化，得到A1(37mg,收率27％)。ESI m/z[M+1]+＝631.2.1H NMR(400MHz,Chloroform-d)δ8.33(d,J＝5.0Hz,1H),8.20(dt,J＝8.2,1.4Hz,1H),8.15–8.04(m,3H),7.13(ddd,J＝17.5,8.4,6.4Hz,2H),6.76(dt,J＝7.8,1.4Hz,1H),4.20(s,2H),4.04(s,1H),3.92(t,J＝5.9Hz,2H),3.34–3.20(m,2H),3.19–3.11(m,2H),2.89(dd,J＝11.7,5.2Hz,2H),1.95(d,J＝6.0Hz,4H),1.80–1.67(m,2H),1.51(dd,J＝59.4,13.4Hz,2H).
生物活性测试
实验例1.酶活性实验
采用酶活性实验评价本申请的化合物对SHP2的抑制活性。待测化合物用DMSO配制，将待测化合物倍比稀释，使得最终在反应体系中的起始浓度为1000nM(1:5倍比稀释，共9个梯度)。将上述不同浓度的待测化合物转移至384孔板中。配制实验缓冲液(60mM HEPES,pH 7.2,75mM NaCl,75mM KCl,1mM EDTA,0.05％ Tween-20,5mM DTT)。用缓冲液分别配制4×SHP2重组蛋白、4×IRS1肽、4×DiFMUP，加入384孔板，使其最终在反应体系中的浓度分别为2.5nM、0.5μM、200μM，室温反应45分钟。在上述体系中加入5μL终浓度为32μM的bpV(Phen)试剂终止反应，在340nm激发下检测450nm的荧光发射强度。计算化合物对酶活性的抑制率，将抑制率数值和化合物浓度对数值采用非线性回归(剂量响应-可变斜率)拟合得到待测化合物的IC50值。
本实验所用试剂信息如下表所示：
实验例2.抗肿瘤细胞增殖活性测试
采用CCL法评价本申请的化合物对人非小细胞肺癌NCI-H358(ATCC:CRL-5807)和人口腔鳞状肿瘤细胞HSC-2(科佰：CBP60260)的抗增殖活性。取上述生长正常的细胞，用胰酶细胞消化液进行消化，离心，计数，以适合的细胞密度铺到96孔板中(3000个/孔)，每孔180μL。24小时之后，待测化合物先用DMSO配制，再用培养基进行稀释，使得最终在反应体系中的起始浓度为1000nM，1:5倍比稀释，共9个梯度。每孔加入上述配制好的化合物，每个浓度点设三个复孔，另外设置相应的DMSO阴性处理对照组。药物处理120h后，将贴壁培养的96孔板中的所有液体拍出，每孔重新加入100μL细胞增殖检测试剂CellCounting-Lite(CCL)与培养基1:1混合的溶液，震荡3min后静置10min，用Thermo Varioskan LUX-3020多功能酶标仪读取化学发光值，以转化为增殖指数从而计算化合物对肿瘤细胞增殖的抑制率，将抑制率数值和化合物浓度对数值采用非线性回归(剂量响应-可变斜率)用GraphPad Prism 7.0软件拟合得到化合物的IC50值。
化合物A1的酶活性和细胞增殖抑制活性如下表所示：
由上述数据可见，化合物A1具有优异的酶活性和细胞增殖抑制活性，远优于已知的SHP2抑制剂TNO-155(Batoprotafib)。
实验例3.肝微粒体稳定性测试
评定受试化合物在CD-1小鼠、Sprague-Dawley大鼠、比格犬、食蟹猴和人的肝微粒体中的一相代谢稳定性。
实验体系：
该测试体系所用到的动物和人肝微粒体购买自Xenotech、Corning或其他有资质的供应商，在使用前储存在低于-60℃冰箱内。
实验简介：
供试品和对照化合物在37±1℃条件下，分别与动物和人肝微粒体孵育一定的时间，最长孵育时间为60分钟，在指定的时间点取出样品，用含有内标的乙腈或其他有机溶剂终止反应。离心后，所产生的上清液用液相色谱-串联质谱(LC-MS/MS)方法进行检测。
实验方法：
1.缓冲液的配制
用4000mL的超纯水溶解73.21g三水磷酸氢二钾和10.78g磷酸二氢钾。使用10％磷酸或者1M氢氧化钾调整溶液pH值在7.40±0.10之间，其终浓度为100mM。
2.工作液的配制
供试品粉末用DMSO或其他的有机溶剂配制成一定浓度的储备液，然后用合适的有机溶剂进行进一步的稀释。
对照化合物睾酮、双氯芬酸和普罗帕酮用DMSO配制成10mM的储备液，然后用合适的有机溶剂进行进一步的稀释。
3.肝微粒体溶液的配制
用100mM磷酸钾盐缓冲液将各种属的微粒体稀释成2×的工作液。在反应体系中微粒体的终浓度为0.5mg/mL。
4.还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)再生体系的配制
称量适量的烟酰胺腺嘌呤磷酸二核苷酸(NADP)和异柠檬酸(ISO)粉末，溶于氯化镁溶液中，振荡混匀。加入适量的异柠檬酸脱氢酶(IDH)轻轻的上下颠倒混合均匀。在反应体系中终浓度分别为：1mM NADP、1mM氯化镁、6mM ISO和1unit/mL IDH。
5.终止液的配制
终止液用含有内标(甲苯磺丁脲或其他合适的化合物)的乙腈或其他有机溶剂来配制。配制好的终止液储存于2-8℃冰箱。
6.孵育过程
孵育将在96孔板中完成。准备8块孵育板，分别命名为T0、T5、T15、T30、T45、T60、Blank60和NCF60。前6块板对应反应时间点分别为0、5、15、30、45和60分钟。Blank60板中不加入供试品或对照化合物，并在孵育60分钟后取样。NCF60板中用磷酸钾盐缓冲液代替NADPH再生体系溶液进行孵育60分钟。所有条件样品为三个平行。
将微粒体和供试品或对照化合物混合，然后将除T0和NCF60外的孵育板Blank60、T5、T15、T30、T45和T60放置于37℃水浴锅中预孵育大约10分钟。孵育板T0中先加入终止液后再添加NADPH再生体系工作液，孵育板NCF60每个样品孔内添加98μL磷酸钾盐缓冲液以启动反应。孵育板Blank60、T5、T15、T30、T45和T60预孵育结束后，每个样品孔内添加98μL NADPH再生体系工作液以启动反应。反应的温度为37±1℃，反应的最终体积是200μL，反应体系中包括0.5mg/mL的微粒体、1.0μM的底物、1mM NADP、6mM ISO和1unit/mL IDH。
分别在5、15、30、45和60分钟时，将含有内标的冷的终止液加入到反应板中以终止反应。
将终止后的所有反应板摇匀，并在4℃、3220×g离心20分钟。将上清液稀释一定比例后进行LC-MS/MS分析。
样品分析
样品分析采用液相色谱-串联质谱(LC-MS/MS)方法进行，不含标准曲线和质控样品。使用分析物峰面积与内标峰面积的比值进行半定量测定。分析物和内标的保留时间、色谱图采集和色谱图的积分采用软件Analyst(Sciex，Framingham，Massachusetts，USA)进行处理。
每个分析批中每种基质中的内标峰面积的CV应在20％之内。
数据分析
通过下面公式中化合物与内标峰面积的比值转化成剩余率求得化合物的体外消除速率常数ke：

当时,
CLint(mic)＝0.693/T1/2/微粒体蛋白含量(孵育时微粒体浓度mg/mL)
CLint(liver)＝CLint(mic)×肝脏中微粒体蛋白量(mg/g)×肝重体重比
根据充分搅拌模型(well stir model)，肝固有清除率和肝清除率可以通过如下公式换算。
CL(liver)＝(CLint(liver)*Qh)/(CLint(liver)+Qh)
公式中的参数见表3。
表3.数据分析公式中的参数
实验例4.肝细胞代谢稳定性测试
本实验例用于测试化合物在肝细胞中的代谢稳定性。
用预热的培养基制备0.5x106/mL的肝细胞悬液，随后将198μL预热的细胞悬液加入至96孔板中。在96孔板的每个孔中加入2μL待测化合物，使得终浓度为1μM，设置2复孔。对于T＝0分钟的样品，将化合物与细胞充分混匀1分钟，随后立即取25μL样品加入到冰浴的125μL终止溶液(含200ng/mL甲苯磺丁脲和200ng/mL拉贝洛尔的乙腈溶液)并混匀。同时，将所有板放置于37℃、5％CO2的培养箱中，摇床设置为600rpm。分别在孵育15、30、60和90分钟时混匀样品，取25μL样品加入到冰浴的125μL终止溶液(含200ng/mL甲苯磺丁脲和200ng/mL拉贝洛尔的乙腈溶液)，混匀后于500rpm振荡10分钟。随后，于4℃、3220×g离心20分钟。离心结束后，从每孔中分别取80μL上清转移至另一个含有240μL超纯水的96孔板中。随后用LC-MS/MS分析并计算内在清除率(CLint)和半衰期(T1/2)。
实验例5.大鼠药代动力学测试
本实验例中测试化合物经静脉注射(IV)和灌胃(PO)给药后在SD大鼠体内的药代动力学行为。
给药当天称量大鼠实际体重并计算给药体积。每组3只大鼠，每个化合物进行两组测试，一组单次静脉注射给药，另一组单次灌胃给药。通过颈静脉采血方式在规定的时间(给药后0.25、0.5、1、2、4、8、24h)采集全血样品。血样采集以后，立即转移至贴有标签的含K2-EDTA(0.85-1.15mg)的商品化样品管中，随后离心处理(3200xg，4℃，10分钟)并取血浆。将血浆转移至预冷的离心管，在干冰中速冻，随后储存在-60℃或更低的超低温冰箱中，直到进行LC-MS/MS分析。
血浆浓度使用LC-MS/MS方法进行测定。使用WinNonlin Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型对化合物的血浆药物浓度数据进行处理。使用线性对数梯形法计算相关药代动力学参数。
表4.化合物A1的大鼠药代动力学结果
由表4结果可见，本发明化合物在大鼠中具有较好的口服暴露量和口服生物利用度，显著优于对照化合物C。对照化合物C的结构为是国际专利申请WO2022089389中的化合物1，按照该专利申请的方法合成得到。
实验例6.小鼠药代动力学测试
本实验例中测试化合物经静脉注射(IV)和灌胃(PO)给药后在BALB/c小鼠体内的药代动力学行为。
给药当天称量小鼠实际体重并计算给药体积。每组9只小鼠，每个化合物进行两组测试，一组单次静脉注射给药，另一组小鼠单次灌胃给药。通过眼眶采血方式在规定的时间(给药后0.25、0.5、1、2、4、8、24h)采集全血样品。血样采集以后，立即转移至贴有标签的含K2-EDTA(0.85-1.15mg)的商品化样品管中，随后离心处理(3200xg，4℃，10分钟)并取血浆。将血浆转移至预冷的离心管，在干冰中速冻，随后储存在-60℃或更低的超低温冰箱中，直到进行LC-MS/MS分析。
血浆浓度使用LC-MS/MS方法进行测定。使用WinNonlin Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型对化合物的血浆药物浓度数据进行处理。使用线性对数梯形法计算相关药代动力学参数。
实验例7.hERG抑制测试
将HEK293细胞在含有10％胎牛血清及0.8mg/mL G418的DMEM培养基中培养，培养温度为37℃，CO2浓度为5％。细胞用TrypLETMExpress消化后离心，调整细胞密度为2×106cells/mL，然后用室温平衡摇床轻混细胞15-20min，上机进行膜片钳检测。将制备好的细胞的培养基置换为细胞外液。从液体池中吸取细胞内、外液分别加到QPlate芯片的细胞内液池、细胞与受试物池中。全细胞膜片钳记录全细胞hERG钾电流的电压刺激，并将试验数据由Qpatch进行采集并储存。化合物以30μM起始，3倍稀释，设置6个浓度点，每个药物浓度设定为两次给药，时间至少为5分钟。将每一个细胞在不含化合物的外液中检测到的电流作为自己的对照组，每个浓度至少使用两个细胞独立重复检测两次。所有电生理试验在室温下进行。
数据分析，首先将每一个药物浓度作用后的电流和空白对照电流标准化然后计算每一个药物浓度对应的抑制率对每一个浓度计算平均数和标准误，并计算每种化合物的半抑制浓度： 用以上方程对剂量依赖效应进行非线性拟合，其中Y代表抑制率、C代表受试物浓度，IC50为半抑制浓度，HillSlope代表希尔系数。曲线拟合以及IC50的计算利用Graphpad软件完成。
表5.化合物A1的hERG抑制结果
由表5结果可见，本发明化合物对hERG没有明显抑制风险，显著优于对照化合物B。对照化合物B的结构为是专利申请CN110143949A中实施例30的化合物，按照该专利申请的方法合成得到。
实验例8.细胞色素氧化酶P450抑制测试
1)缓冲液的配制：
100mM K-Buffer：将9.5mL原液A混合到40.5mL原液B中，用超纯水将总体积调至500mL，用KOH或H3PO4滴定缓冲液至pH 7.4。
原料A(1M磷酸二氢钾):136.5g磷酸二氢钾在1L水中；
储备B(1M磷酸二氢钾):174.2g磷酸二氢钾在1L水。
2)受试物的配制
受试物粉末用DMSO或其他的有机溶剂配制成一定浓度的储备液，然后用合适的有机溶剂进行进一步的稀释。
3)体外孵育
CYP450酶代谢表型研究的肝微粒体体外孵育体系，是由制备的肝微粒体辅以氧化还原型辅酶，再加入酶特异的选择性抑制剂，在模拟生理温度及生理环境的条件下进行的生化反应。
4)原型药物或代谢产物的检测
采用LC-MS/MS测定温孵液中原型药物或其代谢产物的浓度。
实验例9.化合物组织分布测试
对实验动物进行随机分组，根据实验动物体重10ml/kg进行给药，按照试验方案要求的时间点采集全血及所需组织；全血放入含有抗凝剂的离心管，放置在湿冰上，离心(8000rpm/10min/4℃)取上清得血浆，保存于-80℃冰箱，用于药物浓度分析；各组织取材后用生理盐水充分冲洗，用滤纸吸干，称重后放入液氮速冻，组织样品保存于-80℃冰箱，用于药物浓度分析。组织样品按照2mL/g对应体积加入组织匀浆液，60Hz研磨10min进行匀浆。取20μL组织匀浆液于96孔板中，加入80μL含内标乙腈溶液，涡旋振荡10min，4000rpm离心20min，取上清液进行LC-MS/MS分析。
除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (11)

  1. 式(I)的化合物：
    或者其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，
    其中：
    X1和X2各自独立地为N或CR9，并且X1和X2中至少有一个为N；
    X3为N；
    X4为N或CR10；
    L选自O、S、CR7aR7b、C(O)和S(O)p；
    p为1或2；
    R1和R10各自独立地选自H、D、卤素、OH、NH2、CN、NO2、COOH、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-10环烃基、3-10元杂环基、C6-10芳基和5-14元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基、-COC1-6烷基的取代基取代；
    R2选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烃基、3-10元杂环基、C6-10芳基和5-14元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代；或者，
    R2与L以及它们所连接的以“a”和“b”指示的碳原子一起形成由下式表示的环B：
    所述环B选自部分不饱和的C3-10环烃基、部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基，其中所述C3-10环烃基、3-10元杂环基、C6-10芳基和5-14元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基的取代基取代；
    R3和R5各自独立地选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烃基、3-10元杂环基、C6-10芳基和5-14元杂芳基任选地各自独立地被一个或多个独立 地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代；
    R4和R9各自独立地选自H、D、卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、-COC1-6烷基-O-C1-6烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、饱和或部分不饱和的单环或稠环C3-10环烃基、饱和或部分不饱和的3-10元单环或稠环杂环基、C6-10芳基、5-14元杂芳基、C6-11单螺环烷基和6-11元单螺杂环烷基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-11单螺环烷基和6-11元单螺杂环烷基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、-NR8aR8b、CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基的取代基取代；
    U选自O、S、CR11aR11b和NR12；以及
    环A存在或不存在，
    其中当环A不存在时，V和W各自独立地选自O、S、CR13aR13b和NR12，并且m为0；
    或者
    其中当环A存在时，环A选自饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-10元杂芳基，
    V和W各自独立地选自C、N或CR11a，
    R6选自H、D、卤素、OH、NH2、CN、NO2、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOH、-S(O)nC1-6烷基、C1-6烷基和C1-6烷氧基，其中所述-S(O)nC1-6烷基、C1-6烷基和C1-6烷氧基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代，
    m为1、2、3或4，并且
    n为0、1或2；
    R7a、R7b、R11a、R11b、R12、R13a和R13b，在每次出现时，各自独立地选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烃基、3-10元杂环基、C6-10芳基和5-14元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代；
    R8a和R8b，在每次出现时，各自独立地选自C1-6烷基、C1-6卤代烷基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C3-10环烃基、3-10元杂环基、C6-10芳基和5-14元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-6烷基)、N(C1-6烷基)2、CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基和5-14元杂芳基的取代基取代；以及
    表示单键或双键；并且
    条件是：
    (1)所有原子的化合价都被满足；以及
    (2)所述式(I)的化合物不包括以下化合物：

  2. 根据权利要求1所述的化合物，其中当环A不存在时，R2与L以及它们所连接的以“a”和“b” 指示的碳原子一起形成所述环B；或者
    当环A存在时，R2与L以及它们所连接的以“a”和“b”指示的碳原子一起形成所述环B。
  3. 根据权利要求1或2所述的化合物，其中：
    X1为N，并且X2为CR9；或者X1为CR9，并且X2为N；
    其中：
    优选地，在每次出现时，R9独立地选自H、D、卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、-COC1-6烷基-O-C1-6烷基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、单环或稠环C3-10环烷基、单环或稠环3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C6-11单螺环烷基和6-11元单螺杂环烷基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、单环或稠环C3-10环烷基、单环或稠环3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C6-11单螺环烷基和6-11元单螺杂环烷基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、-NR8aR8b、CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基的取代基取代；其中所述单螺环烷基和单螺杂环烷基任选地包括3元/5元环系、4元/4元环系、4元/5元环系、4元/6元环系、5元/5元环系、5元/6元环系和6元/6元环系，其中每个环的计数均包括螺原子；并且其中R8a和R8b，在每次出现时，各自独立地选自C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中关于R8a和R8b所述的C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-6烷基)、N(C1-6烷基)2、CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基的取代基取代；
    更优选地，在每次出现时，R9独立地选自H、D、F、Cl、OH、NH2、CN、NO2、COOH、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-COC1-4烷基-O-C1-4烷基、C1-4烷基、C1-4卤代烷基、C2-4烯基、单环C3-6环烷基、单环4-6元杂环烷基、C7-10单螺环烷基和7-10元单螺杂环烷基，其中所述C1-4烷基、C1-4卤代烷基、C2-4烯基、单环C3-6环烷基、单环4-6元杂环烷基、C7-10单螺环烷基和7-10元单螺杂环烷基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、-NR8aR8b、CN和NO2的取代基取代；其中所述单螺环烷基和单螺杂环烷基任选地包括3元/5元环系、4元/4元环系、4元/5元环系、4元/6元环系、5元/5元环系和5元/6元环系，其中每个环的计数均包括螺原子；并且其中R8a和R8b，在每次出现时，各自独立地选自C1-4烷基、C3-6环烷基和苯基，其中关于R8a和R8b所述的C1-4烷基任选地被一个或多个独立地选自F、Cl、OH、NH2、NH(C1-4烷基)、N(C1-4烷基)2、CN、NO2、C3-6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基的取代基取代；
    更优选地，在每次出现时，R9独立地选自H、D、F、Cl、CN、COOH、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-COC1-4烷基-O-C1-4烷基、C2-4烯基、单环C3-6环烷基、单环4-6元杂环烷基、C7单螺环烷基、7元单螺杂环烷基和被OH取代的C1-4烷基，其中所述单螺环烷基和单螺杂环烷基包括4元/4元环系，其中每个环的计数均包括螺原子；并且其中R8a和R8b，在每次出现时，各自独立地选自C1-4烷基、C3-6环烷基和苯基，其中关于R8a和R8b所述的C1-4烷基任选地被一个或多个独立地选自F、Cl、OH、NH2、NHCH3、N(CH3)2、环丙基、氮杂环丁烷基和苯基的取代基取代；
    更优选地，在每次出现时，R9独立地选自H、D、F、Cl、CN、-CH2OH、乙烯基、环丙基、COOH、-COOCH3、-COOCH2CH3、-CONH2、-COCH3、-COCH2OCH3、-COCH2F、-COCH2OH、-COCH2NH2、-COCH2N(CH3)2、、
    更优选地，在每次出现时，R9独立地为H；
    或者
    X1和X2二者都为N。
  4. 根据权利要求1至3中任一项所述的化合物，其中；
    L选自O、S或CR7aR7b，其中R7a和R7b各自独立地选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代；
    优选地，L选自O、S或CR7aR7b，其中R7a和R7b各自独立地选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、CN、NO2、C1-4烷基和-COC1-4烷基的取代基取代；
    优选地，L选自O、S和CH2，更优选为S；
    和/或
    R2选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代；
    优选地，R2选自H、D、卤素、OH、NH2、CN、NO2、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-4烷基和-COC1-4烷基的取代基取代；
    更优选地，R2选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C3-6环烷基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C3-6环烷基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、CN、NO2、C1-4烷基和-COC1-4烷基的取代基取代；
    更优选地，R2选自H、D、OH、NH2和C1-4烷基；
    更优选地，R2选自H、OH、NH2和CH3；
    更优选地，R2为H；
    或者
    R2与L以及它们所连接的以“a”和“b”指示的碳原子一起形成由下式表示的环B：
    所述环B选自部分不饱和的C3-6环烃基、部分不饱和的4-6元杂环基、C6-10芳基和5-10元杂芳基，其中所述C3-6环烃基、4-6元杂环基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基的取代基取代，并且其中R8a和R8b，在每次出现时，各自独立地选自C1-6烷基、C1-6卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-10元杂芳基，其中关于R8a和R8b所述的C1-6烷基、C1-6卤代烷基、C3-6环烷基、4-6 元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-6烷基)、N(C1-6烷基)2、CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-10元杂芳基的取代基取代；
    优选地，所述环B选自苯基和5-6元杂芳基，更优选地选自5-6元杂芳基，其中所述苯基和杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、5-6元杂环烷基、C6-10芳基和5-6元杂芳基的取代基取代，并且其中R8a和R8b，在每次出现时，各自独立地选自C1-4烷基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中关于R8a和R8b所述的C1-4烷基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-4烷基)、N(C1-4烷基)2、CN、NO2、氧代基、C1-4烷基、C1-4烷氧基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基的取代基取代；
    更优选地，所述环B选自吡咯基、吡唑基、1,2,3-三唑基、呋喃基、噁唑基、异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡啶基、吡嗪基、哒嗪基和嘧啶基，更优选地为吡唑基，上述基团中的每一个任选地独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、5-6元杂环烷基、C6-10芳基和5-6元杂芳基的取代基取代，并且其中R8a和R8b，在每次出现时，各自独立地选自C1-4烷基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中关于R8a和R8b所述的C1-4烷基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-4烷基)、N(C1-4烷基)2、CN、NO2、C1-4烷基、C1-4烷氧基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基的取代基取代；
    和/或
    以“c”指示的键连接至所述环B的可用环原子；
    优选地，R2与L以及它们所连接的以“a”和“b”指示的碳原子一起形成由下式表示的结构：
    其中R14选自H、卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、5-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、5-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-4烷基)、N(C1-4烷基)2、CN、NO2、氧代基、C1-4烷基、C1-4烷氧基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基的取代基取代；
    优选地，R14为H。
  5. 根据权利要求1至4中任一项所述的化合物，其中：
    选自 优选为或者
    R2与L以及它们所连接的以“a”和“b”指示的碳原子一起形成环，从而形成由下式表示的结构：
  6. 根据权利要求1至5中任一项所述的化合物，其中：
    R5选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代；
    优选地，R5选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、CN、NO2、C1-4烷基和-COC1-4烷基的取代基取代；
    优选地，R5选自OH和NH2，更优选为OH；
    和/或
    R6选自H、D、卤素、OH、NH2、CN、NO2、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOH、-S(O)nC1-6烷基、C1-6烷基和C1-6烷氧基，其中所述-S(O)nC1-6烷基、C1-6烷基和C1-6烷氧基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代，并且其中R8a和R8b，在每次出现时，各自独立地选自C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-6烷基)、N(C1-6烷基)2、CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基的取代基取代；
    优选地，R6选自H、D、卤素、OH、NH2、CN、NO2、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOH、-S(O)nC1-4烷基、C1-4烷基和C1-4烷氧基，其中所述-S(O)nC1-4烷基、C1-4烷基和C1-4烷氧基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧 代基、C1-4烷基和-COC1-4烷基的取代基取代，并且其中R8a和R8b，在每次出现时，各自独立地选自C1-4烷基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-4烷基)、N(C1-4烷基)2、CN、NO2、C1-4烷基、C1-4烷氧基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基的取代基取代；
    m为1、2或3，并且
    n为0、1或2；
    优选地，R6为H，并且m为1；
    和/或
    X4为N；或者
    X4为CR10，
    其中R10选自H、D、卤素、OH、NH2、CN、NO2、COOH、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基、-COC1-6烷基的取代基取代；
    优选地，R10选自H、D、F、Cl、OH、NH2、CN、NO2、COOH、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中所述C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、C1-4烷基、-COC1-4烷基的取代基取代；
    更优选地，R10为H。
  7. 根据权利要求1至6中任一项所述的化合物，其中所述化合物具有式II或式III的结构：
    其中优选地，在式(II)的化合物中，环A存在；
    其中在式(III)的化合物中，环A存在或不存在。
  8. 根据权利要求1至7中任一项所述的化合物，其中：
    R1选自H、D、卤素、OH、NH2、CN、NO2、COOH、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基、-COC1-6烷基的取代基取代；
    优选地，R1选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基、C1-4烷氧基、C1-4卤代烷基和C3-6环烷基，其中所述C1-4烷基、C1-4烷氧基、C1-4卤代烷基和C3-6环烷基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、CN和NO2的取代基取代；
    更优选地，R1选自F、Cl、OH、NH2、CN、NO2、甲基、乙基、丙基、异丙基、CH2F、CHF2和CF3，更优选地选自Cl和CF3；
    和/或
    R3选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代；
    优选地，R3选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、4-6元杂环烷基、C6-10芳基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、CN、NO2、C1-4烷基和-COC1-4烷基的取代基取代；
    更优选地，R3选自H、D、F、Cl、OH、NH2、CN、NO2和C1-4烷基，更优选为H；
    和/或
    R4选自H、D、卤素、OH、NH2、CN、NO2、COOH、-NHR8a、-NR8aR8b、-CONH2、-CONHR8a、-CONR8aR8b、-COR8a、-COOR8a、-NHCOR8a、-N(R8a)COR8b、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、单环或稠环C3-10环烷基、单环或稠环3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C7-10单螺环烷基和7-10元单螺杂环烷基，其中所述C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、单环或稠环C3-10环烷基、单环或稠环3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C7-10单螺环烷基和7-10元单螺杂环烷基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、-NR8aR8b、CN、NO2、氧代基、C1-6烷基、C1-6烷氧基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基的取代基取代，并且其中R8a和R8b，在每次出现时，各自独立地选自C1-6烷基、C1-6卤代烷基、C3-6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基，其中关于R8a和R8b所述的C1-6烷基、C1-6卤代烷基、C3-6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、NH(C1-6烷基)、N(C1-6烷基)2、CN、NO2、C1-6烷基、C1-6烷氧基、C3-6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基的取代基取代；
    优选地，R4选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基和C3-6环烷基；
    更优选地，R4为H；
    和/或
    R12，在每次出现时，独立地选自H、D、F、Cl、OH、NH2、CN、NO2、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自F、Cl、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代；
    和/或
    U选自O、S和CR11aR11b，其中R11a和R11b各自独立地选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代，优选地R11a和R11b各自为H；
    优选地，U为O或CH2；
    和/或
    当环A不存在时，V和W各自独立地选自O、S和CR13aR13b，其中R13a和R13b各自独立地选自H、D、卤素、OH、NH2、CN、NO2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基，其中所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-10元杂芳基任选地各自独立地被一个或多个独立地选自卤素、OH、NH2、CN、NO2、氧代基、C1-6烷基和-COC1-6烷基的取代基取代；优选地，R13a和R13b各自独立地选自H、卤素、C1-4烷基；更优选地，R13a和R13b各自独立地选自H、F、Cl、甲基和乙基；
    优选地，当环A不存在时，V选自O、CH2、CHF2和CHCH3，优选为O；和/或W选自CH2、CH2F、CHCH3和CHCH2CH3，优选为CHCH3；
    更优选地，当环A不存在时，部分具有下式的结构：
    或者
    当环A存在时，V和W各自为C，并且所述环A选自苯基和5-6元杂芳基，更优选地选自苯基、吡咯基、吡唑基、1,2,3-三唑基、呋喃基、噁唑基、异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡啶基、吡嗪基、哒嗪基和嘧啶基，更优选为苯基或吡啶基；
    更优选地，当环A存在时，部分具有下式的结构：
    和/或
    部分具有下式的结构：
  9. 根据权利要求1至8中任一项所述的化合物，其中所述化合物：


  10. 药物组合物，其包含权利要求1至9中任一项所述的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，以及一种或多种药学上可接受的载体，所述药物组合物优选是固体制剂、液体制剂或透皮制剂。
  11. 权利要求1至9中任一项所述的化合物或者其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药、或者权利要求10所述的药物组合物在制备用于预防和/或治疗通过SHP2活性介导的疾病、病症或病况、减轻其症状、延缓其发展或发作的药物中的用途；优选地，所述疾病、病症或病况选自努南氏综合征、豹皮综合征和癌症，其中优选地，所述癌症包括实体癌和血液癌，所述实体癌优选地选自神经母细胞瘤、黑色素瘤、头癌、头颈部鳞状细胞癌、乳腺癌、食道癌、肝癌、胰腺癌、胃癌、结肠癌、肺癌(优选非小细胞肺癌)、间变性大细胞淋巴瘤和成胶质细胞瘤，以及所述血液癌优选为白血病，优选为青少年骨髓单核细胞白血病或急性髓性白血病。
PCT/CN2024/104630 2023-07-11 2024-07-10 用作shp2抑制剂的杂环化合物、包含其的药物组合物及其制备方法和用途 WO2025011568A1 (zh)

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109415360A (zh) * 2016-06-14 2019-03-01 诺华股份有限公司 用于抑制shp2活性的化合物和组合物
WO2020177653A1 (zh) * 2019-03-04 2020-09-10 勤浩医药（苏州）有限公司 吡嗪类衍生物及其在抑制shp2中的应用
CN112368272A (zh) * 2018-03-21 2021-02-12 新标立亚医疗有限公司 Shp2抑制剂及其用途
WO2021249057A1 (zh) * 2020-06-12 2021-12-16 石药集团中奇制药技术（石家庄）有限公司 杂环化合物及其用途
CN114195799A (zh) * 2020-09-02 2022-03-18 勤浩医药（苏州）有限公司 吡嗪类衍生物及其在抑制shp2中的应用
WO2022089389A1 (zh) * 2020-10-30 2022-05-05 赣江新区博瑞创新医药有限公司 杂环化合物及其制备方法、药物组合物和应用
CN114502165A (zh) * 2019-09-23 2022-05-13 苏州浦合医药科技有限公司 Shp2抑制剂及其用途
CN115340561A (zh) * 2021-05-14 2022-11-15 药雅科技(上海)有限公司 Shp2磷酸酶稠环类抑制剂的制备及其应用
CN115340559A (zh) * 2021-05-12 2022-11-15 药雅科技(上海)有限公司 Shp2磷酸酶杂环类抑制剂的制备及其应用
CN116354960A (zh) * 2023-03-19 2023-06-30 药雅科技(上海)有限公司 Shp2磷酸酶抑制剂

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109415360A (zh) * 2016-06-14 2019-03-01 诺华股份有限公司 用于抑制shp2活性的化合物和组合物
CN112368272A (zh) * 2018-03-21 2021-02-12 新标立亚医疗有限公司 Shp2抑制剂及其用途
WO2020177653A1 (zh) * 2019-03-04 2020-09-10 勤浩医药（苏州）有限公司 吡嗪类衍生物及其在抑制shp2中的应用
CN111647000A (zh) * 2019-03-04 2020-09-11 勤浩医药（苏州）有限公司 吡嗪类衍生物及其在抑制shp2中的应用
CN114502165A (zh) * 2019-09-23 2022-05-13 苏州浦合医药科技有限公司 Shp2抑制剂及其用途
WO2021249057A1 (zh) * 2020-06-12 2021-12-16 石药集团中奇制药技术（石家庄）有限公司 杂环化合物及其用途
CN114195799A (zh) * 2020-09-02 2022-03-18 勤浩医药（苏州）有限公司 吡嗪类衍生物及其在抑制shp2中的应用
WO2022089389A1 (zh) * 2020-10-30 2022-05-05 赣江新区博瑞创新医药有限公司 杂环化合物及其制备方法、药物组合物和应用
CN115340559A (zh) * 2021-05-12 2022-11-15 药雅科技(上海)有限公司 Shp2磷酸酶杂环类抑制剂的制备及其应用
CN115340561A (zh) * 2021-05-14 2022-11-15 药雅科技(上海)有限公司 Shp2磷酸酶稠环类抑制剂的制备及其应用
CN116354960A (zh) * 2023-03-19 2023-06-30 药雅科技(上海)有限公司 Shp2磷酸酶抑制剂

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