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WO2022194192A1 - Composé hétéroaromatique, son procédé de préparation et son utilisation - Google Patents

Composé hétéroaromatique, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2022194192A1
WO2022194192A1 PCT/CN2022/081102 CN2022081102W WO2022194192A1 WO 2022194192 A1 WO2022194192 A1 WO 2022194192A1 CN 2022081102 W CN2022081102 W CN 2022081102W WO 2022194192 A1 WO2022194192 A1 WO 2022194192A1
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Prior art keywords
alkyl
compound
alkylene
cycloalkyl
hydrogen
Prior art date
Application number
PCT/CN2022/081102
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English (en)
Chinese (zh)
Inventor
刘金明
唐建川
任云
何婷
刘谦
田强
宋宏梅
葛均友
王晶翼
Original Assignee
四川科伦博泰生物医药股份有限公司
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Application filed by 四川科伦博泰生物医药股份有限公司 filed Critical 四川科伦博泰生物医药股份有限公司
Priority to CN202280010512.9A priority Critical patent/CN116801883A/zh
Publication of WO2022194192A1 publication Critical patent/WO2022194192A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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 invention belongs to the field of medicinal chemistry, and in particular relates to a class of heteroaromatic compounds, a preparation method thereof, a pharmaceutical composition comprising the same, and uses thereof.
  • the RAS family is a class of guanine nucleotide-binding proteins with GTPase activity. As a molecular switch, RAS can realize the conversion of GDP-bound inactive state and GTP-bound activated state, transmit upstream signals received by cells to downstream various signaling pathways, and regulate protein synthesis, gene transcription, cell growth, differentiation, and apoptosis. and migration, etc.
  • the RAS gene is one of the most prevalent proto-oncogenes in human cancers.
  • RAS mutation can lead to the continuous activation of downstream signaling pathways, which promotes the occurrence and development of tumors.
  • the RAS family includes HRAS, NRAS, and KRAS, and about 85% of RAS mutations in all tumor types occur in KRAS.
  • KRAS-mutated tumors the GTPase activity of KRAS itself decreased, and KRAS remained active.
  • KRAS mutation is closely related to the occurrence of lung cancer, pancreatic cancer and colorectal cancer, and the highest frequency (about 34%) is the mutation of glycine at position 12 on KRAS to aspartic acid (KRAS G12D).
  • KRAS G12D small molecule inhibitors of KRAS G12D has always been one of the difficulties in the field of medicine.
  • Boehringer Ingelheim's BI-2852 uses the principle of molecular glue to induce KRAS G12D to form a dimer and block the interaction between KRAS and downstream proteins;
  • Revolution uses mTOR inhibitors to induce KRAS G12D protein to form a ternary complex, block The interaction of KRAS and downstream effector proteins;
  • Mirati Company disclosed a new class of KRAS G12D inhibitors in WO2021041671A1, but did not disclose its mechanism of action.
  • KRAS has become an excellent tumor therapy target, there are no clinically validated drugs targeting KRAS G12D. Therefore, there is an urgent need in the art to develop KRAS G12D targeting inhibitors with novel structures, good biological activity and high druggability.
  • the present invention provides a class of heteroaromatic compounds, which have a strong inhibitory effect on the target KRAS G12D, and thus have better tumor treatment effects.
  • the compounds of the present invention also possess various excellent properties, such as good physicochemical properties (eg solubility, physical and/or chemical stability) and good safety.
  • the compound is a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound or metabolite thereof Object:
  • X 1 is selected from N and CR 5 ;
  • L is selected from covalent bonds, -O-, -S- and -NR 6 -;
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being replaced by one or more R 7 substituted;
  • R 2 is selected from
  • each X 2 is independently selected from N and CR 9 ;
  • R 3 is selected from C 1-6 alkyl and C 1-6 haloalkyl
  • R 4 is selected from C 6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with one or more R 10 ;
  • R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 6 is selected from hydrogen and C 1-6 alkyl
  • R 7 is selected from hydrogen, halogen, cyano, -OR 11 , -OC(O)-NR 11 R 12 , -OC(O)-R 11 , -NR 11 R 12 , -NR 12 -C(O)- R 11 , -NR 12 -C(O)-NR 11 R 12 , -NR 12 -C(O)-OR 11 , -C(O)-R 11 , -C(O)-OR 12 , -C( O)-NR 11 R 12 , C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, C 1-6 alkyl, -C 1-6 alkylene -R 13 , -C 1-6 al
  • R 8 is selected from halogen, hydroxyl, cyano, C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-cyano and C 1-6 haloalkyl;
  • R 9 is selected from hydrogen, hydroxyl and C 1-6 alkyl
  • R 10 is selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, each of said alkyl, cycloalkyl, heterocyclyl and heteroaryl is optionally selected from one or more of hydrogen, halogen, hydroxy, cyano Substituent substitution of C 1-6 alkyl and C 1-6 haloalkyl;
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkyl-OC 1-6 alkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl , the cycloalkyl and heterocyclyl groups are each optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl;
  • R 12 is selected from hydrogen and C 1-6 alkyl
  • R 13 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, each of said cycloalkyl and heterocyclyl optionally being One or more substituents selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl substituted;
  • R 14 is selected from hydrogen and C 1-6 alkyl
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • o, p, q, r and s are each independently selected from 0, 1, 2 or 3, provided that o and r are not both 0 and p and q are not both 0.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph thereof , solvates, N-oxides, isotopically-labeled compounds or metabolites, and one or more pharmaceutically acceptable carriers.
  • the present invention provides a kit comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N- Oxides, isotopically-labeled compounds or metabolites, or pharmaceutical compositions of the invention, and optionally, packaging and/or instructions.
  • the present invention provides compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds thereof Or metabolites, or pharmaceutical compositions of the present invention, for inhibiting KRAS G12D.
  • the present invention provides compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds thereof Or metabolites, or the pharmaceutical composition of the present invention, which is used for the prevention or treatment of KRAS G12D-mediated related diseases.
  • the present invention provides compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds thereof Or metabolite or use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating KRAS G12D-mediated related diseases.
  • the present invention provides a method of preventing or treating KRAS G12D-mediated related diseases, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, Stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds or metabolites, or pharmaceutical compositions of the invention.
  • the present invention provides methods of preparing the compounds of the present invention.
  • alkyl is defined as a straight or branched chain saturated aliphatic hydrocarbon group.
  • C 1-6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which are optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen.
  • alkenyl refers to a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds.
  • C 2-6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms and one, two or three (preferably one) carbon-carbon double bonds (eg vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexene group, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.), which are optionally separated by one or more (such as 1 to 3) Suitable substituents such as halogen are substituted.
  • alkynyl refers to a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds.
  • C 2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms and one, two or three (preferably one) carbon-carbon triple bonds, such as ethynyl , 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3 -hexynyl, 4-hexynyl, 5-hexynyl, etc.), optionally substituted with one or more (eg 1 to 3) suitable substituents such as halogen.
  • cycloalkyl refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl) , cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic rings, including spirocyclic, fused or bridged systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo [3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), optionally substituted with one or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl
  • cyclohexyl cycloheptyl
  • C 3-6 cycloalkyl refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, cyclopropyl, cyclo) having 3 to 6 ring carbon atoms butyl, cyclopentyl or cyclohexyl) optionally substituted with one or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
  • halo or halogen group is defined to include fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group substituted with one or more, such as 1 to 3, the same or different halogen atoms.
  • C1-6 haloalkyl refers to a haloalkyl group having 1 to 6 carbon atoms, such as -CF3 , -C2F5 , -CHF2, -CH2F , -CH2CF3 , - CH 2 Cl or -CH 2 CH 2 CF 3 etc.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic group, eg, having 2, 3, 4, 5, 6, 7, 8 or 9 carbons in the ring atom and one or more (eg 1, 2, 3 or 4) heteroatoms independently selected from N, O or S(O) t (where t is 0, 1 or 2), eg 3- 12-membered heterocyclyl, 3-7-membered heterocyclyl, 3-6-membered heterocyclyl, 5-6-membered heterocyclyl, etc.
  • the polycyclic group can be a parallel, spiro or bridged ring, such as 5-12 A membered ring, a 5-12 membered spiro ring, or a 5-12 membered bridged ring.
  • Representative examples of heterocyclyl include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, hexahydro- 1H-pyrrolinyl, hexahydropyrrolizinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl , piperazinyl, etc.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated pi electron system.
  • C6-10 aryl or “ C6-10 aromatic ring” refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl (ring) or naphthyl (ring).
  • the aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, -NO2 , C1-6 alkyl, etc.).
  • heteroaryl or “heteroaromatic ring” refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, for example 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, in addition, in each case may For benzo-fused.
  • a heteroaryl or heteroaryl ring can be selected from thienyl (ring), furyl (ring), pyrrolyl (ring), oxazolyl (ring), thiazolyl (ring), imidazolyl (ring), pyrrolyl (ring) oxazolyl (ring), isoxazolyl (ring), isothiazolyl (ring), oxadiazolyl (ring), triazolyl (ring), thiadiazolyl (ring), etc., and their benzos derivatives; or pyridyl (ring), pyridazinyl (ring), pyrimidinyl (ring), pyrazinyl (ring), triazinyl (ring), etc., and their benzo derivatives.
  • substituted means that one or more (eg, 1, 2, 3, or 4) hydrogens on the designated atom are replaced by a selection from the designated group, provided that no more than the designated atom is at Normal valences in the present case and the substitutions form stable compounds. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be independently and/or together independently The selected substituents are substituted or unsubstituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected substituents Substitute or not.
  • 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 under reasonable conditions, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • the point of attachment of a substituent can be from any suitable position on the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically-labeled compounds that are identical to the compounds of the present invention, except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature or atomic substitution of mass numbers.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (eg, 2 H, 3 H, deuterium D, tritium T); isotopes of carbon (eg, 11 C, 13 C, and 14 C); chlorine isotopes of fluorine (eg 37 Cl); isotopes of fluorine (eg 18 F); isotopes of iodine (eg 123 I and 125 I); isotopes of nitrogen (eg 13 N and 15 N); isotopes of oxygen (eg 15 O, 17 O and 18 O); isotopes of phosphorus (eg 32 P); and isotopes of sulfur (eg 35 S).
  • isotopes of hydrogen eg, 2 H, 3 H, deuterium D, tritium T
  • isotopes of carbon eg, 11 C, 13 C, and 14 C
  • chlorine isotopes of fluorine eg 37
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (eg, assays).
  • the radioisotopes tritium (ie 3 H) and carbon-14 (ie 14 C) are particularly useful for this purpose due to their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes such as11C , 18F , 15O , and13N can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies.
  • Isotopically-labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically-labeled reagent in place of the previously employed non-labeled reagent.
  • Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg, D2O , acetone-d6, or DMSO - d6.
  • stereoisomer refers to isomers formed due to at least one asymmetric center. In compounds having one or more (eg, 1, 2, 3, or 4) asymmetric centers, it may give rise to racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of this application covers all such in any ratio (eg 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% %) of isomers or mixtures thereof.
  • 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.
  • compositions of the present invention may exist in free form for use in therapy, or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates or metabolites, which, upon administration to a patient in need thereof, can directly or indirectly provide the present invention compounds or their metabolites or residues. Accordingly, references herein to "compounds of the present invention" are also intended to encompass the various derivative forms of the compounds described above.
  • 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. Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts.
  • suitable salts see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.
  • the compounds of the present invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the present invention comprise a polar solvent as a structural element of the crystal lattice of the compound.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • Nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides; Nitrogen-containing heterocycles. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines.
  • MCPBA m-chloroperoxybenzoic acid
  • hydrogen peroxide alkyl Hydrogen peroxides such as t-butyl hydroperoxide
  • sodium perborate and dioxiranes such as dimethyldioxirane
  • metabolites of the compounds of the present invention ie substances formed in the body upon administration of the compounds of the present invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like, of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds prepared by methods of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
  • the present invention also encompasses compounds of the present invention that contain 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 relevant molecule, thereby forming chemically protected forms of the compounds of the present invention. This can be accomplished by conventional protecting groups, as described, for example, 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 those protecting groups, these references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • An object of the present invention is to provide a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof Labeled compounds or metabolites:
  • X 1 is selected from N and CR 5 ;
  • L is selected from covalent bonds, -O-, -S- and -NR 6 -;
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being replaced by one or more R 7 substituted;
  • R 2 is selected from
  • each X 2 is independently selected from N and CR 9 ;
  • R 3 is selected from C 1-6 alkyl and C 1-6 haloalkyl
  • R 4 is selected from C 6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with one or more R 10 ;
  • R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 6 is selected from hydrogen and C 1-6 alkyl
  • R 7 is selected from hydrogen, halogen, cyano, -OR 11 , -OC(O)-NR 11 R 12 , -OC(O)-R 11 , -NR 11 R 12 , -NR 12 -C(O)- R 11 , -NR 12 -C(O)-NR 11 R 12 , -NR 12 -C(O)-OR 11 , -C(O)-R 11 , -C(O)-OR 12 , -C( O)-NR 11 R 12 , C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, C 1-6 alkyl, -C 1-6 alkylene -R 13 , -C 1-6 al
  • R 8 is selected from halogen, hydroxyl, cyano, C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-cyano and C 1-6 haloalkyl;
  • R 9 is selected from hydrogen, hydroxyl and C 1-6 alkyl
  • R 10 is selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, each of said alkyl, cycloalkyl, heterocyclyl and heteroaryl is optionally selected from one or more of hydrogen, halogen, hydroxy, cyano Substituent substitution of C 1-6 alkyl and C 1-6 haloalkyl;
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkyl-OC 1-6 alkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl , the cycloalkyl and heterocyclyl groups are each optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl;
  • R 12 is selected from hydrogen and C 1-6 alkyl
  • R 13 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, each of said cycloalkyl and heterocyclyl optionally being One or more substituents selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl substituted;
  • R 14 is selected from hydrogen and C 1-6 alkyl
  • n 0, 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • o, p, q, r and s are each independently selected from 0, 1, 2 or 3, provided that o and r are not both 0 and p and q are not both 0.
  • R 7 is selected from hydrogen, halogen, cyano, -OR 11 , -OC(O)-NR 11 R 12 , -OC(O)-R 11 , -NR 11 R 12 , - NR 12 -C(O)-R 11 , -NR 12 -C(O)-NR 11 R 12 , -NR 12 -C(O)-OR 11 , -C(O)-R 11 , -C(O )-OR 12 , -C(O)-NR 11 R 12 , C 3-10 cycloalkyl and 3-12 membered heterocyclyl, optionally by one or more independent is substituted with a substituent selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, C 1-6 alkyl and C 1-6 haloalkyl.
  • X 1 is selected from N and CH. In a preferred embodiment, X 1 is N.
  • X 2 is selected from CR 9 .
  • X 2 is selected from CH.
  • L is selected from covalent bonds, -O-, -S-, -NH- and -N(C 1-3 alkyl)-.
  • L is selected from -O-, -NH- and -N(C 1-3 alkyl)-.
  • L is -O-.
  • R 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, and 3-12 membered heterocyclyl, each of which is optional is substituted with one or more R 7 , each R 7 is independently selected from hydrogen, halogen, cyano, -OR 11 , -OC(O)-NR 11 R 12 , -NR 11 R 12 , -NR 12 -C(O)-R 11 , -NR 12 -C(O)-OR 11 , -C(O)-R 11 , -C(O)-NR 11 R 12 , C 3-10 cycloalkyl, C 6-10 membered aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, each of said cycloalkyl, aryl, heteroaryl and heterocyclyl optionally being independently selected by one or more Substituted from the following substituents: hydrogen, halogen, hydroxy, amino, cyano, C
  • R 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being replaced by one or more substituted with R 7 , each R 7 is independently selected from hydrogen, halogen, cyano, -OR 11 , -OC(O)-NR 11 R 12 , -NR 11 R 12 , -NR 12 -C(O) -R 11 , -NR 12 -C(O)-OR 11 , -C(O)-R 11 , -C(O)-NR 11 R 12 , C 3-10 cycloalkyl and 3-12 membered heterocycle each of the cycloalkyl and heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, C1-6 alkyl, and C1 -6 haloalkyl.
  • R 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of which is optional is substituted with one or more R 7 , each R 7 is independently selected from -OR 11 , -OC(O)-NR 11 R 12 , -NR 11 R 12 , -NR 12 -C(O)-R 11 , -NR 12 -C(O)-OR 11 , -C(O)-NR 11 R 12 , C 3-6 cycloalkyl, 5-10-membered heteroaryl and 3-12-membered heterocyclyl, the The cycloalkyl, heteroaryl and heterocyclyl groups are each optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, -C 1-6 alkylene -R 13 , -C 1-3 alkylene-OH, -C 1-6 alkylene-NR 13 R 14
  • R 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being replaced by one or more R 7 substitutions, each R 7 is independently selected from -OR 11 , -OC(O)-NR 11 R 12 , -NR 11 R 12 , -NR 12 -C(O)-R 11 , -NR 12 -C(O)-OR 11 , -C(O)-NR 11 R 12 and 3-12 membered heterocyclyl optionally substituted with one or more substituents independently selected from : hydrogen, halogen, hydroxyl, amino, cyano and C 1-6 alkyl.
  • R 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of which is optional is substituted with one or more R 7 , each R 7 is independently selected from -OR 11 , -OC(O)-NR 11 R 12 , -NR 11 R 12 , -NR 12 -C(O)-R 11 , -NR 12 -C(O)-OR 11 , -C(O)-NR 11 R 12 , 5-10-membered heteroaryl and 3-12-membered heterocyclyl, said heteroaryl and heterocyclyl Each is optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, -C 1-6 alkylene -R 13 , -C 1-3 alkylene -OH, -C 1-6 alkylene-NR 13 R 14 , -C 1-6 alkylene-OC(O)-R 13
  • R 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being replaced by one or more R 7 substitutions, each R 7 is independently selected from -OR 11 , -OC(O)-NR 11 R 12 , -NR 11 R 12 , -NR 12 -C(O)-R 11 , -NR 12 -C(O)-OR 11 , -C(O)-NR 11 R 12 and 3-12 membered heterocyclyl optionally substituted with one or more substituents independently selected from : hydrogen, halogen, hydroxyl, amino, cyano and C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with one or more R 7 , each R 7 is independently selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl and 5-8 membered heterocyclyl, each of said C 3-6 cycloalkyl, 5-6 membered heteroaryl and 5-8 membered heterocyclyl is optionally independently selected by one or more Substituted from the following substituents: halogen, C 1-6 alkyl, -C 1-6 alkylene-R 13 , -C 1-3 alkylene-OH, -C 1-6 alkylene-NR 13 R 14 , -C 1-6 alkylene-OC(O)-R 13 and C 1-3 haloalkyl; wherein R 13 is selected from C 1-6 alkyl and 5-6 membered heterocyclyl; R 14 is selected From hydrogen and C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with one or more R 7 , each R 7 is independently selected from 5-6 membered heteroaryl and 5-8 membered heterocyclyl, each of the 5-6 membered heteroaryl and 5-8 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkyl, -C 1-6 alkylene-R 13 , -C 1-3 alkylene-OH, -C 1-6 alkylene-NR 13 R 14 , -C 1-6 alkylene-OC(O) -R 13 and C 1-3 haloalkyl; wherein R 13 is selected from C 1-6 alkyl and 5-6 membered heterocyclyl; R 14 is selected from hydrogen and C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with one or more R 7 , each R 7 is independently selected from cyclopropyl, pyrrolidinyl, hexahydropyrrole azinyl and imidazolyl, each of said cyclopropyl, pyrrolidinyl, hexahydropyrrolazinyl and imidazolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkane group, -C 1-6 alkylene-R 13 , -C 1-3 alkylene-OH, -C 1-6 alkylene-NR 13 R 14 , -C 1-6 alkylene-OC ( O)-R 13 and C 1-3 haloalkyl; wherein R 13 is selected from C 1-6 alkyl and morpholinyl; R 14 is C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with one or more R 7 , each R 7 is independently selected from pyrrolidinyl, hexahydropyrrolizinyl, and imidazole each of the pyrrolidinyl, hexahydropyrrolazinyl and imidazolyl groups is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkyl, -C 1-6 alkylene Alkyl-R 13 , -C 1-3 alkylene-OH, -C 1-6 alkylene-NR 13 R 14 , -C 1-6 alkylene-OC(O)-R 13 and C 1 -3 haloalkyl; wherein R 13 is selected from C 1-6 alkyl and morpholinyl; R 14 is C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with one or more R 7 , each R 7 is independently selected from cyclopropyl, pyrrolidinyl, hexahydropyrrole azinyl and imidazolyl, each of said cyclopropyl, pyrrolidinyl, hexahydropyrrolazinyl and imidazolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkane group, -C 1-6 alkylene-morpholinyl, -C 1-3 alkylene-OH, -C 1-6 alkylene-N(C 1-6 alkyl) 2 , -C 1- 6 alkylene-OC(O)-(morpholinyl) and C 1-3 haloalkyl.
  • R 1 is C 1-6 alkyl optionally substituted with one or more R 7 , each R 7 is independently selected from pyrrolidinyl, hexahydropyrrolizinyl, and imidazole each of the pyrrolidinyl, hexahydropyrrolazinyl and imidazolyl groups is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkyl, -C 1-6 alkylene Alkyl-morpholinyl, -C 1-3 alkylene-OH, -C 1-6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-OC(O )-(morpholinyl) and C 1-3 haloalkyl.
  • R 1 is selected from where the wavy line Indicates the point of attachment of this group to the rest of the molecule.
  • R 1 is selected from where the wavy line Indicates the point of attachment of this group to the rest of the molecule.
  • R 1 is C 1-6 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-6 alkyl, C 1- 6 -alkylene-OH or C 1-6 -haloalkyl-substituted 5-12-membered cycloheterocyclyl and 5-10-membered heteroaryl.
  • R 1 is C 1-6 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-6 alkyl, C 1- 6 -alkylene-OH or C 1-6 haloalkyl-substituted 5-12-membered cycloheterocyclyl.
  • R 1 is C 1-6 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-3 alkyl, C 1- 3 -alkylene-OH or C 1-3 haloalkyl-substituted 5-8-membered cycloheterocyclyl and 5-10-membered heteroaryl.
  • R 1 is C 1-6 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-3 alkyl, C 1- 3 -alkylene-OH or C 1-3 haloalkyl-substituted 5-8 membered cycloheterocyclyl.
  • R 1 is C 1-3 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-3 alkyl, C 1- 3 -alkylene-OH or C 1-3 haloalkyl-substituted 5-8-membered nitrogen-containing heterocyclic and 5-10-membered heteroaryl groups.
  • R 1 is C 1-3 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-3 alkyl, C 1- 3 -alkylene-OH or C 1-3 haloalkyl-substituted 5-8 membered nitrogen-containing heterocyclic group.
  • R 1 is C 1-3 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-3 alkyl, C 1- 3 alkylene-OH or C 1-3 haloalkyl substituted hexahydropyrrolizinyl and imidazole.
  • R 1 is C 1-3 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-3 alkyl, C 1- 3 alkylene-OH or C 1-3 haloalkyl substituted hexahydropyrrolazinyl.
  • R 1 is C 1-3 alkyl optionally substituted with one R 7 selected from the group consisting of optionally substituted with one or more of F, Cl, methyl, chloromethyl, Fluoromethyl or hydroxymethyl substituted hexahydropyrrolizinyl and imidazole.
  • R 1 is selected from
  • R 4 is selected from C 6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with one or more R 10
  • each R 10 is each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-3 alkyl, C 3-6 ring Alkyl and 3-8 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being selected from the group consisting of one or more hydrogen, halogen, hydroxyl, cyano, C1-3 alkyl and Substituent substitution of C 1-3 haloalkyl.
  • R 4 is selected from C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more R 10 , each R 10 are each independently selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, -OC 1-3 alkyl and C 3-6 cycloalkyl, the alkyl optionally being One or more hydrogen and halogen substitution.
  • R4 is selected from phenyl, naphthyl, and indazolyl, each of which is optionally substituted with one or more R10, each R10 Each is independently selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkynyl, -OC 1-3 alkyl and C 3-6 cycloalkyl.
  • R 4 is selected from
  • R 1 is C 1-6 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-6 alkyl, C 1- 6 alkylene-OH or C 1-6 haloalkyl substituted 3-6 membered heterocyclic group; and R 4 is selected from C 6-10 aryl, which is optionally substituted with one R 10 , R 10 selected from halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, optionally by one or more selected from halogen, hydroxy, cyano, C 1 Substituent substitution of -6 alkyl and C 1-6 haloalkyl.
  • R 1 is selected from C 1-6 alkyl optionally substituted with one R 7 selected from C 1-6 alkyl optionally substituted with one or more halogens, C 1-6 alkyl, C 1-6 alkylene-OH or C 1-6 haloalkyl substituted 5-6 membered nitrogen-containing heterocyclic group; and R 4 is naphthyl, which is optionally substituted by one R 10 , R 10 selected from halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, optionally by one or more selected from halogen, hydroxy, cyano, C 1 Substituent substitution of -6 alkyl and C 1-6 haloalkyl.
  • R 1 is selected from C 1-6 alkyl optionally substituted with one R 7 selected from tetrahydropyrrolyl optionally substituted with C 1-3 alkyl ; and R 4 is naphthyl optionally substituted with one R 10 selected from halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, the The alkyl group is optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl and C1-6 haloalkyl.
  • each R 3 is each independently selected from C 1-6 alkyl and C 1-6 haloalkyl, or two R 3 attached to the same carbon atom and said carbon atom together form carbonyl or C 3-6 cycloalkyl.
  • each R3 is independently selected from C1-3 alkyl, or two R3 attached to the same carbon atom and said carbon atom together form a carbonyl or C3-6 ring alkyl.
  • each R3 is independently selected from methyl, or two R3s attached to the same carbon atom and said carbon atom together form carbonyl or cyclopropyl.
  • R 2 is selected from
  • R 2 is selected from
  • the present invention encompasses compounds of formula (I) resulting from any combination of the above preferred groups.
  • the compounds of the present invention have the structure of formula (II-A), formula (II-B) or formula (II-C):
  • each of the groups L, R1, R3 , R4 , R8 , m, n , o, p, q, r and s are as defined above.
  • the compounds of the present invention have the structure of formula (II-A) or formula (II-C), wherein L is selected from covalent bonds, -O-, -S- and -NH-; preferably Typically, L is selected from -O- and -S-; more preferably, L is selected from -O-.
  • the compounds of the present invention have the structure of formula (II-A) or formula (II-C), wherein o, p, q, r and s are each independently selected from 0, 1 or 2; Preferably, o, p, q and r are each independently selected from 0 or 1, and s is selected from 1 or 2; preferably, o and p are selected from 0 or 1, q and r are selected from 1, and s is selected from 1 or 2; preferably, o and p are selected from 0, q and r are selected from 1, and s is selected from 2.
  • the compounds of the present invention have the structure of formula (II-A) or formula (II-C), wherein n is 0 or 1; preferably 0.
  • the compounds of the present invention have the structure of formula (II-A) or formula (II-C), wherein m is 0, 1 or 2.
  • the compounds of the present invention are of formula (II-A-1), (II-A-2), (II-C-1), (II-C-2) or (II-C -3) structure:
  • the present invention encompasses compounds resulting from any combination of the various embodiments.
  • the compounds of the present invention are selected from:
  • Another object of the present invention is to provide a process for the preparation of the compounds of the present invention.
  • the present invention provides a method for preparing a compound of formula (II-A) comprising the steps of:
  • L, R 1 , R 3 , R 4 , R 8 , m, n, o, p, q, r and s are as defined above;
  • LG 1 , LG 2 and X represent leaving groups, which include but are not limited to halogen atoms, trifluoromethanesulfonate, methylthio, methylsulfinyl, methylsulfonyl, and the like;
  • PG 1 , PG 2 and PG 3 represent protective groups for hydroxyl or amino groups, including but not limited to benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), methyl, benzyl and the like.
  • Step (1) reacting compound II-A-1 with compound II-A-2 to obtain compound II-A-3;
  • the reaction is preferably carried out in a suitable organic solvent, which can be selected from methanol, toluene, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably methanol.
  • a suitable organic solvent which can be selected from methanol, toluene, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably methanol.
  • the reaction is preferably carried out in the presence of a suitable organic or inorganic base, which can be selected from diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, preferably sodium methoxide.
  • a suitable organic or inorganic base which can be selected from diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, preferably sodium methoxide.
  • the reaction is carried out at a suitable temperature, preferably 0-80°C.
  • the reaction is carried out for a suitable time, eg, 2-24 hours.
  • Step (2) coupling reaction of compound II-A-3 and compound II-A-4 to obtain compound II-A-5;
  • the coupling reaction is preferably carried out in the presence of a metal catalyst, a ligand and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium acetate, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • the ligands are phosphorus ligands such as 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphorus-2',6'-diisopropoxy- 1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl Benzene, preferably 4,5-bisdiphenylphosphino-9,9-dimethylxanthene.
  • the base is an organic or inorganic base, such as diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (3) deprotecting compound II-A-5 to obtain compound II-A-6;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from ethyl acetate, methanol, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the deprotection reaction is preferably carried out in the presence of a suitable acid.
  • the acid may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 0-40°C.
  • the reaction is carried out for a suitable time, eg, 2-12 hours.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst, a ligand and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium acetate, preferably tris(dibenzylideneacetone)dipalladium.
  • a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium
  • the ligands are phosphorus ligands such as 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphorus-2',6'-diisopropoxy- 1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl Benzene, preferably 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl.
  • the base is an organic or inorganic base, such as sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (5) deprotecting compound II-A-8 to obtain compound II-A-9;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from alcohol-based protic solvents, tetrahydrofuran, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethylformamide.
  • the deprotection reaction is preferably carried out in the presence of sodium ethanethiolate.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 50-100°C.
  • the reaction is carried out for a suitable time, eg, 1-12 hours.
  • step (6) compound II-A-9 is subjected to condensation reaction with compound II-A-10 to obtain compound II-A-11;
  • the condensation reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, N,N-dimethylformamide, dichloromethane and any combination thereof, preferably N,N-dimethylformamide.
  • the condensation reaction is preferably carried out in the presence of a suitable organic base, which can be selected from diisopropylethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec -7-ene, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • a suitable organic base which can be selected from diisopropylethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec -7-ene, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • the condensation reaction is carried out in the presence of a suitable condensing agent, and the condensing agent can be selected from Carter condensing agent, 1-hydroxybenzotriazole, 2-(7-azobenzotriazole)-N,N ,N',N'-tetramethylurea hexafluorophosphate, preferably Carter condensing agent.
  • a suitable condensing agent can be selected from Carter condensing agent, 1-hydroxybenzotriazole, 2-(7-azobenzotriazole)-N,N ,N',N'-tetramethylurea hexafluorophosphate, preferably Carter condensing agent.
  • the deprotection reaction is carried out at a suitable temperature, preferably 20-100°C.
  • the reaction is carried out for a suitable time, eg, 2-24 hours.
  • Step (7) deprotecting compound II-A-11 to obtain compound II-A;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from ethyl acetate, methanol, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the deprotection reaction is preferably carried out in the presence of a suitable acid.
  • the acid may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 0-40°C.
  • the reaction is carried out for a suitable time, eg, 2-12 hours.
  • the present invention provides a second method for preparing the compound of formula (II-A), which comprises the following steps:
  • L, R 1 , R 3 , R 4 , R 8 , m, n, o, p, q, r and s are as defined above;
  • LG 1 , LG 2 and X represent leaving groups, which include but are not limited to halogen atoms, trifluoromethanesulfonate, methylthio, methylsulfinyl, methylsulfonyl, and the like;
  • PG 1 and PG 3 represent amino protecting groups, including but not limited to benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc) and benzyl, etc.;
  • Step (1) reacting compound II-A-1 with compound II-A-10 to obtain compound IIa-A-2;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from N,N-dimethylformamide, N,N-dimethylacetamide, toluene, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably N,N-dimethylformamide formamide.
  • the reaction is preferably carried out in the presence of a suitable organic or inorganic base, which can be selected from N,N-diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, N,N-diisopropylethylamine is preferred.
  • a suitable organic or inorganic base which can be selected from N,N-diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, N,N-diisopropylethylamine is preferred.
  • the reaction is carried out at a suitable temperature, preferably 20-100°C.
  • the reaction is carried out for a suitable time, eg, 1-12 hours.
  • Step (2) coupling reaction of compound IIa-A-2 and compound II-A-4 to obtain compound IIa-A-3;
  • the coupling reaction is preferably carried out in the presence of a metal catalyst, a ligand and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium acetate, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • the ligands are phosphorus ligands such as 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphorus-2',6'-diisopropoxy- 1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl Benzene, preferably 4,5-bisdiphenylphosphino-9,9-dimethylxanthene.
  • the base is an organic or inorganic base, such as diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (3) deprotecting compound IIa-A-3 to obtain compound IIa-A-4;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from ethyl acetate, methanol, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the deprotection reaction is preferably carried out in the presence of a suitable acid.
  • the acid may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 0-40°C.
  • the reaction is carried out for a suitable time, eg, 2-12 hours.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst, a ligand and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium acetate, preferably tris(dibenzylideneacetone)dipalladium.
  • a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium
  • the ligands are phosphorus ligands such as 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphorus-2',6'-diisopropoxy- 1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl Benzene, 1,1'-bis(diphenylphosphino)ferrocene, preferably 1,1'-bis(diphenylphosphino)ferrocene.
  • the base is an organic or inorganic base, such as sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane and toluene.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane and toluene.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (5) deprotecting compound II-A-11 to obtain compound II-A;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from alcoholic protic solvents, tetrahydrofuran, dichloromethane, N,N-dimethylformamide and any combination thereof, preferably dichloromethane.
  • the reaction is carried out in the presence of a suitable deprotection reagent.
  • the deprotection reagent can be selected from trimethyliodosilane, hydrobromic acid acetic acid solution, trifluoroacetic acid, preferably trimethyliodosilane or hydrobromic acid acetic acid solution.
  • the deprotection reaction is carried out at a suitable temperature, preferably 0-100°C.
  • the reaction is carried out for a suitable time, eg, 0.5-12 hours.
  • the present invention provides a third method for preparing the compound of formula (II-A), which comprises the following steps:
  • L, R 1 , R 3 , R 4 , R 8 , m, n, o, p, q, r and s are as defined above;
  • LG 1 and X represent a leaving group, and the leaving group includes but is not limited to halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl and methylsulfonyl, etc.;
  • PG 1 and PG 3 represent amino protecting groups, including but not limited to benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc) and benzyl, etc.;
  • Step (1) subjecting compound IIb-A-1 to a ring closure reaction to obtain compound IIb-A-2;
  • the ring closure reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from methanol, ethanol, tetrahydrofuran and any combination thereof, preferably methanol.
  • the reaction is preferably carried out in the presence of a suitable organic base, which can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, preferably sodium methoxide.
  • a suitable organic base which can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, preferably sodium methoxide.
  • the reaction is carried out at a suitable temperature, preferably 20-60°C.
  • the reaction is carried out for a suitable time, eg, 12-36 hours.
  • Step (2) subjecting compound IIb-A-2 to a substitution reaction to obtain compound IIb-A-3;
  • the reaction is carried out in the presence of a suitable substitution reagent, which is trifluoromethanesulfonic anhydride, phosphorus oxychloride, phosphorus oxybromide, a Carter condensing agent, preferably trifluoromethanesulfonic anhydride.
  • a suitable substitution reagent which is trifluoromethanesulfonic anhydride, phosphorus oxychloride, phosphorus oxybromide, a Carter condensing agent, preferably trifluoromethanesulfonic anhydride.
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from dichloromethane, toluene, tetrahydrofuran and any combination thereof, preferably dichloromethane.
  • the reaction is preferably carried out in the presence of a suitable organic or inorganic base such as N,N-diisopropylethylamine, triethylamine, N,N-dimethylaniline, preferably N,N - Diisopropylethylamine.
  • a suitable organic or inorganic base such as N,N-diisopropylethylamine, triethylamine, N,N-dimethylaniline, preferably N,N - Diisopropylethylamine.
  • the reaction is carried out at a suitable temperature, preferably 0°C to 120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (3) reacting compound IIb-A-3 with compound II-A-10 to obtain compound IIb-A-4;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from N,N-dimethylformamide, N,N-dimethylacetamide, toluene, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably N,N-dioxane Methylformamide.
  • the reaction is preferably carried out in the presence of a suitable organic or inorganic base, which can be selected from N,N-diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, N,N-diisopropylethylamine is preferred.
  • a suitable organic or inorganic base which can be selected from N,N-diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, N,N-diisopropylethylamine is preferred.
  • the reaction is carried out at a suitable temperature, preferably 20-100°C.
  • the reaction is carried out for a suitable time, eg, 1-12 hours.
  • Step (4) deprotecting compound IIb-A-4 to obtain compound IIb-A-5;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from ethyl acetate, methanol, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the deprotection reaction is preferably carried out in the presence of a suitable acid.
  • the acid may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 0-40°C.
  • the reaction is carried out for a suitable time, eg, 2-12 hours.
  • Step (5) coupling reaction of compound IIb-A-5 and compound II-A-7 to obtain compound IIb-A-6;
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) Phenylphosphine) palladium, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino) -1,1'-biphenyl-2-yl)palladium(II), preferably methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1' -
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably toluene.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably toluene.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (6) subjecting compound IIb-A-6 to oxidation reaction to obtain compound IIb-A-7;
  • the oxidation reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from ethyl acetate, methanol, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the oxidation reaction is carried out in the presence of a suitable oxidizing agent.
  • the oxidant can be selected from hydrogen peroxide, m-chloroperoxybenzoic acid, potassium hydrogen persulfate. Meta-chloroperoxybenzoic acid is preferred.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 0-40°C.
  • the reaction is carried out for a suitable time, eg, 0.5-12 hours.
  • step (7) compound IIb-A-7 is subjected to substitution reaction with compound II-A-4 to obtain compound II-A-11;
  • the substitution reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from dichloromethane, toluene, tetrahydrofuran and any combination thereof, preferably toluene.
  • substitution reaction is preferably carried out in the presence of a suitable organic or inorganic base, such as sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, preferably potassium tert-butoxide.
  • a suitable organic or inorganic base such as sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, preferably potassium tert-butoxide.
  • the substitution reaction is carried out at a suitable temperature, preferably 0°C to 40°C.
  • the reaction is carried out for a suitable time, eg, 0.5-16 hours.
  • Step (8) deprotecting compound II-A-11 to obtain compound II-A;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from alcoholic protic solvents, tetrahydrofuran, dichloromethane, N,N-dimethylformamide and any combination thereof, preferably dichloromethane.
  • the reaction is carried out in the presence of a suitable deprotection reagent.
  • the deprotection reagent can be selected from trimethylsilyl iodide, hydrobromic acid acetic acid solution, and trifluoroacetic acid. Preference is given to trimethylsilyl iodide or hydrobromic acid in acetic acid.
  • the deprotection reaction is carried out at a suitable temperature, preferably 0-100°C.
  • the reaction is carried out for a suitable time, eg, 0.5-12 hours.
  • the present invention provides a method for the preparation of a compound of formula (II-C), comprising the steps of:
  • L, R 1 , R 3 , R 4 , R 8 , m, n, o, p, q, r and s are as defined above;
  • LG 1 represents a leaving group, which includes but is not limited to halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl, methylsulfonyl, etc.;
  • PG 3 represents a protecting group for amino, including but not limited to benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc) and benzyl, etc.;
  • the reaction is carried out in the presence of a suitable halogenated or pseudohalogenated reagent, which is trifluoromethanesulfonic anhydride, phosphorus oxychloride, phosphorus oxytribromide, preferably trifluoromethanesulfonic anhydride.
  • a suitable halogenated or pseudohalogenated reagent which is trifluoromethanesulfonic anhydride, phosphorus oxychloride, phosphorus oxytribromide, preferably trifluoromethanesulfonic anhydride.
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from dichloromethane, toluene, tetrahydrofuran and any combination thereof, preferably dichloromethane.
  • the reaction is preferably carried out in the presence of a suitable organic or inorganic base such as N,N-diisopropylethylamine, triethylamine, N,N-dimethylaniline, preferably N,N - Diisopropylethylamine.
  • a suitable organic or inorganic base such as N,N-diisopropylethylamine, triethylamine, N,N-dimethylaniline, preferably N,N - Diisopropylethylamine.
  • the reaction is carried out at a suitable temperature, preferably -70°C to 100°C.
  • the reaction is carried out for a suitable time, eg, 1-16 hours.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex compound, tetrakis(triphenylphosphine) palladium, palladium acetate, preferably [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex.
  • a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex compound, tetrakis(triphenylphosphine) palladium, palladium acetate, preferably [1,1'
  • the base is an organic base or an inorganic base, such as N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably sodium carbonate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably a combination of 1,4-dioxane and water.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably a combination of 1,4-dioxane and water.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • the reduction reaction is preferably carried out in the presence of a metal catalyst.
  • the metal catalyst is a palladium metal catalyst or a platinum metal catalyst, such as palladium on carbon, palladium hydroxide, platinum dioxide, preferably palladium on carbon.
  • the reduction reaction is preferably carried out in the presence of hydrogen.
  • the reaction is preferably carried out in a suitable organic solvent, and the organic solvent can be selected from methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran and any combination thereof, preferably methanol.
  • the reaction is carried out at a suitable temperature, preferably 20-60°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from alcoholic protic solvents, tetrahydrofuran, dichloromethane, N,N-dimethylformamide and any combination thereof, preferably dichloromethane.
  • the reaction is carried out under suitable deprotection reagents.
  • the deprotection reagent can be selected from trimethylsilyl iodide, hydrobromic acid acetic acid solution, and trifluoroacetic acid. A solution of hydrobromic acid in acetic acid is preferred.
  • the deprotection reaction is carried out at a suitable temperature, preferably 0-100°C.
  • the reaction is carried out for a suitable time, eg, 0.5-12 hours.
  • the present invention provides a second method for the preparation of compounds of formula (II-C) comprising the steps of:
  • L, R 1 , R 3 , R 4 , R 8 , m, n, o, p, q, r and s are as defined above;
  • LG 1 , LG 2 and X represent a leaving group, and the leaving group includes but is not limited to halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl and methylsulfonyl, etc.;
  • PG 1 and PG 3 represent amino protecting groups, including but not limited to benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc) and benzyl, etc.;
  • Step (1) coupling reaction of compound II-A-1 and compound II-C-2 to obtain compound IIa-C-3;
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex compound, tetrakis(triphenylphosphine) palladium, palladium acetate, preferably [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex.
  • a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex compound, tetrakis(triphenylphosphine) palladium, palladium acetate, preferably [1,1'
  • the base is an organic or inorganic base, such as N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, potassium acetate, sodium carbonate, preferably potassium acetate.
  • organic or inorganic base such as N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, potassium acetate, sodium carbonate, preferably potassium acetate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably a combination of 1,4-dioxane and water.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably a combination of 1,4-dioxane and water.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (2) coupling reaction of compound IIa-C-3 and compound II-A-4 to obtain compound IIa-C-4;
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, (2-dicyclohexylphosphino-2',6'-diisopropoxy-1, methanesulfonic acid) 1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium, tetrakis(triphenylphosphine)palladium, palladium acetate, preferably methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2 -Amino-1,1'-biphenyl-2-yl)palla
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably toluene.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably toluene.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (3) deprotecting compound IIa-C-4 to obtain compound IIa-C-5;
  • the reaction is preferably carried out in the presence of a metal catalyst.
  • the metal catalyst is a palladium metal catalyst or a platinum metal catalyst, such as palladium on carbon, palladium hydroxide, platinum dioxide, preferably palladium on carbon.
  • the reaction is preferably carried out in the presence of hydrogen.
  • the reaction is preferably carried out in a suitable organic solvent, and the organic solvent can be selected from ammonia methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran and any combination thereof, preferably ammonia methanol.
  • the reaction is carried out at a suitable temperature, preferably 20-60°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst, a ligand and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium acetate, preferably tris(dibenzylideneacetone)dipalladium.
  • a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium
  • the ligands are phosphorus ligands such as 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphorus-2',6'-diisopropoxy- 1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl Benzene, preferably 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl.
  • the base is an organic or inorganic base, such as sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (5) deprotecting compound II-C-4 to obtain compound II-C;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from alcoholic protic solvents, tetrahydrofuran, dichloromethane, N,N-dimethylformamide and any combination thereof, preferably dichloromethane.
  • the reaction is carried out in the presence of a suitable deprotection reagent.
  • the deprotection reagent can be selected from trimethyliodosilane, hydrobromic acid acetic acid solution, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 0-80°C.
  • the reaction is carried out for a suitable time, eg, 0.5-12 hours.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or polymorph thereof , solvates, N-oxides, isotopically-labeled compounds or metabolites, and one or more pharmaceutically acceptable carriers.
  • Another object of the present invention is to provide a kit comprising the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N- Oxides, isotopically-labeled compounds or metabolites, or pharmaceutical compositions of the invention, and optionally, packaging and/or instructions.
  • “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact with humans and/or tissue from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions or formulations of the present invention include, but are not limited to, sterile liquids such as water and oils.
  • the pharmaceutical composition may, for example, be in the form of a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation and the like.
  • compositions of the present invention may act systemically and/or locally.
  • they may be administered by a suitable route, eg by injection (eg intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally or by oral administration.
  • a suitable route eg by injection (eg intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally or by oral administration.
  • the compound of the present invention may be present in the pharmaceutical composition in an amount or amount of about 0.001 mg to about 1000 mg.
  • the present invention provides a method of preparing a pharmaceutical composition of the present invention, the method comprising combining a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph
  • a pharmaceutically acceptable salt e.g., a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph
  • the form, solvate, N-oxide, isotopically-labeled compound or metabolite is combined with one or more pharmaceutically acceptable carriers.
  • Another object of the present invention is to provide the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds Or metabolites, or pharmaceutical compositions of the present invention, for inhibiting KRAS G12D.
  • Another object of the present invention is to provide the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds Or metabolites, or the pharmaceutical composition of the present invention, which is used for the prevention or treatment of KRAS G12D-mediated related diseases.
  • Another object of the present invention is to provide the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds Or metabolite or use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating KRAS G12D-mediated related diseases.
  • Another object of the present invention is to provide a method for preventing or treating KRAS G12D-mediated related diseases, which comprises administering to an individual in need thereof a prophylactically or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, Stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds or metabolites, or pharmaceutical compositions of the invention.
  • the KRAS G12D-mediated related disease is a tumor, preferably, the KRAS G12D-mediated related disease is cancer.
  • an effective amount refers to an amount sufficient to achieve the desired prophylactic or therapeutic effect, eg, an amount to achieve relief of one or more symptoms associated with the disease to be treated.
  • Dosage regimens can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the composition.
  • the amount of the compound of the invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In general, effective doses range from about 0.0001 to about 50 mg per kg body weight per day. In some cases, dose levels not higher than the lower end of the foregoing ranges may be sufficient, while in other cases larger doses may be employed without causing any deleterious side effects, provided that the larger dose is first The dose is divided into several smaller doses to be administered throughout the day.
  • treating means reversing, alleviating the progression of a disorder or condition to which such term is applied or one or more symptoms of such a disorder or condition, or preventing such disorder or A condition or one or more symptoms of such a disorder or condition.
  • prevention includes inhibiting and delaying the onset of the disease, and includes not only prevention before the disease develops, but also prevention of the recurrence of the disease after treatment.
  • an “individual” as used herein includes a human or non-human animal.
  • exemplary human subjects include human subjects (referred to as patients) or normal subjects with a disease (eg, a disease described herein).
  • Non-human animals in the present invention include all vertebrates such as non-mammals (eg birds, amphibians, reptiles) and mammals such as non-human primates, livestock and/or domesticated animals (eg sheep, dogs) , cats, cows, pigs, etc.).
  • the structures of the compounds were determined by nuclear magnetic resonance ( 1 H NMR) or mass spectrometry (MS).
  • the measuring instrument of 1 H NMR is JEOL Eclipse 400 nuclear magnetic instrument, and the measuring solvent is deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or hexadeuterated dimethyl sulfoxide (DMSO-d 6 ), and the internal standard is is tetramethylsilane (TMS) and chemical shifts ([delta]) are given in parts per million (ppm).
  • the MS measuring instrument was an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
  • Instrument model Agilent 1260, chromatographic column: Waters SunFire Prep C18OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); column temperature: 25°C; flow rate: 20.0mL/min; detection wavelength: 214nm; elution gradient: (0min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% formic acid in water.
  • the thin-layer chromatography silica gel plate used an aluminum plate (20 ⁇ 20cm) produced by Merck, and the specification adopted for the separation and purification of thin-layer chromatography was GF 254 (1mm) produced in Yantai.
  • the monitoring of the reaction adopts thin layer chromatography (TLC) or LC-MS;
  • the used developing solvent systems include: dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system, the volume of solvent The ratio is adjusted according to the polarity of the compound or by adding triethylamine or the like.
  • Microwave reactions were performed using a Biotage Initiator+ (400W, RT ⁇ 300°C) microwave reactor.
  • the eluent system includes: dichloromethane and methanol system, and petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.
  • the temperature of the reaction is room temperature (20 °C ⁇ 35 °C);
  • the reagents used in the present invention were purchased from companies such as Acros Organics, Aldrich Chemical Company, and Teber Chemical.
  • the first step Preparation of 8-benzyl-3-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate
  • Step 2 Preparation of benzyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-8-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((hexahydro-1H-pyrrolazine- Preparation of 7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate tert-butyl ester
  • the third step 3-(2-((Hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4 -yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate benzyl ester
  • the first step the preparation of 4-hydroxy-2-(methylthio)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate tert-butyl ester
  • methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1 ,1'-biphenyl-2-yl)palladium(II) (160.82 mg, 0.19 mmol), and stirred at 100°C for 12 hours.
  • the sixth step 3-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3, Preparation of 4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester
  • the fourth step the preparation of (2S,7aR)-2-fluorotetrahydro-1H-pyrroleazine-7a(5H)-carboxylate methyl ester
  • the fifth step the preparation of ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol
  • the first step 4-(8-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2S,7aR)-2 -Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate tert-butyl ester preparation
  • the second step 3-(2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro Preparation of pyrid[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester
  • the second step 3-(7-benzyl-2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetra Preparation of Hydropyrido[3,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester
  • the third step 3-(2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3 Preparation of ,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
  • the first step the preparation of 2-(4,5-dibromo-2-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
  • 1,8-Dibromonaphthalene (1 g, 3.46 mmol), bis(1,5-cyclooctadiene)bis-M-methoxydiiridium (I) (114.49 mg, 173.10 ⁇ mol), 4,4' -Di-tert-butyl-2,2'-bipyridine (56.31 mg, 207.72 ⁇ mol) was dissolved in tetrahydrofuran (15.0 mL), replaced with nitrogen three times, and 4,4,5,5-tetramethyl was added by injection under stirring -1,3,2-dioxaborolane (4.48 g, 34.62 mmol), the system was stirred at 70°C for 10 hours.
  • the third step preparation of 1,8-dibromo-3-(methoxymethoxy)naphthalene
  • the first step 3-(7-(8-chloronaphthalen-1-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8 - Preparation of tert-butyl tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate
  • Example 2 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-( Preparation of ((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 2)
  • the second step 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-( Preparation of ((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 2)
  • Example 3 4-(4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrole Preparation of oxazin-7a(5H)-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-ol (Compound 29)
  • the first step 3-(7-(3-benzyloxy-1-naphthyl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H))-yl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Preparation of benzyl carboxylate
  • reaction system was stirred at 0°C for 2 hours.
  • Step 2 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrole Preparation of oxazin-7a(5H)-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-ol
  • the first step 3-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7 Preparation of ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester
  • Step 2 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((hexahydro-1H-pyrroazin-7a-yl)methoxy) Preparation of -5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol
  • the first step 3-(7-(8-Bromonaphthalen-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8- Preparation of benzyl tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the second step 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-bromonaphthalen-1-yl)-2-((hexahydro-1H - Preparation of pyrrozin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • Example 6 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(8-bromonaphthalen-1-yl)-2-((((2S,7aR) - Preparation of 2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 31)
  • the first step 3-(7-(8-bromonaphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy benzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • esters 3-(7-(8-bromonaphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy benzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-bromonaphthalen-1-yl)-2-((((2S,7aR) - Preparation of 2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • Example 7 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-((((2S,7aR) - Preparation of 2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 30)
  • the first step 3-(7-(8-chloronaphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrroazin-7a(5H)-yl)methoxy benzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • esters 3-(7-(8-chloronaphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrroazin-7a(5H)-yl)methoxy benzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-((((2S,7aR) - Preparation of 2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • Example 8 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-((hexahydro-1H- Preparation of pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 33)
  • the first step 3-(7-(8-chloronaphthalen-1-yl)-2-(hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydro
  • the second step 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-((hexahydro-1H- Preparation of pyrrolizin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • the first step 3-[7-(3-benzyloxy-1-naphthyl)-2-[2-(2-methylimidazol-1-yl)ethoxy]-5,6,7,8 - Preparation of benzyl tetrahydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the second step 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(2-(2-methyl-1H-imidazol-1-yl)ethyl Preparation of oxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol
  • Example 10 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-(((S)-1-methylpyrrolidine Preparation of -2-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol (Compound 35A or 35B)
  • Step 1 Preparation of 7-benzyl-2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • the seventh step 3-(7-(3-(benzyloxy)naphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5, Preparation of 6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester
  • the eighth step 3-(7-(3-(benzyloxy)naphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5, Preparation of 6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
  • Step 9 4-(4-(8-azabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy) Preparation of -5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol (Compound 35)
  • Step 10 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-(((S)-1-methylpyrrolidine Preparation of -2-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol (Compound 35A or 35B)
  • the crude product of the ninth step was purified by high performance liquid chromatography to obtain the title compound 35A (2.10 mg, yield: 4.58%) and compound 35B (2.56 mg, yield: 5.58%).
  • Compound 35A retention time is 7.0 minutes
  • Compound 35B retention time is 7.8 minutes
  • Example 11 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- Preparation of pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 37)
  • the first step 3-(7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetra
  • the second step 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- Preparation of pyrrolizin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • Example 12 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((hexa Preparation of Hydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 36)
  • the first step 3-(7-(8-Chloro-7-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7 Preparation of ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester
  • the second step 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((hexa Preparation of Hydrogen-1H-Pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrazin[3,4-d]pyrimidine
  • Example 13 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoronaphthalen-1-yl)-2-((hexahydro Preparation of -1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 38)
  • the first step 3-(7-(7,8-difluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7, Preparation of 8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester
  • the second step 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoronaphthalen-1-yl)-2-((hexahydro Preparation of -1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • the reaction raw material of the second step 3-(7-(8-bromonaphthalen-1-yl)-2-((hexahydro-1H-pyrroazin-7a-yl)methoxy )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate benzyl ester Replaced with 3-(7-(7,8-difluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8- Benzyl tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate to give the title compound (22 mg, yield: 42.1%).
  • Example 14 4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-(( 2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 86A or 86B ) preparation
  • the first step 3-(7-(8-chloronaphthalen-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrroazin-7a-yl)methoxy)-5
  • Step 2 4-(-8-azabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-((2R,7aS)-2- Preparation of fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 86)
  • reaction solution was concentrated, the residue was diluted with ethyl acetate (3 mL), washed three times with sodium bicarbonate solution (10 mL), the organic phases were combined, backwashed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and then reduced The solvent was removed by rotary evaporation to give the title compound (40.0 mg, crude).
  • the third step 4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-(( 2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 86A or 86B ) preparation
  • the crude product of the second step was purified by high performance liquid chromatography to obtain the title compound 86A (18.0 mg, yield: 21.82%) and compound 86B (10.0 mg, yield: 11.85%).
  • Example 15 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro -1H-Pyrrolazin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-fluoronaphthalen-2-ol (compound 89A or 89B) preparation
  • the first step 3-(7-(8-Fluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrroleazine -7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8 - Preparation of tert-butyl carboxylate
  • Step 2 4-(4-(-8-Azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrroleazine-7a Preparation of -yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-fluoronaphthalen-2-ol (Compound 89)
  • the third step 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro -1H-Pyrrolazin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-fluoronaphthalen-2-ol (compound 89A or 89B) preparation
  • the crude product of the second step was purified by high performance liquid chromatography to obtain the title compound 89A (5.0 mg, yield: 9.6%) and compound 89B (6.1 mg, yield: 11.5%).
  • Example 16 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro -1H-Pyrolazin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5,6-difluoronaphthalene-2- Preparation of alcohols (compounds 90A or 90B)
  • the first step 3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1H -Pyrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane
  • Step 2 4-(4-(8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolazine-7a- Preparation of yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5,6-difluoronaphthalen-2-ol (Compound 90)
  • the third step 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro -1H-Pyrolazin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5,6-difluoronaphthalene-2- Preparation of alcohols (compounds 90A or 90B)
  • the crude product of the second step was purified by high performance liquid chromatography to obtain the title compound 90A (3.0 mg, yield: 4.1%) and compound 90B (1.6 mg, yield: 2.3%).
  • Compound 90A retention time is 5.15 minutes
  • Compound 90B retention time is 5.53 minutes
  • Example 17 4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-(8-bromonaphthalen-1-yl)-2-(( 2R,7aS)-2-fluorohexahydro-1H-pyrroazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 87A or 87B ) preparation
  • the first step 3-(7-(8-bromonaphthalen-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrroazin-7a-yl)methoxy)-5
  • Example 14 Using the synthetic route of Example 14, the first reaction raw material 1-bromo-8-chloronaphthalene was replaced with 1,8-dibromonaphthalene to obtain the title compound (272 mg, yield: 58.1%).
  • Step 2 4-(8-azabicyclo[3.2.1]octan-3-yl)-7-(8-bromonaphthalen-1-yl)-2-((2R,7aS)-2-fluoro Preparation of hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 87)
  • the third step 4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-(8-bromonaphthalen-1-yl)-2-(( 2R,7aS)-2-fluorohexahydro-1H-pyrroazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 87A or 87B ) preparation
  • the crude product of the second step was purified by high performance liquid chromatography to obtain the title compound 87A (8.2 mg, yield: 17.5%) and compound 87B (7.0 mg, yield: 15.3%).
  • Example 18 4-(4-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-2-((hexahydro-1H-pyrroazin-7a-yl)methoxy) Preparation of -5,6-dihydropyrid[3,4-d]pyrimidin-7(8H)-yl)-5-fluoronaphthalen-2-ol (Compound 40)
  • the first step 3-(7-(8-Fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(hexahydro-1H-pyrroazin-7a-yl)methoxy) -5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate benzyl ester preparation
  • Step 2 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((hexahydro-1H-pyrroazin-7a-yl)methoxy) Preparation of -5,6-dihydropyridine[3,4-d]pyrimidin-7(8H)-yl)-5-fluoronaphthalen-2-ol
  • Example 19 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro -1H-Pyrrolazin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-bromonaphthalen-2-ol (compound 88A or 88B) preparation
  • the first step 3-(7-(8-bromo-3-(methoxymethoxy)naphthalene-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrroleazine -7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8 - Preparation of tert-butyl carboxylate
  • Step 2 4-(4-(8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolazine-7a- Preparation of yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-bromonaphthalen-2-ol (Compound 88)
  • the third step 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro -1H-Pyrrolazin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-bromonaphthalen-2-ol (compound 88A or 88B) preparation
  • the crude product of the second step was purified by high performance liquid chromatography to obtain the title compound 88A (3.0 mg, yield: 10.09%) and compound 88B (2.5 mg, yield: 8.41%).
  • Compound 88A retention time is 6 minutes
  • Proteins Tag1-SOS1 and Tag2-KRAS G12D
  • Buffer Diluent Buffer and Detection Buffer
  • KRAS-G12D/SOS1 binding assay kit components Tag1-SOS1, Tag2-KRAS G12D, Anti tag1 tb 3+ and Anti tag2 XL665 are all 1x
  • Protein and label reaction time Incubate at 4°C for 3 hours or extend to overnight
  • Microplate reader parameters BMG PHERAstar Fluorescence, Homogeneous Time Resolved Fluorescence (HTRF) method, excitation wavelength 337nm, emission wavelengths 620nm and 665nm
  • the compounds to be tested were incubated with a mixture of Tag1-SOS1 and Tag2-KRAS G12D and GTP in Diluent Buffer system for 15 minutes at room temperature for protein binding. Add the label diluted in Detection Buffer to the reaction plate, incubate at 4°C for 3 hours or extend to overnight, put the reaction plate in a microplate reader, and use the HTRF method to read the signal value of each well in the plate.
  • the curve was fitted according to a four parameter model and the median inhibitory concentration ( IC50 ) of the compound was calculated.
  • the compounds of the present invention showed strong inhibitory activity.
  • Protein immobilization buffer 10mM HEPES, 150mM NaCl, 0.05% Tween-20 and 10 ⁇ M GDP
  • Running buffer A 10mM HEPES, 150mM NaCl, 0.05% Tween-20 and 10 ⁇ M GDP
  • Running buffer B 10mM HEPES, 150mM NaCl, 0.05% Tween-20 and 10 ⁇ M GDP, 1% DMSO
  • Binding and dissociation time 120s on/200s off
  • Chip surface activation select flow cell 2, automatically inject 10mM NiCl2, the flow rate is 4 ⁇ L/min, and the injection time is 500s.
  • the binding and dissociation signals of the compound and the protein were recorded in real time, and the signal values of the reference channel and the built-in blank control were subtracted (double subtraction) during data processing (Biacore T200 evaluation software).
  • the sensorgrams of the double-subtracted signal values of the reference channel and the built-in blank were fitted with Kinetics or steady-state Affinity (1:1) mode.
  • the affinity of the compound with the protein was characterized by K D value (K d /K a ) , where K d is the dissociation constant and Ka is the binding constant.
  • the compound of the present invention showed a strong affinity.

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Abstract

La présente invention concerne un composé représenté par la formule I ou un sel pharmaceutiquement acceptable, un stéréoisomère, un tautomère, un polymorphe, un solvate, un N-oxyde, un composé marqué par un isotope ou un métabolite de celui-ci, une composition pharmaceutique et un kit le contenant, un procédé de préparation associé, et l'utilisation de celui-ci dans la préparation d'un médicament pour la prévention ou le traitement de maladies associées à médiation par G12D KRAS.
PCT/CN2022/081102 2021-03-18 2022-03-16 Composé hétéroaromatique, son procédé de préparation et son utilisation WO2022194192A1 (fr)

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WO2023198191A1 (fr) * 2022-04-15 2023-10-19 杭州多域生物技术有限公司 Composé à six et six chaînons, procédé de préparation, composition pharmaceutique et application
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2024186680A1 (fr) * 2023-03-03 2024-09-12 Frontier Medicines Corporation Procédés de préparation de composés de pyrrolizidine
US12145947B2 (en) 2023-11-07 2024-11-19 Quanta Therapeutics, Inc. Pyrimidine based modulators and uses thereof

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DATABASE REGISTRY 14 December 2017 (2017-12-14), ANONYMOUS : "-2-Naphthalenol, 4-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-[2- (dimethylamino)-1-methylethoxy]-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)- yl]-(CA INDEX NAME) ", XP055968399, retrieved from STN Database accession no. 2158303-78-5 *

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US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2023198191A1 (fr) * 2022-04-15 2023-10-19 杭州多域生物技术有限公司 Composé à six et six chaînons, procédé de préparation, composition pharmaceutique et application
WO2024186680A1 (fr) * 2023-03-03 2024-09-12 Frontier Medicines Corporation Procédés de préparation de composés de pyrrolizidine
US12145947B2 (en) 2023-11-07 2024-11-19 Quanta Therapeutics, Inc. Pyrimidine based modulators and uses thereof

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